June 3-7; Boston, MA Highlights, Draft

Executive Highlights

Boston played a warm host to The Endocrine Society's 93rd Annual Meeting and Expo. A full 12-hour ensemble of workshops and symposia were dedicated to diabetes on a sunny Friday, where about 300 endocrinologists attended a pre-workshop to the full ENDO meeting. The morning started with a call for reform from Dr. Robert Vigersky (Walter Reed Army Medical Center, Washington, DC), who believes that diabetes guidelines should include greater transparency on conflicts of interest, explicit grading of evidence, and guidance on individualizing glycemic targets based on disease state, socioeconomic factors, and other considerations. Also on the guidelines front, we heard expert forecasts on what to expect from the 2012 updates to blood pressure and lipid management guidelines. Following these lectures, we attended a number of “Meet the Professor” workshops on topics such as incretin use, continuous glucose monitoring, obesity management, and U-500 insulin – we note that this is yet another meeting where CGM is getting its share of attention and more.

Saturday marked the official launch of Endo 2011 and included a huge variety of workshops. The exhibit hall was inviting, as crowds gathered to enjoy posters and large, espresso-purveying booths from many diabetes companies, including both pharmaceutical and device firms. In the morning, we saw impressive 24-week data from a small study of Victoza in type 1 diabetes and encouraging interim results of a pilot study for metreleptin in patients without confirmed leptin deficiency, and we sat in on a session about islet cell development that featured local stem cell superstar Dr. Doug Melton (Harvard University, Cambridge, MA). At the poster hall we heard from inpatient glycemic control pioneer Dr. Greet Van den Berghe (University of Leuven, Leuven, Belgium), just finished with a 4,000-patient RCT finding that early parenteral nutrition leads to worse complications and much higher costs (1,100 Euros [$1,600] per patient, excluding the price of the parenteral nutrition itself). Later in the day, a standing- room-only crowd gathered for a multidisciplinary symposium about weight loss and weight-loss maintenance. Things ended on a strong note with a Novo Nordisk dinner symposium on GLP-1 receptor agonists, which drew 300 attendees and a 40-plus-person line that had to be turned away. The four panelists discussed their thoughts on hot off-label indications such as weight loss and combination with insulin, and they explained their skepticism of an upcoming Gastroenterology paper on possible links between incretin therapies and pancreatic cancer. Sunday included a basic science review of insulin signaling in cancer, a year-in-review talk on obesity (negative on current pharmacologic prospects but positive on new insights into neurological energy balance), and the first product theater from Boehringer Ingelheim that we have seen since Tradjenta’s approval – a thorough review of 11 antihyperglycemic drug classes and six clinical practice guidelines. The final days included a rich debate about treatment algorithms between Dr. David Nathan (Harvard University, Boston, MA) and Dr. Jaime Davidson (University of Texas Southwestern, Dallas, TX), as well as a fascinating oral presentation about the effects of insulin therapy on IGF-1 levels.

Detailed Discussion and Commentary

Oral Presentations

LIRAGLUTIDE AS ADDITIONAL TREATMENT IN TYPE 1 DIABETES

Ajay Varanasi, MD (State University of New York at Buffalo, Buffalo, NY)

Dr. Ajay Varanasi presented promising results from a small (n=14), uncontrolled study of liraglutide (Novo Nordisk’s Victoza) in adult patients with type 1 diabetes and low A1c (mean 6.6%). Almost immediately into a week of therapy with 0.6 mg liraglutide daily, subjects experienced significant improvements in hyperglycemia, insulin dose, and glycemic variability, with no clinically significant increases in hypoglycemia. A subset of patients (n=8) increased their daily liraglutide dose to 1.8 mg and continued in the study for 24 weeks, demonstrating continued glycemic and insulin dosage improvements. These patients’ mean A1c fell from 6.5% to 6.1%, and their hypoglycemia rates were not significantly different from baseline. The audience was clearly excited by the fast, powerful, and sustained glycemic improvements, as were the researchers – Dr. Varanasi closed his talk with a call for a prospective, randomized controlled trial beyond the resources of an academic laboratory. The first published paper (Varanasi et al., European Journal of Endocrinology 2011) includes somewhat more detail than was given in the oral presentation; we think the use of CGM in this study presents promising opportunities for granular analysis, especially on the effects of liraglutide and insulin titration. We hope that future studies can further elucidate liraglutide’s mechanism in type 1 diabetes (e.g., by evaluating postprandial glucagon levels). We were especially impressed by the reduction in standard deviation from this group. Although they started with what would be defined by anyone as a healthy A1c for type 1 patients with average duration of diabetes of 24 years, it was great to see that these eight patients had lower fasting glucose, lower A1c, lower standard deviation of blood glucose, lower weight, and virtually the same hypoglycemia after six months.

• The study enrolled 14 adult patients with type 1 diabetes, defined as plasma C- peptide below 0.10 nmol/l with positive GAD antibodies. Five patients were female and nine male, with baseline characteristics as follows: age 39.5 ± 4.8 years, BMI 24.0 ± 2.0 kg/m², diabetes duration 24 ± 4 years, basal insulin dose 24.5 ± 6 U/d, bolus insulin dose 22.5 ± 5 U/d, and A1c 6.6% 0.5%. Thirteen subjects used insulin pumps and one used MDI (four or more injections daily).
• After one week of baseline glycemic measurement with continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG), patients spent a week using 0.6 mg liraglutide daily while still wearing CGM. At the start of liraglutide treatment, patients were instructed to reduce their daily basal insulin dose by 25% and their daily bolus dose by 33%. During Q&A, Dr. Varanasi explained that no changes were made to insulin- carb ratios, although notably, patients were instructed to bolus after meals rather than before. 
• Eight patients, who used CGM for long-term diabetes management, remained in the study for a mean duration of 24 weeks, increasing their daily liraglutide dose to 1.2 mg after one week and 1.8 mg after two weeks. The other six patients stopped Victoza treatment after one week and spent a third week using CGM (as we understand it, all six of these patients used CGM provided by the researchers’ clinic, which limited the duration that these patients could participate in the trial without affecting other patients’ CGM access).
• The one-week results were highly positive, with statistically significant decreases in basal and bolus insulin dose, statistically significant improvements in mean fasting plasma glucose, mean weekly blood glucose, and percent of time spent with CGM readings above 150 mg/dl, 200 mg/dl, or 250 mg/dl. Notably, these benefits took effect quickly: Dr. Varanasi presented graphs showing that the majority of the decreases in glycemia and insulin dose occurred after only two days on 0.6 mg liraglutide. Percentage of time spent in hypoglycemia was miniscule (under 3% of the time, likely rare for patients with such tightly controlled diabetes) although increased with a trend toward statistical significance, while glycemic variability (as measured by weekly standard deviation) decreased significantly.

n=14	Before treatment (one week)	On Liraglutide (one week)	P-value
Basal insulin dose (U/d)	24.5 ± 6	16.5 ± 6	< 0.01
Bolus insulin dose (U/d)	22.5 ± 4	15.5 ± 4	< 0.01
Mean FBG (mg/dl)	130 ± 10	110 ± 8	< 0.01
Mean weekly BG (mg/dl)	137.5 ± 20	115 ± 12	< 0.01
> 150 mg/dl (% time)	28 ± 6	22.5 ± 5	0.03
> 200 mg/dl (% time)	18 ± 5	9 ± 2	<0.01
> 250 mg/dl (% time)	8 ± 2	1.5 ± 1	<0.01
< 70 mg/dl (% time)	2.0 ± 2	2.4 ± 2	0.06
< 40 mg/dl (% time)	0.12 ± 0.2	0.14 ± 0.3	0.08
Mean weekly SD (mg/dl)	56 ± 10	26 ± 6	<0.01

BG = blood glucose; FBG = fasting blood glucose; SD = standard deviation

• The results at 24 weeks showed weight loss, maintenance/further improvement of glycemic benefit, and hypoglycemia rates that were more similar to patients’ pre- liraglutide profiles. Mean A1c fell from 6.5% to 6.1%, demonstrating the room for substantial improvements even in patients whose baseline A1c suggests very good control. The researchers found that patients generally experienced less hypoglycemia later in the trial as they adjusted their insulin regimen.

n=8	Before treatment (one week)	On Liraglutide (24 weeks)	P-value
Weight (kg)	68 ± 5	63.5 ± 4	0.02
A1c (%)	6.5 ± 0.5	6.1 ± 0.4	0.02
Basal insulin dose (U/d)	26.5 ± 7	13.5 ± 5	<0.01
Bolus insulin dose (U/d)	25.5 ± 6	14 ± 4	<0.01
Mean FBG (mg/dl)	128 ± 10	108 ± 8	<0.01
Mean weekly BG (mg/dl)	134 ± 20	111 ± 12	<0.01
> 150 mg/dl (% time)	27.5 ± 6	21 ± 5	0.02
> 200 mg/dl (% time)	17.5 ± 5	6.5 ± 2	<0.01
> 250 mg/dl (% time)	8.0 ± 2	2.0 ± 1	<0.01
< 70 mg/dl (% time)	2.1 ± 2	2.3 ± 2	0.08
< 40 mg/dl (% time)	0.11 ± 0.2	0.12 ± 0.3	0.12
Mean weekly SD (mg/dl)	53 ± 10	27 ± 6	<0.01

BG = blood glucose; FBG = fasting blood glucose; SD = standard deviation

• No data were provided on non-glycemic adverse effects such as nausea, although 1.8 mg daily was tolerated at least well enough that all eight patients who continued past one week remained at this dose.
• Dr. Varanasi outlined three possible mechanisms contributing to the observed glycemic effects. These include 1) suppression of postprandial increases in glucagon concentration, 2) decrease in postprandial glucose excursion due to delayed gastric emptying, and3) suppression of appetite and weight loss (which Dr. Varanasi said might be involved in long-term maintenance of benefit). Given the fast response to liraglutide, the researchers speculate that glucagon suppression is especially important. C-peptide values measured at 24 weeks showed no response, suggesting that endogenous insulin secretion played a minimal role.

Questions and Answers

Q: Intensive control was associated with roughly a threefold greater rate of hypoglycemia in DCCT. As I understand it you didn’t see that?

A: We did see an increase in the time spent in hypoglycemia, which was reduced in the long term – as patients titrated their insulin dosage, we found it wasn’t a factor anymore. Given that baseline A1c was in the 6.5% range, we expected hypoglycemia to be a factor, but in the long term we didn’t see this effect.

Q: Did you measure glucagon?

A: No.

Q: Why did only eight of the patients complete the study?

A: Of the 14 total patients, only eight were included in the long-term subset of the trial. One reason for this was that we wanted to see if glucose would come back to baseline after one week of being on liraglutide. All the subjects who went on for 24 weeks raised their dosage to 1.8 mg/dl.

Q: Could you predict the effects in patients with A1c greater than 9.0%?

A: We would expect some response in this group as well. However, we have to look at the long-term.

Q: Could you speculate on what would happen to hepatic glucose production, independent of insulin concentration?

A: It might be lowered, if glucagon is being stimulated. We ought to look at this.

Q: How might you decrease insulin-carb ratios on initiation of liraglutide?

A: In the initial stages of insulin dose adjustment we told patients to take insulin boluses only after they had eaten, but we did not change the insulin-carb ratio.

Q: Leptin also has a suppressing effect on glucagon secretion. Might liraglutide and leptin have a synergistic effect?

A: Possibly these therapies could be used concurrently in type 1 diabetes someday.

Q: I am struck by the immediateness of the effect. I might have thought the response would take several weeks. Were you surprised?

A: Yes. We don’t know why this happened, but the effects were pretty robust. Maybe glucagon shows a faster response in type 1 diabetes compared to type 2 diabetes.

Q: Have you used this in C-peptide positive type 1 patients, i.e., those with LADA (latent autoimmune diabetes in adults)?

A: A study published in Diabetes Care last month included C-peptide positive patients with type 1 diabetes who took liraglutide and insulin. The effects were positive, and two patients even came off insulin (Kielgast et al., Diabetes Care 2011).

Dr. Paresh Dandona (Dr. Varanasi’s principal investigator; State University of New York at Buffalo, Buffalo, NY): An excellent recent paper from Dr. Unger and colleagues in Diabetes studied knockout of the glucagon receptor in mice. Even at doses of beta-cell-destroying chemicals that were more than sufficient to cause type 1 diabetes, they found a total absence of hyperglycemia or ketosis. This was a remarkable observation bringing to light for the first time the potential pathogenic role of glucagon in type 1 diabetes. Also, we were absolutely startled by the effect of liraglutide within 24 hours. It can’t be immunological, and it is probably too fast to be changes in insulin resistance. The results suggest effects on glucagon secretion, which in type 1 diabetes is totally uninhibited.

METRELEPTIN FOR TREATMENT OF DIABETES MELLITUS AND/OR HYPERTRIGLYCERIDEMIA ASSOCIATED WITH LIPODYSTROPHY: TRANSLATION FROM CLINICAL TRIALS TO CLINICAL ENDOCRINOLOGY PRACTICE

Suma Amarnath, MD, MPH (University of Michigan, Ann Arbor, MI)

Dr. Amarnath presented interim results of an ongoing clinical study of Amylin’s metreleptin in patients with partial lipodystrophy. In order to determine if lipodystrophy diagnosis is sufficient to predict response to metreleptin therapy, the researchers did not assess patients’ baseline leptin deficiency (which cannot yet be assessed in a commonly available clinical assay). The Amylin-sponsored study showed statistically significant reductions in A1c at six and nine months, with statistically non- significant improvement in triglyceride levels and body weight. Dr. Amarnath noted that the results were not as dramatic as those of studies in which moderately or severely low leptin levels were confirmed, but she said that metreleptin still seems to hold promise in patients with partial lipodystrophy who are selected for therapy based only on their metabolic abnormalities. Future research areas include assessing how response to therapy is affected by baseline leptin levels.

• As background, lipodystrophy is a rare set of syndromes characterized by the inability to store normal fat depots, resulting in adipose tissue loss, and ectopic fat deposition (such as in the liver and muscle), severe insulin resistance, type 2 diabetes, and severe hypertriglyceridemia. Because of adipose tissue loss, many of these individuals have a deficiency in leptin, a hormone secreted by adipocytes that plays important roles in regulating appetite and energy expenditure. The NIH is currently investigating the efficacy and safety of metreleptin (a leptin analog) to improve hyperglycemia and hypertriglyceridemia in people with this condition, which can be familial or acquired. Amylin has estimated that roughly 3,000 people worldwide have lipodystrophy, including 1,000-1,200 in the US. For details on the company’s plans to complete filing of a rolling Biologics License Application in late 2011 and for analyses of two ongoing NIH trials of metreleptin in people with lipodystrophy and confirmed low leptin levels, please see the April 18, 2011 Closer Look.
• The prospective, open-label study includes people with diabetes and/or hypertriglyceridemia associated with lipodystrophy (NCT00677313). The protocol begins with a three-month dose escalation period with follow-up planned to continue for two years. Dosing was titrated based on clinical response and ranged from 0.04 to 0.12 mg/kg (2.2 to 12 mg) per day. So far 19 patients have enrolled.
• Nine-month data showed statistically significant improvements in glycemic control. The six participants for whom nine-month data were given were all female, ranging in age from 29 to 63 years and in BMI from 21-39 kg/m². At nine months they experienced statistically significant mean A1c reductions (from 8.7±1.4% to 6.8±0.4%; p=0.036) and a statistical trend toward large reductions in mean triglyceride levels (from 306±315 to 176±110 mg/dl; p=0.10). All of the patients reduced their insulin dosage, and five of the six patients dropped by more than 50% of their baseline insulin dose. Patients with baseline BMI greater than 27 kg/m² experienced weight loss of 3-7%. Six-month data, available for nine patients, also showed statistically significant improvements in A1c, with statistically non-significant mean weight loss of 3%; treatment effect seems to peak in the nine to 12 month range.
• Adverse events possibly related to metreleptin were described for the nine patients who had completed at least six months of leptin dosing and included: fatigue (in four patients), nausea (three), injection site reactions (two), and hypoglycemia (in one patient; Dr. Amarnath noted that this likely reflected improved insulin sensitivity).

Questions and Answers

Q: What was the range of leptin levels? If I had to predict baseline leptin, some patients were likely low and others in the high range. It would be interesting to see whether the metabolic response was determined by baseline leptin levels.

A: We are still not aware of leptin levels, but are planning to study this. We agree it is important.

Q: What was mean BMI?

A: In the 26-27 kg/m² range.

Q: Dr. Unger has talked about the role of glucagon in hyperglycemia. Is it possible that some of the effect is glucagon-related? Are you planning to measure glucagon at baseline?

A: We have not measured baseline glucagon levels, but this is something to consider in the future.

Q: How did you determine to increase the dose of metreleptin?

A: Based on metabolic parameters, and if they could tolerate higher doses without adverse effects.

Q: Was greater efficacy seen at higher doses?

A: Some patients did respond to higher doses.

Comment: Very obese patients don’t respond to metreleptin therapy, but we don’t know what the cutoff is. It would also be interesting to know what the therapeutic limiting dose is. But it is important to know that these patients were taken without selection based on leptin levels and still showed a response.

Comment: Studies have suggested that patients with severely and moderately low levels of leptin respond equally well. The question is whether patients with lipodystrophy who have normal-to-high leptin levels would also respond equally well.

IGF-I BIOACTIVITY DECREASES DURING INSULIN THERAPY IN TYPE 2 DIABETIC PATIENTS: COMPARISON OF HIGH DOSES OF INSULIN GLARGINE AND NPH INSULIN IN THE LANMET STUDY

AJ Varewijck, MD (Erasmus Medical Center, Rotterdam, Netherlands)

Dr. Varewijck presented results of a retrospective analysis of the LANMET study to compare the effects of insulin glargine (sanofi-aventis’ Lantus) and NPH insulin on the bioactivity of IGF-1. The researchers found that at 36 weeks, serum IGF-1 bioactivity decreased significantly in both the glargine and NPH groups, with no differences between the groups. Although IGF-1 bioactivity has often been thought to increase with insulin administration, these results (and those of several other recent human studies) have suggested the reverse. Dr. Varewijck emphasized that the implications on the link between insulin and cancer remains unclear, and she said that she and her colleagues are now planning to study the LANMET results using assays for bioactivity of insulin receptor isoform A (also involved in mitogenic signaling).

• Insulin-like growth factor 1 (IGF-1) is involved in mitogenic signaling and is believed to contribute to cancer growth. IGF-1’s receptor, IGF-1R, is a receptor tyrosine kinase that shares many structural and functional similarities to the insulin receptors (IR-A and IR-B). Insulin can stimulate all three receptors. IGF-1R signaling has been associated with cancer in a variety of studies, although the mechanisms of this link are not fully understood.
• Dr. Varewijck and her colleagues at Erasmus Medical Center have previously reported that insulin glargine (sanofi-aventis’ Lantus) promotes greater bioactivity of the IGF-1 receptor compared to human insulin and insulin detemir (Novo Nordisk’s Victoza) (Varewijck et al., Growth Hormone and IGF Research 2010). These experiments followed a controversial epidemiological study that linked high doses of insulin glargine to increased cancer risk (Hemkens et al, Diabetologia 2009), a finding not confirmed by subsequent epidemiological analyses (Pocock and Smeeth, Lancet 2009). To assess the effects of insulin binding on IGF-1 activity in vitro, the Erasmus researchers performed a kinase receptor activation (KIRA) bioassay. They found that at concentrations of 10-100 nM, insulin glargine was significantly more potent than human insulin or insulin detemir at activating IGF-1R (p<0.001). However, differences in the in vitro and in vivo environments mean that these results may not be directly applicable to in vivo IGF-1 signaling, metabolic and mitogenic activity, or cancer risk.
• The researchers analyzed data from the sanofi-aventis-sponsored LANMET study, in which 110 poorly controlled type 2 diabetes patients were randomized to receive insulin glargine or NPH insulin for 36 weeks on a baseline of metformin or metformin- plus-sulfonylurea (Yki-Järvinen et al., Diabetologia 2006). Specifically, they looked at serum samples from the subset of patients who were taking higher-than-median insulin doses (over 70 U/day). The glargine-plus-metformin (G+MET) and NPH-plus-metformin (NPH+MET) groups were statistically equivalent at baseline in age (54.6±1.0 years), BMI (34.3±0.8 kg/m²), and A1c (9.5±0.25%). After 36 weeks of therapy, the G+MET and NPH+MET groups were comparable in BMI (35.4 vs. 36.7 kg/m²), A1c (7.1% vs. 7.1%), and total daily insulin dose (106.8 vs. 105.4 U/day). Thus the LANMET results lend themselves to the study of potential differences between high doses of glargine and NPH in type 2 diabetes, with minimal confounding factors.
• Serum IGF-1 bioactivity decreased significantly from baseline to 36 weeks, without a difference seen between the glargine and NPH groups. As measured in a KIRA bioassay, baseline serum IGF-1 bioactivity was similar in the G+MET and NPH+MET groups (118±16 vs. 129±14 pmol/l; p=0.49). 36-week serum IGF-1 was significantly lower than baseline in both groups (p=0.02), but the 36-week data were similar between the G+MET and NPH+MET groups (102±15 vs. 114±8 pmol/l; p=0.49). Total serum concentration of IGF-1 was similar in both groups at baseline and at 36 weeks. Daily insulin dose was inversely related to total IGF-1, but no correlation was observed between daily insulin dose and bioactive IGF-1.
• Several recent studies have also suggested that high-dose insulin administration suppresses IGF-1 bioactivity. In one study, IGF-1 bioactivity was reduced during a hyperinsulinemic clamp in both healthy patients (n=24) and those with impaired glucose tolerance (n=19) (Arafat et al., JCEM 2009). The Erasmus researchers have performed a cross- sectional analysis of elderly patients (n=1,036) suggests that IGF-1 bioactivity is related by an upside-down U-shaped curve to fasting glucose levels (peaking at FBG of roughly 7.0 mmol/l [126 mg/dl]) and the metabolic syndrome (peaking in patients with three metabolic syndrome criteria) (Brugts et al., Diabetes 2010). Most recently, in collaboration with Dr. Greet Van den Berghe’s group at Leuven, the Erasmus researchers published an analysis of IGF-1 levels from a previously conducted randomized controlled trial of insulin administration in pediatric ICU patients (Gielen et al., JCEM 2011). Here too, insulin administration was associated with lower IGF-1 bioactivity. The authors hypothesized that exogenous insulin administration leads to lower hepatic exposure to insulin, which could plausibly affect hepatic IGF-1 production and IGF-1 bioactivity.
• Dr. Varewijck emphasized that their findings in the LANMET analysis apply only to IGF-1 bioactivity, not necessarily cancer incidence or even metabolic and mitogenic activity. She said that slight differences in insulin structure might still be found to promote abnormal metabolic:mitogenic signaling ratios, especially when insulins are given at high doses. During Q&A, Dr. Varewijck said that she and her colleagues are now performing a similar analysis of the LANMET data to assess the bioactivity of insulin receptor A (the receptor isoform associated with mitogenic signaling). Previously, insulin glargine and human insulin were found to promote IR-A bioactivity to a similar degree in vitro (Varewijck et al., Growth Hormone and IGF Research 2010).

Questions and Answers

Q: What do you think are the implications of decreased IGF-1 bioactivity in other processes, such as growth in children?

Dr. Varewijck: Physicians are likely not thinking of this when they treat children with insulin therapy. I think that given these results we should look at these implications.

Q: Did you measure insulin levels, or did you calculate insulin exposure based only on the dose?

Dr. Varewijck: We didn’t measure serum insulin concentrations, since commonly available clinical immunoassays don’t effectively measure glargine.

Q: What are your next steps?

Dr. Varewijck: Observational studies, though inconclusive, found possible links between insulin glargine and elevated cancer risk. We are testing the LANMET samples with bioassays for insulin receptor A bioactivity to see if glargine might differ from NPH in this respect.

SITAGLIPTIN EXERTS AN ANTI-INFLAMMATORY EFFECT

Paresh Dandona (State University of New York at Buffalo, Buffalo, NY)

DPP-4, the enzyme that degrades incretins including GLP-1, is also expressed on the surface of cell membranes where it is called CD26. Circulating CD26 is thought to mediate pro-inflammatory signals. Dr. Dandona and colleagues therefore investigated whether DPP-4 inhibitors might exert an anti- inflammatory effect through inhibiting cell surface CD26. They randomized 22 patients with type 2 diabetes to receive either sitagliptin 100 mg or placebo, and found that sitagliptin was associated with significant reductions in the mRNA expression in MNC of the pro-inflammatory cytokine TNFα (by 39±10%), the receptor for endotoxin, TLR-4 (23±11%), and the pro-inflammatory kinases JNK-1 and IKKβ (19±8% and 17±9%, respectively). CD26 expression was reduced by 23% in the sitagliptin treatment arm. These results indicate that in addition to lowering blood sugar through increasing the bioavailability of incretin hormones, DPP-4 inhibitors may have a beneficial anti-inflammatory effect.

News Conference: Latest Therapeutic Discoveries on the Impact and Management of Diabetes

CONTROL OF TYPE 1 DIABETES MAY IMPROVE WITH LIRAGLUTIDE ADDED TO INSULIN THERAPY

Paresh Dandona, MD, PhD (State University of New York at Buffalo, Buffalo, NY)

In an intimate press conference featuring diabetes research, Dr. Paresh Dandona gave additional details on his group’s study of liraglutide (Novo Nordisk’s Victoza) in type 1 diabetes. Dr. Dandona especially emphasized the benefits on glycemic variability (49% lower standard deviation at 24 weeks); he said that liraglutide has great potential to make glucose changes more predictable and manageable, taming the “wild horse” of diabetes. Next month more complete 24-week results of the trial will be published, and full-year data may be submitted for publication at a later date. The first trial was independently conducted, but Novo Nordisk has since given Dr. Dandona’s group a grant to run a small trial taking physiological data (e.g., glucagon concentration) to better understand mechanism of action. If the NIH thinks subsequent research worth funding, a multicenter randomized controlled trial in the US and Canada could begin by the end of this year. We think this would be great news for type 1 patients who currently do not receive reimbursement as Victoza is not approved for people with type 1 diabetes (Dr. Dandona characterized reimbursement as a problem in his remarks), and we look forward to reporting on progress in the coming months.

• This study represents the most promising data we have yet seen on liraglutide (Novo Nordisk’s Victoza) in type 1 diabetes. As a reminder, the small (n=14 for one week; n=8 for 24 weeks) uncontrolled study enrolled type 1 patients with mean baseline A1c of 6.6%, mean BMI 24.0 kg/m², mean total daily dose 47 U/day, and mean age 39.5 years (diagnosed with diabetes for 24 years on average). Within 48 hours of taking liraglutide 0.6 mg per day, subjects experienced dramatic improvements in hyperglycemia (measured by both SMBG and CGM), glycemic variability (standard deviation), and required insulin dose (both basal and bolus). The fast onset of benefit suggests a mechanism involving hormones (very plausibly suppression of glucagon). At 24 weeks, glycemic benefits translated to an A1c decline of 0.5%, patients had lost on average a whopping 9.9 pounds, and glycemic variability, basal insulin, and bolus insulin were all decreased by nearly 50%. Hypoglycemia increased initially with borderline statistical significance, but 24-week hypoglycemia rates were statistically equivalent to baseline (for additional details, see our June 6, 2011 Closer Look).
• Given that the majority of glycemic benefits were seen within 48 hours of starting on liraglutide 0.6 mg, Dr. Dandona noted that titrating to higher doses might add few glycemic benefits. However, the weight-loss benefits of 1.8 mg might be a reason to titratehe said that roughly half of US type 1 patients have the metabolic syndrome.
• Subjects experienced nausea (rate, severity, and duration unspecified), but Dr. Dandona said that they generally found the benefits worth the tradeoff. One patient dropped out in the first week, but all of the patients who remained past one week raised their daily dosage to 1.8 mg and completed the full-year trial. These eight patients lost a mean of 4.5 kg (9.9 lbs) over 24 weeks, and Dr. Dandona said that weight loss continued – albeit more gradually through 52 weeks.
• Dr. Dandona said that his group was “lucky” to enroll a majority of patients who already used pumps and CGM and who managed their diabetes relatively carefully (13 of 14 subjects were pumpers, and as we understand it, all eight of the 24-week patients used CGM prior to enrolling). He said that these patients were highly invested in optimizing their control with liraglutide, but he noted that this might also be the case in patients who manage their diabetes less attentively. Dr. Dandona said that he has often worked with patients who are depressed and pessimistic due to the “chaos and frustration” of poorly controlled diabetes, but whose outlook improves if they can make their condition more controllable and predictable. Liraglutide, he proposed, could help many such patients “tame the wild horse” of diabetes, promoting engagement and improving quality of life.
• The trial was conducted in patients with good average glycemic control (mean A1c 6.6%); the effects in higher-A1c patients can be determined only through a clinical trial. Dr. Dandona thinks it logical that benefits would extend to patients with worse A1c, though he said that the titration of insulin might differ. The pilot study’s protocol called for patients to reduce their basal and bolus insulin by 25% and 33%, respectively, at the start of liraglutide therapy; at 24 weeks patients had dropped their doses even further (basal by 49% from baseline, and bolus by 45% from baseline). However, patients with higher initial A1c might actually wind up increasing their insulin dose, Dr. Dandona explained. If liraglutide reduces these patients’ glycemic variability, then they would theoretically be able to raise their insulin dose with less risk of hypoglycemia.
• Full 24-week results will be published in July in the European Journal of Endocrinology, and the paper (by Varanasi et al.) is already available online. Although Dr. Dandona’s group is presenting several abstracts at ADA 2011, he did not indicate that further data on liraglutide and type 1 diabetes would be released at the meeting.
• The trial has now run for a full year, and one of Dr. Dandona’s fellows in Rochester has studied liraglutide in an additional 15-20 patients with type 1. Dr. Dandona said that they might pool the yearlong data for inclusion in a future paper.
• In the meantime, Dr. Dandona said that reimbursement of liraglutide is a major barrier for many type 1 patients who would like to use the drug off label. He said that liraglutide costs roughly $350 per month, but that his clinic has had success convincing payors that this cost is worth reimbursing due to the improvements in patients’ quality of life and long- term complications risk (he noted that only 25% of diabetes treatment costs go toward patients without complications). For type 1 patients interested in trying liraglutide, he recommended working with an experienced endocrinologist (preferably a diabetologist) who monitors their patient’s progress regularly.
• Dr. Dandona speculated that other GLP-1 agonists would likely have similar effects in type 1 diabetes, though he emphasized the importance of action profile and dosing schedule. He said that “in principle” exenatide (Amylin/Lilly’s Byetta) could be great for type 1 patients, but its twice-daily schedule (two injections, two peaks, two troughs) means that it would likely not reduce the “chaos” of diabetes management to the same degree as liraglutide.
• Two other abstracts were also presented during the press conference, one on the effects of topical thyroid hormone on wound healing in mice and another on cardiac capacity of adolescents with type 2 diabetes. We think it unlikely that these studies will have dramatic effects on clinical practice in the near term.

On the Quest for the Artificial Pancreas

CONTINUOUS GLUCOSE SENSORS: THE FOUNDATION FOR THE ARTIFICIAL PANCREAS

Robert A Vigersky, MD (Walter Reed Army Medical Center, Washington DC)

Dr. Vigersky opened a packed session on the artificial pancreas with an overview of continuous glucose monitoring (CGM) technology. He outlined the steps toward an artificial pancreas and discussed several issues with CGM accuracy, emphasizing that calibration with blood glucose meters is a major weak link.

• Dr. Vigersky described several combined pump/CGM systems that provide increasing levels of closed-loop control. CGM-protected devices automatically alter insulin delivery to reduce the incidence of hypoglycemia (e.g., the low-glucose suspend function of Medtronic’s Veo) or hyperglycemia. CGM partially controlled devices would provide round-the- clock automatic control but would require manual pre-meal boluses for optimal results. The end goal for artificial pancreas research is a fully automatic system that can provide physiological responses with zero patient input. His slide referenced an A1c target of 6.0% for such a system, although Dr. Vigersky said that he thought that lower levels of control would also be beneficial.
• Dr. Vigersky reviewed some of the ways CGM accuracy is assessed. He explained that the gold standard for accurate blood glucose measurement is a Yellow Springs Instruments (YSI) glucose analyzer (we note that YSI measurements are themselves associated with error relative to more accurate laboratory methods). He reviewed Clarke Error Grid Analysis, which involves comparing measured values to reference values and ranking inaccurate values based on whether they would have led to treatment errors. Dr. Vigersky said that readings are deemed acceptable if they fall into either the A zone (measurement within 20% of reference) or the B zone. However, during Q&A Dr. Tamborlane argued that the Clarke Error Grid’s B zone is no longer relevant in today’s realm of tight control, since it includes reference values of 100 mg/dl that the sensor interprets as over 200 mg/dl.
• Calibration with blood glucose meters (BGM) is a major weak link in CGM accuracy. Blood glucose meters are susceptible to conditions such as ketoacidosis, shock, high doses of vitamin C, and strip manufacturing issues, while human factors such as strip storage and testing technique can also play a role. He also Dr. Vigersky reviewed a comparison of several companies’ blood glucose meters and said that the most accurate were within 10% of the YSI reference value only 70% of the time; we note that accuracy has gotten better since then but agree that there is room (and need) for further improvement (Thomas et al., Diabetes Technol Ther 2008). (There is also a need for improvement on such fronts as carb counting accuracy – this is also “off” quite a lot, although patients don’t tend to complain about it as much.) Interestingly, he pointed out that continuous glucose sensors and BGM appear similarly accurate when they are both calibrated using YSI, suggesting that improving the accuracy of calibration has great potential to improve CGM accuracy.
• Dr. Vigersky reviewed several other issues that can affect CGM accuracy, including interfering substances, time lag, biofouling, and biomechanics. Dr. Vigersky lamented the dearth of data on substances that interfere with CGM given the technology’s comparatively wide use, and he said that studies suggest inotropes may be problematic (one reason that he said CGM should not be used in acute care settings) and that high levels of insulin also have potential to interfere. Time lag results from the fact that CGM measures subcutaneous glucose; he said the delay is now thought to be 5-10 minutes rather than the much longer delays seen in some early studies. He also noted that sensors become less accurate with duration of wear. The Dexcom Seven Plus user’s guide includes data that sensors are more accurate on day four than on day one (80% vs. 77% of readings within 20% of YSI), but accuracy falls off by day seven (70% of readings within 20% of YSI). Biofouling around the area of the sensor may play a role in skewing results. For example IL-1 is a cytokine that could alter CGM readings by promoting inflammation. Dr. Vigersky outlined a proposal whereby IL-1 antagonists could be embedded into the sensor to increase the life of the sensor, building on the research of Dr. Ulrike Klueh in mice. Dr. Vigersky said that closed-loop systems will also have to account for real-world events that can affect the sensors, such as sensor dropout when the wearer rolls on the sensor during sleep (Helton, J Diabetes Sci Technol 2011). We have not recently heard compression of the sensor discussed as a major issue in overnight closed-loop research, and we are curious to see how it affects outpatient studies.

Questions and Answers

Dr. William Tamborlane: You said that the A and B zone of the Clarke Error Grid are clinically benign, but this was true only in 1980. For the B zone, you could have a reference value of 100 mg/dl that the sensor thinks is anywhere from 80 to 220 mg/dl. Back in the day we didn’t have insulin-to-carb ratios and correction doses. The real ISO criterion for blood glucose meters is to get 95% or more readings within the A zone – plus or minus 20%.

Dr. Vigersky: I think that is a good point. We are not doing well even at those criteria at the present time.

CLOSED-LOOP SYSTEMS OR ARTIFICIAL PANCREAS: LIMITATIONS OF CURRENT TECHNOLOGIES

William Tamborlane, MD (Yale University, New Haven, CT)

An admitted Yankee fan in Red Sox nation, Dr. Tamborlane gave an away-game talk on efforts to improve insulin delivery and glucose monitoring in the artificial pancreas. He stressed the need for closed-loop systems to be as safe as possible, aligning with the FDA’s perspective to a greater extent than in some previous statements. He commended the Juvenile Diabetes Research Foundation, mentioning the foundation’s emphasis that the AP should be available on multiple platforms. He noted that in addition to research with Medtronic products, Dexcom CGM is being studied in conjunction with Animas and Insulet pumps, and he highlighted several other major industry projects to improve closed- loop insulin delivery. Dr. Tamborlane acknowledged the National Institutes of Health for supporting research as well. Leaving the specifics of upcoming trials to Dr. Sue Brown, Dr. Tamborlane closed his talk by saying that the artificial pancreas “is a lot closer than we thought just a few years ago.”

• Dr. Tamborlane said that a mechanical artificial pancreas is a more reasonable way to address type 1 diabetes than islet cell replacement. Islet cell replacement is limited by the supply of donors, and rejection issues mean that immunosuppression is required – a burden especially ill-suited to pediatric patients. By contrast, a mechanical artificial pancreas would be based on technologies that are already widely used by people with diabetes.
• The ultimate closed loop system might consist of implantable CGM and insulin pumps, but Dr. Tamborlane believes that externally worn systems can provide great benefit in the immediate future. He noted that users would interact with the system regularly: changing infusion sites, calibrating CGM, etc. Thus, there is “no reason we can’t let them help us out” by delivering pre-meal “priming boluses,” which address the postprandial hyperglycemia (and subsequent hypoglycemia) that resulted from delayed insulin action in early closed-loop studies. Since hypoglycemia is the biggest concern for a closed-loop system, Dr. Tamborlane suggested that glycemic targets be raised at night to account for sensor error (“Every one of our patients’ parents would be thrilled with an average of 120 mg/dl per night with consistent glucose levels and a minimal chance of hypoglycemia.”)
• Several other strategies have been studied to further improve insulin delivery in closed-loop trials. These efforts include Dr. Tamborlane’s and his colleagues work with pramlintide (to blunt postprandial excursions) and Insuline’s InsuPatch (an infusion kinetics with a built-in heating coil to give a “major improvement” in insulin absorption – efforts that Dr. Tamborlane noted have been “heavily supported” by JDRF). Dr. Tamborlane mentioned several other ongoing projects as well, such as faster insulins from Novo Nordisk (NN1218, phase 1) and Biodel (BIOD-105 and BIOD-107, phase 1), coformulation of insulin with Halozyme’s PH20 (an enzyme that facilitates subcutaneous fluid dispersal, completing phase 2), and BD’s intradermal microneedles (in early development). Dr. Tamborlane also mentioned encouraging results seen with systems that deliver insulin and glucagon, as studied by Dr. Ed Damiano (Boston University, Boston, MA); he noted that a major challenge is the development of a stable glucagon preparation.
• It is important for researchers and companies to ensure the AP’s safety in cooperation with the FDA. Dr. Tamborlane acknowledged the FDA’s Dr. Patricia Beaston in the audience, saying that she is very important in this area at the agency. (For a more colorful interaction between Drs. Tamborlane and Beaston, see their discussion at the Public Workshop on the Artificial Pancreas in our December 31, 2010 Closer Look.) Dr. Tamborlane noted that although closed-loop control would likely improve many patients’ glycemic control, it must be proven extremely safe, as even a few deaths due to system malfunctions would raise serious questions for a device that removes user control from the equation. He acknowledged that no human system is perfect, “but we have to get as close as possible” with the artificial pancreas.
• Dr. Tamborlane listed several areas of improvement for CGM in the artificial pancreas, including more accurate sensors, dual sensors on the same piece of hardware (so that the system would alarm if the sensor readings diverged), integrity of radio frequency transmissions (“you don’t want to turn on the microwave and give yourself 30 units of insulin”), preventing computer malfunctions, limits to maximum delivery rates, improved algorithms for detecting sensor failure, and minimizing the risk of user error (e.g., requiring that calibration blood glucose values be communicated wirelessly from a meter rather than entered manually; Dr. Tamborlane explained that many current pump and CGM patients make up BG values rather than testing.)
• Dr. Tamborlane forecasted that early commercial versions of the closed loop will be set up in patients’ bedrooms for overnight control. The “smallest possible step” toward such a system is the Medtronic Veo sensor-augmented pump, which suspends glucose delivery in the hypoglycemic range for up to two hours. Predictive low-glucose suspend “would make even more sense.” In a retrospective analysis of their first closed-loop study in adolescents, Dr. Tamborlane’s group found that a predictive low-glucose suspend would have avoided 78% of the observed hypoglycemic events and 56% of the hypoglycemic alarms (important, since alarm fatigue limits many patients’ use of diabetes technology). Further down the road, full 24-hour versions of the AP might integrate with smart phones and other remote telemetry devices.

Questions and Answers

Q: In previous studies, it has been shown that a priming bolus may help at breakfast. Are you now in agreement that patients who aren’t on the artificial pancreas should use pre- meal priming boluses at all three meals?

Dr. Tamborlane: I used to think it a waste of breath to tell teens to give their meal boluses early, but I don’t now. One patient said he didn’t know what he would eat for lunch on a given day at school. But I said: you always take at least seven or eight units, so take five ahead of time.

Q: In 1979 you taught me how to use an insulin pump. One of my biggest disappointments is that we don’t yet have an artificial pancreas. It is so cost-effective, as we know, to cut down complications. Why isn’t the government doing a crash program? We should be advocating for us as a society to spend millions of dollars into this effort. Companies are spending research money, but we still need a better glucose sensor.

Dr. Tamborlane: You’re mistaken; I was actually in high school then. It was a great summer project. [Laughter] For fairness, Dr. Fratkin from the NIH is here, and they are making a major investment. It’s not hundreds of millions of dollars, but our government is currently running at a $1.6 trillion deficit, so I think there are some reality issues. I think the people who support research are supporting it. I’m not just saying this because she manages our funding!

ARTIFICIAL PANCREAS: EMERGING TECHNOLOGY?

Sue Brown, MD (University of Virginia, Charlottesville, VA)

Dr. Brown discussed the University of Virginia’s strategy of developing modular control algorithms for closed-loop systems and presented data on these systems’ clinical performance. She described a recent study in which one set of patients underwent closed-loop control with a hyperglycemia mitigation system (HMS, which works as needed to correct postprandial hyperglycemia) overlaid atop a more conservative safety supervision system (SSS, which works continuously to prevent hypoglycemia), while another group of patients were managed by a more intensive control-to-range algorithm in addition to the SSS and HMS. Both groups of patients spent significantly more time in their glycemic target range when using the control algorithms, and Dr. Brown looked forward to the initiation of outpatient studies later this year.

• The artificial pancreas researchers at the University of Virginia advocate for a modular design of the closed-loop control algorithm (i.e., the software that instructs the pump how much insulin to dose based on CGM readings). The advantage of such an approach is that each separate layer of the control algorithm can be developed, tested, and introduced separately. Dr. Brown and her colleagues have developed a system using three distinct layers. The most basic level is a safety supervision system (SSS) that continuously monitors for imminent hypoglycemia, attenuating insulin doses as needed (while also working to improve the safety of insulin pumping and the accuracy of CGM). Above that is hyperglycemia mitigation system (affectionately known as the HMS Virginia), which is designed to blunt post-meal glucose excursions. The HMS is notably conservative: it can make recommendations at most once per hour, and the dose recommendation is half of what the system estimates would be needed to bring glucose back into the normal range. The topmost layer enables control-to-range; every five minutes the algorithm adjusts basal insulin delivery or delivers a pre-meal bolus as necessary to maintain glycemia within a broad target range. Dr. Brown explained that although these algorithms are technically all separate, a user would recognize them as a seamless unit when they are overlaid in a closed-loop system.
• In the first arm of the randomized, crossover-design study that Dr. Brown described, patients with type 1 diabetes (n=24) were studied when using open-loop control by pump and CGM, with or without an overlaid safety module (SSS+HMS). The comparison occurred during an 18-hour timeframe (2 pm to 8 am) that included light exercise, eating, and sleep. (Patients were free to manage their own insulin dosage throughout the study period, although they were not allowed to eat carbohydrates prior to exercise.) Compared to when they used open-loop control, patients using the SSS experienced clinically significantly fewer instances of hypoglycemia below 70 mg/dl during the entire trial period (10 vs. 26), the three hours between the onset of exercise and dinner (1 vs. 6), and at night (i.e., between midnight and 8 am; 2 vs. 11). Time in range increased significantly with the safety module: for 70- 250 mg/dl, the increase was from 87% to 97% overall (91% vs. 96% during the day, 82% to 99% at night); for 70-180 mg/dl, the increase was from 60% to 75% overall (65% to 75% during the day, 52% to 74% at night), and average blood glucose improved significantly as well. Adolescents and adults experienced broadly similar hypoglycemic protection with SSS.
• The second arm of the trial included a smaller group of patients with type 1 diabetes (n=9) who were studied with and without a system that included the SSS, HMS, and control-to-range module. The target range for daytime control was 70-180 mg/dl, with an overnight target of 80-140 mg/dl. The system had the capacity to adjust pre-meal boluses; Dr. Brown noted that the system conservatively underdosed insulin relative to what it estimated would be necessary to cover a meal. The results of the study were positive: percentage of time spent in the target range improved significantly, most notably at night.
• Dr. Brown closed with a look toward important upcoming closed-loop studies, including the deployment of the Virginia team’s SSS in outpatient settings this fall. The Juvenile Diabetes Research Foundation is currently recruiting for a multicenter inpatient control-to-range trial (estimated n=50; sites include the University of Virginia, UC Santa Barbara, Stanford, the University of Colorado, the Jaeb Center in Florida, Israel, France, and Italy). The “iAP Study Group” (which includes researchers at the University of Virginia; the University of Santa Barbara / Sansum Diabetes Research Institute; Montpellier, France; and Padova, Italy) plans to launch outpatient trials in late 2011/2012; Dr. Brown said these would likely involve closed-loop control with mealtime injections of pramlintide (Amylin’s Symlin). Dr. Brown also mentioned the work of the European AP@Home Project, a four-year initiative to develop an integrated pump/CGM system that requires only one access point through the skin. The project began in the spring of 2010 and includes researchers in England, Holland, France, Germany, Italy, and Austria.

AACE vs. ADA Guidelines for Diagnosis & Management of Type 2 Diabetes

GUIDELINES & CASE STUDIES

Dr. David Nathan (Harvard University, Boston, MA)

Dr. Jaime A Davidson (University of Texas Southwestern, Dallas, TX)

Dr. Nathan, chair of the committee that developed the ADA/EASD consensus statement on type 2 diabetes, and Dr. Davidson, a member of the committee that developed the AACE/ACE algorithm, argued about the strengths and weaknesses of the two algorithms. As a reminder, the ADA/EASD algorithm encourages the use of older therapies like sulfonylureas rather than “less well-validated” therapies like GLP-1 receptor agonists and TZDs, with an A1c target of 7.0%. The AACE/ACE algorithm includes more new drugs, with regimens stratified by initial A1c and an A1c target of 6.5%. Over the course of three case studies and a lively question-and-answer session, Dr. Nathan emphasized cost, relative efficacy, and lack of long-term safety data as weaknesses of new therapies, while Dr. Davidson focused on the favorable safety and tolerability profiles seen in clinical trials of newer agents. Both stressed the importance of individualizing glycemic targets, a topic that we believe should be more explicitly addressed in future treatment algorithms. Also on the individualization side, Dr. Nathan mentioned the upcoming GRADE study, a large, long-term comparison of five different antihyperglycemic agents in conjunction with metformin, as a way to get more head-to-head data on diverse patient populations to inform clinical decision-making. Below are some of the main takeaways from the discussion, broken down by topic rather than the case-study structure of the debate.

• Efficacy. Dr. Nathan compared results from separate studies to argue that metformin lowers A1c by roughly 1.5% as compared to 1% or lower for GLP-1 receptor agonists and DPP-4 inhibitors. He displayed an advertisement for one DPP-4 inhibitor that referred to “powerful A1c reductions as monotherapy.” Saying that the A1c reduction with DPP-4 inhibitor monotherapy is typically in the range of 0.6%, Dr. Nathan said of the drug, “it ain’t powerful – it’s weak!” Dr. Davidson argued that the therapies are similarly effective and that Dr. Nathan’s comparisons are misleading, since the 1995 metformin study included patients with significantly higher baseline A1c than seen in recent studies. (From a patient perspective, if one isn’t receiving appropriate and helpful information on titration and side effect management in particular and diabetes management in general, some patients may well prefer to be on therapy that lowers A1c less but which they can adhere to, rather than “stronger” drugs that are too challenging to take.)
• Hypoglycemia minimization. Dr. Davidson explained that the AACE/ACE algorithm puts a high priority on avoiding hypoglycemia. Thus, this document recommends insulin analogs rather than regular insulin or NPH and encourages other oral drugs instead of sulfonylureas. Dr. Davidson recalled that the intensively managed arm of the ACCORD study had both higher rates of hypoglycemia and higher rates of mortality. Dr. Nathan asserted that the ACCORD researchers themselves do not know what caused the higher mortality in that study, and he said that hypoglycemia induced by sulfonylurea is rarely severe and that the incidence is low (roughly three incidents per 100 patient-years). Dr. Nathan recommended pioglitazone for people for whom hypoglycemia must be absolutely avoided (e.g., police officers, construction workers); both physicians recommended monitoring for hypoglycemia in all patients.
• Weight gain. Dr. Davidson generally put a greater emphasis on minimizing weight gain than Dr. Nathan. Dr. Davidson said, “Even if you are heavy, you don’t want to gain two kilograms. Ask [the patients].” He recommended incretin therapies for their neutral-to-positive effects on body weight. However, Dr. Davidson recommended that patients with fatty liver use TZD therapy, given that the benefits for this condition seem to overrule the weight-gain side effects.
• Other side effects. Dr. Davidson argued that sulfonylureas would never get approved by the FDA today, given their negative effects on hypoglycemia and weight gain as well as the suggestion of worse CV outcomes in some studies. Dr. Nathan, acknowledging that he is also not personally a proponent of sulfonylureas, emphasized that the serious adverse events associated with sulfonylureas are based on speculation and/or observational data. He also reminded the audience that sulfonylureas have been used in many studies showing the long-term benefits or neutral effects of intensive glucose lowering (though he noted the possibility that sulfonylurea toxicity could have counteracted some benefits of glycemic control). Dr. Nathan was also notably cautious about potential long-term side effects of newer therapies, noting that “we’ve been burned by troglitazone [Warner Lambert’s Rezulin], and maybe rosiglitazone [GSK’s Avandia].”
• Cost. Dr. Nathan said that as a country “we are going bankrupt from medical costs, and diabetes drugs cost a lot.” He noted that diabetes medications have contributed to rising costs more than any other class of drugs, including biologics; cost was one of the reasons that newer drugs are de-emphasized in the ADA/EASD algorithm. Dr. Davidson retorted that “at the end of the day, the cost of diabetes is not in paying for a pill that costs three dollars a day versus one that costs five cents”; he noted that the cost of training a patient who goes blind is $100,000, while dialysis therapy costs roughly $70,000 per year. During the question-and-answer period, an audience member disputed Dr. Davidson’s implication that using older drug classes leads to higher rates of complications, and Dr. Nathan commended her statement. Again, from a patient perspective, we could certainly see patients less able to take older drugs due to side effects; it seems logical that if someone has trouble with side effects, they may wind up with worse management and complications – this comes back, of course, to individualizing patient therapy, which we believe is harder to due with older drugs, but it also depends on the doctors and how much time they have to spend with patients.
• Individualizing therapeutic options. The AACE/ACE algorithm gives physicians more therapeutic options at a given stage of therapy, whereas Dr. Nathan said that the ADA/EASD algorithm was designed to simplify prescribing decisions for primary care physicians (and even specialists). Dr. Nathan also noted that few head-to-head trials have compared different diabetes therapies, with data especially rare on long-term treatment durability and how effects differ across subgroups. On this note, Dr. Nathan looks forward to the NIH’s Glycemic Reduction Approaches in Diabetes: A Comparative Effectiveness study (GRADE), a large (n=7,500), long- term study (roughly four-year follow-up, with enrollment to occur over three years) that will compare five different diabetes medications in patients using metformin who have been diagnosed for three years or less; combination therapy and sequential therapy will be compared. The NIH’s notice of opportunity says that potential industry collaborators could provide metformin, sulfonylureas, TZDs, DPP-4 inhibitors, GLP-1 receptor agonists, long- and intermediate-acting insulin, and glucose meters and strips. We think that this study, which Dr. Nathan is chairing, has great potential for insights that will improve physician decision-making and patient outcomes, and we are excited to hear details as the design is finalized. We wish that CGM were a part of this study for each patient so that time in target zone could be analyzed.
• Individualizing glycemic targets. Both physicians agreed that A1c targets should be raised for older or less healthy patients, given the observed dangers of intensive management in high- risk patients in ACCORD. They also both reminded the audience to manage lipids and blood pressure in addition to glycemia.

Questions and Answers

Q: I’m surprised the ADA stopped targets at 7.0% rather than 6.5%, as AACE did. There’s evidence that lower A1c is better at the get-go. The real question isn’t whether lower A1c is better, but how you create the lowering. The issue isn’t that 7.0% is somehow good enough. If you can do it safely without other risks, there is no danger.

Dr. Nathan: That’s all well and good, but you have to prove it. Attempts to prove that A1c-lowering reduces macrovascular events have been negative. There may be explanations for this, but the premise that lowering A1c in a purposeful way improves CV outcomes has to be proven. All three studies were negative. You can do meta-analyses and secondary analyses, but whatever the reason was, in ACCORD it was dangerous. It is not all surprising to me that we aren’t aiming for 6.5%. (Editor’s note: Dr. Nathan did not address the value in reducing microvascular complications.)

Q: It really depends on how you do it.

Dr. Davidson: In ACCORD and VADT, the patients were relatively old, with elevated CV risk. The AACE target of 6.5% is based on many clinical trials where we’ve gotten patients there safely. There are no long-term outcomes with these, but in that period we saw no CV events. ACCORD and VADT show that we don’t want to go to 6.5% in patients at high risk for CV events. We agree that targets should be higher in these populations.

Q: If you get hypoglycemia, it’s a slam dunk not to use aggressive therapy. And the newer agents don’t have the outcomes data we’re looking for. But the only reason the cutoff is 7.0% is because we caused hypoglycemia to get there.

Dr. Nathan: I was on the data monitoring and safety board for ACCORD, and I told them that the confounder on level of A1c would be the means used to reach it. The studies Dr. Davidson is talking about ran for six months to a year, while ACCORD lasted several years with more than 5,000 patients in each study arm. I’d like to say we should lower A1c to reduce CV risk, but randomized clinical trial data don’t support this. Now UKPDS, if you believe the 10-year follow-up data, showed that A1c lowering had long- term benefits with drugs purportedly unsafe, sulfonylurea and insulin.

Q: When they stratified the 10-year follow-up data by treatment, metformin was remarkable, but sulfonylureas and insulin were barely significant. How you lower blood sugar matters.

Dr. Nathan: Again, that’s if you believe the follow-up data. I was an editorialist for UKPDS, and I told them they analyzed the study wrong. [Jokingly] Since then I haven’t been allowed in the UK.

Q: Some people who look like they have type 2 diabetes actually have LADA.

Dr. Nathan: We cover that in the text.

Dr. Davidson: So do we. If patients are not responding to treatment, we say that it might be LADA.

Q: There are huge differences in safety between basal and prandial insulin. Basal insulins, as we know, are incredibly safe. But prandial insulin is not safe unless patients understand how to carb count, and it is especially bad for patients with dysregulated eating.

Dr. Davidson: In Europe, Drs. Monnier and Evans were involved in a study where they gave an injection of prandial insulin before breakfast, and it helped normalize their glucose throughout the day. The study included patients in France, eating coffee and bread, or the UK, where they ate scrambled eggs, bacon, and milk. To my surprise, there was very little difference in their response. Given insulin in small amounts, they behaved very similarly.

Dr. Nathan: The enthusiasm for lowering postprandial hyperglycemia is a total farce. It is promoted by the companies that make the drugs. If you look at them, fasting and postprandial levels primarily change in parallel. The NAVIGATOR study of nateglinide showed no improvement in cardiovascular outcomes. The postprandial glucose issue is nice mechanistic work, but the idea of attacking that in particular rather than lowering basal glycemia – I just don’t get it. I do train patients, though.

Comment: I am from Argentina, and I am not an expert in diabetes. Diabetes treatment is a headache for us because of the guidelines. I don’t understand why the AACE/ACE guidelines put metformin and insulin in the same line close to DPP-4 inhibitors and TZDs. We don’t know if they are safer or more powerful. The cost is so much higher. I’ve been pushed to approve liraglutide, but I don’t know why – we don’t know if this drug can induce thyroid tumors or pancreatitis. It’s a nightmare. The pharmacy is pushing and pushing, but we can’t afford such.

Dr. Davidson: First of all, you cannot afford to have patients poorly controlled, dying, and going blind. High, unsuppressed glucagon levels are a pathophysiological problem in type 2 diabetes. The costs of one emergency room visit or one patient going onto dialysis pay for a lot of prescriptions. The requirements for cardiovascular safety studies were established because the rules were different when rosiglitazone was approved. In Europe, the drug was approved based only on combination therapy studies – no monotherapy. With troglitazone we missed signs. Several DPP-4 inhibitors are now available, and the safety looks very good. You ask about thyroid cancer with GLP-1 receptor agonists – humans don’t have enough GLP-1 receptors on their C-cells. You can’t transfer animal studies to humans.

Comment: I am also from Argentina, in Buenos Aires. I don’t agree with your assessment about the risk of dying. No one is talking of letting people die or go blind. We are talking about using affordable and secure medicines. When you say we are putting patients at risk of dying or going blind by not using new medicines, I do not agree. I reviewed the medullary cancer data submitted to the FDA. Patient studies showed rates of medullary carcinoma double the amount of those not receiving liraglutide. I don’t think this is a solved question or a done deal. I think these drugs are very seductive and sexy – no weight gain, no hypoglycemia. But we don’t have outcomes data and aren’t sure if they are safe. The problem with the AACE/ACE guidelines is that people see proven and unproven drugs at the same level. When you go to consult with new doctors, they say they started the patient on two drugs: metformin and a DPP-4 inhibitor or metformin and a GLP-1 receptor agonist.

Dr. Nathan: Now I have another reason to love Buenos Aires.

Q: Dr. Nathan, I resent your implication that 90% of PCPs don’t know their ass from a hole in the ground. We do train physicians. To say that it is bad to give them choices is disingenuous. Also, all of the references in your slides are pre-1995. The rules of engagement have changed since then. None of the drugs that you endorse have been put to the rigorous tests of the new ones. Look at NPH vs. glargine. The absolute rate of hypoglycemia was low, but glargine had a significantly lower relative risk. Also, the problem in ACCORD was not that hypoglycemia occurred, but that metabolic derangement because of hypoglycemia was longstanding enough to irritate the myocardium.

Dr. Nathan: First, the only data I showed from before 1995 were several historic papers that I wrote and Dr. DeFronzo’s work with metformin, the major research of the drug in the US. All the modern studies with ‘gliptins and GLP-1s have been done within the past five years. Second, we designed this algorithm recognizing that many physicians treating people with type 2 diabetes typically see them for 10 or 15 minutes. We wanted to make something relatively straightforward and remove some of the confusion of numerous permutations. We meant no disrespect, and I think this algorithm is also useful for endocrinologists. What’s good for the goose should be good for the endocrinologist gander. I think that this algorithm would stand up to any audience, whether primary care or subspecialty.

Dr. Davidson: Metformin continues to be studied, and it has been consistently associated with decreased risk of cancer. However, it has also been repeatedly shown how unsafe sulfonylureas are. Unlike the DPP- 4s and GLP-1 receptor agonists, we will never have prospective CV outcomes trials with sulfonylureas.

Dr. Nathan: I remembered the third thing I wanted to say. Your comment about ACCORD is total speculation. The ACCORD investigators themselves don’t know the source of the increased mortality. I’m not the greatest fan of sulfonylureas, but the ADA/EASD guideline was a consensus document and different voices had different enthusiasm. But the only long-term randomized clinical trial data is from UKPDS, where sulfonylureas were not associated with increased cardiovascular risk. That said, I am suspicious of sulfonylureas.

Comment: I am from Portugal, and I have two points. One is that although we have ACCORD data, we also have ADVANCE, in which targeting a 6.5% rate was associated with no harm. Second, you have to consider patients with low and high risk separately in diabetes. Unlike with something like lipids, the targets should actually not be as tight in high-risk patients.

Dr. Davidson: We both recommend exactly what you say – be careful with patients at high risk of myocardial infarction. I think Dr. Nathan and I agree 100% that if someone is at risk, 7.0% or 7.5% is okay.

Dr. Nathan: ADVANCE didn’t show any CV danger, but it didn’t show any benefit either. And it was a sulfonylurea study. Now, could a toxic effect from the sulfonylureas have erased the possible benefits of lowering A1c? Possibly, but at this point that is all speculation.

Q: As a member of both AACE and the ADA, I appreciate the hard work on both sides. We have to pay attention to the physiology of the patient and what they can handle. If they are overweight and have a high A1c, maybe select a certain kind of drug; if they have a lower A1c, a different one. My wife and I take care of many indigents who can’t afford any of them. I think that it is important to get out the information about adjusting and individualizing treatment based on what the patient can handle.

Dr. Nathan: I think everyone would agree that precious few studies look at head-to-head comparisons. Drug companies for the most part have not been willing to compare their drugs to more recent drugs. The GRADE (Glycemic Reduction Approaches in Diabetes: A Comparative Effectiveness) study from NIH will compare five different combinations over time, with regard to A1c-lowering, safety, and tolerability. The data today are really picking things from different areas, and there is little in the way of a comprehensive look. The other thing missing from these studies is phenotyping. Drug companies rarely publish sub- analyses of men vs. women, black vs. white. They want to sell the drug to as many people as possible, and if some don’t work then they’ll fall off. Right now we treat all patients as if they are the same; the data to guide us are scant. This is the biggest epidemic in the world, and we treat every patient as if they have the same disease.

Dr. Davidson: Wait two-to-three months, and then if the regimen isn’t working, make a change. That’s the most important thing we can tell you today. Hopefully in two years we can debate again and have more data.

Dr. Nathan: (puts arm around Dr. Davidson) I’ll debate anywhere!

Endocrine “Year In...” Session

YEAR IN OBESITY

Michael Schwartz, MD (University of Washington, Seattle, WA)

We had trouble finding seats in the Grand Ballroom for this highly educational session. Dr. Schwartz noted that the FDA’s extensive regulatory requirements (e.g., requesting a large pre-approval clinical trial for Orexigen’s drug Contrave) have had a chilling effect on obesity drug development. Indeed, he said that no large US pharmaceutical company has an active obesity drug discovery focus. Turning to new research that may hold promise for future treatments, Dr. Schwartz explained how obesity is associated with resistance to leptin, a hormone that acts in the hypothalamus to inhibit appetite. He showed evidence that leptin resistance is caused by inflammation in the hypothalamus, which occurs earlier than inflammation in the rest of the body. Using mice, Dr. Schwartz identified a number of inflammatory markers within 24 hours that resulted from a high-fat chow mix. Dr. Schwartz expressed his hopes that ongoing research into the mechanisms of obesity can lead to a richer understanding of the condition and more effective ways of treating it.

• At the cellular level, nutrient excess induces inflammation. Depending on cell type, reactive oxygen species, cytokine signaling, endoplasmic reticulum stress, mitochondrial dysfunction, or TLR4 activation may be the cause. Nutrient excess and the corresponding inflammation are detrimental to the cell, shutting off insulin receptors and limiting further nutrient uptake. Once insulin resistance has developed, elevated levels of circulating nutrients are observed.
• Dr. Schwartz’s lab has explored the role of tissue inflammation in obesity pathogenesis and identified a feedback loop involving leptin, a hormone that inhibits appetite. In most forms of obesity, food intake is normal or increased despite elevated leptin levels. Thus, leptin resistance appears to be a common feature of obesity.
• Leptin and insulin receptors are concentrated in the arcuate nucleus (ARC). NPY neurons secrete peptides that stimulate food intake, while POMC neurons have a negative impact on food impact. Leptin is stimulatory for POMC neurons and inhibitory for the NPY variety. If weight is lost, leptin levels drop, which should theoretically stimulate appetite and thus encourage a return to the previous weight.
• Based on the leptin pathways described, Dr. Schwartz hypothesized that hypothalamic inflammation promotes weight gain as a result of impaired leptin responsiveness. To play a causal role in weight gain, inflammation would need to occur much earlier in the hypothalamus than in peripheral tissues. Dr. Schwartz predicted that this would be the case, but he was nonetheless surprised to see hypothalamic inflammation within 24 hours of a high fat diet in mice. His group found a rapid onset of inflammation, prompting them to pursue deeper investigation.
• In mice, a host of proinflammatory markers were upregulated within 24 hours of a high fat diet (HFD), causing researchers to suspect acute neuron injury. Microglia, macrophages in the brain that promote inflammation during immune responses, responded noticeably within a week of HFD. The researchers also observed that the ARC contained a high number of tangled astrocytes, another cell type that play a major role in response to brain injury. This result was indicative of gliosis, a response commonly associated with stroke and other injurious conditions. Levels of heat shock protein (hsp72), a marker of neuronal injury, changed within seven days of HFD. Autophagosomes, which respond to cellular damage, were seen in increased numbers after 20 weeks of HFD. Finally, POMC cells were reduced by 25% after eight months of HFD. This suite of findings along with research cited above indicate that neurons were injured in response to HFD. This injury in turn appears to promote obesity. Dr. Schwartz proposed that this research could assist in development of novel therapies against obesity.

Symposium: Future Guidelines

CRITIQUE OF CURRENT GLYCEMIA ALGORITHMS IN T2DM

Robert A Vigersky, MD (Walter Reed Army Medical Center, Washington DC)

Dr. Vigersky highlighted the importance of transparency and individualization in the development of diabetes guidelines. Currently, conflicts of interest are ubiquitous among experts in the field, including the authors of most key consensus algorithms. Dr. Vigersky delved into five of the nine guideline documents for type 2 diabetes management, choosing to focus on AACE, ADA, NICE (British), SIGN (Scottish), and the Department of Defense/Veterans Affairs (DoD/VA) guidelines. He highlighted the pros and cons of each, proposing that future documents should give clear guidance on individualization of A1c goals. He also noted that current algorithms for diabetes care are mostly consensus documents since few head-to-head long-term trials have been conducted; he said that clinical experience is valuable but that documents should identify the evidence for their recommendations.

• The authors of diabetes guidelines often have conflicts of interest (COI), which Dr. Vigersky believes should be clearly disclosed. Aside from the DoD/VA guidelines, all the guidelines showed high rates of COI (60-80%) among their authors, with some authors receiving over $100,000 in various fees, grants, and honoraria.
• Although meta-analyses are often seen as the highest level of evidence, published meta-analyses often fail to consider COIs. In a recent study of 29 influential meta-analyses used to shape guidelines, 27 failed to report funding source. When examining the 509 randomized controlled trials (RCT) in the 29 meta analyses, 318 (62%) did not report this information. Moreover, 377 (74%) of these studies did not report their funding sources. Of the 132 studies that did report funding sources, almost 70% had a COI.
• Dr. Vigersky believes that individualizable A1c guidelines are superior to the strict cutoffs that pervade today’s guidelines. AACE and NICE set a goal of 6.5%, while the ADA, SIGN, DoD/VA have chosen 7%. However, the problem with using these cutoffs is that they are derived from observational studies, Dr. Vigersky explained. The A1c goals may not be achieved safely with current therapy; strict glycemic targets are not associated with positive macrovascular outcomes in many high-risk patients. He recalled that the ACCORD trial led to higher mortality on average, while ADVANCE and VA Diabetes showed no difference in CV outcomes and mortality when the same “one-size-fits-all” glycemic targets were used for all patients.
• Dr. Vigersky first examined the current AACE/ACE guideline algorithm, noting that limited evidence underlies recommendations for expensive drugs and early initiation of combination therapy. As a reminder, the AACE/ACE guidelines stratify recommended therapy by range of initial A1c as follows: 6.5-7.5% (monotherapy), 7.5-9% (dual therapy), and >9% (triple therapy). The guidelines also specify the duration that each therapy should be prescribed before intensifying the regimen, which Dr. Vigersky commended. However, he criticized the guidelines for being unclear in several other respects. .For the 6.5-7.5% group, the first choice is metformin, followed by DPP-4 inhibitors, GLP-1 agonists, and other drugs that do not have to be prescribed in any particular order. The choice of therapeutic agents should be based on their differing metabolic actions and adverse effect profiles as described in 2009 AACE/ACE Diabetes Algorithm for Glycemic Control. They should also consider cost- effectiveness. Efficacy of monotherapy shows that A1c reduction is similar across the board (0.5- 2%). If reduction in A1c is not seen, then doctors are to move on to dual therapy. If patients present A1c > 9%, today’s guidelines suggest triple therapy. The problem is that there is no evidence that this is necessary. Moreover, this course of action seems rushed. There is increased risk of drug-drug interaction, and the ACCORD study even showed that aggressive treatment might lead to increased risk for poor health outcomes. The AACE algorithm does specify duration of therapy for each stage, and the A1c target is inappropriate for many patients. Additionally, the guidelines do not provide clearly stated reasons for stratification of A1c levels. The guidelines also incorporate use of newer, more expensive, and non-superior drugs that do not appear to lead to improved health outcomes.
• Dr. Vigersky took a generally negative view of the ADA/EASD consensus algorithm. This algorithm relies on stratification of A1c levels and has two tiers of therapy, of which the first tier is basal insulin and sulfonylurea. The problems include lack of evidence grading due to a paucity of high quality data, no explicit individualization of A1c goals, and a reliance on collective knowledge and clinical experience. In fact, Dr. Vigersky noted that he attended a meeting where one of the authors said, “I would never prescribe a sulfonylurea, but this was a consensus process.” (We believe he was referring to Dr. David Nathan’s remarks during a panel discussion at the Seventh Annual Clinical Diabetes Technology Meeting; see our April 12, 2011 Closer Look.)
• The NICE algorithm involves many potential pathways for intensification of therapy; these rely on a 7.5% cutoff rather than 6.5-7%. The A1c gradient is inappropriate for many patients, no evidence for the grading is given, and declarations of interest are not included.
• Dr. Vigersky believes that the Scottish SIGN guidelines appear to be the clearest, simplest, and most elegant of the discussed guidelines. The guidelines include individualizable A1c targets, synthesize all data, and are easy to follow. However, the declarations of interest are difficult to obtain (Dr. Vigersky eventually succeeded with a Freedom of Information Act request).
• The DoD/VA guidelines lack COI but have many of the same problems as its sister guideline documents. DoD/VA guidelines allow A1c targets to best established via shared decision making and provide clear evidence tables. However, these guidelines fail to provide clear guidance on alternative drug therapies, and guidance on combination therapy is also limited. COI information is not available in the present guidelines but will appear soon; Dr. Vigersky noted that none of the authors happen to have any disclosures.

Questions and Answers

Q: What is your opinion of how to proceed in light of new data from European studies regarding higher incidence of bladder cancer of patients on Actos?

Dr. Vigersky: Newer agents that are available have not been available for that long. With the passage of time, we are discovering potential adverse effects. Whether or not ill effects outweigh positive gains is yet to be determined. To assess the benefit of any drug, you may have same A1c reduction but unknown risk of long-term adverse effects.

Meet-the-Professor Sessions

USE OF CONTINUOUS GLUCOSE MONITORING

Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA)

Dr. Bode spoke on continuous glucose monitoring, using several in-depth case studies to engage roughly 40 audience-members on the clinical management of patients using CGM. He briefly addressed the features of currently available products and reviewed the major studies of CGM in type 1 diabetes (he mentioned that expectations are also high for a yearlong trial in non-insulin-dependent type 2 diabetes, which will be presented at ADA 2011 as a late-breaker). He noted that CGM is “pretty much covered” by private payers even if it takes time and effort, while Medicare reimbursement is more difficult to achieve. Dr. Bode also discussed progress toward the artificial pancreas; he noted that the Medtronic Veo (the first sensor-augmented pump system to automatically shut off in hypoglycemia) is scheduled to begin outpatient trials in the US this summer, pending regulatory green lights. He ended the talk with a look at other promising advances in glucose management, including sanofi-aventis’ iBGStar iPhone- integratable blood glucose meter (which Dr. Bode said will hopefully be available in the US in August) and Ford/Medtronic’s in-vehicle system to sync with CGM (an early-stage research project recently presented in Dearborn, MI; see our May 27, 2011 Closer Look).

• Dr. Bode reviewed the CGM products currently available in the US. Medtronic offers separate products for professional CGM (the iPro is on the market and the iPro2 is before the FDA) and personal CGM (the Guardian REAL-Time standalone system and the Paradigm REAL- Time sensor-integrated pump, both approved for three days at a time), while Dexcom currently provides its third-generation Seven Plus (the only system approved for a week, which he said also has strong data at 10 days). Dr. Bode praised Abbott’s FreeStyle Navigator for its built-in BG meter and low calibration requirements (four times over a period of five days), but the product is unavailable in the US due to issues with Abbott’s “manufacturing and management” (Dr. Bode explained that the company says CGM hurts its bottom line, since users who previously performed SMBG six-to-eight times a day test only three times daily when on CGM).
• “They can’t deny you if you have two peer-reviewed articles.” A strong body of evidence supports that CGM is highly effective when worn six or more days per week. Consequently, Dr. Bode said managed care organizations will inevitably reimburse the therapy for patients who need it because of hypoglycemia (definitions vary) or hyperglycemia (FPG > 180 mg/dl); he noted that and that the process is usually easiest with pediatric or pregnant patients.
• Dr. Bode mentioned that Medtronic’s Veo is scheduled to enter outpatient trials in the US this summer. We hope to hear more about Medtronic’s plan once the trial designs have been finalized and approved by the FDA. As we understand it, the company is currently wrapping up inpatient trials that the FDA required before outpatient trials could be conducted – an excessive precaution in our view. As we understand the inpatient trials, the roughly 50 subjects were brought into the hypoglycemic range in a controlled fashion, with and without the Veo’s low- glucose suspend (patients served as their own controls in separate hospital visits).
• During Q&A, Dr. Bode referenced a yearlong trial of CGM in non-insulin-dependent type 2 diabetes that will be presented at this year’s ADA and published in Diabetes Technology and Therapeutics. He said that he hasn’t seen the study but has heard the results are good, and he hopes that the findings spark interest in CGM as a way to give type 2 patients feedback that helps them engage.

PRACTICAL MANAGEMENT USING INCRETINS

Lawrence Blonde, MD, FACP, FACE (Ochsner Medical Center, New Orleans, LA)

Dr. Blonde led an interactive session about practical use of incretin-related therapy in the management of type 2 diabetes patients. The topic prompted major discussion amongst the 120 people in the intimate presentation hall. GLP-1 agonists and DPP-4 inhibitors were reviewed, and much attention was given to their mechanisms of action, efficacy, and safety. He stressed the importance of weight loss in patients of type 2 diabetes and noted the ability of GLP-1 agonists to produce significant weight reduction and reduce the risk for hypoglycemia. However, he also highlighted the popularity of DPP-4 inhibitors because they can be taken orally, also are associated with a low risk for hypoglycemia, and are weight- neutral.

• Dr. Blonde compared the ADA/EASD and AACE/ACE type 2 diabetes treatment algorithms, noting that the AACE/ACE algorithm uses almost all of the presently approved antihyperglycemic medications, stratifies recommendations by baseline A1C and stresses the value of agents that reduce the risk for hypoglycemia and weight gain. By contrast, he observed that the ADA/EASD algorithm uses only six of the 13 approved antidiabetes drug classes. Dr. Blonde also noted that a recent editorial (Owens, Ann Intern Med 2011) observed “to the extent that guideline developers can further tailor recommendations to specific patient circumstances and maintain usability…, they have an important opportunity to make guidelines more helpful to clinicians and to improve outcomes for patients.”.
• Dr. Blonde reviewed data on the two currently available GLP-1 receptor agonists, exenatide (Amylin/Eli Lilly’s Byetta) and liraglutide (Novo Nordisk’s Victoza), including a head-to-head study comparing exenatide 10 ug twice daily and liraglutide 1.8 mg once daily administered to patients uncontrolled on metformin, sulfonylurea, or both. In that study liraglutide treatment reduced fasting plasma glucose and A1c to a greater degree than did exenatide (A1c declines of 1.12% vs. 0.79%, respectively). Exenatide treatment decreased postprandial glucose increments more than did liraglutide after breakfast and dinner. Weight loss was similar with the two agents; typically GLP-1 receptor agonist-associated weight loss involves both visceral and subcutaneous fat. Hypoglycemia was less frequent and nausea frequency decreased more rapidly with liraglutide. In the extension trial, patients on exenatide were switched to liraglutide, and A1c fell along with weight and blood pressure.
• The most common adverse effect with GLP-1 receptor agonists is nausea, which can cause some patients to not tolerate these medications. Dr. Blonde said that patients can be helped to better tolerate these agents by encouraging them to stop eating as soon as they are no longer hungry and avoid overeating. In addition one should wait until nausea or other gastrointestinal symptoms have resolved before uptitrating the medications to the next dose level.
• Dr. Blonde reviewed incretin therapy safety. Case reports of pancreatitis with exenatide, liraglutide, and sitagliptin (Merck’s Januvia) led to label warnings/precautions, but a causal relationship between incretin therapy and pancreatitis has not been established, and Dr. Blonde noted that all patients with diabetes appear to have an increased risk for pancreatitis. He said that patients should stop taking these agents if signs or symptoms of pancreatitis occur and if confirmed should not restart them and physicians should consider other antihyperglycemic therapies in patients with a past history of pancreatitis. Exenatide should not be used in people with severe renal impairment or end-stage renal disease and should be used with caution in patients with moderate renal impairment, while liraglutide should be used with caution in people with renal impairment because of limited data in these patients. In rodents, liraglutide caused c- cell tumors. While, there are important species differences between rodent and human c-cell pathophysiology and response to GLP-1 receptor agonists that would be expected to result in a low risk for humans, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2. DPP-4 inhibitors are generally well tolerated, but Dr. Kahn said that hypersensitivity reactions have been reported in addition to peripheral edema.
• Dr. Blonde then turned to the presently FDA-approved DPP-4 inhibitors: sitagliptin, the single pill combination sitagliptin+metformin (Merck’s Janumet), saxagliptin (BMS/AZ’s Onglyza) and its single pill combination saxagliptin+metformin ER (Kombiglyze), and linagliptin (BI/Eli Lilly’s Tradjenta). He showed efficacy data for the agents as monotherapy and as add-on to metformin, sulfonylureas and TZDs and noted that studies of initial combination therapy with sitagliptin or saxagliptin plus metformin have demonstrated substantial and additive glycemic improvement in patients with type 2 diabetes.

• Head to head studies comparing GLP-1 receptor agonists and DPP-4 inhibitors were also discussed. In one recently reported study, sitagliptin and liraglutide were added to patients not at goal on metformin. Liraglutide was associated with greater A1C lowering and more weight loss. As expected, liraglutide-treated patients experienced more nausea.
• Dr. Blonde concluded his presentation by reminding attendees of the importance of treating the often-associated hypertension and dyslipidemia in addition to hyperglycemia in people with type 2 diabetes. Lifestyle interventions (medical nutrition therapy and appropriately prescribed physical activity) remain the cornerstone of antihyperglycemic therapy. However, Dr. Kahn said that most people will also require treatment with combinations of pharmacologic antihyperglycemic agents with complementary mechanisms of action. Because incretin-related agents have good glycemic lowering efficacy, a low risk for hypoglycemia and weight neutrality or weight loss, he believes they will likely have a prominent position in the management of type 2 diabetes.

CO-MANAGEMENT OF OBESITY & T2DM

Holly R Wyatt, MD (University of Colorado, Denver, CO)

In an entertaining and highly interactive session, Dr. Wyatt discussed the rise of the obesity epidemic. Dr. Wyatt refused to lecture in a traditional style, instead asking the 50 attendees a number of questions to prompt discussion. The session showed that doctors are resistant to prescribe weight-loss medications since they want their patients to alter their lifestyle rather than providing “the easy way out.” Dr. Wyatt played devil’s advocate by noting that doctors are quick to prescribe drugs for glucose control. She also observed that regardless or specific physicians’ attitudes, their pharmacological options are limited, with potential new therapies facing an uphill battle with the FDA. Dr. Wyatt concluded with suggestions for lifestyle adjustments that people with diabetes must make.

• BMI, waist circumference, and weight gain can help doctors “paint a picture.” Dr. Wyatt clarified that BMI is not a direct measure of body fat, but she said it is a valid proxy for the vast majority of patients who come to the doctor’s office, BMI will serve as a valid proxy for body fat. Waist circumference describes where the body fat is carried, while weight gain suggests potential to develop type 2 diabetes.
• Dr. Wyatt engaged in a discussion to determine why patients are obese, suggesting a combination of genetics and environmental factors. When asked to name causes of the obesity epidemic, audience members gave answers including food choices, sedentary lifestyle, excess calories, and socio-economic conditions; Dr. Wyatt expressed surprised that they did not mention genetics. She said that genetics do not take away responsibility for the patient to watch their weight but argued that they can certainly play a role in obesity. Dr. Wyatt stressed that it is not exclusively genetics or environment, but rather a combination of both, that explains the obesity epidemic.
• There is no single specific weight-loss plan for people with diabetes, and the use of weight-loss medication remains a thorny issue. There is no one diet that is superior. Rather, the best diet is one that maintains adherence. Dr. Wyatt asserted that any plan that forces caloric restriction and promotes adherence is the best for a weight-loss plan. The quantity of calories is most important for weight loss, while the quality of those calories matters more for weight maintenance. Dr. Wyatt touched on the use of weight-loss medication in people with diabetes, noting that doctors are quick to prescribe insulin but are resistant to weight-loss medication. Dr. Wyatt did not suggest medication as the best course of action but was curious why doctors in the room expressed resistance to weight-loss pills. What complicates the matter is that the only drugs for weight loss on the market are phentermine, indicated only for short-term use, and orlistat (Roche’s prescription Xenical, GSK’s over-the-counter alli), which is associated with GI side effects. She also mentioned the benefits of GLP-1 receptor agonists, which lead to weight loss as a side effect. Additional drugs and combination therapies are undergoing the regulatory process and in development, but Dr. Wyatt lamented that drug makers face an uphill battle with the FDA.
• Exercise is the “magic pill” that can solve the obesity problem, and Dr. Wyatt offered tips to promote an active lifestyle. Exercise is safe, cheap, and effective, increases metabolism, burns fat, and allows individuals to eat more food without gaining weight. Furthermore, Dr. Wyatt noted that it makes people healthier and is the best way to maintain weight. To promote activity, Dr. Wyatt suggested that doctors emphasize exercise as a priority, tell their patients to use pedometers, and use a combination of lifestyle and planned activities.

U-500 INSULIN

Irl B Hirsch, MD (University of Washington, Seattle, WA)

Dr. Hirsch led an in-depth and engaging workshop on Eli Lilly’s U-500 regular insulin, sharing a host of “pearls” such as how to identify patients who might benefit, how to manage dosage, and how to avoid confusion with other concentrations of insulin. Dr. Hirsch believes U-500 insulin can be an effective and relatively inexpensive therapy for severely insulin resistant patients, including those with maternally inherited mitochondrial diabetes (a condition that he emphasized as under-diagnosed; telltale signs include deafness). Pharmacokinetic and pharmacodynamic data, although limited, suggest that U-500’s action peaks at roughly six hours and can continue for over 20 hours – important to consider when making therapeutic adjustments. He also discussed the off-label use of U-500 in an insulin pump and in combination with basal insulins, supplementing the dearth of published data with clinical experience, common sense, and the comfort that severely insulin-resistant patients rarely go into hypoglycemia.

• Dr. Hirsch briefly discussed the history of insulin, highlighting the introduction of beef U-500 insulin in 1952. He reminded the audience that Eli Lilly developed U-500 to treat patients with type 1 diabetes who had antibodies to insulin, not the highly insulin-resistant type 2 patients typically prescribed U-500 today.
• For patients with severe insulin resistance, U-500 offers several advantages over U- 100 insulin. He used the example of a patient who requires more than 100 units (1 ml) of U-100 insulin at a time. Not only would this require multiple shots, such a large depot of insulin would be painful and would have an unpredictable absorption pattern.
• Dr. Hirsch listed a variety of patients in whom to consider U-500 insulin. For non- syndromic insulin resistance, the list included: obese people with type 2 diabetes requiring over 200 units of insulin per day, post-operative or post-transplant patients, those taking high-dose steroids or pressors, patients with systemic infection, and pregnant women with underlying (i.e., not gestational) type 2 diabetes. Types of syndromic insulin resistance include: lipodystrophy, type A insulin resistance (“extremely rare”), leprechaunism (“I have never seen this”), type B insulin resistance (which involves anti-insulin receptor antibodies and is rarely diagnosed), and mitochondrial diabetes, which Dr. Hirsch said is “by far” the most common reason he prescribes U-500 in his own practice. Dr. Hirsch noted that people with this condition (also called maternally inherited diabetes and deafness, or MIDD) tend to be deaf and susceptible to coronary artery disease as early as age 30 or 40 despite having normal lipid levels, with non-diabetic retinopathy, proteinuria unrelated to diabetes, intolerance to metformin, severe insulin resistance, and mothers with similar symptoms. He also reminded clinicians to test insulin resistance for themselves in the clinic, since patients (e.g., some with eating disorders) might be prescribed high doses of insulin but not be taking them.
• Clinical data on U-500 efficacy is sparse, but suggests that U-500 can be a good therapeutic option even though it is available only as regular insulin. In a review of the eight studies published between 1969 and mid-2008 (n=160), several authors (including Dr. Hirsch) found that switching from U-100 to U-500 insulin was associated with A1c decline of 1.6% (from 10.0% to 8.4%; p<0.001), a non-statistically significant 11% increase in insulin dose (286 to 317 U/day), and a weight increase of 4.2 kg (9.2 lbs; p=0.002) (Lane et al., Endo Pract 2009).
• The most recent data on insulin U-500’s pharmacodynamics and pharmacokinetics were presented by Dr. Jeffrey Jackson and colleagues as a late-breaking poster at ADA 2010 in Orlando, FL. Healthy obese subjects without diabetes (n=24, mean age = 39 years, mean weight = 98 kg [215.6 lbs], mean BMI = 34 m/kg²) were assessed via euglycemic clamp after injection of 50 U and 100 U of U-100 regular insulin and U-500 regular insulin. The peak concentration (Cmax) of U-500 was found lower than U-100 at both doses (p<0.001), although the duration of action for U-500 was longer, leading to equivalent overall effect (Gtot) for equivalent doses of the two insulins. Dr. Hirsch proposed that U-500 should be treated as both a basal and prandial insulin, given both its distinct peak and its long duration.
• Given the long action profile of U-500, Dr. Hirsch emphasized the importance of pre-meal dosing and frequent SMBG. He shared tips on various clinical considerations around U-500, such as how to avoid confusion when ordering U-500 in the hospital (ideally by writing both units in U and volume in ml) and how to give U-500 off-label in an insulin pump (Dr. Hirsch generally opts for a 40% basal rate, with total daily dose based on the patient’s MDI regimen; given U-500’s long action profile, dosage adjustments often need to be made far in advance of any hypo- or hyperglycemia). He said that most U-500 management (and most insulin management in general) is largely based on anecdotal evidence. Fortunately, the margin for error is relatively high, since patients on U-500 insulin very rarely go hypoglycemic.
• Per unit, U-500 regular tends to be the cheapest insulin option, especially given recent increases in the price of U-100 regular and analogs. Addressing an issue that we rarely hear discussed at conference presentations, Dr. Hirsch presented data on insulin price taken from drugstore.com (and from a mean of three pharmacies for U-500, which is not sold on drugstore.com). While U-500 costs $320 for a 20 ml vial (3.2 cents per unit of U-100 equivalent), the price of U-100 regular insulin has risen 34% in the past three years to reach $73 per 10 ml vial(7.3 cents per unit). Noting that regular insulin is “not the cheap drug it was years ago,” Dr. Hirsch speculated that the price increases might be related to the imminent availability of biosimilar insulins. Pricier options include vials of NPH (roughly 7 cents per unit) and analogs like glargine and detemir (each roughly 12 cents per unit) or lispro (12.6 cents per unit); these insulins are more expensive per unit volume when sold for pens.

CONTINUOUS GLUCOSE MONITORING AND ITS ROLES IN DIABETES MANAGEMENT- MAKING SENSE OUT OF SENSING

Dace L. Trence, MD (University of Washington, Seattle, WA)

Since Dr. Trence’s talk took place on the last day of the conference, this session was not as well attended as other talks about CGM technology. She began with a broad overview of CGM technology and the three systems currently available in the US, proceeding to case studies of patients who were able to improve their diabetes management with CGM.

• Dr. Trence described case studies in which CGM helped patients understand how foods affect their blood sugar and when to take insulin boluses. In general, she said that especially good candidates include those who exhibit hypoglycemia unawareness and pump users who struggle to optimize glycemic control. She recommended against prescribing CGM to individuals who are addicted to technology, those who are forced into CGM by family, or patients who desire accurate readings at every minute.
• Patient education to minimize risk for hypoglycemia from over-bolusing is critical. Doctors must clarify types carbohydrates, role of exercise, influence of alcohol, and other events that can influence glucose. However, patients will learn how they respond to particular events as they get acquainted with their CGM and examine their data.

INSULIN PUMPS

Anthony McCall, MD (University of Virginia, Charlottesville, VA)

Dr. McCall discussed the clinical use of insulin pumps in a case-based lecture that encouraged the audience to practice pattern management to adjust basal and bolus insulin levels. He emphasized the importance of training patients in pump features (e.g., types of bolus), basal rate validation, and even carb counting, noting that pumping requires motivation and commitment. “People have to be willing to do more work,” he said, “not less….” in order to have better diabetes management.

DIFFICULT DIABETES CASES

Graham T McMahon, MD (Brigham & Women’s Hospital, Boston, MA)

Dr. McMahon presented diabetes case studies in an interactive session. The first case highlighted the different effects of diabetes medications on weight, with metformin and GLP-1 agonists recommended for their weight-neutrality / -loss. The second case described an individual with diabetes and end stage renal disease (ESRD). He cautioned that A1c tests often underestimate glycemia in individuals with ESRD, so direct measurements of blood glucose should be used. Dr. McMahon also noted that ESRD coupled with diabetes tends to allow a five-year survival rate. Given the unfavorable risk-benefit ratio of intensive glucose management in such high-risk patients, Dr. McMahon recommended a relatively moderate glycemic target.

GLUCOSE HOMEOSTASIS AND INSULIN ACTION

Kwame Osei, MD (Ohio State University, Columbus, OH)

Dr. Osei discussed ethnic differences in diabetes onset and severity, emphasizing the need for early diagnosis, especially in minority populations. He reviewed the many differences in metabolic and cardiovascular risk between white and black patients, suggesting that diagnosis criteria and targets for should take ethnic and gender differences into account. For example, black patients tend to have higher insulin resistance but lower visceral adiposity at a given BMI, which means they are under-diagnosed for metabolic syndrome based on current criteria. He concluded with two case studies that raised several issues about individualizing therapies based on patients’ lives outside the clinic. One featured a woman who elected to receive gastric banding rather than gastric bypass (because she feared stigmatization if she lost too much weight), while another patient refused to go on multiple daily insulin injections because he would be fired for bringing insulin to his job.

Treatment Advances

NEW TREATMENTS AND COMBINATIONS FOR T2DM ON THE HORIZON

Clifford Bailey, PhD, FRCP (Aston University, Birmingham, UK)

Dr. Bailey took a look ahead to new therapies for type 2 diabetes, discussing a number of late- and early-stage candidates. Some areas of research are relatively far along (selective PPAR modulators) and others are less active (small-molecule insulin mimetics), but Dr. Bailey was generally optimistic about the future growth of diabetes drug classes.

• Dr. Bailey discussed Bydureon (Amylin/Eli Lilly/Alkermes’ exenatide once weekly), listing several pros (convenience, consistently raised exenatide levels, and potential efficacy gains for glucose lowering and weight loss) and cons (missing one shot would affect therapy for the entire week, large needle size, some instances of local reactions to the injection, antibodies, possible desensitization from continuous long-term agonism of the GLP-1 receptor, and the potential for side effects that have been associated with incretin therapy such as pancreatitis and C-cell hyperplasia).

CAN WE PREVENT BETA CELL FAILURE?

Jack Leahy, MD (University of Vermont, Colchester, VT)

Dr. Leahy explained that beta cell failure is necessary for metabolic disease to turn into diabetes, and he discussed efforts to preserve beta cell function using glucose-lowering therapies. The “oldest and most established approach” to preserving insulin secretion is simply to improve glucose control and reduce glucotoxicity. Some evidence suggests that certain therapies may have separate benefits on beta-cell function, but Dr. Leahy said that this cannot be determined definitively without long-term trials (five years or more). Thiazolidinediones seem to improve beta cell function in the short term, but rosiglitazone’s effects five years into the ADOPT study are similar to metformin’s. Promising pre-clinical evidence suggests that incretin therapy could have profound benefits; currently little clinical evidence exists to support these prospects. Dr. Leahy also looked forward to the long-term ORIGIN trial of insulin glargine that will be presented at ADA 2012.

Plenary Sessions

GERALD D. AURBACH AWARD LECTURE – OBESITY, TYPE 2 DIABETES & CANCER: THE INSULIN & IGF CONNECTION

Derek LeRoith, MD, PhD, FACP (Mt. Sinai School of Medicine, New York, NY)

Dr. LeRoith presented his group’s research on the role of the insulin-like growth factor 1 receptor (IGF- 1R) and insulin receptor (IR) in cancer, as studied in a mouse model of non-obese insulin resistance. Their findings suggest that hyperinsulinemia and insulin resistance promote tumor growth and metastasis independently of hyperglycemia and hypertriglyceridemia. Epidemiologic studies show an inverse relationship between the extent of IR expression and breast cancer survival, suggesting that similar pathways may be operative in human cancer. Dr. LeRoith briefly addressed the potential for the IGF-1 and insulin pathways as potential therapeutic targets in oncology, but he said little about implications for insulin administration or other therapies for metabolic disease.

• Dr. LeRoith briefly listed several factors that potentially link obesity and/or type 2 diabetes with cancer. These included nutrients, IGF-1 (insulin-like growth factor receptor), sex steroids, leptin, adiponectin, cytokines, and chemokines, as well as hyperinsulinemia, hyperglycemia, and hyperlipidemia. Acknowledging that many of these are important, he said that his talk would focus on his own and others’ research on IGF-1 and insulin signaling pathways.
• Dr. LeRoith illustrated the structure and function of the IGF-1 and insulin receptors, for the benefit of anyone in the audience unfamiliar with the biology (“my wife and son”). He reminded listeners that the insulin receptor (IR) comes in two types, IR-B (mainly activates metabolic pathways) and IR-A (mainly promotes mitogenesis). The IGF-1 receptor (IGFR-1) binds extracellular IGF-1 and IGF-2 and activates pathways that promote cell survival, growth, and proliferation. Because IGF-1 and IR are structurally similar, they can hybridize to form IGF-1R/IR-B (mainly metabolic signaling) or IGF-1R/IR-A (mainly mitogenic signaling).
• Dr. LeRoith explained that a link between IGF-1R and cancer was uncovered from both biological and epidemiological studies. Some researchers found that a high proportion of epithelial cancer cells demonstrated high expression of IGF-1R relative to nearby, non-cancerous cells. Epidemiological studies showed greater relative risk of many cancer types when circulating IGF-1 were in the highest quartile of the normal range, compared to the lowest quartile. Subsequently, loss-of-function mutations in tumor suppressor genes (e.g., p53, Wt1, BRCA, etc.) were found to enhance IGF-1R expression. Many studies have confirmed a relationship between IGF-1R signaling and cancer, and several companies are conducting phase 1 or phase 2 trials of potential oncology therapies that target this pathway.
• Insulin receptor A signaling may also be important in cancer development and progression. Studies of IGF-1R antibodies in cancer showed some strong results but some non- responders, and Dr. LeRoith noted that IR-A might be a compensatory mechanism when IGF-1R signaling is blocked. Multiple elements of the metabolic syndrome have been linked to cancer. Cancer mortality was much lower in severely obese patients who received gastric bypass surgery than a control population of similarly obese individuals who did not receive surgery (Adams et al., NEJM 2007), and epidemiologic data have shown that higher levels of endogenous insulin are associated with significantly worse prognoses in breast cancer (Goodwin et al., J Clin Oncol 2002).
• Dr. LeRoith and his colleagues developed a mouse model of non-obese insulin resistance (MKR), which allowed them to better isolate the effects of hyperinsulinemia on cancer development and progression (Fernandez et al., Genes & Dev 2001). The mice overexpress a dominant-negative IGF-1R in the muscle, abrogating the action of IGF-1R/IR heterodimers. Male MKR mice have severe insulin resistance in their skeletal muscles from birth, and they progressively develop insulin resistance in fat (leading to lipolysis that raises free fatty acid levels) and hyperinsulinemia (while still at normal glucose levels). The onset of insulin resistance in the liver leads to more gluconeogenesis, and the mice progress from impaired glucose tolerance to type 2 diabetes. Female MKR mice also develop severe insulin resistance and hyperinsulinemia, but they lack the moderate hyperglycemia and hyperlipidemia of the males. Female MKR mice thus offered the researchers a relatively clear look at the link between hyperinsulinemia/insulin resistance and cancer. A downside, Dr. LeRoith noted, is that the MKR model differs from metabolic disease as typically seen in humans.
• The researchers crossed the MKR mice with a mouse model of breast cancer and found that the growth of precancerous lesions was accelerated; similar effects were seen when inoculating MKR mice with mammary tumor cell lines. These effects were dramatically reduced when signaling was inhibited with a small-molecule tyrosine receptor kinase inhibitor (BMS-536924) (Novosyadlyy et al., Cancer Res 2010). In a follow-up study, insulin-sensitizing therapy (CL-316243) also led to reductions in the growth of the tumor, further supporting the process that Dr. LeRoith outlined (Fierz et al., Diabetes 2010).
• Dr. LeRoith noted that the MKR mutations seem also to increase metastasis, which tends to be more correlated with mortality than tumor size. When cancer cells were intravenously injected into MKR mice and controls, the MKR mice developed significantly more pulmonary metastases. This suggests that impaired IGF-1R/IR signaling promotes metastasis even independently of tumor size.
• Human data support the relevance of IR signaling in breast cancer. Analysis of preserved samples of breast cancer tissues suggests that extremely high IR expression is associated with lower five-year disease-free survival in patients with node-negative breast carcinoma (Mathieu et al., Proc Assoc Am Physicians 1997).

PRESIDENTIAL PLENARY LECTURE – THE NUCLEAR RECEPTOR SUPERFAMILY: HOW PHYSIOLOGY RISES OUT OF THE GENOME

Ronald M Evans (Salk Institute/Howard Hughes Medical Institute, San Diego, CA)

Dr. Evans suggested that an “exercise pill” that provides the same physiologic benefits as exercise may be feasible in the future. An important muscle endurance pathway is centered on the enzyme AMP- Kinase, which can be activated by nuclear receptors including ERR-gamma. When AMP-Kinase is upregulated in mice, the result is improved exercise tolerance.

• Dr. Evans reviewed the role of the nuclear receptor in tissue response to exercise. He discussed the remarkable blackpoll warbler, a bird that doubles in weight with fat in the summer before embarking on a 2,300-mile winter journey to Venezuela. This is a “feat of endurance” that is incredible because the bird is essentially obese and does not train for this length of flight. How endurance is encoded is an important question that is not well understood, but it is likely that nuclear receptors play an important role. Nuclear receptors can act like on-off switches in tissue that therefore promote fitness.
• One of the key enzymes determining fitness is AMP-Kinase. This enzyme is known to be activated by PCG-1 alpha, which is acted on by the histone deacetylase SIRT-1. Another recently discovered activator of AMP-Kinase is ERR-Gamma. This is an estrogen related receptor, with intrinsic activity that can also be acted on by estrogens such as tamoxifen. ERR-gamma is a transcription marker of type 1 (i.e., oxidative, or endurance) muscle fibers. Remarkably, when ERR-gamma is transferred into type 2 (quick-twitch) muscle fibers, it promotes the type 2 muscle fiber’s oxidative capabilities and promotes vasculogenic function.
• Nuclear receptors may represent an important drug target for “unlocking endurance.” Dr. Evans argued that energy utilization may ultimately be a better drug target than appetite suppression for diabetes and obesity, because appetite is extremely well regulated and hard to change due to tremendous evolutionary pressure. Aicar is an important proof of concept for unlocking endurance with a drug. When aicar, a natural product of adenosine metabolism that activates AMP-Kinase, is injected in mice, the mice can run roughly 45% farther. Dr. Evans joked that just months after publishing this finding, Tour de France riders were caught doping with aicar.

What Can Be Unified & What Needs To Be Individualized In Obesity & Type 2 Diabetes? (Sponsored by the Endocrine Society, the American Diabetes Association, and EASD)

PATHOGENESIS

Michael W Schwartz (University of Washington, Seattle, WA)

Dr. Schwarz reviewed current research about the pathogenesis of obesity and diabetes, underscoring that although some key questions remain unanswered, much progress has been made in recent years. He called attention to the role of obesity in inducing inflammation, leading to insulin resistance and eventually diabetes.

• There are multiple factors that contribute to obesity: genetics, development, socioeconomic status, and lifestyle. More than 40 gene variants have been identified that contribute to the development of diabetes or obesity. However, these variants collectively account for only about 15% of disease risk for diabetes and only 5% of disease risk for obesity – much less than one might assume. It is possible that there are other variants that have not been identified, but a more likely explanation is that gene-gene, gene-environment, and epigenetic factors are more important than genes alone.
• Nutrient excess induces peripheral insulin resistance through increasing inflammation. The mechanisms by which nutrient excess causes inflammation include: reactive oxygen species, cytokine signaling, ER stress, mitochondrial dysfunction, and TLR4 signaling. Once tissues become packed with adipose tissue, invading macrophages also contribute to inflammation. Visceral fat contributes more to hyperglycemia than subcutaneous fat. This is likely because visceral fat releases more pro-inflammatory molecules and acts directly on the liver.
• Type 2 diabetes occurs when the body can no longer compensate for the obesity- induced insulin resistance. Many factors impair beta-cell compensation, such as glucose toxicity, genetic factors, and inflammatory signals. The brain may also play an important role in the link between energy homeostasis and glucose metabolism. Various parts of the brain, particularly the NPY and POMC pathways, receive signals from leptin, other adiposity signals, and nutrients. These pathways in turn coordinate energy intake and expenditure. Defects in these neuronal pathways may predispose the body to peripheral insulin resistance and positive energy balance.

Questions and Answers

Q: Is it possible that bromocriptine (Santarus' Cycloset ) affects inflammation in the hypothalamus?

A: I do believe the effect is mediated centrally, but I don’t believe it is related to that pathway. I don’t think the mechanism has been worked out.

Q: Why are diabetes rates going up in Asia without a concomitant increase in obesity?

A: There is a link in those populations, although they don’t have the marked obesity that we see in Western countries. Many of these Asian individuals do have a marked increase in visceral fat.

TREATMENT

Allison B Goldfine (Joslin Diabetes Center, Boston, MA)

Dr. Goldfine reviewed current interventions in the treatment of obesity and diabetes. She discussed the current paucity of effective pharmacotherapies for obesity, and indicated that clear regulatory requirements and a permissive environment are necessary for the development of novel obesity therapies. Finally, she lamented that there is a treatment and knowledge deficiency regarding the treatment of obesity, especially in the mid-BMI range.

• Lifestyle modification: Self-monitoring of weight, group based behavior intervention, individual contact, caloric restriction, physical activity, and meal replacement have all shown efficacy in the treatment of obesity. Lifestyle modification can produce an initial weight loss of 5- 10% over 6-12 months, but the effect is not durable, and patients typically return to their baseline weight. Changes in metabolic hormones such as leptin, ghrelin, and GLP-1 may be responsible for the body’s “weight-defense” or resistance to weight loss. Nonetheless, even modest changes in weight can produce dramatic clinical benefits and a significant reduction in the cumulative incidence of type 2 diabetes.
• Pharmacotherapy: Effective pharmacotherapy for obesity needs to cause durable weight loss, improved cardiometabolic risk, and improved outcomes, with acceptable adverse events and tolerability. Unfortunately these goals have proven to be difficult. For example, sibutramine (Abbott’s Meridia) did cause significant weight loss when used with lifestyle modification, but the SCOUT trial demonstrated increased hazard with sibutramine leading to market withdrawal. Dr. Goldfine said that in order to foster the development of novel obesity therapies, clear regulatory requirements and a permissive environment are necessary. Pharmacotherapy for diabetes today is problematic because many diabetes medications cause weight gain. Therefore, weight gain limits the therapeutic benefit of treating hyperglycemia. A small degree of weight gain is intrinsic to diabetes treatment because hyperglycemia directly increases energy expenditure.
• Surgery: Bariatric surgery is coming into increasing attention for having profound effects on diabetes and obesity. In the Swedish Obesity Study, the weight loss from bariatric surgery (nearly 40% on average) was associated with a 29% decrease in overall mortality. Multiple bariatric procedures exist, and they produce somewhat different results. All of the procedures improve diabetes, but some of the procedures cause a more marked decrease in blood glucose than would be expected based solely on the weight loss that is achieved. Altered GI, endocrine, and neuronal signaling mechanisms may underlie this additional glycemic benefit. In the future, integrated neurohormonal therapy for obesity may mimic these changes in endocrine signaling from bariatric surgery. In a proof-of-concept study, mice treated with leptin, amylin, and PYY demonstrated markedly improved changes in body weight in rats that approach Roux-en-Y bariatric surgery.

Therapeutic Interventions for Childhood Obesity: What Should We Expect?

CHILDHOOD OBESITY & PREMATURE MORTALITY: TARGETING CO-MORBIDITIES FOR THERAPEUTIC INTERVENTIONS

Sonia Caprio, MD (Yale University, New Haven, CT)

Speaking to a full crowd in a large presentation hall, Dr. Caprio focused on fat distributions and noted that fatty liver can be used as a predictor for insulin resistance. She described relationships between childhood obesity and cardiovascular (CV) outcomes, showing that higher body mass index (BMI) in childhood led to increased CV risk in adulthood. She then focused on the danger of subcutaneous fat; though two individuals with similar BMIs may present, the individual with greater subcutaneous fat is at risk for more complications. Dr. Caprio showed data from studies that she has conducted, and the results indicated that intrahepatic fat accumulation was associated with impaired insulin action. She closed her presentation by describing a family-oriented, non-diet program that would promote weight reduction. The program is dubbed the Bright Bodies program, and Dr. Caprio suggested this model should be scaled up to a grander level.

• Relationships between childhood obesity and cardiovascular (CV) outcomes were examined. 200,000 children were followed in a study that showed a positive, linear correlation between body mass index (BMI) and coronary hearth disease (CHD). Franks et al. explored childhood obesity and premature death and found that children in the highest quartile of BMI tended to die earlier (NEJM 2010). He hypothesized that insulin resistance and hypertension developed in childhood played a role in this.
• Visceral fat is associated with higher cardiovascular risk. Dr. Caprio showed MRI images to illustrate fat distribution. The images showed that a 15-year-old Hispanic male with BMI of 36 had much more visceral fat than a 16-year-old African-American male with BMI of37.6. Dr. Caprio connected this to the notion that African Americans are less prone to fatty liverdisease than Hispanics.
• Children with high liver fat appeared more likely to develop metabolic syndrome. In a study, Dr. Caprio enrolled 118 obese adolescents with similar levels of overall adiposity. OGTT, MRI imaging and DEXA scans were performed to collect data.
• Dr. Caprio sought to determine if intrahepatic fat, independently of visceral and intramyocellular lipid (IMCL), contributes to the development of insulin resistance. She recruited 60 obese adolescents and collected OGTT, abdominal MRI and proton NMR data. 23 subjects were in the high liver fat content group, while 38 were in the low group. Triglycerides were higher in the high liver fat group. Also, insulin resistance was elevated as indicated by fasting plasma glucose and fasting C-peptide levels. Low dose insulin infusion did not suppress lipolysis in the high liver fat group. Independent of visceral fat and IMCL, intrahepatic fat accumulation seems to be associated with impaired insulin action in the liver and muscle and early defects in beta cell function.
• Dr. Caprio noted that lifestyle changes are difficult to implement, and discussed her efforts with the “Bright Bodies Weight-Management Program for Children.” This program has behavioral, nutritional, and physical activity components. Only children aged 7-16 whose BMI exceeded the 85^th percentile were included. The program is family-oriented and uses a non-diet approach. After six months, BMI dropped by two points and this change lasted into one and two year time points. Additionally, positive changes insulin resistance and triglycerides were seen.

Questions and Answers

Q: Do you know how families insurance coverage was involved in this program?

Dr. Caprio: Most of the participants did not have insurance.

Q: We have struggled to implement lifestyle changes program. We especially struggle with long term. What do you think about this?

Dr. Caprio: Long-term maintenance is difficult. Though we have positive data to show for two years, I will tell you we had significant dropout from the program. Still, I am optimistic. If this doesn’t work, we’ll move onto the other speakers’ ideas (laughs).

PRESENT & FUTURE OF PHARMACOLOGICAL INTERVENTIONS IN PEDIATRIC OBESITY: WHO, WHEN, & WHICH

Jean-Pierre Chanoine (British Columbia Children’s Hospital, Vancouver, Canada)

Dr. Chanoine discussed the challenge of treating childhood obesity with lifestyle modification and pharmacotherapy. Orlistat (Roche’s prescription Xenical, GSK’s over-the-counter alli) is the only pharmacotherapy approved for childhood obesity and should be considered in children above the age of 12 years of age who have achieved insufficient weight loss with lifestyle modification alone. Metformin can also be considered in children above the age of 10 years who have obesity as well as either insulin resistance or polycystic ovary syndrome (PCOS), however weight loss with metformin is minimal.

• Orlistat (Roche’s prescription Xenical, GSK’s over-the-counter alli) is the only pharmacotherapy approved for the treatment of childhood obesity. In a randomized controlled trial of orlistat in children aged 12-16, orlistat was associated with 1.8 kg of weight loss from a baseline of ~100 kg compared to 0.4 kg of weight gain in children who were treated with placebo. As expected, orlistat was associated with GI side effects but no significant safety issues. Encouragingly, blood pressure was decreased in the treatment arm of the study.
• Metformin is sometimes used off-label for the treatment of obesity in children. Reviewing published studies of metformin in children, Dr. Chanoine highlighted small but nonetheless potentially clinically meaningful benefits of metformin therapy. In a one-year randomized controlled study of metformin in children over 12 years of age that was published last year, children treated with metformin experienced statistically significant weight loss. However, when the study was extended (open label) for an additional year, the difference in weight become non-significant between the two groups. In a separate study of hyperinsulinemic children age 6- 12, metformin did reduce homeostatic model assessment (HOMA, a method used to quantify insulin resistance and beta-cell function), but did not change insulin sensitivity or body composition. In yet another study of metformin in children with PCOS, metformin did successfully restore menses in a majority of patients but did not cause weight loss.
• Dr. Chanoine reviewed how pharmacotherapy in pediatrics can be improved. He listed three areas of focus: 1) decreased attrition rates in pharmacotherapy studies, 2) better prediction of responders vs. non-responders for current pharmacotherapy, and 3) development of newer and more effective pharmacotherapies. One future treatment strategy of childhood obesity may involve upregulating brown adipose tissue (BAT) or brown fat, a type of adipose tissue that burns large quantities of fat to produce heat in babies.

Questions and Answers

Q: Is it appropriate to use metformin in an eight-year-old child with metabolic syndrome?

A: We know it is relatively safe in children, but we don’t have much data for children below the age of 10 years. It is outside of the approved indications, but I think if you are cautious it could be considered.

Fat on Fire

OBESITY, INFLAMMATION & MACROPHAGES

Anthony W Ferrante (Columbia University, New York City, NY)

Dr. Ferrante provided an overview of the adipose tissue macrophage (ATM), a cell that is present in large quantities within adipose tissue. He showed that ATMs are recruited to adipose tissue during periods of lipolysis, and ATMs buffer the rise in free fatty acids and decrease lipolysis.

• Adipose tissue contains specialized macrophage-like cells called adipose tissue macrophages (ATM’s). As obesity increases, the concentration of these ATMs also increases. ATMs are also preferentially found in visceral adipose tissue and can accumulate to form giant cells in severe obesity. These ATMs have been implicated in the production of pro-inflammatory molecules found in obesity, insulin resistance, and atherosclerosis. Short-term fasting leads to ATM recruitment in fat cells, whereas ATM content decreased following an extended period of weight loss.
• Local lipid fluxes seem to regulate ATM recruitment, and ATM recruitment likewise appears to affect local lipid fluxes. Experiments have shown that ATM number increases as lipolysis increases during a short term fast, suggesting that lipolysis drives ATM accumulation. Along the same lines, dietary and genetic manipulations that reduce the rate of lipolysis decreased the rate of ATM accumulation. Meanwhile, experiments have demonstrated that macrophages decrease expression of adipose triglyceride lipase and genes regulated by FFA, while decreasing macrophage concentration increases lipolysis. Taken together, these results suggest that lipolysis attracts ATMs, and ATMs when they arrive form lipid-laden macrophages that buffer rises in free fatty acids.

ANTI-INFLAMMATORIES IN TYPE 2 DIABETES: CLINICAL TRIAL

Allison B Goldfine (Joslin Diabetes Center, Boston, MA)

Inflammation is highly correlated with diabetes and has been proposed as a target of diabetes therapy. Salsalate is a type of non-steroidal anti-inflammatory drug (NSAID) that reduces inflammation and has shown efficacy in an NIH-sponsored 14 week randomized control trial called TINSAL-T2D; a 48-week trial of salsalate is ongoing.

• Inflammatory markers are highly predictive of type 2 diabetes. For example, higher levels of CRP and IL-6 are associated with a 16-fold greater incidence of type 2 diabetes. This observation has raised an interest in treating diabetes by treating inflammation. IL-1 has shown potential in the modulation of inflammation and the treatment of diabetes. High glucose levels induce IL-1b in beta-cells, and IL-1 antagonists improve metabolic measure in patients with type 2 diabetes.
• Another promising anti-inflammatory class for the treatment of diabetes is non- steroidal anti-inflammatory drugs (NSAIDs). Whereas low doses of aspirin (81-650 mg) inhibit platelet aggregation and help with aches, pains and fevers, treatment with higher doses of aspirin (4-10 g) can improve insulin sensitivity through modulating IKKB, NF-kB, and other mediators of inflammation. Salsalate can also reduce glucolipotoxicity, enhance insulin action, improved insulin secretion, increase insulin levels, and improve vasodilation. Salicylic acid is an NSAID that is structurally similar to aspirin but does not inhibit platelets. It is generic, inexpensive, and has a well demonstrated safety profile.
• The NIH funded a successful phase 2 trial of salsalate, the TINSAL-T2D study. In this 14-week trial, salsalate (3-4 g/day) produced placebo controlled reductions in A1c from 0.4-0.6% from a baseline of 7.7%. Salsalate also demonstrated improvements in triglycerides and adiponectin. Salsalate was generally well tolerated in the trial and did not cause significant changes in liver functions or cause GI toxicity. The only safety issue that was observed as a very small increase in microalbuminurea, which warrants further study.
• Based on the positive results of TINSAL-T2D, the NIH is supporting a 48-week study of salsalate. Originally a 26-week study was planned, but the study was lengthened to 48 weeks based on the positive results of the initial 14-week study. The study is fully enrolled and should have results in the winter/spring of 2012.

ORAL DELIVERY OF SIRNA TO MACROPHAGES TARGETING INFLAMMATION

Michael P Czech (University of Massachusetts Medical School, Worcester, MA)

Dr. Czech described macrophages as a potential drug target for inflammation and diabetes. He proposed that orally delivered siRNA could effectively inhibit macrophages.

• Insulin resistance is associated with an upregulation of inflammatory markers, and a downregulation of lipogenic genes. This suggests a causative relationship between inflammation and inhibition of lipogenesis.
• Macrophages may be a fruitful drug target because they engulf large molecules, secrete TNF and other inflammatory cytokines, and induce insulin resistance. Furthermore, macrophages are present in the gut and subsequently relocate to other parts of the body, which suggests that an oral agent inhibiting macrophages would be feasible. One way to inhibit macrophages may be to utilize RNAi. The advantage of RNAi is that it can silence any of the 25,000 human genes (whereas traditional drugs can silence only the 500 or so known druggable proteins). In the future, orally-administered glucan-encapsulated siRNA particles (GeRP) could be used to silence gut macrophages, which would subsequently move throughout the body and infiltrate other tissues. The challenge of using RNAi has to do with drug delivery, because of difficulty with cellar uptake of this type of therapy.

Biological Mechanisms for Global Disparities in Type 2 Diabetes & Its Complications: Controversies & Advances

FLATBUSH DIABETES: UNIQUE PATHOPHYSIOLOGY FEATURES OF TYPE 2 DIABETES IN PATIENTS OF AFRICAN OR SOUTHEASTERN ASIAN DESCENT

Mary Ann Banerji (New York Health Science Center, Brooklyn, NY)

Dr. Banerji spoke about flatbush diabetes, a subtype of type 2 diabetes that has been described in people of African and Asian descent. Typically it presents with fulminant (i.e., sudden and severe) diabetic ketoacidosis. Flatbush diabetes has become a global phenomenon since it was first described in Brooklyn in 1994, and research has begun to elucidate the disease course and the underlying pathophysiology of this diabetes subtype.

• Flatbush diabetes is a unique subtype of type 2 diabetes that was first described in African-American and Asian-American patients in Brooklyn in 1994. Similar to type 1 diabetes, flatbush diabetes often presents with fulminant (i.e., sudden and severe) diabetic ketoacidosis (DKA). However, these patients typically lack autoantibodies, are insulin resistant, respond to oral medications, have family histories of type 2 diabetes and not type 1 diabetes, and can recover insulin secretion. These findings indicate that flatbush diabetes is a subset of type 2 diabetes, not type 1 diabetes. Since the first description of flatbush diabetes in Brooklyn in 1994, flatbush diabetes has become a global phenomenon described in multiple Asian and African populations around the world. It is important for clinicians to recognize that diabetes is heterogeneous and that a presentation of DKA is not necessarily diagnostic of type 1 diabetes; in fact, in some studies 60% of patients who present with DKA are type 2s, and the number is even higher for African-American and Asian-American populations.
• Dr. Banerji discussed the underlying pathophysiology of flatbush diabetes. Possible pathophysiology of this disease includes an underlying immune basis, hormonal counterregulation, defects in insulin secretion, gluco- and lipotoxicity, and inflammation. Although many candidate genes have been studied, none of them has shown a clear association with flatbush diabetes, and it is therefore appropriate to conclude that flatbush diabetes is not a monogenetic syndrome. Likewise, data regarding hormonal regulation have not identified any statistically significant differences in metabolic hormones. Approximately 40% of patients with flatbush diabetes have low levels of auto-antibodies and GAD responsive T1 cells. One notable biochemical feature of flatbush diabetes is a decrease in glucose-6-phosphate dehydrogenase (G6PD) levels. Because G6PD is antioxidant, it has been proposed that oxidative stress is responsible for flatbush diabetes.
• Flatbush diabetes frequently remits following a brief period of intensive glucose control. In a US study, the remission rate for flatbush diabetes is approximately 42%. On average, remission lasts 39 months, although this is highly unpredictable and patients have variable courses punctuated by ketotic relapses. In China, where flatbush diabetes is sometimes called “fulminant type 1 diabetes mellitus,” a similar remission rate has been observed with insulin therapy. In China, this disease is more common in women, and it is marked by severe ketoacidosis, flu-like and GI symptoms, and low pancreatic beta cell reserve. Clinicians in China believe that it can be triggered by drug hypersensitivity, viral titers, and pregnancy. Given that glucose normalization can restore insulin secretion in flatbush diabetes, it is possible that glucose toxicity contributes to disease pathology. Supporting such a theory, it has been suggested that flatbush diabetes can be induced by acute soft drink consumption and vending machine food. However, a study of 3-4 days of glucose infusion failed to induce ketotic relapses in patients with a history of flatbush diabetes.

Questions and Answers

Q: Are there any data on GLP-1s in this population?

A: No.

Q: You said that there was no significant difference in flatbush diabetes counterregulatory hormones, but it seemed like glucagon levels were lower in your graph. Can you comment?

A: Glucagon may play a role, and this was a small data set. I wonder if we should replicate it in a larger study because the standard deviations were very large and we got no statistically significant differences.

Q: Would you test G6PD in someone who presents with potential flatbush diabetes?

A: We have not done that. There’s only one paper on the G6PD connection.

DISPARITIES IN TYPE 2 DIABETES AMONG INDIGENOUS POPULATIONS AROUND THE WORLD

Jaakko Toumilehto (University of Helsinki, Helsinki, Finland)

Dr. Toumilehto gave a sobering talk about the increasing incidence of diabetes around the world. He pointed to a “socioeconomic paradox” wherein socioeconomic development at a population level is associated with increasing diabetes incidence as people adopt a more sedentary lifestyle and high-fat diet, but higher socioeconomic class within a population is associated with better diabetes treatment and outcomes.

• Changing environmental factors with genetic predisposition have caused a dramatic rise in the incidence of diabetes among native peoples around the world. For example, in the United States, the Pima Indians have a 42% prevalence of diabetes. Although Pima Indians have a unique genetic predisposition to diabetes, it is the intersection of genes and the environment that is problematic, as the same Pima population in Mexico has a much lower incidence of diabetes than Pima Indians in the US (7% in Mexico vs. 42% in the US). Lifestyle modification in native peoples can dramatically reduce diabetes incidence. For example, a study of Australian aborigines demonstrated that seven weeks of temporary reversion to a hunter- gatherer lifestyle can produce dramatic weight loss, improvement in glucose tolerance, improvement in insulin response, and normalization of dyslipidemia. Dr. Toumilehto lamented that it would be impossible to reproduce this type of lifestyle modification around the world.
• The nations with the highest incidence of diabetes are (in order): Nauru, UAE, Saudi Arabia, Mauritius, Bahrain. Middle Eastern countries represent a global hot spot of diabetes, and India and China are also experiencing a dramatic rise in diabetes prevalence. In India, the incidence of diabetes has increased fourfold in the last 16 years, and in urban areas the prevalence of diabetes now approaches 19%. Dr. Toumilehto attributes this increase to the arrival of large multinational food companies, and called this phenomenon “coca-colonization.” Indians may be genetically predisposed to diabetes, as the threshold for developing diabetes is a BMI of only 23 among Indians, much lower than in whites. China, which has historically had an extremely low incidence of diabetes, has also seen a remarkable increase in diabetes incidence. Whereas only 0.7% of the Chinese population had diabetes in 1980, the incidence had already increased to 4.5% in 2002. Diabetes prevalence increases with age, and 20% of people above the age of 70 in China have diabetes and another 26% have impaired glucose tolerance.
• Dr. Toumilehto concluded his talk by describing an apparent “socioeconomic paradox.” Within a population, it is well documented that people of lower socioeconomic status receive inferior diabetes care and ultimately have worse diabetes outcomes. However, at a population level, populations with lower socioeconomic status are protected against diabetes, as diabetes at a population level can be attributed largely to lifestyle changes resulting from increasing socioeconomic development.

GENETIC & ETHNIC CONSIDERATIONS IN TYPE 2 DIABETES – COMPLICATIONS AROUND THE WORLD: HOW MUCH DOES BIOLOGY MATTER?

Harold E Lebovitz (State University of New York Health Science Center at Brooklyn, Staten Island, NY)

There are significant differences in type 2 diabetes complications rates between Caucasians, Latinos, Asians, and people of African descent. Blacks are much more likely to develop renal disease and less likely to develop cardiovascular disease than matched whites. There are many possible explanations for these observed differences, such as environmental factors, economic factors, and genetic factors, which include differences in the genetic susceptibility of the end organs.

• Black patients with diabetes may have a lower risk of macrovascular disease than white patients with diabetes. Black patients have much more subcutaneous fat and less visceral fat than whites. In the UKPDS (which enrolled whites, south Asians, and Afro-Caribbean patients), the Afro-Caribbean patients had significantly higher HDL cholesterol, lower triglycerides, and lower insulin sensitivity at study baseline than other patients enrolled in the study. As a result, blacks with diabetes are much less likely to have the metabolic syndrome (which includes lipids and waistline in the diagnostic criteria). It is likely that African Americans have genetic differences in their lipid metabolism that confers a cardiovascular disease risk reduction. This trend has been reproduced in numerous studies. A Kaiser study that included 62,432 patients with type 2 diabetes showed that the adjusted African American to Caucasian hazard ratio was 0.56 (in other words, African Americans had approximately half the risk of cardiovascular disease).
• The risk of end-stage renal disease is higher in Asian-, Latino-, and African- American people with diabetes than Caucasians with diabetes. The risk of end-stage renal disease is approximately 6.8% for blacks, 4.5% for Latino- and Asian-Americans, and 3.2% for whites with diabetes. This data has been reproduced in several studies, including studies that correct for possible differences in care. In a similar VA study, African Americans had twice the risk of end stage renal disease as Caucasians.

Mechanisms of Islet Cell Development

USING STEM CELLS TO RECONSTRUCT A PANCREAS

Doug A Melton (Harvard University/Howard Hughes Medical Institute, Boston, MA)

Although laboratory beta-cell differentiation is not yet possible on a practical scale, Dr. Melton suggested that growth factor and small molecular directed differentiation can and will eventually work. Low efficiency remains a limitation, but significant expansion by self-renewal without differentiation can be achieved.

• We are beginning to understand the differentiation of beta-cells from embryonic stem cells. There are several stages to differentiation, and the factors involved are (in order): Oct4 →→ Sox 17 →→ Pdx1 →→ Ngn3. Small molecules including EGF receptor kinase inhibitors can induce development from pancreas progenitor to an endocrine progenitor (Ngn3+) cells.
• One of the barriers to differentiating beta-cells on a large scale is low conversion efficiency. Only approximately 40% of stem cells are appropriately converted in each step (Oct4 →→ Sox 17 →→ Pdx1 →→ Ngn3) towards beta cells. Therefore, only a minority are converted to insulin positive cells using even the most efficient differentiation techniques. To increase the efficiency of conversion it may be important to self-renew progenitors without differentiation.
• Another problem is that insulin-positive cells developed using current mechanisms are immature and do not respond appropriately to glucose. A fully mature beta cell secretes insulin only in response to glucose, whereas an immature beta cell secretes insulin even when glucose levels are low. Ucn3 (uricortin 3) is a gene that is a strong marker for mature beta- cells and may be important in developing mature beta-cells.

Questions and Answers

Q: Have you examined whether the expanded cells retain developmental potential?

A: Yes, we have shown that there is no deficit in differentiation potential.

POSTNATAL MATURATION OF THE BETA CELL

Susan Bonner-Weir (Joslin Diabetes Center, Boston, MA)

Dr. Bonner-Weir discussed the transcription factors that induce maturation of the beta cell, focusing on the role of MafA. The increase of MafA mRNA toward adult levels of expression induces glucose responsiveness. Thyroid hormone appears to induce MafA and subsequent maturation of the beta cell.

• Neonatal islets have less insulin content and impaired insulin responsiveness compared to mature islets. Insulin-secreting cells undergo a transition of transcription factor expression during their development, and these transcription factors may underlie the transition from immature to mature islets. Two key transcription factors, PDX1 and MafA, show nuclear localization during maturation. In neonatal islets both PDX1 and MafA are at less than 15% of adult levels. Increasing MafA improves glucose responsiveness, whereas Pdx1 increases insulin content. MafA also increases functional subpopulations. Therefore, MafA is a key factor in the functional maturation of postnatal beta-cells
• Dr. Bonner-Weir discussed the factors that induce MafA and subsequent beta-cell maturation. Thyroid hormones appear to be one of the most important physiologic factors, along with changes in other signals such as metabolic change, leptin, and corticosteroid surge. Thyroid hormone receptors transiently increase in neonates. In vitro, thyroid hormone enhances MafA expression, which induces glucose responsive insulin secretion. In vivo serum T4 levels and thyroid hormone receptor mRNA peak early in the maturation of the functional beta cell.

Questions and Answers

Q: What are insulin levels in the neonate? Does maternal hyperglycemia drive maturation?

A: Insulin levels are low in the neonate. The insulin is most responsive to fatty acids and amino acids rather than glucose. We haven’t studied this specifically, but hyperglycemia in the mother does appear to drive maturation somewhat in other studies.

Q: Do you know what induces translocation of PDX1 and MafA into the nucleus?

A: Nobody has figured out the mechanism yet.

Mitochondrial Insulin Action

INCREASED FATTY ACID OXIDATION IS NOT OBLIGATORILY LINKED TO REDUCED ADIPOSITY

Dr. Gregory J Cooney (Garvan Institute of Medical Research, Sydney, Australia)

AMPK and its metabolic target, ACC2, are both thought to convey many of the beneficial effects of exercise and have been described as potential drug targets for weight loss. However, Dr. Cooney showed that while AMPK/ACC2 modulation can induce fatty acid oxidation, they cannot increase energy expenditure.

• Activation of AMP-activated protein kinase (AMPK) is thought to convey many of the beneficial effects of exercise. AMPK inhibits acetyl-CoA carboxylase 2 (ACC2), promotes fatty acid oxidation, and increases exercise tolerance. This exercise-induced switch to fatty acid oxidation is thought to cause weight reduction, and therefore AMPK and ACC2 have been described as potential drug targets for weight loss. The compound AICAR (AMPK agonist 5′ aminoimidazole-4-carboxamide-riboside) is a proof of concept AMPK activator.
• AMPK activation does increase whole body fatty acid oxidation but does not increase energy expenditure. Using AICAR treatment in mice as well as a genetic mouse model with downregulated CC2 gene expression, Dr. Cooney showed that inhibition or absence of ACC2 leads to increased fatty acid oxidation in muscle and in the whole animal. Unfortunately, this did not translate to increased energy expenditure or weight loss in his experiments. Instead, the researchers observed substrate switching (increased fatty acid oxidation with reduced glucose oxidation). Therefore, Dr. Cooney cast doubt on targeting the AMPK/ACC2 pathway as a means for weight loss and concluded by arguing that negative energy balance (rather than increased fatty acid oxidation) is the key to weight reduction.

EPIGENETIC REGULATION OF METABOLIC DISEASES

Yoshihiro Ogawa (Tokyo Medical & Dental University, Tokyo, Japan)

Intra-uterine environment during neonatal development may be a determinant of diabetes risk for the child, a concept called “epigenetic memory.” Dr. Ogawa showed compelling data suggesting that environmental factors such as nutritional status affect DNA methylation, particularly involving a gene called DGAT1.

• Dr. Ogawa explained the concept of “epigenetic memory.” The concept is that the metabolic state of a pregnant mother can cause changes in the development of the fetus that can predispose the offspring to obesity and diabetes. Although the actual genetic sequence of the fetus DNA does not change, there may be changes in the methylation of the promoter sequence of some genes, leading to the upregulation or downregulation of various obesity genes. Epigenetic memory may contribute to the current obesity and diabetes epidemic, because it could predispose offspring of obese or diabetic mothers to diabetes later in life. The proof of concept for this theory was a previously reported mouse model in which offspring were subject to fetal undernutrition. These offspring later developed weight gain and impaired glucose metabolism caused by a premature onset of neonatal leptin surge.

• Decreased methylation of the gene diacylglycerol acyltransferase 1 (DGAT1) promoter may contribute to epigenetic memory for obesity. DGAT1 is one of the DGAT enzyme isoforms catalyzing the final step in triacylglycerol synthesis. Dr. Ogawa showed that methylation of DGAT1 changes during neonatal development in response to weaning. This may be because neonates predominantly utilize milk (rich in lipids) as an energy source prior to weaning, and afterwards they primarily use glucose as an energy source. Therefore, increased expression of DGAT1 may be physiological in mice to help respond to the increased physiologic demand of lipogenesis during the weaning period. He also showed that a high fat and fructose diet in a pregnant mouse can increase the methylation of DGAT1 in the neonate. Therefore, DGAT1 is a candidate for epigenetic memory.

MITOCHONDRIAL DYSFUNCTION IN OBESITY & DIABETES: CHICKEN OR EGG?

Mary Elizabeth Patti (Joslin Diabetes Center, Boston, MA)

Dr. Patti provided an overview of the role of mitochondrial dysfunction in insulin resistance and diabetes. Diabetes may impair mitochondrial function, and mitochondrial dysfunction can worsen diabetes; this can become a vicious cycle of worsening diabetes. As to which pathology (insulin resistance, mitochondrial dysfunction) starts the cycle, Dr. Patti said that data are inconclusive but that it seems that mitochondrial dysfunction is by itself not sufficient to induce insulin resistance.

• Mitochondrial dysfunction is a hallmark of type 2 diabetes. Insulin resistance is present in multiple tissues in patients with type 2 diabetes, including the muscle, liver, adipose tissue, and brain; however, muscle is the most important of these providing about 85% of the body glucose uptake. There are many pieces of data that suggest that mitochondrial dysfunction in muscle is closely related to skeletal muscle insulin sensitivity. For example, mitochondrial oxidative activity is decreased in muscle of humans with insulin resistance and type 2 diabetes. There is a striking lack of respiratory quotient during fasting in obesity and diabetes, and a subsequent decrease in substrate oxidation. In theory, dysregulated mitochondrial metabolism may lead to lipid accumulation in muscle and reactive oxygen species, leading to insulin resistance; however, no causal pathogenic relationship has been demonstrated.
• Expression of PGC-1 alpha, a key gene regulating mitochondrial biogenesis, is decreased by ~50% in diabetes. PGC-1 alpha plays a role in many tissues, and it regulates thermogenesis, glucose transport, and exercise capacity. PGC 1-alpha is also decreased in people with a family history of type 2 diabetes and in mouse models of diabetes such as the ob/ob mouse. While it is compelling to argue that decreased PGC 1-alpha expression leads to mitochondrial dysfunction and diabetes (and is therefore the first step towards diabetes), lifestyle can also decrease PGC 1-alpha expression. Obesity, changes in activity, hyperinsulinemia, and insulin resistance have all been shown to reduce PGC 1-alpha expression.
• Addressing the “chicken and the egg problem” regarding mitochondrial dysfunction and diabetes, Dr. Patti showed mouse and human data suggesting that mitochondrial dysfunction is by itself not sufficient to induce insulin resistance. While increased expression of PGC-1 alpha increases mitochondrial mass, and exercise endurance, it has somewhat variable effects on whole-body insulin sensitivity in mice. High levels of PGC 1- alpha produces no difference in insulin sensitivity. Furthermore, deleting PGC 1-alpha and beta from skeletal muscle does decrease exercise tolerance but does not increase susceptibility in mice to insulin resistance. Therefore, in mice, altered mitochondrial function is not sufficient to induce insulin resistance and diabetes. In humans, gene studies have revealed that there are problems with multiple mitochondrial oxidative pathways (branched chain AA, fatty acid metabolism, malate shuttle pathway) but surprisingly there are no problems with mitochondrial oxidative phosphorylation genes.

Poster Presentations

IMPACT OF EARLY PARENTERAL NUTRITION TO COMPLETE FAILING ENTERAL NUTRITION IN ADULT CRITICALLY ILL PATIENTS: A RANDOMIZED CONTROLLED TRIAL

MP Casaer, D Mesotten, G Hermans, PJ Wouters, M Schetz, G Meyfroidt, S Van Cromphaut, C Ingels, P Meersseman, J Muller, D Vlasselaers, Y Debaveye, L Desmet, J Dubois, A Van Assche, A Wilmer, G Van den Berghe (University of Leuven, Leuven, Belgium)

Dr. Greet Van den Berghe presented results of the first large (n=4,640), multi-center randomized controlled trial that we have seen comparing early parenteral nutrition (PN) and late parenteral nutrition for patients in the intensive care unit who do not tolerate enough calories via the enteral route alone. The data indicate that early PN (the standard in Europe) is associated with higher rates of many complications, longer hospital stay, and higher cost of treatment, as compared to late PN (the standard in the US). Although mortality was similarly low in both groups of very sick patients, this was possibly explained by the fact that both groups received intensive insulin therapy to maintain normoglycemia (on average around 105 mg/dl). Even in the presence of such strict normoglycemia, early PN evoked more infections and delayed recovery. Whether the results of this trial would have been different in the context of more loose targets for blood glucose controls remains speculative, but the higher risk of hyperglycemia with parenteral nutrition might increase the adverse effects of early parenteral nutrition (e.g., patients in the control group of Dr. Van den Berghe’s landmark ICU glucose control trials). Alternatively, whether tolerating moderate hyperglycemia, as is currently been advised by several guidelines, is deleterious in the absence of early parenteral nutrition, remains unclear. Generally, we hope that these new findings will lead to better ICU nutrition practices and improved patient outcomes worldwide.

• Adult intensive care unit patients in the early parenteral nutrition group (n=2,312) received parenteral (i.e., intravenous) nutrition within 48 hours of ICU admission, to supplement insufficient enteral nutrition (i.e., through a feeding tube) to reach the caloric needs, in accordance with European guidelines. Those in the late parenteral group (n=2,328) received only enteral nutrition, and a significant caloric deficit was tolerated until day 8 in the ICU, as recommended by American guidelines. Patients in the two groups had similar mean age (64 years), mean weight (75-76 kg [165-167 lbs]), incidence of diabetes (16.9- 17.9%), and mean APACHE II score upon admission (23). Over 60% of both groups consisted of cardiac surgery patients, and 40% were a mixed group of other diagnoses, such as roughly 7% consisting of complicated abdominal/pelvic surgery patients and roughly 7% who had received transplantation surgery. Both groups were intensively managed with intravenous insulin therapy so that hyperglycemia was minimized.
• Statistically significantly more patients in the late parenteral nutrition (PN) group were discharged alive within eight days (75.2% vs. 71.7%; p=0.007), and median duration of ICU stay was significantly lower in the late PN group as well (three days vs. four days; p=0.02). The late PN group also had a lower percentage of patients who experienced a new infection (22.8% vs. 26.2%; p=0.008), lower percentage of patients who spent more than two days on mechanical ventilation (36.3% vs. 40.2%; p=0.006), lower incidence of tracheotomy (5.8% vs. 7.0%; p=0.08), and shorter duration of renal replacement therapy (7 vs. 10 days; p=0.008). Also, patients in the late PN group experienced significantly higher rates of hypoglycemia below 40 mg/dl (3.5% vs. 2.0%) and had a higher median value for maximum C- reactive protein levels (a measure of inflammation) during ICU stay (190.6 vs. 159.7 mg/l; p<0.001). No statistically significant differences were observed in ICU mortality, hospital mortality, or 90-day mortality, and need for hemodynamic support was statistically similar between groups.
• Payers bore significantly lower costs for patients receiving late PN than those receiving early PN (mean of €16,863 vs. €17,983 [roughly $24,160 vs. $25,770]; p=0.04]. Notably, these figures did not include 75% of costs for the parenteral nutrition itself nor 80% of the costs associated with hospital stay itself, which were funded directly to hospitals. Had these expenses been factored in, the savings associated with delaying PN would have been even greater.
• Autophagy, a key process for clearing cellular debris, may be impaired by administration of nutrition during critical illness (Vanhorebeek et al., JCEM 2011). Damage to cell organelles and proteins is evoked by critical illness and is aggravated by pronounced hyperglycemia (Van den Berghe et al., NEJM 2001). Damage removal requires autophagy, a cellular housekeeping system that is suppressed by nutrients. So, the presence of hyperglycemia during critical illness may be particularly deleterious when early PN is given to patients as the latter may impair damage removal. This could partially explain why the NICE- SUGAR trial, which used late PN and allowed moderate hyperglycemia in the control group, did not see any benefits of further tightening glucose control in the ICU (Finfer et al., NEJM 2009). Pronounced hyperglycemia in a setting of early PN, as in the control group of the 2001 study on the benefits of insulin therapy by Van den Berghe et al. (Van den Berghe et al., NEJM 2001), may have been the most disadvantageous combination. Whether tolerating moderate hyperglycemia in the absence of early PN has adverse effects for patients in the ICU remains unresolved, given several issues with the precision of glycemic monitoring and control in NICE-SUGAR (for a recent debate between Dr. Van den Berghe and Dr. Finfer, see our March 23, 2011 Closer Look).

DEVELOPMENT OF AN ANTI-GHRELIN VACCINE FOR OBESITY TREATMENT

Dr. Sara Andrade (Instituto de Ciencias Biomedicas Abel Salazar, Porto, Portugal)

Dr. Andrade presented a poster showing mouse pilot data for a new anti-obesity vaccine that blocks the appetite-stimulating hormone ghrelin. The vaccine produces small but statistically significant changes in food consumption, but they did not observe statistically significant changes in weight over two months.

• Ghrelin is a hormone that is produced by human stomach and binds to the hypothalamus to stimulate hunger, making it a potential target of anti-obesity research. Dr. Mariana Monteiro MD, PhD (University of Porto in Portugal) and her colleagues have developed a vaccine that causes an immunologic response against native ghrelin, by conjugating ghrelin to virus-like particles.
• The vaccine produces small but statistically significant changes in food consumption. Compared with unvaccinated controls, the vaccinated mice developed anti- ghrelin antibodies, increased their energy expenditure and decreased their food intake (3.8g/dayvs. 3.9 g/day for controls). Vaccinated obese mice also displayed a reduced expression of neuropeptide Y (NPY). The authors did not see significant weight loss over the course of the two- month study, but they describe this as a proof-of-concept effort and hope to see weight loss in a longer-duration study. There were no safety issues identified in the study.
• Overall, we think the potential of a ghrelin vaccine in humans is limited for several reasons. 1) There was no weight loss in this study and we think it is unlikely that this approach will produce as meaningful weight loss in humans as combination hormonal approaches such as metreleptin + pramlintide + PYY (in preclinical investigations at Amylin), 2) the regulatory environment is unlikely to tolerate vaccine risk in this space, and 3) ghrelin has many important endogenous functions including regulating growth hormone, and therefore a vaccine against this target may be problematic.

Hot Seat Discussion on GLP-1 Receptor Agonists

Moderator: Jack Leahy, MD (University of Vermont, Colchester, VT) EFFICACY AND TOLERABILITY OF GLP-1 RECEPTOR AGONISTS AND DPP-4 INHIBITORS: WHAT ARE RECENT DATA?

Laurence Blonde, MD, FACP, FACE (Ochsner Medical Center, New Orleans, LA)

Dr. Blonde explained that GLP-1 receptor agonists have greater efficacy and weight-loss effects than DPP-4 inhibitors; nausea rates are initially much higher for GLP-1 receptor agonists but become more similar over time.

• Dr. Blonde compared the mechanisms of GLP-1 receptor agonists and DPP-4 inhibitors to promote activity of the GLP-1 receptor. GLP-1 agonists directly stimulate the body’s GLP-1 receptors, while DPP-4 inhibitors prolong the half-life of the body’s own GLP-1 (and that of another incretin hormone, GIP). Two hours after a meal, endogenous GLP-1 levels in patients with type 2 diabetes are twice as high when taking metformin and sitagliptin (Merck’s Januvia) compared to metformin alone (15 pM vs. 7 pM). However, the concentration of the GLP- 1 agonist exenatide is more than fourfold higher again (64 pM) in patients taking metformin and exenatide twice daily (BID) (Amylin/Lilly’s Byetta).
• Compared to DPP-4 inhibitors, GLP-1 receptor agonists promote greater glucose reductions and higher weight loss with similar long-term tolerability and side effect profiles, as seen in head-to-head trials of liraglutide (Novo Nordisk’s Victoza) vs. sitagliptin, exenatide BID vs. sitagliptin, and exenatide once weekly (QW) (Amylin/Lilly/Alkermes’ Bydureon) vs. sitagliptin vs. pioglitazone (Takeda’s Actos) in patients on background metformin therapy. He noted that although GLP-1 agonists are initially associated with higher levels of reported nausea, the rates decline over time. After eight weeks of the liraglutide vs. sitagliptin study, reported nausea with liraglutide 1.2 mg and 1.8 mg daily had fallen below 10%; by 20 weeks nausea rates were below 4%.

Questions and Answers

Q: GLP-1 agonists seem to have better efficacy than DPP-4 inhibitors. What about combination therapy?

Dr. Blonde: Both sitagliptin-plus-metformin and saxagliptin-plus-metformin have greater efficacy than a DPP-4 inhibitor or metformin alone. This might be considered in people that you don’t expect to get to goal with a single agent. Also, DPP-4 inhibitors and pioglitazone have been shown fairly robust in combination.

Q: Is there quality of life information on these different therapies?

Dr. Blonde: Patient-reported outcomes have been embedded in several studies. As seen in one of the slides I didn’t have time to show, treatment satisfaction, weight-related quality of life, and health utility were significantly improved from baseline with both exenatide QW and sitagliptin. In a study of patient- reported outcomes related to LEAD-3 (liraglutide vs. glimepiride), patients who took liraglutide noticed a weight difference, achieved a better weight image, and had less weight concern.

Q: Could you tell us about the combination of DPP-4 inhibitors and GLP-1 agonists?

Dr. Blonde: We expect that adding DPP-4 inhibitors to GLP-1 agonists wouldn’t further raise GLP-1 receptor signaling, but it would raise GIP levels three-to-four-fold. Possibly this could provide additional benefit. But until someone conducts a trial, I wouldn’t recommend this combination.

WHAT DO RECENT DATA INDICATE REGARDING THE COMPARATIVE EFFICACY AND TOLERABILITY OF DIFFERENT GLP-1 RAS?

Alan J. Garber, MD, PhD, FACE (Baylor College of Medicine, Houston, TX)

Dr. Garber reviewed data suggesting that liraglutide has a better efficacy profile than exenatide (and possibly exenatide once weekly), although exenatide once weekly may have better tolerability.

• The duration of action and degree to which GLP-1 receptors are saturated are the key mechanistic differences between exenatide and liraglutide. Exenatide is often used twice daily while liraglutide is once daily. Dr. Garber suggested that liraglutide’s more persistent saturation of the GLP-1 receptor leads to the larger A1c drop seen in clinical trials. In a head-to- head study in which exenatide users ultimately switched to liraglutide, the shift to liraglutide led to statistically significant improvements in A1c, a trend toward better systolic blood pressure, and similar weight loss.
• Dr. Garber reviewed the top-line results of DURATION-6, an international trial in which exenatide once weekly failed to meet the pre-specified study endpoint of noninferiority to liraglutide (A1c reduction of 1.3% vs. 1.5%). However, he noted that exenatide once weekly might be more tolerable, as it was associated with less nausea, vomiting, and diarrhea.

Questions and Answers

Q: What happens when Symlin is used in conjunction with GLP-1 RAs?

Dr. Garber: I don’t think that’s been published.

Q: What about TZD with GLP-1? Dr. Garber: The weight loss is still there. Q: How do you reduce nausea?

Dr. Garber: You should not up-titrate until the nausea goes away. You could tell the patient to vary the diet and consume less fat.

A: I think it’s important to remind patients not to overeat and to eat more slowly.

Q: Why do we see hypoglycemia with GLP-1 when in theory this shouldn’t happen?

Dr. Garber: Even metformin can leads to hypoglycemia. This problem isn’t unique to GLP-1 agonists. Anything that tightens glucose levels can lead to hypoglycemia.

WHAT DO RECENT DATA INDICATE REGARDING THE USE OF GLP-1 RECEPTOR AGONISTS OVER THE COURSE OF DISEASE PROGRESSION?

Robert Ratner, MD, FACE, FACP (Georgetown University School of Medicine, Washington, DC)

Dr. Ratner presented evidence that GLP-1 receptor agonists provide benefits throughout the progression of type 2 diabetes.

• GLP-1 receptor agonist therapy has been shown to normalize glycemia in prediabetes, defined as impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). In a 24-week randomized controlled study, glycemia normalized in 56% of prediabetes patients in the placebo group (lifestyle intervention only) and 77% of those who received both lifestyle intervention and exenatide BID (Rosenstock et al., Diabetes Care 2010). In a similar study involving liraglutide, 20-week prediabetes incidence barely changed from baseline in the groups treated with lifestyle intervention alone or lifestyle intervention plus orlistat (Roche’s prescription Xenical, GSK’s over-the-counter alli). However, prediabetes incidence was nearly halved in patients taking liraglutide 1.2 mg, with greater reductions seen with liraglutide1.8 mg (but no further improvement at higher doses).
• In randomized, controlled trials, GLP-1 receptor agonists showed consistent glycemic reductions whether patients were treatment naïve or already using two oral agents. Dr. Ratner showed that this observation held across five randomized controlled trials of both exenatide BID (A1c reduction of 0.8-0.9% from baseline of 7.8-8.5%) and five randomized controlled trials of liraglutide (reduction of 1.0-1.5% from baseline of 8.3-8.6%).
• “Secretagogues become less effective throughout the course of disease.” In a yearlong head-to-head comparison, patients with diabetes duration less than one year saw similar initial reductions with liraglutide and glimepiride, although after 52 weeks the glimepiride group began to show the “characteristic swoosh-shaped curve of secondary failure” (52-weeek A1c reductions of 1.4% vs. 1.0%). Patients with baseline diabetes duration greater than one year were less responsive to liraglutide (A1c decline of 1.2%) but even less responsive to glimepiride (A1c decline of 0.6%) compared to patients with shorter diabetes duration.

Questions and Answers

Q: Have there been any studies of GLP-1 agonists in type 1 diabetes?

Dr. Ratner: We know that they are not a substitute for insulin in type 1 diabetes. When liraglutide was instituted in Japan, several type 1 patients had their insulin withdrawn, because there was not a label for combination with insulin. What happened was two occurrences of diabetic ketoacidosis with death. Clearly GLP-1 receptor agonists are not sufficient to treat diabetes. Whether there might be an advantage to the combination, I can think there might be benefit, especially for type 1 patients with insulin resistance who have lots of weight gain. This needs to be examined.

Q: What are these drugs doing? Promoting insulin secretion? Suppressing glucagon? Slowing gastric emptying?

Dr. Ratner: They do cause glucagon suppression, except in hypoglycemia. Glucagon suppression is glucose-dependent, so GLP-1 receptor agonists don’t abrogate the response to hypoglycemia. There is no question that gastric emptying helps slow post-meal excursions. In type 2 diabetes, no matter how little C- peptide you secrete, you can see it go up with GLP-1 receptor agonist therapy. The question is whether C- peptide-positive t1 could benefit from this effect; I know of no data.

Dr. Blonde: Yes, late in disease when sulfonylureas wouldn’t show response, we seem to see improvement in beta-cell function.

Q: Is there a future for GLP-1 receptor agonists in diabetes prevention?

Dr. Ratner: My opinion is that these would be slam-dunk therapies for prevention.

Dr. Leahy: Off-label.

Dr. Ratner: Yes, off-label! [laughter] This is because they give more than 50% greater prevention of diabetes in clinical trials, and they also cause weight loss. But nobody is reimbursing for diabetes prevention currently. Clinical trials are looking at these agents in terms of weight loss per se.

Dr. Garber: The amount of weight loss you get is far greater than at merely glucose-lowering doses. If you look at the dose-response curves, it basically does not saturate; it just keeps going and going. Of course, so does the adverse event profile. Glucose-lowering efficacy peaks at roughly 10 ug exenatide or 1.2-1.8 liraglutide. The weight-loss effect is apparently limited only by tolerability.

WHAT DO RECENT DATA INDICATE REGARDING GLP-1 RAS COMPARED TO OR IN COMBINATION WITH INSULIN?

Lawrence Blonde, MD, FACP, FACE (Ochsner Medical Center, New Orleans, LA)

Dr. Blonde noted that although GLP-1 receptor agonists are not a substitute for insulin in insulin- dependent patients, they promote comparable or better A1c lowering compared to basal insulin, with weight loss as well. The combination of GLP-1 receptor agonists and basal insulin is not yet FDA approved, but clinical trials are promising.

• Dr. Blonde reviewed data of GLP-1 receptors compared to insulin. In a pooled analysis of four trials comparing exenatide to either short- or long-acting insulin (glargine or aspart), researchers found that exenatide led to similar improvements in A1c but with weight loss as opposed to weight gain. Dr. Blonde also noted that fasting plasma glucose (FPG) was better lowered with insulin at 26 weeks. Exenatide once weekly, compared to insulin glargine, showed better A1c drop (1.5% vs. 1.3%), less potent FPG reduction (37.8 vs. 50.4 mg/dl), and notably better weight effects (2.6 kg loss vs. 1.4 kg gain [5.7 lbs loss vs. 3.1 lbs gain]). Both exenatide and exenatide once weekly are associated with smaller postprandial glucose excursions. Liraglutide showed significantly better A1c effects vs. glargine (1.3% vs. 1.1%) and significantly better weight effects (1.8 kg loss vs. 1.6 kg gain [4.0 lbs loss vs. 3.5 lbs loss]); changes to FPG were not statistically significantly different.
• The FDA has not approved GLP-1 RAs for concomitant use with basal insulin, although a trial of exenatide alongside insulin glargine (sanofi-aventis’ Lantus) showed a substantial A1c reduction compared to glargine with placebo and weight loss as opposed to weight gain. Again, more weight loss was seen when exenatide was utilized. Nocturnal and overall hypoglycemia were lower when the GLP-1 RA was used.

Questions and Answers

Q: Have you ever used insulin with exenatide?

A: I think it could be a promising therapy.

WHAT DO AVAILABLE DATA REVEAL ABOUT THE PHYSIOLOGY OF WEIGHT LOSS ASSOCIATED WITH GLP-1 RECEPTOR AGONISTS?

Alan Garber, MD, PhD, FACE (Baylor College of Medicine, Houston, TX)

Dr. Garber discussed the mechanism and benefits of weight loss induced by GLP-1 receptor agonist weight loss, which is dependent on neither GI side effects nor delayed gastric emptying.

• Weight loss occurs with GLP-1 receptor agonist therapy even in patients who do not experience GI side effects like nausea, vomiting, and diarrhea (NVD), although patients with these symptoms tend to lose even more weight. Dr. Garber noted that the relationship between nausea and GI side effects is unknown: possibly the additional weight loss comes as a result of nausea, but possibly the patients who are most sensitive to the weight-loss effects are also the ones who experience nausea. He added that glycemic control has been shown to be independent of GI side effects as well, although “that accusation was also leveled at metformin 10-15 years ago.”
• In rodent studies, liraglutide and exenatide both delay gastric emptying at the start of treatment, but after two weeks the gastric emptying effects have largely normalized with liraglutide. Dr. Garber suggested that this difference might explain the higher incidence of nausea and vomiting with exenatide compared to liraglutide. However, he noted that even with exenatide, long-term nausea affects only one in seven patients.
• GLP-1 receptor agonists activate neurons in regions involved in appetite regulation, as seen in animal studies. Dr. Garber said that this is true for both available drugs, although liraglutide has “a more diffuse uptake in the lower brain.”
• Weight loss with GLP-1 receptor agonists seems to involve both visceral fat (believed to be more metabolically harmful) and subcutaneous fat (believed to be less metabolically harmful). Dr. Garber showed a slide of a month-long observational trial in which exenatide BID did not lead to significant loss of fat mass, although he noted that this is consistent with the gradual weight-loss profile of GLP-1 receptor agonists. Data from the LEAD-2 study suggest that liraglutide’s visceral weight-loss effects plateau at 1.2 mg, while the subcutaneous weight-loss effects seem to continue dose-dependently. Dr. Garber observed that to lose a significant amount of weight, some subcutaneous fat must be lost.
• Liraglutide 1.8 mg is associated with statistically significantly better liver-to-spleen signaling, suggesting improvement in fatty liver (a condition that can lead to many serious health problems).

Questions and Answers

Q: Where does Symlin (Amylin’s pramlintide) fit into this? Is this potentially a drug for type 2 diabetes?

Dr. Garber: As you know, Symlin has to be given before each meal. When we investigated this, patients with type 2 diabetes were uniformly displeased with the notion of taking a drug before each meal. A once- daily or even once-weekly GLP-1 receptor agonist is more appealing.

Q: Weight loss, visceral fat loss, and improvement in NASH (non-alcoholic hepatic steatosis) – I don’t push GLP-1 receptors as insulin sensitizers. But this sounds like an insulin-sensitizing profile.

Dr. Garber: We don’t see insulin sensitization. But reducing glucagon turns out to be major effect. Dr. Roger Unger has shown a major effect of reducing glucagon independent of insulin dose.

Q: What about the off-label use of these agents in obese patients without diabetes?

Dr. Ratner: Weigh-loss studies are ongoing. One randomized controlled trial compares liraglutide in obese patients with diabetes to obese patients with type 2 diabetes. Dosage is going up to 3.0 mg. We have to wait for data.

Dr. Blonde: In some of these studies, everyone is getting an intensive lifestyle intervention, which I think makes sense.

Dr. Garber: At 3.o mg liraglutide, in the pilot study at 20 weeks there was more than 8.0% weight loss. That is to my eye the best pharmacologic effect to be produced in any reliable, scientifically based clinical trial that I know of.

Q: We talk about these data as causing weight loss by promoting satiety. Are there any known data on resting energy expenditure?

Dr. Garber: Some data suggest that resting energy expenditure goes up, not down, which is paradoxical – usually weight loss decreases energy expenditure. Liraglutide and other GLP-1 data suggests that energy expenditure goes up in both humans and animals.

WHAT DO RECENT DATA INDICATE REGARDING CV SAFETY OF GLP-1 RAS AND THEIR EFFECTS ON CV RISK FACTORS?

Robert E. Ratner, MD, FACP, FACE (Georgetown University, Washington, DC)

Dr. Ratner discussed the large ongoing outcomes studies to assess cardiovascular safety of incretin therapies. He noted that observational studies suggest possible cardioprotective effects of GLP-1 receptor agonists.

• The FDA’s focus cardiovascular (CV) safety has led to the creation of many trials that are to end three to eight years from now. Dr. Ratner observed that pharmaceutical industry has identified 60,000 high-risk type 2 diabetes patients to prove a negative result.
• Early signs point to potentially improved CV safety with GLP-1 receptor agonists. GLP-1 receptor agonists have been associated with improved blood pressure and better lipid profiles, and the risk of severe hypoglycemia appears minimal when the drugs are not used in conjunction with sulfonylureas. A health insurance database analysis of exenatide use has shown a statistically significantly lower risk for major CV events (Best et al., Diabetes Care 2011). CV events in pooled clinical trial data are numerically lower with GLP-1 RAs, however the confidence intervals are too wide to provide a meaningful interpretation.

Questions and Answers

Q: Are the new studies powered to find cardio protection?

Dr. Ratner: Some are like the TECOS study (sitagliptin) and SAVOR study (saxagliptin) are both looking for CV protection, indicating why their subject numbers are so high. They aim to find cardio protection as opposed to cardio neutrality.

Q: What CV indicators are seen with DPP-4 inhibitors?

Dr. Ratner: Positive BP and lipid changes with the DPP-4 are seen but to a lesser degree.

Q: Are you proposing that GLP-1 RAs lead to direct cardiovascular effects?

Dr. Ratner: We will talk about this later in the session. In retrospective analysis, metformin was neutral, sulfonylurea increased risk, while exenatide reduced CV outcomes. This is provocative and has generated many hypotheses.

WHAT HAS RECENT EVIDENCE ADDED TO OUR UNDERSTANDING OF GLP-1 RA SAFETY?

Lawrence Blonde, MD, FACP, FACE (Ochsner Medical Center, New Orleans, LA)

Dr. Blonde explained the evidence linking GLP-1 receptor agonists to pancreatitis and thyroid cancer in animal and human studies, suggesting that potential risks have not been shown very relevant for the general population. He also discussed the judicious use of GLP-1 receptor agonists in patients with renal impairment and the evidence that antibodies reduce exenatide’s efficacy in many patients.

• Case reports of pancreatitis with exenatide BID, liraglutide, and sitagliptin led to label warnings or cautions on the respective labels. This evidence does not prove a causal relationship, and Dr. Blonde noted that pancreatitis incidence is already 1.5-3-fold higher in people with diabetes than the general population. Studies of insurance claims databases have not supported a link between incretin therapy and pancreatitis, although Dr. Blonde said that such studies may be limited by confounding factors. He said that he “might recommend other agents in patients with pancreatic cancer.”
• Dr. Blonde said that although the effects of GLP-1 receptor agonists on thyroid cancer is not known in humans, he said that liraglutide should not be used in those with MEN 2 (multiple endocrine neoplasia syndrome type 2) or a family history of medullary thyroid carcinoma. That said, he thinks that the theoretical risk in humans is “quite low.” Although liraglutide promotes thyroid tumors and C-cell hyperplasia promote C-cell hyperplasia and thyroid tumors in rodents, rodents have more than 20-fold greater density of C- cells, greater density of GLP-1 receptors per C-cell, and higher incidence of tumors. (Continuous infusion of exenatide is also associated with higher incidence of C-cell hyperplasia in rodents.) Cynomolgus monkeys, physiologically more similar to humans, did not develop C-cell hyperplasia after 20 months of exposure to liraglutide (at 60-fold human doses). Studies of human C-cells showed no GLP-1 receptor activation, and calcitonin release in humans is unaffected at 52 weeks.
• Exenatide BID is contraindicated in severe renal impairment and end-stage renal disease due to statistically significant differences in renal clearance of exenatide observed in these populations. Limited evidence exists on liraglutide in patients with any degree of renal impairment, and the label recommends caution with renal impairment. Dr. Blonde noted that a single-dose study of liraglutide shows no difference in liraglutide clearance across any stage of renal disease, suggesting but not establishing that any risk with liraglutide is small.
• Patients treated with exenatide appear to develop antibodies to the drug at higher rates than with liraglutide, and anti-exenatide antibodies seem to have a greater effect on efficacy than anti-liraglutide antibodies. Stratified by antibody titer, all groups taking exenatide BID and exenatide QW showed statistically significant responses to treatment at 26 weeks. However, those in the high-titer group (10% of those on exenatide BID and 24% of those on exenatide QW) experienced comparatively lower A1c reductions than other exenatide patients. In a separate study of liraglutide, low-titer antibodies appeared in 8.3-8.7% of patients at 26 weeks (3.1-3.5% at two years), without any correlation between antibody presence and A1c reduction or adverse event rate. In a recent study of patients who spent 26 weeks on exenatide and then switched to liraglutide for 14 weeks, those with high-titer exenatide antibodies had the highest 26-week A1c and the greatest liraglutide-induced A1c change (Buse et al., JCEM 2011).

Questions and Answers

Q: Is there any routine reason to measure amylase or calcitonin?

Dr. Blonde: Calcitonin monitoring and ultrasound was done in clinical trials and seemed to be associated with unnecessary thyroid surgeries. I personally don’t think measurement of calcitonin in asymptomatic patients makes sense.

Q: Is medullary cancer unique to liraglutide or is it a class effect?

Dr. Blonde: As mentioned earlier, there is higher binding over time with liraglutide than exenatide. Infused exenatide showed negative effects in animals, so I think with longer-duration exenatide you would need to look at data. That said, although the warning in the label is appropriate, I think these therapies are appropriate in humans.

Dr. Leahy: I know we’re over time, but we ought to discuss the upcoming publication that we are all talking about.

Dr. Ratner: This is with regards to a study of pancreatic cancer that will appear next month in Gastroenterology from a group in Los Angeles. The FDA-reporting system analysis suggests that exenatide twice daily and sitagliptin both have increased risk of causing pancreatic cancer and cancer in general. It should be noted that anyone can access the data from the FDA reporting system online, where the website prominently says that these data should not be used in order to calculate incidence rates. There is no adjudication; the same event can be reported by three different people. I think that alone should answer the issue.

Dr. Leahy: Our feeling generally in the field is that the data are early, incomplete, and not persuasive. Is that a fair summary? (Panelists nod)

WHAT DO RECENT DATA INDICATE REGARDING GLP-1 RA EFFECTS ON BETA CELL SURVIVAL AND/OR PROLIFERATION?

Alan J. Garber MD, PhD, FACE (Baylor College of Medicine, Houston, TX)

Dr. Garber reviewed evidence that GLP-1 receptor agonists improve proxies of beta cell function and survival.

• GLP-1 RAs have been reported to promote beta cell proliferation and survival in rodents, but beta cell proliferation is hard to study in humans outside of autopsy studies. As such, disposition index (first-phase C-peptide secretion), HOMA-B (a formula involving basal insulin levels and basal glucose levels), proinsulin:insulin ratio, transplantation evidence, and durability of treatment effect are used as proxies.
• A study in which patients used exenatide for one year showed a positive effect on the disposition index (DI) relative to insulin glargine. The between-group difference was lost four weeks after stopping treatment, but a two-year off-drug extension showed better DI with exenatide. Liraglutide meta-analyses show HOMA-B and proinuslin:insulin ratio improvements relative to placebo, rosiglitazone, and glimepiride. In a pilot study of transplant patients, patients receiving exenatide demonstrated better graft survival and more sustained function.
• Extension studies have suggested sustained efficacy, though Dr. Garber noted that these results should be considered in light of possible survivor bias (i.e., patients in whom the drug is efficacious are more likely to enroll in extensions). Two years beyond an initial 30-week study, patients on exenatide still had good control of A1c. Two-year liraglutide data also showed sustained glycemic benefit, with better treatment durability at 1.8 mg than 1.2 mg dosing.

Questions and Answers

Q: Do we know if these drugs do anything to the beta cell durability in humans?

Dr. Garber: No, we don’t know.

Q: Are companies doing anything to give us that information in the near future?

Dr. Garber: No, and they can’t since patients are being siphoned to CV trials that are dominating the pharmaceutical industry right now.

WHAT DO DATA INDICATE REGARDING DIRECT CV EFFECTS OF GLP-1 RAS?

Robert E. Ratner, MD, FACP, FACE (Georgetown University School of Medicine, Washington, DC)

Dr. Ratner explained that GLP-1 receptor agonists may have both receptor-dependent and receptor- independent effects on the cardiovascular system.

• Receptor-dependent benefits of GLP-1 therapy include reductions in weight, systolic blood pressure, and lipids; while receptor-independent effects (involving the fragment of GLP-1 that remains after cleavage by DPP-4) include post-ischemic contractile recovery, glucose uptake, and improved endothelial function. Animal models have shown decreased infarct size with exenatide and liraglutide treatment, and human studies have suggested benefits ranging from better postprandial endothelial function left ventricular function improvement in high-risk cardiac patients.

Questions and Answers

Q: A few years ago, cardiologists thought this would be an amazing area, and then interest seemed to stop. Is this still an active area of investigation?

Dr. Ratner: I get concerned that publication bias might have affected some negative studies, so we are left with positive human data from 2006. Preconditioning is still a very active area, and I know of some post- conditioning work in Copenhagen.

Q: Could you discuss the role of GLP-1 receptor agonists in first-line therapy, prediabetes, and outside of diabetes?

Dr. Garber: For first-line therapy, it is approved if you have failed metformin or sulfonylureas. In prediabetes, you can’t find much data with exenatide and only preliminary data with liraglutide. For weight loss, Orexigen is closing down its efforts in the US because they see no path to approval. Apparently the FDA is applying the CV standard uncritically to obesity drugs even in the absence of diabetes.

Q: Is there any information on GLP-1 receptor agonists post-gastric-bypass?

A: It’s been thought that part of the benefit of gastric bypass surgery is increasing the incretin effect. You may be looking at an either-or situation.

Dr. Ratner: GLP-1 levels depend on the type of bariatric surgery. With Roux-en-Y gastric bypass, they are much higher than anything we see pharmacologically. It is highly unlikely that drugs would provide further benefit.

Q: Are there any proposed negative effects of DPP-4 inhibitors?

Dr. Ratner: That is a great question, but no one knows. If you use a DPP-4 inhibitor and block degradation of GLP-1, do you lose receptor-independent benefits? We will have to wait to see.

Final comments

Dr. Ratner: Over the last five years, I think we have discovered that people aren’t afraid of needles if they can get weight loss. People might be willing to go on glp-1 agonists who wouldn’t choose to go on insulin.

Dr. Garber: I think we have a remarkable class of agents contending for earlier use. They are very desirable, they might have effects on beta cells in addition to weight and glucose control. They are more powerful than DPP-4 inhibitors. They obviate the need for sulfonylureas, which have a remarkably deleterious profile and are beneficial only for insurance companies.

Dr. Blonde: Hopefully, with 13 antihyperglycemic therapies available, we are entering an area where we can pick the therapies that are most efficacious and tolerable for patients. GLP-1 receptor agonists look like they will have a prominent role in future therapy.

Individualizing Diabetes Treatment for Improved Glycemic Control and Management of Comorbidities (Sponsored by Boehringer Ingelheim)

PATHOPHYSIOLOGY OF TYPE 2 DIABETES AND THE INCRETIN PATHWAY

Adrian Vella, MD, MRCP (Mayo Clinic, Rochester, MN)

In a technical review, Dr. Vella described the defects in insulin action and secretion associated with prediabetes and possible insights to be gained from genetics. He noted that most genetic variants linked to diabetes involve insulin secretion (including some that alter the incretin effect). However, none of these genetically associated defects in insulin secretion seems to contribute significantly to the onset of type 2 diabetes.

MANAGEMENT OF DIABETES AND COMORBIDITIES AFTER FAILURE OF ORAL MONOTHERAPIES

Richard Pratley, MD (Sanford-Burnham Translational Research Institute, Orlando, FL)

Dr. Pratley discussed options for patients who have failed metformin monotherapy, focusing on incretin agents, particularly GLP-1 receptor agonists. He noted that the DPP-4 inhibitors all have similar efficacy (including similarly “substantial” A1c reductions in combination with metformin) and similar tolerability, although linagliptin (BI/Lilly’s Tradjenta) relies significantly less on renal clearance than the other DPP-4 inhibitors. He then offered an in-depth review of GLP-1 agonists. In Dr. Pratley’s view, the main difference between liraglutide (Novo Nordisk’s Victoza) and exenatide (Amylin/Eli Lilly’s Byetta) is liraglutide’s greater efficacy (A1c reduction of 1.0-1.5% vs. 0.8-1.0%), while exenatide LAR (Amylin/Lilly/Alkermes’ Bydureon) also gives greater A1c reductions than exenatide.

• Five DPP-4 inhibitors have been launched in the US and/or internationally, all with similar efficacy. The DPP-4 inhibitors available in the US are sitagliptin (Merck’s Januvia), saxagliptin (BMS/AZ’s Onglyza), and linagliptin (BI/Lilly’s Tradjenta). International-only offerings include vildagliptin (Novartis’ Galvus, which Dr. Pratley said is unlikely ever to come to the US) and alogliptin (Takeda’s Nesina, which he said that US patients “may see” some day). He broadly described the drugs as reducing A1c by 0.7-1.0% from a baseline in the mid 7-8% range, efficacy he said was comparable to that of TZDs or the sulfonylurea glipizide. Significantly greater efficacy has been seen in combination therapy (especially initial combination therapy) with metformin, and he said that the triple combination of TZD, metformin, and DPP-4 inhibitor is a particularly good therapeutic approach, especially for minimizing hypoglycemia. He noted that sitagliptin is the only DPP-4 inhibitor approved for use with insulin.
• Dr. Pratley said that the defining feature of the DPP-4 inhibitors is that they are “very well tolerated” – so much so that healthcare providers in clinical trials can’t distinguish between the active group and control group based on side effect profile. He said that the risk for drug-drug interactions is generally low, although the labels for saxagliptin (BMS/AZ’s Onglyza) and linagliptin describe potential interactions with drugs that affect CYP3A4/5. Most DPP-4 inhibitors require dose adjustment in patients with impaired renal function, but linagliptin is cleared through other pathways and thus can be used at full strength in these patients.
• Dr. Pratley reviewed the many advantages of GLP-1 receptor agonist therapy, including A1c reductions, dose-dependent weight loss, and improvement in biomarkers of cardiovascular risk without any observed CV safety signal. He said that the main difference between liraglutide (Novo Nordisk’s Victoza) and exenatide (Amylin/Lilly’s Byetta) is liraglutide’s greater efficacy (1.0-1.5% vs. 0.8-1.0%), and he noted that exenatide long-acting release (Amylin/Lilly/Alkermes’ Bydureon) has also been shown more effective than exenatide. He concluded that duration of GLP-1 receptor agonism appears to be important up to a point. Comparing across trials, he noted that liraglutide and exenatide LAR seem to have similar efficacy, suggesting that the once-weekly vs. once-daily formulation seems to off negligible efficacy improvements. (He did not emphasize the head-to-head comparison of the two therapies in the DURATION-6 trial, in which exenatide LAR failed to meet non-inferiority against liraglutide.)

INDIVIDUALIZING TYPE 2 DIABETES TREATMENT

Silvio E. Inzucchi, MD (Yale University, New Haven, CT)

Dr. Inzucchi provided a broad overview of the available pharmacotherapies for type 2 diabetes and current treatment guidelines, noting the controversy and complexity surrounding treatment choices. He forecasted that the emphasis in future drug development will be on safety and tolerability, especially with regard to cardiovascular profiles, Dr. Inzucchi emphasized the importance of individualizing both therapeutic regimen and A1c targets to minimize risks and side effects.

• Dr. Inzucchi opened his talk with a review of the currently available type 2 diabetes medications, discussing their advantages, their disadvantages, and how to minimize adverse events. The most common advice across drug classes was to start with low doses and titrate slowly. Notably, no adverse events were listed for DPP-4 inhibitors.

• Dr. Inzucchi reviewed several guideline documents for treating type 2 diabetes. He said that although he likes the way the AACE/ACE algorithm stratifies therapy by initial A1c level, the algorithm is aggressive (e.g., by automatically recommending triple therapy for a patient with initial A1c greater than 9.0%). The VA/DoD guidelines offer a “very cost-conscious” mindset, recommending NPH and regular insulin unless the patient has issues with hypoglycemia. The NICE Algorithm used in the UK also takes cost into account. Although the initial A1c target is 6.5%, if triple therapy or insulin is used the target becomes 7.5%. Dr. Inzucchi considers this shift reasonable given the health risks of intensifying treatment in patients who aren’t responding.
• Many of the guidelines are similar. Dr. Inzucchi displayed a simplified, generalized treatment algorithm: step one is metformin, then two oral agents, then triple therapy, and finally two oral agents used with basal insulin. To Dr. Inzucchi, the existence of so many different drugs (and so many treatment algorithms) makes it clear that a perfect diabetes drug does not yet exist.
• Dr. Inzucchi reviewed several “unmet needs” for type 2 diabetes therapy, focusing on better safety and tolerability. He discussed: cardiovascular risk reduction (suggested but unproven for pioglitazone and GLP-1 receptor agonists), beta-cell preservation (which he said have been shown for TZDs in DREAM and ACT-NOW, with possible effects from incretin-based therapies), and weight reduction (demonstrated for GLP-1 receptor agonists; he noted that anti- obesity drug development per se has been “a very frustrating area” of late, with no new drugs approved in the past five years.
• He briefly mentioned many early- and late-stage investigational agents for type 2 diabetes, including SGLT-2 inhibitors, novel PPAR agonists, 11(R) HSD-1 inhibitors, glucokinase activators, GPR-40 and GPR-119 agonists, PTB-1b inhibitors, CPT-1 inhibitors, ACC-1 and ACC-2 inhibitors, and glucagon receptor agonists.
• Dr. Inzucchi closed by discussing individualization of A1c targets. The AD/EASD have published a target of less than 7% A1c while ACE and IDF recommend targets less than 6.5%. However, he said individualization is necessary rather than standardized cutoffs. He noted that this complex decision-making requires clinical judgment, but he referenced a recently published chart that he co-authored to assist the process. The chart suggest that young patients who are highly motivated and knowledgeable, with short disease duration and minimal risk of complications or hypoglycemia, could be targeted to A1c of 6.0%. Those who exhibit the opposite characteristics would be targeted to 8% A1c, with intermediate targets for patients of intermediate characteristics and risk levels (Ismail-Beigi et al., Ann Intern Med 2011).

PANEL DISCUSSION

Moderator: David D’Alessio, MD (University of Cincinnati, Cincinnati, OH)

Q: Can you comment on the macrovascular benefits of antidiabetic agents in prediabetes?

Dr. Vella: Outside of established diabetes, glucose-lowering therapy is a far inferior treatment than treatment of hypertension and dyslipidemia, in practice.

Dr. Inzucchi: We can’t confuse markers of CV risk with actual targets. As you know, A1c and one-hour postprandial glucose have been associated with CV risk, as in the Honolulu heart study. But based on ACCORD, ADVANCE, and VADT, it would seem overly optimistic that lowering glucose in the prediabetic range has a significant impact on risk. ORIGIN may shed some light on this, but I suspect that it will be negative like every other diabetes trial in the past ten years.

Q: Can you talk about adding basal insulin earlier in the course of therapy than would be typically done?

Dr. Pratley: I think there is a rationale for starting insulin earlier since you don’t really get tight glucose control with orals. It’s possible that less glucotoxicity would even change the course of the disease, although that hasn’t been shown in the long term. But I think the wrong thing to do is keep adding drugs that don’t get the patient to goal.

Comment [in response to a case study that involves a patient at BMI 48 kg/m² whose therapy is changing]: Pioglitazone would just make them gain more weight.

Dr. Inzucchi: It’s a tricky issue, because pioglitazone is more effective in patients who are more obese.

Dr. D’Alessio: It isn’t the option I chose either. That said, moving from a BMI of 48 to 49 is a bummer, but I’m not sure that it measurably changes the risks of obesity. Someone with a BMI of 48 can hide a kilogram or two better than someone at BMI 30.

[In response to a comment about altering dosage of metformin based on kidney function as measured by plasma creatinine]

Dr. D’Alessio: I think that the risk of metformin-induced lactic acidosis is the most overrated side effect in diabetes medicines. Most of what we know comes from overdoses; patients have taken as much as 60 grams and survived. If you look at the five-year results of the Fremantle Diabetes study in general practice, there were over thousands of patient-years’ worth of data on metformin users, including many with one or more contraindication, like renal insufficiency. Lactic acidosis occurred fewer than ten times in over 10,000 patient years among metformin users, which was not different from the non-metformin users. If there has to be some side effect of metformin discussed, I think it’s much more reasonable to worry about vitamin B12 deficiency. Using plasma creatinine would rule out about half my patients at the Veterans Administration. I think eGFR is better.

Dual Perspectives in Diabetes Care: The Intersection of Endocrinology and Cardiology (Supported by Abbott Laboratories, Genentech, Lilly USA LLC, Merck & Co., and sanofi-aventis US)

THE INTERSECTION OF DIABETES AND CARDIOVASCULAR DISEASE: INTRODUCTION FROM THE PERSPECTIVE OF AN ENDOCRINOLOGIST

Jack L. Leahy, MD (University of Vermont, Colchester, VT)

Dr. Leahy gave an overview of recent and upcoming developments in the field of CV disease in type 2 diabetes, noting that the recent major trials (ACCORD, ADVANCE, and VADT) might not be as negative as often portrayed. He reminded the audience that for patients in ACCORD whose A1c was below 8.0% and/or who had no baseline CV disease, intensive glycemic management was found to be cardioprotective. Thus, he said that the ongoing challenge for endocrinologists will be identifying which patients to treat at which goals, and he shared his hope that they would learn from cardiologists about the relative risks and benefits of aggressive lipid, blood pressure, and glycemic management.

• Dr. Leahy emphasized the need to study the long-term CV effects of diabetes therapies, alluding to the “complicated” CV issues surrounding rosiglitazone (GSK’s Avandia). He looked forward to results from CV outcomes trials on therapies including GLP-1 receptor agonists, DPP-4 inhibitors, and (in the ORIGIN trial) basal insulin. Other key areas of interest include biological memory (i.e., positive long-term CV effects from short-term diabetes management) and agreed-upon goals for people with diabetes who have had myocardial infarction or coronary artery disease.

THE INTERSECTION OF CARDIOVASCULAR DISEASE AND DIABETES: INTRODUCTION FROM THE PERSPECTIVE OF A CARDIOLOGIST

Donna M. Polk, MD, MPH, FACC (Hartford Hospital, Hartford, CT)

Dr. Polk emphasized that diabetes is in large part a cardiovascular disease even though patients often worry more about complications such as blindness and amputation. She said that diabetes is presenting many challenges for cardiologists, including determining how to diagnose the disease, when to refer to the endocrinologist, and when to begin treatment.

Corporate Liaison Board Forum - Nuclear Receptors: From Bench to Bedside (Supported by the Endocrine Society’s Corporate Liaison Board)

ADIPOGENESIS, PPAR-GAMMA, AND THERAPEUTICS

Bruce M. Spiegelman, PhD (Harvard Medical School, Boston, MA)

Dr. Spiegelman described the possibility of developing PPAR-gamma modulators that achieve the metabolic benefits of PPAR-gamma agonists like rosiglitazone and pioglitazone, but without the PPAR- gamma agonism (which seems to cause adverse side effects but not glycemic benefits). He described his group’s promising animal studies of a non-agonist called SR1664, which improves insulin sensitivity without evidence of bone deterioration or hematocrit changes. Although its dosage profile makes it unsuitable for continuation into clinical trials and many are skeptical of the research area (“we’ve been told that PPAR is a four-letter word more than once”), Dr. Spiegelman sees his group’s work as supporting the prospect of future insulin sensitizing agents with more favorable risk-benefit profiles than TZDs.

-- by Joseph Shivers, Mark Yarchoan, Omar Bari, and Kelly Close