June 21-25, 2013, Chicago IL Report – SGLT Inhibitors and Other Oral Therapies (Non-Incretin) – Draft

Executive Highlights

To an even larger extent than at ADA 2012, the discussion of non-incretin oral agents focused on SGLT-2 inhibitors. The recent regulatory approvals of BMS/AZ’s dapagliflozin (Forxiga) in the EU and of J&J’s canagliflozin (Invokana) in the US prompted an air of excitement, which grew as we heard more data on the potential benefits of SGLT-2 inhibitors in specific patient populations. Posters on dapagliflozin and BI/Lilly’s empagliflozin in type 1 diabetes presented the first results we’ve seen for SGLT-2 inhibitors in this indication (part of a trend of medicines created for type 2 patients being studied more widely in type 1 patients). A phase 2a study of dapagliflozin showed that the drug provided a reduction in total daily insulin requirement (-19% on the 5 mg and -16% on the 10 mg doses), as well as a trend toward lower glucose levels and less glycemic variability (both measured by CGM). Furthermore, the investigators observed slightly higher rates of hypoglycemia with the dapagliflozin doses (no dose-dependent effect), as well as higher rates of urinary glucose excretion (that were dose-dependent; 70-LB). We were also encouraged to see data from a single-arm open-label pilot study investigating the effects of empagliflozin, which compared the results of the eight-week treatment period to those from a preceding baseline two-week placebo run-in period. Empagliflozin therapy led to a decline in total daily insulin requirement (from 55 units/day to 46 units/day), a reduction in glucose levels (mean A1c decreased 0.4% from a baseline A1c of 8.0%), and lower rates of hypoglycemia (from 0.12 to 0.04 episodes a day), as well as short-term improvements in body weight. These results are more notable than the data from early DPP-4 inhibitor trials; we think that SGLT-2 inhibitors are likewise headed toward blockbuster status. 

An oral session on SGLT-2 inhibitors provided a closer look at Lexicon Pharmaceutical’s SGLT-1/SGLT-2 dual inhibitor (LX4211) and the first data we’ve seen for its SGLT-1 inhibitor, LX2761. Preclinical results for LX2761 shows that the candidate delays intestinal glucose absorption, increases intestinal GLP-1 secretion, decreases postprandial glucose excursions, and improves glycemic control (240-OR). We were especially interested in the data showing that LX2761 can act synergistically with sitagliptin (to increase postprandial GLP-1 levels), as it reinforces the potential for an SGLT-1 inhibitor/DPP-4 inhibitor fixed-dose combination that we have been discussing for some time now. (We would not be surprised if in a decade, long-term monotherapy – with any drug class – has become a thing of the past). The two oral presentations on LX4211 supplemented the topline phase 2 data reported last summer – in patients with type 2 diabetes, LX4211 provided dose-dependent decreases in systolic blood pressure (SBP), with the 400 mg dose providing an average reduction of 14 mmHg vs. placebo in patients with elevated SBP (≥130 mmHg). However, LX4211 had little effect on SBP in patients with normal baseline SBP levels and did not lead to dose-dependent changes in diastolic blood pressure (241-OR). Additional data also showed that LX4211 provided significant reductions in weight in patients with a BMI ≥30 kg/m², as well as significant reductions in triglycerides in patients with elevated levels at baseline (200-500 mg/dl; 243-OR).

The same oral session included several presentations with more nuanced data on dapagliflozin and canagliflozin. Interestingly, a study presented by Dr. Muhammad Abdul-Ghani (University of Texas Health Science Center, San Antonio, TX) showed that lowering the plasma glucose concentration with dapagliflozin improved both insulin sensitivity and glucose-stimulated insulin secretion. However, the glucosuria produced by the inhibition of SGLT-2 stimulated a compensatory increase in hepatic glucose production, which attenuated the clinical efficacy of dapagliflozin (242-OR). Another study showed that, a greater percentage (31%) of patients on dapagliflozin achieved an A1c reduction ≥0.5% and a weight loss ≥3 kg (7 lbs) compared to glipizide (4%; 236-OR). We imagine that the next step will be to investigate cost-effectiveness: glipizide is less expensive, but is also associated with weight gain rather than weight loss, as well as higher risk of hypoglycemia. Lastly, a presentation on canagliflozin showed that canagliflozin 300 provided a greater A1c reduction (0.88%) compared to canagliflozin 100 mg and sitagliptin (0.73% for both), and that both doses of canagliflozin provided greater weight loss (4.2% for the 300 mg dose and 3.8% for the 100 mg dose) compared to sitagliptin (1.3%; 238-OR).

The conference also included a debate on whether sulfonylureas should remain an acceptable first-line add-on therapy to metformin. In the “yes” presentation, Dr. Martin Abrahamson (CMO, Joslin Diabetes Center, Boston, MA) argued that there is no compelling evidence for stopping the use of SFUs – evidence has not shown that SFUs accelerate beta cell decline or that they increase beta cell apoptosis when used with metformin. (We would love to see more conclusive studies done, but who would fund them?) He reminded the audience that there is no evidence that SFU are less safe than other medications when used appropriately (obviously a big caveat), and that data actually exists to show that the drugs are effective, cheap, and well tolerated. Presenting the “con” view, Dr. Saul Genuth, (Case Western Reserve University, Cleveland, OH) noted that three drug classes – TZDs, DPP-4 inhibitors, and GLP-1 agonists – provide the same glycemic efficacy as SFUs with lower risks of hypoglycemia, and that the two latter drug classes have a neutral or beneficial effect on body weight. In the end, both speakers seemed to acknowledge that not all SFUs are created equal, and that glyburide in particular should be avoided. We also understand that Dr. Abrahamson may not personally agree with the side he was asked to argue – but he did argue it quite persuasively.

 

 

SGLT-2 Inhibitors

Oral Sessions: On the Horizon – Selective Sodium Glucose Co-Transporter Inhibition

LX2761, an SGLT-1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice (240-OR)

David Powell, MD (Lexicon Pharmaceuticals, The Woodlands, TX)

Dr. David Powell presented the results from a series of mouse studies characterizing the effects of the SGLT-1 inhibitor LX2761. In these mouse studies, Lexicon demonstrated: 1) LX2761 has poor systemic exposure, and causes little, if any, increase in urinary glucose excretion (as assessed by oral gavage to adult C57 mice); 2) LX2761 delays intestinal glucose absorption and increases intestinal GLP-1 release; 3) LX2761 acts synergistically with a DPP-4 inhibitor (sitagliptin) to increase postprandial levels of GLP-1; 4) LX2761 decreases postprandial excursions 15 hours after delivery to healthy mice fed ad libitum; and 5) LX2761 improves glycemic control in the KKAy mouse model of type 2 diabetes and in adult male C57 mice with STZ-induced diabetes. In conclusion, Dr. Powell stated that selective inhibition of SGLT-1 can improve glycemic control in mice, and as such, further studies are warranted to test whether SGLT-1 inhibition can improve glycemic control in people with diabetes.

Questions and Answers

Q: How do you speculate this drug would compare to alpha-glucosidase inhibitors?

A: We’re averaging once a day, and don’t have to give the drug with meals. I think with those drugs you have to give them with meals. Those don’t block absorption of glucose, but rather, disaccharides. The gut is fairly good at absorbing glucose fermented to short-chain fatty acids, but complex carb metabolites are produced with alpha-glucosidase inhibitors, so I wonder whether that is associated with GI side effects.

Q: Do you expect to dose this drug once daily in humans?

A: Based on what we’re seeing in mice, once-daily dosing improved glycemic control. That’s what we’re hoping for.

Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX): This is a very important study. Although people have shied away from combining SGLT-1 and SGLT-2, I actually strongly advocated that pharmaceutical companies think about this. As long as you do not cause GI symptoms, this could be an added benefit. Having said that, you didn’t tell us if the rats had GI side effects.

A: We got interested in this because LX4211 inhibits SGLT-1, yet there were no GI side effects seen relative to placebo. So, it made us realize there’s a therapeutic window. That’s why LX2761 was developed. Are there more side effects when you target the gut? The bottom line is, yes, if you give enough, you will cause loose stools. It’s dependent on the amount. We do see a therapeutic window of maybe ten fold between the dose that gives a 50% decrease in glucose excursion and the dose that gives you loose stool.

 

The Impact of LX4211, a Dual Inhibitor of Sodium Glucose Transporters SGLT-1 and SGLT-2, on Blood Pressure in Patients with Type 2 Diabetes (241-OR)

Pablo Lapuerta, MD (Lexicon Pharmaceuticals, The Woodlands, TX)

In this 12-week dose-ranging study (n=299), patients with inadequately controlled type 2 diabetes taking metformin were assigned to receive placebo or one of four doses of LX4211 – 75 mg QD, 200 mg QD, 200 mg BID, or 400 mg QD. Patients in the study were 18-75 years of age, had BMI ≤45 kg/m², and A1c between 7.0-10.5%; at baseline, patients were on average 56 years old, with A1c of 8.1%, BMI of 33 kg/m², and blood pressure of 125/79 mmHg. Both patients with and without hypertension were allowed in the study, and there were no restrictions on antihypertensive medication use. LX4211 reduced systolic blood pressure (SBP) in a dose-dependent manner (estimating from the chart presented, the 75 mg QD, 200 mg QD, 200 mg BID, and 400 mg QD doses reduced SBP approximately 0.1, 4.0, 4.5, and 6.0 mmHg, respectively, while SBP lowered approximately 0.3 mmHg with placebo). For the 400 mg dose, patients with elevated SBP (≥130 mmHg) experienced an average reduction of 14 mmHg versus placebo (p=0.002), while those with normal SBP (<130 mmHg) experienced minimal change in SBP – Dr. Pablo Lapuerta noted that these decreases were consistent with approved antihypertensive therapies. In contrast, there were no dose-dependent changes in diastolic blood pressure (DBP). For the trial’s A1c-lowering efficacy results, please see our AHA 2012 coverage at http://close.cx/AHA2012Day4.

• Dr. Lapuerta noted several strengths and limitations of the study. In terms of strengths, the study had precise blood pressure data, demonstrated a clear dose response, had clear separation between treatment and placebo, used trough measures of blood pressure, and demonstrated systolic-blood-pressure-lowering efficacy consistent with that of approved antihypertensive agents. As for limitations, the study had a limited sample size, many patients already had good blood pressure control at baseline, the study duration was short, there were no blood pressure measures taken at the peak, and GLP-1 was not measured.

 

Plasma Glucose Reduction with the SGLT-2 Inhibitor, Dapagliflozin, Improves Insulin Sensitivity and Insulin Secretion in T2DM (242-OR)

Muhammad Abdul-Ghani, MD, PhD (University of Texas Health Science Center, San Antonio, TX)

Dr. Muhammad Abdul-Ghani presented results from a study examining the effects lowering plasma glucose concentrations with dapagliflozin has on insulin sensitivity and insulin secretion in patients with type 2 diabetes. In the study, patients (n=18; baseline BMI 31.1 kg/m², baseline A1c 8.2%) were randomized to dapagliflozin or placebo in a 2:1 fashion. Five days and three days prior to randomization (Days -5 and -3), respectively, subjects received a 75-gram OGTT and an insulin clamp ³H-glucose infusion. Following randomization (Day 0), subjects were admitted to the clinical research center (on Day 1) for measurement of basal hepatic glucose production with ³H-glucose on Days 1-3. Subjects were administered dapagliflozin from Day 2 through Day 15 of the study, and were given a repeat OGTT on Day 14 and insulin clamp ³H-glucose infusion on Day 15. In the study, lowering the plasma glucose concentration with dapagliflozin improved insulin-stimulated tissue glucose uptake (insulin sensitivity) and glucose-stimulated insulin secretion. However, the glucosuria produced by the inhibition of SGLT-2 stimulated a compensatory increase in (hepatic) glucose production, which attenuated the clinical efficacy of dapagliflozin.

Questions and Answers

Q: What do you suppose the signal for glucagon secretion in your study was?

A: We don’t know. We’re searching for that now.

Q: Did you do any follow-up studies where you gave a DPP-4 inhibitor?

A: We don’t have results yet, but that’s the obvious thing to look into.

Q: Are there other drug candidates you may consider combining with SGLT-2 to knock down hepatic glucose production?

A: DPP-4 inhibitors are the obvious option, but I am a little bit skeptical about their efficacy. GLP-1 agonists may be more efficacious, but I am still skeptical. Maybe glucagon antagonists, but I’m not sure if they’d be good for clinical use.

Q: What about metformin?

A: Subjects were already receiving metformin. Also, metformin doesn’t affect glucagon. This study exposes the interaction between the liver and kidney, and their crosstalk in glucose homeostasis. I personally think they are related through the central nervous system. When we are giving dapagliflozin, we are forcing the kidney to excrete glucose, and producing a difference in glucose between the renal artery and the renal vein. It could possibly be that the brain is detecting the difference, and acting directly on the liver to compensate. For example, someone with normal glucose tolerance would be at the immediate risk of hypoglycemia. The brain has to react in order to prevent hypoglycemia. This compensatory response is problematic in people with type 2 diabetes, as they are already hyperglycemic.

 

LX4211, a Dual SGLT-1/SGLT-2 Inhibitor, Decreases Body Weight and Triglycerides in Patients with Type 2 Diabetes Mellitus and Elevated Baseline Values (243-OR)

Brian Zambrowicz, PhD (Lexicon Pharmaceuticals, The Woodlands, TX)

In this 12-week dose-ranging study (n=299), patients with inadequately controlled type 2 diabetes taking metformin were assigned to receive placebo or one of four doses of LX4211 – 75 mg QD, 200 mg QD, 200 mg BID, or 400 mg QD. Patients in the study were 18-75 years of age, had BMI ≤45 kg/m², and A1c between 7.0-10.5%; at baseline, patients were on average 56 years old, with A1c of 8.1%, BMI of 33 kg/m², and blood pressure of 125/79 mmHg. In the subgroup of patients with BMI ≥30 kg/m² at baseline, patients in the 75 mg QD, 200 mg QD, 200 mg QID, and 400 mg QD LX4211 lost an average 0.9 kg (2.0 lb), 1.8 kg (4.1 lbs), 2.9 kg (6.4 lbs), and 2.0 kg (4.3 lbs), while patients on placebo lost an average 0.4 kg (1.0 lb) (the 200 mg QD, 200 mg BID, and 400 mg QD were statistically significant versus placebo [p<0.001]). In the subgroup of patients with elevated triglycerides (200-500 mg/dl) at baseline, LX4211 treatment resulted in significant reductions from baseline in the 75 mg QD, 200 mg QD, and 400 mg QD arms (67.6 mg/dl, 49.0 mg/dl, and 81.8 mg/dl, respectively; p<0.05). Side effects appeared balanced with placebo; there were no major increases in GI side effects such as diarrhea, nausea, vomiting, and constipation beyond placebo. For the trial’s A1c-lowering efficacy results, please see our AHA coverage at http://close.cx/AHA2012Day4.

Questions and Answers

Q: In your study, there were relatively fewer mycotic infections with your dual SGLT-1/SGLT-2 inhibitor than with SGLT-2 alone. Can you explain the reason behind that?

A: One of the things I did mention was that LX4211 had relatively low urinary glucose excretion. I think there is a mechanistic reason for that. The amount of glucose you’re going to spill is dependent on how well you inhibit SGLT-2, but you also have to look at how much blood glucose can be filtered. SGLT-1 addresses mainly postprandial glucose. If you lower postprandial glucose all meals of the day, there is less glucose to filter in the blood. The maximum glucose excretion we’ve seen in trials is 45 grams in a day with LX4211, whereas [other SGLT-2 inhibitors had maximum glucose excretion of 60-70 grams] over 24 hours.

Q: Can you elaborate on what happened to LDL? Triglycerides went down, but what happened to LDL, and how does it compare to SGLT-2 inhibitors?

A: There was no significant increase from baseline; however, I would say there’s probably a trend there. The increase is quite small. It may become significant in larger studies. I would say that the effect is clearly SGLT-2 dependent. Though we don’t understand why, we think it may be related to the level of urinary glucose excretion as well.

Q: Did you look at leptin levels in the study?

A: Not in this study. But, we are planning to look at that. There’s a cascade, because short-chain fatty acids are absorbed fermentation of glucose in the colon, and when they reach the bloodstream they can trigger the release of leptin.

 

Combined HbA1c and Weight Reduction is Achieved More Frequently with Add-On Dapagliflozin than Add-On Glipizide in Patients with Type 2 Diabetes Inadequately Controlled on Metformin (236-OR)

Katja Rohwedder, MD (AstraZeneca, Cambridge, UK)

Dr. Katja Rohwedder discussed a post-hoc analysis of a 52-week non-inferiority trial comparing dapagliflozin (2.5-10 mg/day) to glipizide (5-20 mg/day) as adjuncts to metformin (≥1,500 mg/day) in ~800 type 2 patients (at baseline, mean age of 58-59 years, diabetes duration of 6-7 years, weight of 88 kg [194 lbs], and A1c of 7.7%). At 52 weeks, 78% of participants remained in the study and drop-out rates were comparable between the two treatment groups. The two drugs provided the same A1c reduction (0.52%); furthermore, a similar percentage of participants in each arm experienced an improvement in A1c (75% with dapagliflozin vs. 74% with glipizide). Not surprisingly, more patients on dapagliflozin exhibited weight loss (83%) than those on glipizide (27%). An A1c reduction coupled with weight loss was observed in 67% of the dapagliflozin group vs. 21% of the glipizide group (difference of 46 percentage points; 95% CI: 39-52); furthermore, 31% of those on dapagliflozin achieved an A1c reduction ≥0.5% with a weight loss ≥3 kg (7 lbs), compared to only 4% of those on glipizide (difference of 27 percentage points; 95% CI: 22-32). While response to drug therapy did not differ by baseline weight, disease duration, or gender, the patients who achieved A1c reductions ≥0.5% had higher A1c levels at baseline (this is consistent with previous studies). Regarding safety data, dapagliflozin was associated with less hypoglycemia compared to glipizide; however, both urinary tract infections and genital infections were more commonly observed with dapagliflozin, though Dr. Rohwedder commented that these events rarely led to study discontinuation.

Efficacy Data
Drug	A1c Reduction	Weight Reduction	Both A1c & Weight Reduction	A1c Reduction >0.5% & Weight Reduction >3 kg (7 lbs)
Dapagliflozin	74.7%	83.4%	66.9%	30.8%
Glipizide	73.8%	26.8%	21.3%	3.8%
Safety Data
Drug	No Hypoglycemia	Genital Infections	Urinary Tract Infections
Dapagliflozin	96.4%	10.8%	8.6%
Glipizide	59.6%	1.7%	5.4%

 

Questions and Answers

All questions were asked by the session moderator, Dr. Ralph DeFronzo.

Q: Is it time to get rid of SFUs and go to drugs that really work without causing safety issues?

A: I hope so.

Q: Did you look at glucose excretion in the urine and was it related to weight loss in either group?

A: No, we haven’t looked at that specific analysis.

Q: Did you measure insulin levels, since insulin is related to weight gain and hypoglycemia?

A: We have the information on fasting insulin levels and we have done OGTTs in a subgroup of patients, but we haven’t looked at the specific correlation. It’s a good idea.

Q: What was the definition of hypoglycemia and severe hypoglycemia?

A: Major hypoglycemia episodes were defined as less than 3 mmol/l (54 mg/dl) or if the investigator saw symptoms. It was only reported in the glipizide arm, in three patients. In general, every blood glucose measurement below 3.5 mmol (63 mg/dl) was considered hypoglycemia. Investigators could also report cases of hypoglycemia if they saw symptoms.

Comment: I would say this is a pretty clear-cut distinction between oral agents in terms of weight gain, an important side effect that we’re all concerned with in diabetes.

 

Canagliflozin (CANA) Compared With Sitagliptin (SITA) in Subjects With Type 2 Diabetes Mellitus (T2DM) on Metformin (MET) Over 52 Weeks (238-OR)

Fernando Lavalle González, MD (Universidad Autonoma de Nuevo Leon, Nuevo Leon, Mexico)

Dr. Fernando Lavalle González presented data showing that canagliflozin provided greater reductions in A1c and in weight compared to sitagliptin. The 52-week study randomized 1,294 type 2 patients to canagliflozin 300 mg, canagliflozin 100 mg, sitagliptin 100 mg, or placebo (2:2:2:1 ratio). After 26 weeks, those assigned to placebo were switched to sitagliptin 100 mg (PBO/sita group). The modified intent-to-treat analysis showed that at 52 weeks, canagliflozin 300 mg provided a larger A1c reduction (-0.88%) than canagliflozin 100 mg and sitagliptin (-0.73% for both). Greater improvements in fasting plasma glucose were also observed with canagliflozin 300 mg (-35 mg/dl) and 100 mg (-26 mg/dl) compared to sitagliptin (-18 mg/dl; p<0.001 for both comparisons). As expected, the weight loss observed with canagliflozin 300 mg (4.2%; 3.7 kg [8.1 lbs]) and 100 mg (3.8%; 3.3 kg [7.3 lbs]) was significantly more than that observed with sitagliptin (1.3%; 1.2 kg [2.6 lbs]; p<0.001 for both comparisons). Canagliflozin was associated with reductions in blood pressure, as well as elevations in LDL and HDL cholesterol. On the safety front, canagliflozin was associated with a higher rate of genetic mycotic infections compared to sitagliptin and PBO/sita, as well as a higher rate of osmotic diuresis, though Dr. González noted that these events led to few study discontinuations. Interestingly, the incidence of documented hypoglycemia was higher with both doses of canagliflozin (6.8%) compared to sitagliptin (4.1%) and PBO/sita (2.7%). 

• Canagliflozin was associated with reductions in blood pressure, as well as elevations in HDL and LDL cholesterol (data in table below). Dr. González mentioned during Q&A that the rise in HDL-C was unexpected.

	Δ LDL cholesterol	Comparison to SITA              (percentage points)	Δ HDL cholesterol	Comparison to SITA (percentage points)
CANA 300 mg	8.8% (4.4 mg/dl)	2.8 (95% CI: -1.8, 7.4)	13.2% (5.5 mg/dl)	7.2 (95% CI: 4.4, 10.0)
CANA 100 mg	7.7% (4.3 mg/dl)	1.7 (95% CI: -2.8, 6.2)	11.2% (4.5 mg/dl)	5.2 (95% CI: 2.5, 7.9)
SITA 100 mg	6% (3.1 mg/dl)	------	6% (2.4 mg/dl)	------
	Δ Systolic Blood  Pressure	Comparison to SITA	Diastolic Blood Pressure	Comparison to SITA
CANA 300 mg	-4.7 mmHg	-4.0 mmHg p<0.001	-0.3 mmHg	------
CANA 100 mg	-3.5 mmHg	-2.9 mmHg  p<0.001	-1.8 mmHg	------
SITA 100 mg	-0.7 mmHg	------	-1.8 mmHg	------

 

• While the rates of adverse events (AE) were comparable between the groups, canagliflozin was associated with higher rates of genital infections and hypoglycemia:

	PBO/SITA	SITA 100 mg	CANA 100 mg	CANA 300 mg
Any adverse event	66.7%	64.5%	72.3%	62.7%
Serious adverse event	3.8%	4.9%	4.1%	3.3%
Urinary tract infection	6.6%	6.3%	7.9%	4.9%
Genital infection (M)	1.1%	1.2%	5.2%	2.4%
Genital infection (F)	1.1%	2.6%	11.3%	9.9%
Osmotic diuresis-related adverse events	0.5%	1.9%	8.2%	4.4%
Hypoglycemia	2.7%	4.1%	6.8%	6.8%
Severe hypoglycemia	0%	0.3%	0.3%	0%

 

Questions and Answers

Q: Can you comment on the drop in blood pressure? It looks to me like the drop in blood pressure comes fairly quickly  and the drop in weight comes later. Maybe the weight plays some role in sustaining the drop in blood pressure. Can you comment on the early blood pressure drop?

A: In other studies on blood pressure, half of the drop in blood pressure can be related to losing weight. The other half is a direct effect of ACE inhibition and other mechanisms of the drug.

Comment: In the first three to four days, you get a negative salt and water balance. And this may be playing an important role in the initial drop in blood pressure.

Q: It was a nice surprise for me to see the increase in HDL cholesterol. Do you have any idea why this elevation occurred?

A: It’s an observation seen during the study. There are some comments about this in people who use diuretics. There are some comments from nephrologists saying that this kind of HDL and LDL pattern is seen in people using diuretics. This is an observation and you can see that there is not a relation to the mechanism of action of the drugs.

Q: Have you found an explanation for why the higher canagliflozin dose had less of an effect than the lower dose?

A: No, not really.

Q: Are there any particular side effects of canagliflozin that you found to be part distributing?

A: No, you usually see genital mycotic infections, which are treated rapidly and resolve in patients. We didn’t see any safety concern

Comment: It’s very commonly stated that this class is associated with an increase in urinary tract infections. If you look at the data rather than what’s said, this opinion doesn’t hold up. And you saw this today. At the lower dose, there was a little rise in UTIs, but it was not statistically significant. At the higher dose, there was no increase. I bet that if you combine the two doses, you wont’ see a statistically significant increase.

Q: I was surprised by the LDL cholesterol levels with the sitagliptin group. 

A: This was unexpected but you can see that it’s a small rise, just 6%. This is what we obtained in the study.

Comment: Across studies with canagliflozin, the rise in LDL with canagliflozin 100 mg is 4 mg/dl. It’s 8 mg/dl with canagliflozin 300 mg. If you’re truly treating you patient to goal and their LDL level is 70 mg/dl, the worst case scenario is that you’re going from 70 to 78 mg/dl and most HCPs wouldn’t even increase the dose of statin.

A: Yes, the increase is very small. It’s no more than four to six mg/dl.

 

Posters

Exploring the Potential of Dapagliflozin in Type 1 Diabetes: Phase 2a Pilot Study (70-LB)

Robert Henry, Julio Rosenstock, Alexandros-Georgios Chalamandaris, Sreeneeranj Kasichayanula, Allyson Bogle, and Seven Griffen

This double-blind phase 2a study evaluated the short-term safety, tolerability, and pharmacokinetics and pharmacodynamics (PK/PD) of dapagliflozin (BMS/AZ’s Forxiga) after two-weeks as an add-on to insulin in 70 patients with type 1 diabetes. These are the first clinical results we have seen for an SGLT-2 inhibitor in type 1 diabetes. Patients on insulin (mean baseline A1c 8.5%) were randomized to receive dapagliflozin (1 mg, 2.5 mg, 5 mg, or 10 mg) or placebo once-daily for two weeks. Treatment resulted in a reduction in total daily insulin requirement (-19% on the 5 mg and -16% on the 10 mg doses) while also producing a trend toward reduced glucose levels and reduced glycemic variability (both measured by CGM): mean 24-hour glucose decreased by ~10-20 mg/dl relative to placebo on dapagliflozin 5 mg and 10 mg (no decrease was observed relative to placebo for the lower doses), and placebo-adjusted MAGE decreased by ~50-60 mg/dl on those same doses. Hypoglycemia appeared slightly elevated in the treatment groups compared to placebo, though there was no dose-dependent effect (i.e., the highest rate was observed in the 1 mg group; in contrast, there was a clear dose-dependent urinary glucose excretion effect). As elated conference attendees with type 1 diabetes expressed during the poster session, these findings (though preliminary) are exciting because of the possibility of increasing treatment options for a population challenged by a deficiency of therapies. However, the findings of this study, while encouraging, are very limited due to sample size and would be considered pilot data for larger and longer trials testing dapagliflozin (which Dr. Henry was confident will be underway in the near future).

• Seventy patients (62 completed trial) with inadequately controlled type 1 diabetes were randomized to receive daily doses for 14 days of placebo or dapagliflozin (1, 2.5, 5, or 10 mg) in addition to their insulin regimen. Baseline characteristics across all treatment arms were comparable and included a mean A1c of 8.5%, BMI of 25 kg/m², and age of 35. The mean duration of type 1 diabetes ranged from 16-22 years across all groups. The primary objective was to assess the safety and tolerability of dapagliflozin after 14 days. Secondary objectives included change from baseline to day seven in 7-point monitoring profiles and pharmacokinetics. Exploratory objectives consisted of change from baseline at seven days in 24-hour CGM profiles, total daily insulin dosing (%), fasting plasma glucose (FPG), and 24-hour urine glucose output.
• Dapagliflozin appeared to improve glycemic control and diminish glycemic variability while also decreasing total daily insulin requirement. FPG levels were significantly lowered in the treatment arms compared to placebo (-26, -20, -42, -36 vs. -8 mg/dl for the 1, 2.5, 5, and 10 mg doses vs. placebo, respectively). CGM data suggested a dose-dependent improvement in glycemic control through a decrease in 24-hour average glucose levels relative to baseline (-16, -14, -30, and -41 mg/dl for the 1, 2.5, 5, and 10 mg doses of dapagliflozin, respectively, compared to -20 mg/dl in placebo). There was also a significant reduction in total daily insulin needs (-16, -11, -19, and -16 units for the 1, 2.5, 5, and 10 mg doses, respectively, compared to +2 units in placebo).
• Despite a dose-dependent increase in urine glucose from baseline to day seven (41.9, 48.5, 72.4 and 88.8 g/24 h for the 1, 2.5, 5 and 10 mg doses, respectively and-21.6 g/24 h on placebo), there was no dose-dependent effect on hypoglycemia. The percentage of patients that experienced hypoglycemia was 62% for the placebo group and 92%, 60%, 79% and 67% for the dapagliflozin 1, 2.5, 5 and 10 mg groups, respectively. There were no apparent effects of dapagliflozin on urine output, total fluid output, or fluid intake.
• Genitourinary events, such as genital and urinary tract infections, were rare. One such event was recorded in the placebo arm, one each in the dapagliflozin 1 mg, 2.5 mg, and 5 mg arms, and zero in the 10 mg arm. Dr. Henry mentioned that, in his opinion, the rate of hypoglycemia was the greatest potential safety concern in the use of dapagliflozin.
• Treatment with dapagliflozin appears to have a neutral to slightly positive effect on body weight, though the short duration of the study may be the cause of this meager outcome.

 

The Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitor Empagliflozin Improves Glycemic Control in Patients with Type 1 Diabetes: A Single-ARm Clinical Trial (1074-P)

Bruce Perkins, David Cherney, Helen Partridge, Nima Soleymanlou, Holly Tschirhart, Bernard Zinman, Nora Fagan, Sefan Kaspers, Hans-Juergen Woerle, Uli Broedi, and Odd Johansen

One the earliest clinical trials investigating use of a SGLT-2 inhibitor in type 1 diabetes, this single-arm open-label pilot study explored the effects of empagliflozin on glycemic control and rates of hypoglycemia in 42 patients with type 1 diabetes receiving optimized standard care. Results of the eight-week treatment period were compared to a baseline two-week placebo run-in period that preceded empagliflozin initiation. Treatment with 25 mg/day of empagliflozin resulted in a decline in total daily insulin requirement (from 54.7 ± 20.4 units/day to 45.8 ± 18.8), as well as a reduction in glucose levels (mean A1c decreased by 0.4% from a baseline A1c of 8.0%). Empagliflozin also lowered rates of symptomatic hypoglycemia from 0.12 to 0.04 episodes a day. Overall, empagliflozin as an adjunct to intensive insulin therapy was associated with short-term improvements in glucose levels as well as reductions in daily insulin need, body weight, hypoglycemia, perceived hyperglycemia, and perceived hypoglycemia. These preliminary findings are exciting because of the potential to improve and diversify therapy options for patients with type 1 diabetes. We look forward to hearing the results of randomized clinical trials that further attest to the safety and efficacy of this treatment.

• Forty-two subjects (forty completed trial) with type 1 diabetes, on an intensive basal-bolus insulin regime, and without any clinically notable complications in the past year were treated with empagliflozin 25 mg once daily. The efficacy, safety, and tolerability of eight weeks of this therapy were compared to a baseline two-week placebo run-in period. At baseline, the participants had a mean age of 24.3 ± 5.1 years, BMI of 24.5 ± 3.2 kg/m², A1c of 8.0 ± 0.9%, and fasting plasma glucose (FPG) of 180.0 ± 86.4 mg/dl.
• Empagliflozin substantially improved short-term glycemic control and reduced daily insulin needs. Mean A1c decreased by 0.4% from baseline to 7.6 ± 0.9% (p<0.0001). FGP decreased numerically as well, though the change was not statistically significant. With regards to insulin administration, total daily insulin requirements dropped from 54.7 ± 20.4 units during the placebo run-in period to 45.8 ± 18.8 after the eight-week treatment period (p<0.0001). Further analysis showed that while bolus insulin needs did not change with empagliflozin therapy, daily basal insulin doses decreased from 25.7 ± 10.6 units at baseline to 19.5 ± 7.9 units after eight weeks of empagliflozin treatment (p<0.0001).
• As an add-on to insulin therapy, empagliflozin was associated with a decline in rates of hypoglycemia. Incidences of symptomatic hypoglycemia (defined as <54 mg/dl) were reduced from 0.12 to 0.04 events per day (p=0.0047). The participants also completed a diabetes treatment satisfaction questionnaire that found a reduction in perceived hyperglycemia and hypoglycemia (p<0.05 for both).
• Empagliflozin treatment appeared to cause a reduction in body weight. At the end of eight weeks, participants experienced a weight loss of 2.7 kg (6.0 lbs) to 70.0 ± 12.3 kg (154 lbs; p<0.0001). In addition, waist circumference decreased by 3.8 cm to 79.1 ± 8.0 cm (p<0.0001).
• Regarding non-hypoglycemia adverse events, the following were reported by at least 5% of the study cohort: polyuria (79%), thirst (74%), nasopharyngitis (26%), headache (24%), dry mouth (17%), nausea (17%), genitourinary tract infection (14%), dizziness (14%), vomiting (14%), abdominal pain (12%), influenza-like illness (10%), and back pain (10%). The mean urinary glucose excretion increased significantly with empagliflozin from 19 ± 19 g/day at baseline to 124 ± 61 g/day at treatment completion. Two participants discontinued the study after early occurrence of diabetic ketoacidosis.

 

Empagliflozin Improves Glycemic Parameters and Cardiovascualr Risk Factors in Patients with Type 2 Diabetes (T2DM): Pooled Data from Four Pivotal Phase III Trials (69-LB)

Thomas Hach, John Gerich, Afshin Salsali, Gabriel Kim, Stefan Hantel, Hans-Juergen Woerle, and Uli Broedi

This study pooled data from four randomized phase 3 trials to investigate the effects of the SGLT-2 inhibitor empagliflozin on glycemic parameters, body weight, blood pressure (BP), lipid parameters, uric acid, and hypoglycemia in patients with type 2 diabetes. In the 24-weeks studies, a total of 2,477 participants were randomized to placebo or to empagliflozin once daily (10 or 25 mg) as monotherapy, add-on to metformin, add-on to metformin plus sulfonylurea, or add-on to pioglitazone ± metformin. Both empagliflozin doses resulted in improved glycemic control (mean A1c declined by 0.70% and 0.76% with empagliflozin 10 and 25 mg, respectively, compared to a 0.08% decline with placebo), and also significantly reduced body weight, systolic and diastolic BP, and uric acid levels. The drug had an overall small effect on lipids, with modest increases in LDL- and HDL-cholesterol and slight decreases in triglycerides. More patients in the empagliflozin treatment arms reported confirmed hypoglycemia relative to those in the placebo group, and these episodes appeared to have disproportionally occurred in patients on background metformin and sulfonylurea. These early results are promising on the whole, though more robust data on the effect of empagliflozin on cardiovascular events in patients with type 2 diabetes will hopefully emerge from the drug’s ongoing cardiovascular outcomes trial, EMPA-REG Outcome.

• A total of 2,477 type 2 patients were randomized to receive empagliflozin (10 or 25 mg/day) or placebo for 24 weeks as either: 1) monotherapy, 2) add-on to metformin, 3) add-on to metformin and sulfonylurea, or 4) add-on to pioglitazone ± metformin. Baseline characteristics were similar across treatment arms and included a mean age of 55.6 years, A1c of 7.99%, and BMI of 28.7 kg/m². Primary endpoints consisted of changes in cardiovascular biomarkers (systolic and diastolic blood pressure [BP], lipid parameters, uric acid, body weight) and glycemic parameters (change in A1c and in fasting plasma glucose [FPG] from baseline). 
• Empagliflozin treatment resulted in clinically meaningful improvements in glycemic control, with both the 10 and 25 mg doses providing significant reductions in A1c and FPG relative to placebo at week 24 (see table). Furthermore, the percentage of patients with a baseline A1c over  7.0% who lowered their A1c levels to less than 7.0% by the end of the trial was significantly greater in the empagliflozin groups than the placebo groups (31.5 and 37.2% for the 10 and 25 mg doses, respectively, vs. 10.5% for placebo).

*p<0.001 vs. placebo.

• Regarding cardiovascular biomarkers, empagliflozin treatment provided significant reductions in body weight, systolic and diastolic blood pressure, and uric acid, with slight trends toward increased HDL- and LDL-cholesterol and decreased triglyceride levels (only significant for 10 mg dose) vs. placebo. The small increase in total cholesterol was significant with the 25 mg dose of empagliflozin but not the 10 mg dose, suggesting that the drug has a small effect on lipids. In addition, the magnitude of decline in systolic and diastolic BP was much larger in subjects with uncontrolled BP at baseline (systolic ³ 130 mmHg or diastolic ³ 80 mmHg). The percentage of patients who achieved controlled BP (from uncontrolled at baseline) at week 24 was 33% and 32% for the 10 and 25 mg doses of empagliflozin, respectively, compared to 19% for placebo.

	Placebo	Empagliflozin 10 mg	Empagliflozin 25 mg
Body weight (kg) [lbs] Baseline (SE) Δ from baseline at week 24 (SE) Difference vs. placebo (95% CI)	78.03 (0.66) [172] -0.24 (0.09) [-0.5] --	78.77 (0.65) [174] -2.05 (0.09) [-4.5] -1.81 (-2.05, -1.57)* [-4.0]	79.10 (0.66) [174] -2.25 (0.09) [5.0] -2.01 (-2.25, -1.76)* [4.4]
Systolic BP (mmHg) Baseline (SE) Δ from baseline at week 24 (SE) Difference vs. placebo (95% CI)	128.6 (0.5) -0.5 (0.4) --	129.6 (0.5) -3.9 (0.4) -3.4 (-4.4, -2.3)*	129.0 (0.5) -4.3 (0.4) -3.8 (-4.9, -2.8)*
Diastolic BP (mmHg) Baseline (SE) Δ from baseline at week 24 (SE) Difference vs. placebo (95% CI)	78.0 (0.3) -0.6 (0.2) --	78.7 (0.3) -1.8 (0.2) -1.2 (-1.9, -0.5)*	78.3 (0.3) -2.0 (0.2) -1.5 (-2.0, -0.8)*
Total cholesterol (mmol/l) Baseline (SE) Δ from baseline at week 24 (SE)	4.70 (0.4) 0.04 (0.02)	4.67 (0.04) 0.11 (0.02)	4.70 (0.04)* 0.16 (0.02)*
Triglycerides (mmol/l) Baseline (SE) Δ from baseline at week 24 (SE)	1.86 (0.04) 0.03 (0.04)	1.95 (0.05) -0.11 (0.04)+	1.96 (0.07) -0.02 (0.04)
Uric acid (mmol/l) Baseline (SE) Δ from baseline at week 24 (SE)	321.44 (2.98) 1.03 (1.83)	321.81 (2.89) -28.95 (1.82)*	322.35 (2.96) -29.55 (1.83)*

*p<0.001, ⁺p<0.05, all vs. placebo.

Confirmed hypoglycemia was reported in 5.2% and 4.0% of patients receiving 10 and 25 mg doses of empagliflozin, respectively, vs. 2.9% of patients in the placebo group. None of the episodes of hypoglycemia required assistance. Most of the events were observed in patients on background metformin plus sulfonylurea (8.4%, 16.1%, and 11.5% on placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively – it was a little “random” that there was more hypoglycemia in the middle vs. high dose – we assume the hypoglycemia was due solely to the SFU and not empagliflozin as the SGLT classes are glycemic-dependent).

 

Product Theaters

A New Treatment Option for Type 2 Diabetes (Sponsored by Janssen Pharmaceuticals)

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

Dr. Vivian Fonseca addressed a standing-room only audience to present pooled data on J&J’s Invokana (canagliflozin)..He first reviewed the role of the kidneys in glucose homeostasis, highlighting Invokana’s mechanism of action as an SGLT-2 inhibitor: the drug lowers the renal threshold for glucose excretion (RT_G) in type 2 patients, causing increased urinary glucose excretion. Dr. Fonseca next presented pooled data on the drug as mono-, dual-, and triple-therapy, as well as in an elderly patients. All studies had a primary endpoint of A1c reduction, though Dr. Fonseca noted that in these studies, canagliflozin also reduced plasma glucose levels (both fasting and post-prandial), body weight, and systolic blood pressure, with low rates of hypoglycemia. Dr. Fonseca explained the safety concerns associated with canagliflozin, addressing rates of renal and urinary disorders, as well as increases in LDL-C; on this front, he asserted, “this drug is not going to be used in patients with renal impairment. It’s not going to work, so why use it?”

• Dr. Fonseca reviewed pooled data on the efficacy of canagliflozin, noting that the drug provided significant A1c reductions compared to placebo as both monotherapy and add-on therapy. In a study comparing canagliflozin monotherapy to placebo, canagliflozin 300 mg provided a 1.16% reduction in A1c over 26 weeks (A1c inclusion criteria: ≥7% to ≤10%; n=587). Regarding secondary endpoints, canagliflozin 300 mg was associated with a decrease in fasting plasma glucose of 43 mg/dl and a decrease in post-prandial glucose of 64 (baseline FPG: <270 mg/dl), in addition to a body weight reduction of 3.3% (placebo-adjusted) from a baseline of 192 lbs. Dr. Fonseca also mentioned a drop in systolic blood pressure, noting that the mechanism of this effect needs to be studied further. As add-on therapy, canagliflozin demonstrated greater A1c reductions across placebo-controlled studies where patients had a baseline of roughly 8%. Dr. Fonseca noted that improvements in A1c and weight loss also occurred in patients poorly-controlled on insulin and other oral agents (a group he acknowledged is difficult to manage), as well as in patients on pioglitazone (who are likely to gain weight). Dr. Fonseca emphasized that the incidence of hypoglycemia was generally low, though it increased when canagliflozin was evaluated in combination with insulin or an insulin secretagogue.
• Dr. Fonseca addressed the adverse events associated with canagliflozin, highlighting the increased rates of hyperkalemia, genital infections, and LDL-C levels. Hyperkalemia adverse reactions occurred in 0.7% of the broad study population receiving canagliflozin 300 mg (n=3,085) compared to 0.5% in the control group (n=3,282) – Dr. Fonseca attributed this observation to the fact that many of these patients are also on drugs that cause hyperkalemia. Dr. Fonseca explained that the prevalence of urinary tract infections was similar between the placebo and canagliflozin 300 mg groups (4.0% and 4.3%) in four placebo-controlled 26-week population studies, but that genital infections were more commonly seen with canagliflozin compared to placebo (11.4% vs. 3.2%, respectively). Dr. Fonseca stipulated that genital infections rarely reoccur and can be resolved with routine treatment. Turning to the observed elevated LDL-C levels, he admitted that the mechanism behind this effect is not known.
• Dr. Fonseca noted that canagliflozin is not recommended for patients with moderate renal impairment and mentioned that studies are ongoing to fully evaluate the drug’s effect on renal function. He explained that the canagliflozin’s mechanism of action relies on a normal glomerular filtration rate for maximal efficacy. Dr. Fonseca acknowledged the concerns about renal impairment, and noted that compared to patients with mild renal impairment or normal renal function, patients with moderate renal impairment (eGFR 30 to <50 ml/min/1.73 m²) experienced less glycemic efficacy, as well as a higher rates of adverse reactions related to reduced intravascular volume and decreased eGFR. , However, studies are ongoing and data has not been established in patients with severe renal impairment (eGFR <30 ml/min/1.73 m²) or end-stage renal disease. Dr. Fonseca concluded by emphasizing that renal function must be monitored in patients on canagliflozin.

 

Questions and Answers

Q: By using canagliflozin are you not altering the normal physiology?

A: Yes, to a great extent that is true, but remember that the renal threshold is actually higher in patients with type 2 diabetes. This is based on a small study, and recently, Dr. Ralph DeFronzo has done a study on renal threshold in Diabetes Care. It is an abnormality that represents a maladaptive process that you’re reversing to some degree. We’ve tried drugs that improve insulin sensitivity and they work, but not enough to overcome the problem of diabetes. I’m not saying that canagliflozin is going to do that, but it offers an adjunct to those therapies and it is doing it with a completely insulin-independent mechanism. 

Q: If you ingest more glucose, do you excrete more glucose?

A: The filtering of glucose is dependent on blood glucose levels. When you have more glucose in the blood, you have more excretion. So in fact, this is why it is even better in the post-prandial state than in the fasting state.

Q: What causes the increase in renal glucose threshold in diabetes?

A: I wish I knew. This is a maladaptive process. Any transport system tries to adapt when you overwork it. I don’t think it’s a fundamental defect of diabetes.

Q: In which patients would you use Invokana?

A: It’s been tested across the board. You choose your patients based on their characteristics and their needs.

Q: How long should I keep my patients on the 100 mg dose before moving to the 300 mg dose?

A: There’s actually very little data. There is a dose-response relationship. This not a drug that you titrate because of side effect issues; you titrated up to get the patient to goal. If your patient still has a higher fasting glucose level, you might want to go to the higher dose.

Q: How does sitagliptin compare to canagliflozin 100 mg?

A: That data is not available. The study was done with 300 mg. That is the max dose of both, so it’s a fair comparison.

Q: Can canagliflozin be used with all types of inulin?

A: Yes, it can.

Q: Why is there a weight loss plateau?

A: There are adaptive mechanisms to any weight loss therapy. Thank God, otherwise we would disappear. We really don’t know. This is not the primary reason why you’re using the drug. You’re using it for A1c reduction; everything else is a secondary endpoint.

Q: What side effects are most common?

A: Genital infections. When I first looked at the mechanism of action, I was concerned about urinary tract infections. But these are mycotic infections, so patients take an antifungal and they get over it. We need to explain this to our patients and get them back into the office for appropriate therapy. You may get a few patients where the infection reoccurs. This is not the medication for them.

Q: Of the patients who experience UTIs, how many are recurrent?

A: Recurrent infections were very low. If I saw patients with recurrent infections, I put them on a different medication

Q: Can it be used with other weight loss therapies such as Belviq (Arena/Eisai’s lorcaserin)?

A: It hasn’t been done; however, I’m sure the combination studies will be done in clinical practice, and it will be studied further.

Q: How can we prevent genital mycotic infections?

A: This has not been looked at, but we need to. They might need to drink more fluids or practice more hygiene as a precaution. I hope they will address this over time.

Q: Does it increase nocturia (the need to urinate at night)?

A: I showed you some reported increases in urination, so you might get some patients where this happens overnight.

Q: Can it be used in patients who are taking diuretics?

A: Dehydration occurs most in patients with diuretics. These patients are on hypertensives and need to be monitored for dehydration.

Q: What was the rate of dropout from the studies?

A: I showed you, and it was remarkably low.

Q: Does blocking the SGLT work in other systems like the GI tract?

A: This is an important point to clarify. SGLT-1 is prominent in the gut, while SGLT-2 is prominent in the kidney. SGLT-1 is also present in the kidney, but more distally. A long time ago, a drug called phlorizin was evaluated for type 2 diabetes and was shown to improve insulin sensitivity in rats. We wanted to try it in humans but there were a lot of GI side effects, because when you block SGLT-1 in the gut, you end up with a lot of glucose in the large bowel. This is why SGLT-2 inhibitors have been developed. It is very specific, and it doesn’t block the SGLT-1 co-transporter.

Q: Why do you get the side effect of increased LDL-C?

A: I can’t explain that. This clearly needs more investigation. You need to watch for it, and treat it appropriately.

Q: What do we know about the drug’s effects on the kidney in the short term and the long term?

A: There is a small drop of about 2 or 3 in eGFR when you first start treatment, which flattens out and stays down for the duration of the drug treatment. Long term, we don’t know. This will be monitored in the CVOT (CANVAS). I don’t think the drug is going to be used in patients with renal impairment; it’s not going to work, so why use it?

Q: Any fear of malignancy?

A: Dapagliflozin did have an excess of bladder and breast cancer that was small and unexplained, and that held up approval of dapagliflozin. It was not shown in canagliflozin, which is why it was improved.

Q: Any difficulty in subjects with solitary kidney?

A: This floored me. People with solitary kidney have the same renal function as someone with two kidneys.

 

Exposing Sodium Glucose Co-Transporters: A Hidden Contributor to Persistent Hyperglycemia in Type 2 Diabetes (Sponsored by BI and Lilly)

James Gavin, MD, PhD (Emory University, Atlanta, GA)

Dr. James Gavin attracted a standing-room only crowd for his presentation on the role of glucose co-transporters in the kidney in glycemic homeostasis and the implications for type 2 diabetes. Projecting over the noise of the exhibit hall, Dr. Gavin reviewed the physiological mechanisms behind plasma glucose level regulation, highlighting the kidney as a major player in this process, where normally, 162 g of glucose is filtered and reabsorbed per day until a threshold level is reached (180 mg/dl), when excess glucose is removed by glycosuria. Dr. Gavin emphasized the danger in persistent hyperglycemia, which he stated could cause impaired beta-cell function and decreased insulin sensitivity. He explained that in patients with type 2 diabetes, renal glucose reabsorption increases due to overexpression of SGLT-2, causing the threshold for glucose excretion to increase. Dr. Gavin provided data on the increase in glucose excretion in animal models of type 2 diabetes after treatment with the SGLT inhibitor phlorizin, and an overview of SGLT-2 mutations in patients who experience decreased renal glucose absorption and increased glycosuria without adverse effects. Dr. Gavin concluded by expressing excitement over “a new set of therapeutic possibilities.”

Questions and Answers

Q: When you experience glycosuria, this comes with a loss of calories. If you calculate this, it comes out to a calorie loss of 100,000 calories a year. This is 11-12 kilograms a year, but when we look at new products, we only see a loss of two to three kilograms. Can you comment on that?

A: I can’t tell you what the physiologic answer is. There likely is some form of adaption that occurs. One of the reasons why we don’t expect that kind of weight loss is when we go back to the experience of familial renal glycosuria patients. They don’t become wasted away, and they don’t lose enormous amounts of weight as a result of glycosuria, so clearly there is some adaption that occurs. Having said that, it is still a benefit to this approach to therapy that calorie loss does result in another one of the benefits that we like to see in the vast majority of patients with type 2 diabetes.

 

Corporate Symposium: Scientific Horizons in Diabetes Management – The Emerging Role of the Kidney as a Target for Therapy (Supported by Janssen)

SGLT-2 Inhibition: Rationale, Considerations, and Implications for Therapy

George Bakris, MD (University of Chicago, Chicago, IL)

Dr. George Bakris reviewed the physiology behind the role of the kidney in the regulation of blood glucose, and its implications in patients with diabetes. The kidney contributes to gluconeogenesis, and also is involved in glucose reabsorption through sodium glucose co-transporters 1 and 2 (SGLT-1 and SGLT-2), which account for 10% and 90% of tubular reabsorption, respectively. He outlined the major differences between the two co-transporters, noting that SGLT-1 is mostly found in the intestine with some expression in the kidney, and has a high affinity (Km=0.4 mM) for glucose and a low capacity for its transport, whereas SGLT-2 is found almost exclusively in the kidney, and has a low affinity (Km=2 mM) for glucose, but a high capacity for transport. Because of its location, inhibiting SGLT-1 may cause significant GI side effects. Dr. Bakris discussed the rationale behind SGLT-2 inhibition to combat hyperglycemia in patients with diabetes, noting that it helps to lower the renal threshold for glucose excretion, effectively allowing for patients to urinate excess glucose. In addition, Dr. Bakris highlighted that SGLT-2 inhibition can reduce fasting plasma glucose and improve hyperglycemia even in the absence of substantial amounts of insulin (Rosetti et al., J. Clin Invest 1987). 

 

Current Approaches to Glycemic Treatment in Stage 3-4 CKD

Mark Molitch, MD (Northwestern University, Chicago, IL)

After defining the stages of chronic kidney disease (CKD), Dr. Mark Molitch systematically reviewed current recommendations for oral agent use in patients with type 2 diabetes and CKD. In addition, he highlighted that both insulin sensitivity and insulin clearance are decreased in patients with progressive declines in glomerular filtration rate (GFR), so special considerations should also be taken for insulin users. In a prospective trial of insulin-using patients with type 2 diabetes with eGFR <45 ml/min/1.73 m² (n=107), halving the insulin dose numerically reduced the incidence of hypoglycemia while maintaining glycemic control within the 100-180 mg/dl range a comparable proportion of the time (Baldwin et al., Diabetes Care 2012). 

• Sulfonylureas: Dr. Molitch noted that glyburide clearance is not affected, but renal clearance of its metabolites is reduced with CKD. As such, the risk of hypoglycemia is very high for those with CKD; glyburide should not be used in patients with estimated GFR (eGFR) <60 ml/min/1.73 m². Similarly, glimepiride clearance is not affected, but renal clearance of its metabolites is reduced with CKD. The risk of hypoglycemia is increased (though not nearly as high as with glyburide), so glimepiride should be used with caution in patients with eGFR <60 ml/min/1.73 m² and avoided in patients with eGFR <30 ml/min/1.73 m². Finally, glipizide should be used with caution in patients with eGFR <30 ml/min/1.73 m², even though less than 10% of glipizide is renally cleared.
• Metformin: Dr. Molitch commented that the current FDA package insert recommendation against use of metformin for individuals with serum creatinine levels above 1.4 mg/dl (female) or 1.5 mg/dl (male) seems too conservative. Moving forward, he thinks it would make sense: 1) to have no limitations on dosing for individuals with eGFR ≥60 ml/min/1.73 m²; 2) to proceed with caution dosing patients with eGFR ≥45 and <60 ml/min/1.73 m², and monitor eGFR every three-to-six months; 3) to cap dosing at 1,000 mg/day for patients with eGFR ≥30 and <45 ml/min/1.73 m², and monitor eGFR every three-to-four months; and 4) to stop metformin for patients with eGFR <30 ml/min/1.73 m². Meanwhile, metformin should be stopped for inpatients if they are unstable, hypotensive, hypoxic, septic, or have acute worsening of renal function (Lipska et al., Diabetes Care 2011; KDIGO Controversies, in preparation). 
• Thiazolidinediones: Clearance of pioglitazone is not affected by kidney function; no dose reduction is needed in CKD.
• Incretins: It is recommended for patients with eGFR <30 ml/min/1.73 m² to discontinue exenatide therapy. Meanwhile, no dose adjustments for liraglutide are necessary for progressing CKD. As for DPP-4 inhibitors, dose adjustments are recommended for sitagliptin, saxagliptin, and alogliptin for patients with eGFR <50 ml/min/1.73 m², but no dose adjustments are required for linagliptin as it is not renally cleared. 
• SGLT-2 inhibitors: SGLT-2 inhibitors are less effective with eGFR <60 ml/min/1.73 m², and those with eGFR <45 ml/min/1.73 m² could potentially experience more adverse effects (e.g., volume loss, hyperkalemia). For eGFR <60 ml/min/1.73 m², canagliflozin should be kept at the 100 mg/day dose, and the higher 300 mg/day dose should be avoided. Canagliflozin is not currently approved for use with eGFR <45 ml/min/1.73 m².

 

New Directions and Revolutionary Approaches: The Potential Role of SGLT-2 Inhibitors in Therapy

Zachary Bloomgarden, MD (Mount Sinai Medical Center, New York, NY)

Following a high-level review of the ADA/EASD position statement and the AACE glycemic control algorithm, Dr. Zachary Bloomgarden discussed the benefits and potential safety concerns of drugs in the SGLT-2 inhibitor class. He emphasized that SGLT-2 inhibitors could be a useful addition to the treatment armamentarium, as they bring about improvements in glycemic control with low risk of hypoglycemia, cause modest weight loss, and have a unique mechanism that does not promote increased endogenous insulin secretion. Overall, Dr. Bloomgarden provided a thoughtful and balanced review of the SGLT-2 inhibitor class, along with helpful advice for clinicians to select appropriate patients who would be less likely to experience adverse effects when taking an SGLT-2 inhibitor.

• Dr. Bloomgarden highlighted a number of benefits of SGLT-2 inhibitors, including weight loss, low hypoglycemia risk, and blood pressure lowering. In addition, he posited that SGLT-2 inhibitors could be a good complementary therapy to TZDs, given the incremental reductions in A1c and fasting plasma glucose dapagliflozin provided when added to pioglitazone in a 48-week trial, and the attenuation of weight gain conferred (Rosenstock et al., Diabetes Care 2012). Regarding canagliflozin, he stated that reductions in both A1c and weight appeared to be dose dependent when added to metformin (Rosenstock et al., Diabetes Care 2012). After briefly touching on empagliflozin (as the agent with the highest selectivity for SGLT-2 versus SGLT-1) and ipragliflozin (which brings about similar weight loss across doses), Dr. Bloomgarden discussed Lexicon’s dual SGLT-1/SGLT-2 inhibitor LX4211, noting that a recent phase 2 study documented increases in GLP-1 and PYY following its administration (Zambrowicz et al., Clin Pharmacol Ther 2012). He speculated that it could be possible for SGLT-2 inhibitors to have some action on SGLT-1 receptors in the GI tract, noting that canagliflozin was shown to decrease gut glucose absorption (Polidori et al., Diabetes Care 2013); however, GLP-1 and PYY were not measured in the study. 
• He discussed potential safety concerns of SGLT-2 inhibitors, including genitourinary tract infections, carcinogenicity, volume depletion, and hyperlipidemia. Dr. Bloomgarden noted that vulvovaginal candidiasis occurred more frequently with canagliflozin treatment versus comparator (Nyirjesy et al., Curr Med Res Opin 2012), and there appeared to be an increased frequency of urinary tract infections (Nicolle et al., Curr Med Res Opin 2012), although the data are less clear. He noted that questions remain regarding dapagliflozin’s potential cancer signal, that is, whether the results were a statistical fluke, a class effect, or specific to dapagliflozin; unfortunately, RCTs are simply impractical to assess these very low frequency events. Subsequently, he stated that there is thus far no evidence of carcinogenicity of canagliflozin treatment in humans. Dr. Bloomgarden pointed out that canagliflozin treatment can cause volume depletion, and as such, clinicians should be cautious when prescribing the drug to the elderly, patients on diuretics, renally impaired individuals, and those with low blood pressure. He stated that it does appear that LDL cholesterol increases 5-10 mg/dl with canagliflozin treatment; he does not know how much this may occur with other SGLT-2 inhibitors. Finally, given the significant increase in CV events observed during the first 30 days of the CANVAS CV outcomes trial with canagliflozin treatment, Dr. Bloomgarden suggested clinicians to be cautious when initiating high-risk patients on canagliflozin.

 

Panel Discussion

Zachary Bloomgarden, MD (Mount Sinai Medical Center, New York, NY); George Bakris, MD (University of Chicago, Chicago, IL); Mark Molitch, MD (Northwestern University, Chicago, IL)

Q: If familial renal glucosuria is so rare, how do we know these people don’t carry another mutation, that there aren’t compensations for the deficit in glucose reabsorption? Is this a valid argument for the increase in glucose reabsorption?

Dr. Bakris: The fact is that these are very rare cases. I’m unaware of a full genetic analysis, I think it’s simply an observation that these patients have an absence of glucose reabsorption indicated by higher urinary glucose excretion. We don’t know if there is some compensatory effect. That’s why I hate genetic animal models, because there are compensatory mechanisms. I think we’re just going to have to accept it the way it is.

Q: What role do you see for SGLT-2 inhibitors in the treatment of type 1 diabetes?

Dr. Bloomgarden: The interesting thing is that the prevalence of insulin resistance is roughly 25% in the overall population, and roughly 25% among people with type 1 diabetes. This whole concept of dual diabetes is really important. There is a very significant subset of individuals with type 1 diabetes who have features of both type 1 and type 2 diabetes and are often the most difficult to treat for whom metformin may be useful, and maybe SGLT-2 inhibition might also be beneficial. I wouldn’t jump on using SGLT-2 inhibitors as a treatment across the board, but there may be an important subset for which it does matter.

Dr. Molitch: In studies in patients with type 2 diabetes, the use of SGLT-2 inhibitors with insulin was effective, so there’s no reason to think they wouldn’t be effective in type 1 diabetes, but we don’t have any studies with that data.

Q: What do you think will be the clinical effect of the increased genital infections? Will endocrinologists have to do pelvic exams? And are there studies with GLP-1 and PYY measured during the trials?

Dr. Bloomgarden: I haven’t come across any studies as far as this question of fungal infections. I think that we have some pretty effective standard treatments for symptomatic genital fungal infection, and I don’t think there’s anything that has to be done other than letting women know in advance that this is a potential side effect, and offering one or another appropriate treatments when women develop symptoms. We need more studies.

Dr. Molitch: I’ve started the medication in several patients. You have to talk to the patients, and if it’s a woman you ask, “Have you had multiple vaginal infections in the last several years?” If they only had one 20 years ago instead of multiple in the past few years, then that’s the patient to start it on. The data from some of these studies suggest that if you do develop one infection and you treat it, it rarely recurs. In patients that have reoccurrence, you stop. Uncircumcised men tend to get infections more often, so extra hygiene might be necessary to avoid the risk.

Q: What were the issues that caused the FDA initially not to approve the SGLT-2 inhibitor dapagliflozin?

Dr. Bakris: They came on the heels of all the this cancer and CV stuff with the glitazones, so there was a tremendous amount of pressure on the FDA from Congress not to put anything out there that was not pristine. Unfortunately, because they were in a hurry, and this is based on oncologists’ testimony, they probably let people into the trials who already had bladder cancer, and the whole issue with hematuria gave pause. So, at the end of the day, they really didn’t know, and even though they had experts in oncology testify that it was highly unlikely [patients developed cancer from dapagliflozin treatment] because they are slowly growing cancers, the FDA decided to be conservative and ask for longer follow-up. In Europe, they had [longer-term] data on file, and decided that patients probably already had bladder cancer [going into the trial], that this was just dumb luck. I think all of this stuff in the press hyped by colleagues of ours is great for news, but doesn’t help patients at all. It doesn’t really resolve anything. My comment on rosiglitazone is that it is now impossible to make an honest judgment on the data. Most patients discontinued the drug, so any chance to exonerate it is gone, because it was already accused.

Q: Do you have any ideas about what might mediate the increase in LDL that has been reported?

Dr. Molitch: Not really. The mild LDL elevation seems to be a class effect, and there’s also an increase in HDL, although it’s a more modest increase. If you look at the ratio, it’s not increased, but this doesn’t give us the answer all the time. The mechanism is not known. How clinically significant is it? I think only time will tell.

Q: Based on phase 3 data, it appears that canagliflozin is slightly more effective in A1c and body weight reductions than dapagliflozin and empagliflozin. Can you comment on this?

Dr. Bloomgarden: Without head-to-head trials, you simply can’t compare them. In [their respective] trials, there were differences in baseline A1c, differences in body weight, differences in the conduct of the trials, and so on. One can simply say that the class appears to have a remarkably similar set of characteristics with the published data. If we look in our abstract book, we’ll probably see 100 SGLT-2 posters and orals that we can all go visit over the next couple of days.

Q: Why might there be an interaction of canagliflozin with ACE inhibitors and angiotensin receptor blockers?

Dr. Bloomgarden: There’s likely not going to be an interaction, but it may be that in individuals susceptible to hypotension, those receiving ACE inhibitors could have a greater propensity to dehydration, renal insufficiency and so on. We know sometimes that is seen with these agents.

Dr. Bakris: There’s no drug interaction. Let’s be clear on that. The issue is that of people that are taking these, there’s additional volume loss. You’re going to great a great reduction in GFR and blood pressure. That’s all that you’re seeing here. When they stopped the drug, it came right back up to where it was, which is what you’d see with an ACE or ARBs. If you’re seeing a reduction in GFR or an increase in creatinine, you shouldn’t blink until gets above 30%. A little increase in serum creatinine is not going to hurt anyone, nor has it shown to be adverse. There are two additional papers encouraging nephrologists to not change ACEs or ARBs if GFR goes up. This is a volume effect. That’s why, when I give it to patients, I cut the dose of the diuretic in half, because I’m anticipating some volume issues. There’s no published data but it does make sense.

Dr. Bloomgarden: It would be interesting to look at SGLT-2 inhibitors as diuretics and their role in potentially tying the lowering effects of antihypertensive drugs, etc. They might be potent in people with diabetes. 

Q: Why is SGLT-2 upregulated in diabetes?

Dr. Bloomgarden: One could say this is teleologically an appropriate adaptive response to avoid glucose loss. The fact that a mechanism is available biologically to increase the expression of glucose transporters in people with diabetes is fascinating. I don’t know that I have more of an explanation, but I think it is a very interesting observation.

Q: Is any caution necessary to prescribe SGLT-2 inhibitors for sexually active patients?

Dr. Bloomgarden: No more so than the very appropriate idea of asking patients before we initiate these drugs whether they have had recurrent infections or recent symptoms of vaginitis.

Q: A patient in her 90s on canagliflozin 100 mg lost weight after a month and her edema resolved, but her fasting glucose remained in the 200s. After increasing canagliflozin to the 300 mg dose, what will happen? She worries about hypoglycemia with sulfonylureas, and refused to take insulin.

Dr. Bloomgarden: The answer is nothing. This is not a panacea. If her blood sugar is in the 200s, she needs insulin (or possibly a GLP-1 receptor agonist). The reality is that this [canagliflozin] is probably going to be the wrong agent.

Dr. Molitch: Just to come back to the fact that she is in her 90s – older patients seem to be the ones at risk for volume depletion symptoms, so I probably wouldn’t go up to 300 mg with her because the higher dose is associated with more symptoms. I would advise against use in older individuals. Going back to the infection issue, when you look at upper urinary tract infections (like pyelonephritis) and bladder infections, there is a slight increase or no increase. The major concern is mycotic infections. Clearly they increase, but perhaps they are avoidable if patients are selected appropriately.

Dr. Bloomgarden: With the proviso that we might not have enough experience in at-risk patients yet. Another point on what you had mentioned – the degree of volume depletion is probably going to be proportional to the degree of elevation of blood sugar and the degree of diuresis, so it may be particularly worrisome for those who the drug is just not likely to be potent enough. We’ve all had patients with blood sugar in the 200s, and there are appropriate treatments. Basically, these are people who need insulin to stabilize their blood sugar, and occasionally, they can subsequently withdraw insulin.

Q: Where will SGLT-2 inhibitors enter the treatment algorithm?

Dr. Molitch: I think it would be after metformin, and really in that second layer. It’s pretty much dealer’s choice after metformin, depending on what you want to accomplish with your patients. The efficacy profile is good.

Dr. Bakris: The patients that come to see me are already on a DPP-4 inhibitor and metformin, but if I see that their A1c values are in the eights, I see this as a beautiful add-on choice at that point, but I would probably use it as a second-line also. In my experience, people over 70 tend to not drink a lot of fluid, men especially, and if you use this agent in people who are 80 to 90 years old, you could run into volume issues.

Dr. Bloomgarden: The potential for these agents to be used in combo with TZDs is very intriguing. The fluid retention effect to TZDs could be combated with the diuretic action of these agents. In that one study I talked about, it really appeared that the progressive weight gain seen with the TZD was attenuated by the weight loss of SGLT-2. I think we’ve moved away from TZDs a little too much, and low-dose pioglitazone ought to be part of our own treatment plan, in those not at risk of heart failure or fractures. Maybe this a combination that will allow us to use metformin and pioglitazone in triple therapy in an appropriate fashion.

 

Corporate Symposium: Targeting the Kidney: A New Paradigm in T2DM Management – An Evidence-Based Expert Exchange (Sponsored by Boehringer Ingelheim and Eli Lilly)

Current Therapeutic Options in T2DM: Pros and Cons

Anne Peters, MD (University of Southern California Keck School of Medicine, Los Angeles, CA)

Speaking to a standing-room-only crowd in the Hilton Grand Ballroom, Dr. Anne Peters described the ADA/EASD position statement, which she co-authored (our report on the publication is available at http://www.closeconcerns.com/knowledgebase/r/4d95e564). In opening, she emphasized that the document is a position statement rather than a guideline or an algorithm. Dr. Peters explained that the co-authors of the document were especially concerned with the increased mortality observed in ACCORD, a finding that further underscored the need to avoid severe hypoglycemia. She then outlined the ADA/EASD’s patient-centered approach, which encompasses several points including individualizing treatment targets, promoting shared decision making, and recognizing the pros and cons of each drug class. After walking the audience through the position statement’s main figure, she highlighted the need for drugs that avoid both weight gain and hypoglycemia. Dr. Peter concluded with a high-level overview of the phase 3 programs for dapagliflozin (BMS/AZ’s Forxiga), canagliflozin (J&J’s Invokana), and empagliflozin (Lilly), noting that the drugs generally promote reductions in A1c, body weight, and blood pressure. 

 

What Do SGLT-2 Inhibitors Have to Offer?

George Bakris, MD (University of Chicago Medicine, Chicago, IL)

In starting his presentation, Dr. George Bakris asserted, “If you want a drug that really relieves glucotoxicity, this is the class.” He focused the first portion of his talk on kidney impairment, beginning with a chart that stratifies the risk of chronic kidney disease by GFR and albuminuria (KDIGO 2012).  After describing the general role of the kidneys in regulating glucose levels, Dr. Bakris provided background information on the SGLT proteins, highlighting that SGLT-2 is a low-affinity, high-capacity glucose transporter located in the proximal tubule of the nephron that is responsible for 90% of glucose reabsorption. He explained that people with type 2 diabetes have a greater expression of SGLT-2 and can thus reabsorb a greater amount of glucose back into the bloodstream before excreting it in the urine. SGLT-2 inhibitors lower the renal threshold for glucose excretion, thus limiting the body’s ability to reabsorb glucose and promoting the release of sugar into the urine.

• Sodium glucose transporters (SGLT) are active transporters that use the sodium gradient produced by the NA⁺/K⁺ ATPase pumps at the membranes on the luminal side of the cell. Located in the first two sections of the proximal tubule, SGLT-2 has a low affinity but high capacity for glucose and is responsible for 90% of the tubular reabsorption of glucose. While mostly expressed in the intestines, SGLT-1 is also present in the ending portion of the proximal tubule and is responsible for the remaining 10% of glucose absorption. Unlike SGLT-2, SGLT-1 is a high-affinity, low-capacity glucose transporter.
• Dr. Bakris outlined the rationale for SGLT-2 inhibition. Animal studies of phlorizin (“the prototype SGLT inhibitor”) showed that SGLT inhibition can normalize plasma glucose levels. Mutations in the SGLT-2 transporter linked to hereditary renal glycosuria have been found to be benign, showing potential for manipulating the protein. These observations suggested that selective SGLT-2 inhibitors could increase urinary glucose excretion and promote weight loss.

 

Goals of Treatment in T2DM: Current Perspectives

Paul Jellinger, MD (University of Miami, Coral Gables, FL)

Dr. Paul Jellinger gave a thorough review of the recently published AACE algorithm. Citing evidence from several studies, he voiced support for the AACE-recommended A1c goals – i.e.,  ≤6.5% for healthy patients with type 2 diabetes and >6.5% for patients with concurrent illnesses who are at risk for hypoglycemia. Referencing UKPDS, Dr. Jellinger noted that microvascular and diabetes-related endpoints, diabetes-related deaths, all-cause morality, and fatal and nonfatal myocardial infarctions all parallel a rise in A1c. In a meta-analysis of five randomized controlled trials, patients receiving intensive treatment were able to achieve an A1c of 6.6% compared to an A1c of 7.5% for those receiving standard treatment (Ray KK et al., Lancet 2009). Additionally, the intensive treatment led to a significant decrease in coronary events without an increased risk of death. Dr. Jellinger emphasized that the AACE glycemic control algorithm ranks incretin therapies and SGLT-2 inhibitors higher than TZDs and SFUs, since the former therapies have a more robust effect on post-prandial glucose PPG levels (as well as a more mild effect on fasting plasma glucose level). The DECODE study showed that lower PPG levels is important for decreasing the risk of cardiovascular events and mortality. Dr. Jellinger recommended that for patients such as the one presented in the case study below, a combination therapy including a GLP-1 agonist and an SLGT-2 inhibitor would be most effective. Finally, Dr. Jellinger concluded by arguing that treating obesity should be part of treating pre-diabetes and type 2 diabetes, referencing AACE’s obesity algorithm and CVD risk factor algorithm. For further details on the AACE comprehensive treatment algorithm, please see page 59 of our AACE report at http://close.cx/AACE2013 and our April 24, 2013 Closer Look at http://www.closeconcerns.com/knowledgebase/r/a331db88.

 

Case presentation: Luis - Latino Postal Worker

Om Ganda, MD (Joslin Diabetes Center, Boston, MA)

Dr. Om Ganda began the symposium with a case study of a 47-year-old Latino postal worker with undiagnosed diabetes, a prototypical scenario seen by many of the endocrinologists and diabetologists in the audience in their clinical practices. The fictional patient had a history of diabetes and cardiovascular disease, was a smoker and obese, and had high blood pressure, high cholesterol, normal renal function, and an A1c of 8.2%. When the audience was polled, 48% recommended that the patient make lifestyle changes, receive diabetes education, and take a combination of antihyperglyemic therapies. Dr. Paul Jellinger commented that beyond smoking cessation, the single most significant thing a person could do to reverse cardiovascular risk at this point would be to control glucose levels and begin a statin. The audience then learned that the patient was referred for education, provided a blood glucose monitor, and was prescribed TLC and a statin, which caused him to lose weight and experience reductions in A1c and LDL cholesterol. After this information, 49% of the audience recommended continuing lifestyle intervention and adding a combination diabetes therapy. The case study patient was given metformin, but could not tolerate it. Dr. Ganda concluded by asking the audience what they would recommend at this point, and the majority voted to replace metformin with a DPP-4 inhibitor.

 

Panel Discussion

Moderator: Om Ganda, MD (Joslin Diabetes Center, Boston, MA)

Panelists: Anne Peters, MD (University of Southern California Keck School of Medicine, Los Angeles, CA) ; George Bakris, MD (University of Chicago Medicine, Chicago, IL); and Paul Jellinger, MD (University of Miami, Coral Gables, FL)

 

Q: Dr. Peters, can you comment on the age threshold for setting an A1c target

Dr. Peters: The problem with not having a set age or set “anything” for getting to your A1c target is because it has to be done on a case-by-case basis. In a companion piece of the position statement, we were going to present cases to give you a better sense of how we would adjust the A1c. But we either ran out of time or money so that companion piece didn’t come. What I do for patients is that I write a chart for A1c and it’s mainly based on the risk for hypoglycemia. I don’t want to take a patient I’ve been treating for 20 years and say “you’re 80 years old, who cares what your sugar is.” So I think that you have to look at your patient specifically, and hypoglycemia is really the main risk to mitigate.

Q: Would an SGLT-2 inhibitor have any effect on renal function?

Dr. Bakris: The SGLT-2 inhibitors will affect renal function in the following way. They are diuretics. If you have a patient already on a diuretic and you don’t adjust the dose of the diuretic, you could potentially worsen the volume depletion and it will look like they lose kidney function. So you need to be aware that if the patient is on a diuretic or an ACE inhibitor or ARB, you have to back off the diuretic first and maybe also the other drugs because they will have an effect.

Q: What is the recommendation for using SGLT-2 inhibitors for someone with an eGFR less than 30?

Dr. Bakris: These won’t work because when it goes below 45, you’re filtering less glucose, and the amount of glucose reduction you get is going to be limited. In that range, you have to be very careful with diuretic doses.

Q: Where do the fixed-dose combination therapies (FDCs) fit in the position statement?

Dr. Peters: Just like every patient has different and individual needs, a FDC is something that different HCPs use differently. I had the experience were my patients were put on a glyburide/metformin FDC and we too often saw that patients would stop the drug due to side effects and then, they’ve stopped two drugs. So we took it off the formulary so that the patients would take two drugs singularly. In my own practice, I’ll use a FDC if I get a patient to his target on single drugs, because then I can find the right doses, and then I use the FDC, if it works. However, in my practice I often get patients that want me to fine-tune things. In primary care, there may be a greater need for simplicity, and so a FDC in the beginning could also be OK.

Q: Do you have any insight as to why the LDL-C goes up?

Dr. Jellinger: There is a small rise in LDL; it isn’t terribly significant and I’m not sure if it persists if the patient is on aggressive statin therapy. I don’t know why that happens. This class of drugs may not be suitable for someone whose LDL goal is difficult to achieve.

Dr. Bakris: When you look at the data for people with kidney disease, LDL does not go up and interestingly, in patients that do have normal kidney function, there is a correlation between LDL going up and HDL going up. Why should that be a mechanism? I’m not saying it is; it is an observation. I don’t understand it either.

Q: Does the use of SGLT-2 inhibitors affect the microalbuminuria test?

Dr. Bakris: Directly, it depends. If you’re measuring the albumin concentration, you bet there will be an affect. If you’re measuring the albumin:creatinine ratio, you will not have an affect on that or on 24 hour albuminuria.

Q: When you downplayed the role of ACE inhibitors and ARBs, did you consider their role in the metabolic syndrome?

Bakris: You have to look at all the data. If you’re looking at outcomes and you’re looking at the role of ACE inhibitors, in terms of kidney outcomes, there are zero data that support their use either in people IFG or people with early diabetes that are normotensive or that even have early stage hypertension and certainly that have no albuminuria- in this case, there is zero evidence that ACE inhibitors provide protection. The best example is a paper (NEJM 2009) where the patients are normotensive normoalbuminuria – they were biopsied and randomized to ACE, ARB or placebo and they measured the progression of diabetic nephropathy. At the end of study, there was no difference between the groups. So it’s all BS – smoke and mirrors and retrospective epidemiology studies. If you look at the prospective data, it’s nowhere near as compelling. The data for ACE inhibitors and ARBs for the kidney is that if a person’s eGFR is less than 60, and if they have proteinuria, then all the guidelines say that you have be on an ACE inhibitor or ARB. In impaired fasting glucose or early diabetes, there’s no need to use them.

Q: Do we know anything about the durability of weight loss with SGLT-2 inhibitors compared to GLP-1 agonist?

Dr. Jellinger: If you look at the data, the weight loss seems to be every bit as robust. For the early GLP-1 agonists, it may be a tad more; we’re seeing patients treated with GLP-1 agonists that have far more weight loss than that stated in the PI. Whether that plays out with SGLT-2 inhibitors, we will see.

Q: What is your perception of SGLT-1/SGLT-2 dual inhibitor?

Dr. Bakris: I think jury is out. The problem is that if you inhibit SGLT-1, you’ll have a GI nightmare because of the diarrhea and nausea. The magnitude of SGLT-1 inhibition added to the SGLT-2 inhibition is not that much. That’s assuming you can block SGLT-1 and get away with it clinically, which I don’t think you can.

Q: Do you have any insight into the effect of SGLT-2 inhibitors on beta cell preservation and insulin resistance?

Dr. Peters: it’s a complicated issue. You’re reducing glucotoxicity and weight and you’re restoring normoglycemia. I don’t know the specific effects, and it’s the holy grail to preserve beta cell function. I think it would be nice, but don’t think we can say that yet. 

Dr. Bakris: I think there are some things that you can use to at least posit a hypothesis. Unless you’re doing specific CRC studies that test beta cell function in man, you won’t get a good answer. I would argue that if you catch diabetes early enough and you use these drugs, you probably would have beta cell preservation. If you’re catching it eight to nine years out, you won’t. That’s my hypothesis.

Dr. Peters: We’ll see.

Q: Why is SGLT-2 up-regulated in people with diabetes?

A: Now all of a sudden the tubule is flooded with glucose, and the transporters are not going to be able to handle that. The transporters, with increased synthesis, try to bring the glucose back up. That’s also the thought behind why the threshold goes up, because there’s a change in the homeostasis. That’s the best theory I can give you.

Q: What about the diuresis part? Should patients be worried about going to the bathroom more often?

Dr. Bakris: Well, when you first get diuretics you urinate often but after about three days, that initial diuresis goes away. So you still get diuresis, but its nowhere near as intense as the first three days. With this drug, I think the amount of diuresis is a function of your glucose excretion. I’m speculating about that.

Dr. Peters: Some studies say that it’s just one more time per day. They weren’t running to bathroom constantly. You also start canagliflozin on a lower dose. I tell people to try it on weekends. I’m pretty careful with patients when they start new drugs; I make sure that they’re hydrated and make sure that they’re not dehydrated. I also cut the dose of the diuretic in half so it kind of balances out. So you have to use your judgment for each patient.

Dr. Jellinger: Patients that have used SGLT-2 inhibitors have reported increased urination just for the first few days. It’s really not a big problem.

Q: We didn’t see much about insulin catabolism in terms of kidney failure, can you comment on this?

A: Of course with renal failure we need to reduce our insulin doses and you can’t use the SGLT-2, at least the existing one, so it’s not really pertinent. SGLT-2 is a non-insulin based mechanism. I’m most anxious to see the effect of SGLT-2 inhibitors in patients who are severely insulin resistant.

Q: What is the effect of SLGT-2 inhibition on the myocardium?

Dr. Bakris: To my knowledge, none. SGLT-2 is exclusively in the kidney. SGLT-1 is in the gut and the kidney.

Dr. Jellinger: Want to make a comment: in choosing an antidiabetic agent, what has emerged is the quest for agents that don’t cause hypoglycemia or weight gain. I want to point out that in 2011, the CDC did a very thorough analysis of drug-related emergency room visits across the country. Forty percent of these visits resulted in admission. Out of the top four drugs that caused these visits, two of them were for diabetes. So hypoglycemia is a huge problem in terms of cost as well. I would urge you to keep that in mind. Agents that don’t cause hypoglycemia and weight gain are really the holy grail. And now we have more of them available. 

Q: What is the increase in blood pressure due to?

A: It’s not related to weight, because the effect on blood pressure occurs before you lose substantial amounts weight. The other thing is that they’ve looked at people with relatively low glucose levels, and you still get blood pressure reductions. The argument is that it’s working like an osmotic diuretic. That’s probably what’s going on with the blood pressure effect. The effect is similar to a low dose diuretic. 

Q: What is the role of these agents in type 1 patients?

Dr. Peters: The study that was presented yesterday was looking at dapagliflozin in patients with type 1 diabetes – it was a two-week proof-of-concept study. So you won’t see an A1c reduction. But they did see a reduction of glucose levels over the course of the time; the drug seemed fairly well tolerated. So now we can move on to longer studies. I personally am looking forward to using them in patients with type 1 diabetes because I think they’ll play an important role. We’re just beginning to assess if they are truly safe and efficacious. 

Dr. Bakris: I agree. I think that in type 1  patients, especially in the older ones that are getting a little plump, it will be good.

Dr. Ganda: Now we’re seeing more weight gain in type 1 diabetes – we saw this in DCCT. So theoretically, I think it makes sense. This should work. Obviously those studies had not been done in type 1 diabetes. These drugs are approved for type 2 diabetes.

 

Additional Oral Therapies

Current Issue: Should Sulfonylureas Remain an Acceptable First-Line Add-On Therapy to Metformin? (Supported by an unrestricted educational grant from Merck)

Session chair, Dr. Fred Whitehouse, opened by remarking upon how history repeats itself – at the scientific sessions in the 1970s they argued about what to do with SFUs, and here we are in 2013 debating whether SFUs are an appropriate second-line agent.

Pro

Martin Abrahamson, MD (CMO, Joslin Diabetes Center, Boston, MA)

In front of a standing-room-only audience of roughly 1,000 people, Dr. Martin Abrahamson presented his argument for why sulfonylureas should remain an acceptable add-on to metformin: the crux of his argument was “why not” keep SFUs around when no good evidence exists for stopping their use? He argued that, when used appropriately 1) there is no clear evidence that SFUs accelerate beta cell decline; 2) there is no evidence of increased beta cell apoptosis when used with metformin; 3) there is no evidence that they are less safe than other medications when used appropriately; and 4) there is evidence that they are effective, cheap, and well-tolerated. In our view, the caveat of “if used appropriately” is a huge one and represents a major challenge for prescribers today – since other second-line agents like DPP-4 inhibitors that require less prescriber hassle now exist, we would argue that this is a meaningful argument against using SFUs except in the very poor where there is no other economic choice and metformin is contra-indicated. Dr. Abrahamson identified the appropriate population for SFUs as younger patients early in disease progression with low risk for hypoglycemia. Overall, while we found Dr. Abrahamson’s argument to be well-prepared and thoughtful, we did not find the arguments terribly convincing. After the panel discussion, a consensus seemed to form between Drs. Abrahamson and Genuth that not all SFUs are created equal – they agreed that glyburide (aka glibenclamide), should definitely not be used – and that SFUs are most appropriate for only a select group of patients early in disease progression. See the table below for a summary of Dr. Abrahamson’s comparison of efficacy, tolerability, safety, durability, and cost of the various diabetes drug classes.

• Efficacy: Dr. Abrahamson presented data demonstrating that SFUs have great A1c-lowering efficacy compared to other anti-diabetic agents. He presented data from a newly-published meta-analysis demonstrating that SFUs lowered A1c by 1.5% when used as monotherapy (median study duration was 16 weeks; baseline A1c ranged from 4.7-13.6%; Hirst et al., Diabetologia 2013). In the same study, SFUs added onto metformin or TZD lowered A1c an additional 1.6% (n=4 studies; duration 16-52 weeks; baseline A1c 7.5-9.5%). We note that these are relatively short studies that would not capture SFUs’ lack of durability. Additionally, he cited head-to-head comparative effectiveness studies of liraglutide vs. glimepiride and liraglutide vs. sitagliptin, demonstrating that while liraglutide and glimepride showed similar efficacy over 26 weeks, sitagliptin demonstrated inferior efficacy to liraglutide (Nauck et al., Diabetes Care 2009; Pratley et al., Lancet 2010). He concluded that SFUs, TZDs, GLP-1 agonists, and insulin are highly effective and that DPP-4 inhibitors are moderately effective. Most notably, Dr. Abrahamson presented evidence demonstrating that half-maximal doses of glyburide and glipizide were just as effective as full doses, suggesting that lower doses could be prescribed to minimize side effects (Hurren et al, Diabetologia 2013).
• Tolerability/side effects: Dr. Abrahamson argued that sulfonylureas were “highly tolerable” with the side effects of weight gain and moderate risk of hypoglycemia. He stated that in studies where SFUs have been used as comparators, there are usually no difference in overall rates of adverse events – we speculate that this is because these trials are designed to demonstrate that new agents are non-inferior to the existing standard of care, not to assess the safety of SFUs. He acknowledged that glyburide is the one SFU associated with more hypoglycemia than the other SFUs. However, he cited UKPDS hypoglycemia data as evidence that other SFUs have acceptable rates of hypoglycemia: in the UKPDS long term follow up, the rate of hypoglycemia in the conventional, chlorpropromide, glyburide, and insulin groups, respectively was 0, 1.0, 1.4, and 1.8 per year. We found it quite odd that the rate of hypoglycemia on insulin would be so low and would argue that relatively speaking, a hypoglycemia rate of >50% that of insulin is still quite undesirable. Dr. Abrahamson concluded that SFUs are highly tolerable, more so than TZDs or GLP-1 agonists; that the relevant side effects are hypoglycemia and weight gain; and that the risk for hypoglycemia is moderate compared to a high risk on insulin and a low risk of TZDs, DPP-4 inhibitors, and GLP-1 agonists.
• CV safety: Dr. Abrahamson argued that CV safety of newer-generation SFUs is neutral. While the UGDP study in the 1970s suggested that sulfonylurea use was associated with increased CV harm, Dr. Abrahamson pointed to the UKPDS long-term follow up to show that the insulin/SFU arm actually experienced a legacy effect reduction in overall mortality, any diabetes-related endpoint, and myocardial infarction. Additionally, he stated that the BARI-2D study showed that patients randomized to “insulin-sensitizing therapies vs. insulin-providing therapies” experienced no difference in rates of survival or CV events. He concluded that SFUs, TZDs, and insulins have neutral CV safety, whereas the CV safety of DPP-4 inhibitors and GLP-1 agonists is unknown (he did not mention the recently-announced neutral results of Onglyza’s SAVOR-TIMI trial [see more detail at http://www.closeconcerns.com/knowledgebase/r/c4686fbb], nor the fact that pooled analyses of CV risk for these classes suggest the possibility for CV benefit). Overall, given the chatter about beta cell burnout in at least some SFUs, and given that almost everyone on SFUs gains weight (negative for CV health by any definition) we thought arguing for neutrality was a leap – this may be just because other classes have no questions.
• Durability: Dr. Abrahamson acknowledged that that there was evidence for lack of durability when using glyburide as monotherapy, but stated that there was no evidence for lack of durability of a metformin/SFU combination. In ADOPT, the time to drug failure (defined as A1c ≥7%) was 2.75 years for glyburide, 3.7 years for metformin, and 4.75 years for rosiglitazone. He emphasized that this was not a combination therapy study and that glyburide actually conferred better average glucose control during the first year. Dr. Abrahamson suggested that since none of the drugs tested were sufficient as monotherapy, it was perhaps a moot point to discuss monotherapy data and that combination therapy early in disease progression will be necessary to get more people to goal. He showed that while glyburide by itself at supraphysiological doses has produced beta cell apoptosis in in vivo models, this result has not been reproduced with other SFUs. In addition, metformin appears to be protective on beta cell apoptosis, and there is no data on the effect of metformin and SFU together on beta cell apoptosis.
• Finally, Dr. Abrahamson discussed the economic burden of treating hyperglycemia: he argued that with diabetes costing the US $245 billion/year, and $18 billion of that going towards antihyperglycemic medications, that cost was a significant factor to consider. However, we would counter his argument by saying that since the costs of hospitalization, inpatient care, and treating complications far outweighs the costs of medications and supplies, that actually spending more on the best treatment options would be a better use of money and potentially save money in the end. On an individual level, however, for patients who do not have insurance and cannot afford any non-generic diabetes medications, of course we would argue that cost for the individual becomes a significant consideration.
• Dr. Abrahamson’s comparison of the efficacy, tolerability, safety, durability, and cost associated with diabetes drugs:

	SFU	TZD	DPP-4 Inhibitor	GLP-1 Agonist	Insulin
Efficacy	High	High	Moderate	High	Highest
Tolerability	High	Moderate	High	Moderate	High
Side effects	Hypoglycemia Weight gain	Edema, CHF, Fractures Weight gain	Rare pancreatitis	GI Rare Pancreatitis	Hypoglycemia Weight gain
Risk of Hypoglycemia	Moderate	Low	Low	Low	High
CV Safety	Neutral	Neutral	Unknown	Unknown	Neutral
Durability	?	?	?	?	Yes
Cost	Low	Low/Mod	High	High	Variable

 

Con

Saul Genuth, MD (Case Western Reserve University, Cleveland, OH)

Dr. Saul Genuth represented the con argument in the sulfonylurea debate. While he began by acknowledging the merits of sulfonylureas, he then noted that many other drug classes are as effective as SFUs (if not more) and also safer. He shared a wealth of data drawn from numerous clinical studies which indicate that SFUs have comparable efficacy to TZDs, DPP-4 inhibitors, and GLP-1 agonists. He cited the ADOPT study as an example, as it showed that glyburide provided inferior glycemic control compared to rosiglitazone. Importantly, all three alternative drug classes have demonstrated a lower risk of hypoglycemia compared to SFUs; furthermore, two classes (DPP-4 inhibitors and GLP-1 agonists) have neutral or beneficial effects on body weight, compared to the weight gain seen with SFUs. Dr. Genuth remarked that the cardiovascular data on SFUs to date has been generally poor and thus not conclusive. As a result, he recommended that SFUs be moved to a lower tier in the ADA/EASD algorithm for type 2 diabetes. In concluding Dr. Genuth noted that the low cost of SFUs has real-world significance, and that the medical community should fight to lower the prices of newer and safer therapies to increase patient access.

• Sulfonylureas are no more effective than other drug classes at lowering A1c values. Dr. Genuth acknowledged that combination therapy with SFUs and metformin led to a sizeable reduction in A1c compared to either agent alone; however, the efficacy profile of this combination is comparable to (or worse than) those of other drug classes. He began by comparing SFUs with TZDs – two studies comparing glimepiride to pioglitazone showed comparable efficacy, while another comparing gliclazide to pioglitazone also showed similar reductions in A1c. Dr. Genuth cited the results of the ADOPT study, which showed that glyburide led more significantly more monotherapy failure (sustained A1c above 8%) than TZDs. Moving on to incretin mimetics, he presented evidence from clinical trials demonstrating incretins provide similar glycemic control compared to SFUs.
• Several studies indicate that SFUs have a worse safety profile compared to other drug classes. To Dr. Genuth, this issue is the primary argument against the use of SFUs. Anatomical studies have shown that SFUs lead to an increase in atheroma volume, increasing the risk for adverse cardiovascular events. Dr. Genuth cited an epidemiological study that demonstrated a higher cumulative incidence of cardiovascular disease death with SFUs compared to metformin (Roumie et al., Ann Intern Med 2012), although he noted that the UKPDS did not show a similar finding. Dr. Genuth then turned to the topic of hypoglycemia, starting with the joint ADA/Endocrine Society workgroup statement that SFUs are the oral agents with the greatest risk for hypoglycemia. Many of the same studies that investigated the comparative effectiveness of diabetes drug classes showed that TZDs, GLP-1 agonists, and DPP-4 inhibitors resulted in substantially less hypoglycemia than SFUs. Dr. Genuth mentioned other safety concerns associated with SFUs, including the potential for adverse interactions with a wide range of drugs such as allopurinol, warfarin, ASA, and sulfonamides. He noted that SFUs can cause weight gain, while drug classes such as GLP-1 agonists generally promote weight loss. Of note, one study showed that SFU use led to an increase in the albumin/creatinine ratio compared to TZD use (Matthews et al., Diabetes Metab Res Rev 2005). Dr. Genuth argued that these safety data convincingly demonstrate that SFUs should not occupy the same tier on the FDA/EASD algorithm as other safer drug classes.

 

Panel Discussion

Martin Abrahamson, MD (CMO, Joslin Diabetes Center, Boston, MA); Saul Genuth, MD (Cleveland Clinic, Cleveland, OH)

Q: In this day and age, when people come in with shopping bag of medications, why add another pill? Why not get back on diet and lose some weight?

Dr. Abrahamson: I would be the first person to advocate for lifestyle as a major aspect of managing type 2 diabetes. I think the reality of what we’ve seen in clinic, what we see from clinical studies, is that diet and exercise work to some degree, but adherence to that is difficult. Ultimately the majority of patients are going to need medications in addition to metformin to manage their diabetes and get to goal. I think the challenge when considering use of a SFU is to determine which patients are least likely to develop hypoglycemia. I will commend my colleague Dr. Genuth for focusing on hypoglycemia as an issue, and I would agree with him. But not withstanding that issue, for patients unlikely to develop hypoglycemia using low doses and who start therapy early in the natural history of the disease, you’ll have a positive impact on A1c, which will result in favorable outcomes

Dr. Genuth: SFUs are most effective early in the disease. The UKPDS study began SFU treatment at time of diagnosis. Already, though, these people had had type 2 diabetes probably 5-10 years before they showed up. Lifestyle modification certainly is effective, but it doesn’t last. My argument is it’s not perverseness of patients that we have to fight against; it’s not that our physicians don’t know how to teach people about exercise. I believe that the inability to restrict caloric intake and the inability to exercise consistently are symptoms of type 2 diabetes. I think patients are struggling against their disease. We’re not struggling against their perverseness.

Q: It seems like we have a hung jury. Since both speakers mentioned that the real bad actor is glyburide, is the appropriate compromise to say that SFUs are still a reasonable option if we’re talking about the newer ones and we eliminate glyburide from the list?

Dr. Genuth: I think we should add to the compromise that we should restrict their use to people under age 70.

Dr. Abrahamson: It’s amazing how early we are coming to consensus in this debate. I would concur. I would say that glyburide is an inappropriate drug to use and should be removed from the market, and I agree with Dr. Genuth that restrictions should be placed on its use regarding age. Still, the sad thing is that we’ve got a lot of people developing this disease much earlier on than we would have like to imagine.

Q: I would like to add three comments – first, one big mistake is that we mix all SFUs in one bag. It is very clear that glimepiride and longer-acting glipizide have much lower weight gain than glyburide and short-acting glipizide. I refuse the argument for hypoglycemia and weight gain with longer-acting SFUs. The other comment for Dr. Genuth – in trying to scare people from hypoglycemia, you said that SFUs had a six-times higher risk for hypoglycemia than DPP-4 inhibitors, but the absolute number of cases was low (about 1% in the DPP-4 arm). Additionally, you mentioned hypoglycemia in the VADT and ACCORD trial, though everyone in the audience understands that most hypoglycemia in those trials was caused by insulin. A final point to Dr. Abrahamson – why do you say that CV safety is neutral? The UKPDS showed very clearly that there was a cardioprotective legacy effect, so doesn’t that show a CV benefit for SFUs?

Dr. Genuth: Those are some valid points. I think any one case of serious hypoglycemia that results in death, is too many because it’s iatrogenic. So I’m less interested than you are in the actual incidence being low. I’m more impressed that some people have died and still can die when SFUs are used inappropriately. I think we’re beginning, as pointed out, to develop a consensus, which is a terrific outcome of this discussion, and maybe we all should write the next paper with a little more common sense than the last one [Editor’s note: we believe he was referring to the 2012 ADA/EASD position statement].

Dr. Abrahamson: I think we must not draw too many conclusions about SFUs’ cardiovascular benefit. The UKPDS extension demonstrated that those randomized to intensive therapy had fewer CV events – that was a manifestation of improved glycemic control rather than the specific impact of a drug. At least from my argument perspective, I think these drugs are neutral, which to me is adequate grounds to say there’s no evidence to support that these drugs pose cardiovascular risk.

Dr. Genuth: You may have to remind me, Martin, but my memory for the legacy effect was that the legacy effect was in the SFU/insulin group, so I’m reluctant to say that that demonstrates purely a SFU effect.

Q: We’re looking here at only second-line drugs in trials that last only five years, which in terms of this disease is relatively short term. In the long game, the thing that’s going to limit us in controlling our patients is hypoglycemia, and specifically hypoglycemia awareness. I think we know that the more hypoglycemic patients have, the more they develop hypoglycemia awareness. So if we’re looking at how we responsibly give our patients drugs, I think we need to accelerate hypoglycemia awareness.

Dr. Abrahamson: I think the point here is that nobody wants to cause hypoglycemia in the first place. What you’re referring to is the phenomenon of repeated episodes of hypoglycemia that increase hypoglycemia awareness. We’re all trying to prevent hypoglycemia in the first place. We want to use drugs safely and effectively. I think, as Dr. Genuth said, we’re coming to a consensus. A bad workman blames the tools, but in reality we agree that glyburide is the one that shouldn’t be used, but there are other sulfonylureas that, when used appropriately, and particularly at low doses, especially to start off with, would be much less likely to cause hypoglycemia. And then the issue of hypoglycemia awareness doesn’t become an issue.

Dr. Genuth: That’s very important. Also, we also haven’t talked about insulin. It’s clearly the most effective at lowering glucose levels. One survey that surprised me showed that people with type 2 diabetes taking insulin had one third the incidence of severe hypoglycemia compared to people with type 1 taking insulin. So insulin treatment is even more dangerous compared to sulfonylureas. We have to use it, but we need to work hard to educate our patients to help them avoid troublesome behavior.

Q: I just want to bring to your attention a recent JCEM paper that has shown if you give SFU as a monotherapy, there is an increased risk of CV mortality. Obviously it is registry data, not an RCT, but this is a recent paper.

Dr. Abrahamson: I’ll allude to Dr. Genuth’s work in the Annals of Internal Medicine showing that SFUs may be associated with increased CV events compared to metformin. The point I’d like to make from that paper is that the relative increase in CV events compared to metformin may be because metformin is associated with a reduction in CV events. I think that’s something none of us spoke about today because we all assume metformin is the appropriate first-line drug. So with epidemiologic studies, you have to ask whether metformin is reducing CV events, which may cause the comparator to show a relative increase.

Dr. Genuth: We can’t make the separation, I agree.

Q: The first question I have is about the idea of taking the first generation sulfonylureas out of use, or restricting their use like what we’re doing right now with rosiglitazone. I was wondering regarding second generation sulfonylureas, Dr. Genuth, don’t you think that what we need to do is prioritize and come in with another consensus and move sulfonylureas to a second or third-line treatment rather denying them to patients who cannot afford more expensive drugs?

Dr. Genuth: I am beginning to wonder if the sun is starting to set on sulfonylureas after 70 to 80 years of their use. If we have a lot of alternatives, and if their price comes down, and if they prove to have CV safety, I think sulfonylureas will have had their day.

Dr. Abrahamson: I think we’re all coming to broad agreement that you have to look at any particular drug and compare it to what else is on the market, and look at the pluses and minuses of using the particular product. I think that the GRADE study is going to be an important study, because        includes all the common players, although SGLT-2 inhibitors are unfortunately not going to be in the study because they are too new. This study will ultimately help us determine which of the drugs we should be recommending as the most appropriate first line therapy. It’s a challenge for people in clinical practice to be given that wealth of information to have to decide which drug is most appropriate to use first.

Dr. Genuth: I have another regret about the GRADE study. I think it should have included pioglitazone. The reason I say that is that all these drug classes lower glucose by various mechanisms, but I think that TZDs are unique in that they get at one of the primary pathophysiological problems of type 2 diabetes. They attack insulin resistance directly through various in vitro pathways. I think that that reason alone should have meant they were included, also because the GRADE study is studying pathophysiology.

Comment: Most of the rest of the world, like Korea where I come from, uses glipizide. In studies, the risk of hypoglycemia with glipizide is the same to that of sitagliptin. The newer SFUs do not have the same risk of hypoglycemia or weight gain.

Q: You pointed out that some of the sulfonylureas that are shorter acting may have a higher risk of hypoglycemia. Data on glipizide are mostly on studies where they use the standard release preparation rather than the longer preparation. Can you comment on that?

Dr. Abrahamson: I’m not aware that long preparation of glipizide is associated with increased risk of hypoglycemia. If someone has data to refute that I’d be happy to see it.

Q: One additional argument about the risk analysis. In your data, glimepiride’s risk was 0.8/1,000 with glimepiride. At the same time we know lactic acidosis is 0.3/1,000. Then for pancreatitis, about 2% of cases of pancreatitis can also cause death. With pioglitazone, there is recent data on potential bladder cancer.  In that risk analysis, are we willing to accept 0.8/1,000 of severe hypoglycemia that can be treated?

Dr. Genuth: If your point is that the absolute risk of severe hypoglycemia is low with SFUs, yes you can define low any way you want. But I would agree that the absolute risk is low. My point is simply that as a physician we each have to decide whether we even want to impose that low risk on any individual patient we are treating.

Dr. Abrahamson: I think there is ultimately is a risk/benefit analysis for any drug and any condition. Every single drug you take, including metformin, has a risk associated with its use. If you use the drug when you shouldn’t use the drug, you increase the risk enormously. The data says there is a 0.3/1,000 rate of lactic acidosis, but I haven’t seen it in anyone with normal renal function. SFU has a risk of severe hypoglycemia, so there is a higher risk for people susceptible to hypoglycemia. There is a risk of pancreatitis with incretin mimetics; we don’t know exactly the magnitude, but we as physicians need to tell patients about these risks, however small they may be, and we need to do our damnedest best to avoid using drugs in people who might develop complications.

Dr. Genuth: If we finally conclude that TZDs, when we have pioglitazone’s PROActive results, have a CV benefit, then the benefit/risk ratio of that drug will be considerably greater than SFUs – long or short acting.

Q: But we don’t have the CV benefit with DPP-4 inhibitors or GLP-1 agonists – there is no longer-term data.

Dr. Abrahamson: There is no long-term data yet. We await that data with interest.

Q: I just take up the point about glibenclamide. You’re aware the WHO has recommended the removal of glibenclamide from the essential drugs list for 65 and over. I really can’t see any justification for having glibenclamide on the market. The other point I wanted to challenge is the comment that metformin has clearly been shown to have CV benefits. If you set aside the epidemiological studies, the UKPDS is the only RCT that has shown a cardiovascular benefit for metformin, and systematic meta-analyses of metformin don’t show a cardioprotective effect.

Dr. Abrahamson: I was referring to the UKPDS data, and was only making the comment that when you look at epidemiological comparator studies, and show a relative increase of an event of one particular product, that you could say that the relative increase may be related to the fact that there was a relative decrease of the other product. But your points are well taken. Most of the data from metformin showing a cardiovascular benefit comes from UKPDS.

Dr. Genuth: This is unrelated, but I had showed proactive data showing that there was a reduced rate of stroke and other outcomes with pioglitazone. But I meant to also warn that if you look at the whole population studies, there is no advantage of pioglitazone over placebo regarding the primary outcome. It’s hard to put too much emphasis on a secondary finding when the primary finding wasn’t significant.

Q: The point that I would make is in between the exchange of both speakers: for me, in choosing an SFU I would consider three things: 1) Try to choose the right SFU. What I mean by this is I tend to go for the newer agents or the second or third generation agents. 2) I need to use the right dose of the SFU. Specifically what I mean is that in many studies out there, there is actually clear data supporting use of SFUs at 50% of their maximal recommended dose, which actually the speakers alluded to. 3) Choosing the so-called right patients. Again the speakers mentioned this. You want to get the younger patient and patients without renal impairment. Looking at these three facts, and probably cost as the fourth – maybe in a developing country cost would be #1 – the net result is that you want to maximize benefits and minimize risks while still keeping cost as an issue.

Dr. Abrahamson: We are all in what we call violent agreement. Thank you for those comments. I think we all ideally like to practice that way.

 

Oral Sessions: New Information on DPP-4 Inhibition

Glucose Metabolic Responses to Colesevelam Alone or in Combination with Sitagliptin in Type 2 Diabetes Mellitus: A Randomized Open-Label Mechanism-of-Action Study (379-OR)

Carine Beysen, DPhil (KineMed, Emeryville, CA)

Dr. Carine Beysen’s group evaluated the mechanisms of colesevelam’s (Daiichi Sankyo’s Welchol in the US) glycemic efficacy, both with and without sitagliptin (Merck’s Januvia). In opening, Dr. Beysen noted that experimental evidence suggests that the bile acid sequestrant colesevelam can improve glycemic control and LDL levels in patients with type 2 diabetes (Fonseca et al., Diabetes Care 2008). Her 12-week study randomized 50 participants to colesevelam (3.75 g/day) or to colesevelam plus sitagliptin (100 mg/day). The monotherapy results confirmed that colesevelam decreases fasting plasma glucose levels, LDL cholesterol, and postprandial glucagon secretion while increasing fasting plasma glucose clearance and postprandial glycolysis. Alone, it does not significantly change A1c levels or body weight. Combining colesevelam with sitagliptin resulted in additional benefits such as significantly increasing insulin and GLP-1 concentrations. These early results indicate that colesevelam plus sitagliptin could hold promise as a therapy for type 2 diabetes, especially in patients who could also benefit from colesevelam’s beneficial effect on LDL cholesterol. While not mentioned during the presentation, GI side effects (in particular constipation) have been reported with colesevelam’s use, and we’re interested in whether this poses a barrier to the drug’s uptake.

 

Symposium: Diabetes in Older Adults (Supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company)

Selecting the Best Pharmacological Agent for the Management of Diabetes in the Elderly

Hermes Florez, MD, PhD (University of Miami Miller School of Medicine, Miami, FL)

Dr. Hermes Florez presented risk/benefit analyses associated with several different treatments for type 2 diabetes in elderly patients: biguanides; sulfonylurea; meglitinides; dopamine-2 agonists; SGLT-2 inhibitors; DPP-4 inhibitors; and insulins. He highlighted vildagliptin (Novartis’ Galvus) and the INTERVAL trial as a step in the right direction for clinical trials that address the issues associated with treating elderly diabetes patients. The INTERVAL trial focused on this patient population (including those aged 75+years) and showed that patients on vildagliptin were more likely to achieve their individualized A1c target compared to those on placebo. To conclude, Dr. Florez emphasized that the management of diabetes in the elderly is complicated by factors such as costs and stigma, and that these issues must be addressed adequately in the future, especially since this patient group is growing in number.

 

-- By Poonam Daryani, Jessica Dong, Stephanie Kahn, Adam Kraus, Nina Ran, Phaedra Randolph, Manu Venkat, Vincent Wu, and Kelly Close