June 5-9, 2015; Boston, MA; Full Report – Insulin Therapy – Draft

Executive Highlights

The basal insulin discussion at the past two years’ ADAs have focused on products like Novo Nordisk’s Tresiba (insulin degludec) and Sanofi’s Toujeo (insulin glargine U300) that appear to offer meaningful but not game changing advantages over existing options in terms of hypoglycemia and extended PK/PD. Sanofi’s Toujeo was out on display in a big way at the exhibit hall, while Novo Nordisk’s Tresiba is of course not yet on the market in the US due to the FDA’s 2013 CRL – while it is drawing nearer, this continues to look like one of the less fruitful FDA decisions for the diabetes community, particularly as it is substantially delayed (by years!) one of the most discussed drugs of this year’s ADA, Xultophy (IDegLira). Both new basal products received plenty of attention during symposia and other discussion-based sessions, but the flow of new clinical data has slowed substantially from last year. We do expect Toujeo to do well commercially due to a mix of factors including a major focus on access, a new behavioral program called COACH that is receiving a great deal of investment by Sanofi, and items as simple but meaningful as an easier to use pen (due to less force needed).

Instead, the scientific focus this year moved on to additional areas in basal insulin: the more physiologically compelling though high-risk/high-reward liver-selective peglispro (BIL) from Lilly and new once-weekly basal insulins. The phase 3 data on peglispro was some of the most eagerly awaited data at ADA, although we knew there would be safety issues alongside the benefits that could potentially torpedo the candidate. On the plus side, peglispro is the first basal insulin to demonstrate superior A1c reductions vs. existing insulin across a phase 3 program – it also managed to do this with significantly less nocturnal hypoglycemia than Lantus (insulin glargine). Physiologically, liver-selective insulin more closely mimics endogenous insulin action and also has better weight effects vs. non-liver-selective insulin. However, peglispro also caused aberrations in liver fat, liver enzymes, lipids, injection site reactions, and (in some trials) increases in daytime hypoglycemia. None of these effects individually appeared to be a definite dealbreaker, but taken as a whole (in the context of a conservative FDA) they pose a real threat to the drug’s hopes of approval following further study over the coming years. The combination of basal insulin and GLP-1 agonists continued to receive a great deal of attention. We have included the main block of oral presentations on these combinations in this report, although the majority of our GLP-1 agonist + basal insulin coverage can be found in our GLP-1 Agonists Report.

Pioneering once-weekly basal insulins – still at a fairly early stage – include PhaseBio’s PE0139 (phase 1), Hanmi’s Hm12470 (phase 1), and AntriaBio’s AB101 (soon to begin clinical testing). Notably, PhaseBio is already examining a combination of PE0139 with its once weekly GLP-1 agonist PB1023. The key question for these agents is the degree of appeal of once-weekly insulins vs. once-daily options. In a presentation on that very topic, Dr. Ian Blumer (University of Toronto, Canada) suggested that the connection between insulin injection frequency and adherence exists but may not be as clear-cut as one would assume when considering other factors like discomfort and patient-level motivation. It remains to be seen how the new once-weekly options will stack up to existing options in terms of efficacy. Overall, it did seem clear from this meeting that there has been a delay in the move to MDI (multiple daily injections) around mealtime stemming from success with SGLT-2 inhibitors and GLP-1 – we expect this to continue when there are GLP-1/basal insulin combinations on the market although the field will certainly benefit from the sheer increased influx of patients with diabetes being more frequently diagnosed and with them living longer, creating a longer lifecycle for all products.      

We were eager to hear the dedicated sessions this year on topics beyond science, including the cost and value of new insulins. Dr. Irl Hirsch (University of Washington, Seattle, WA) led off with a dedicated presentation on day #1 critiquing the sharp rise in insulin prices over the past decade. He considers it unethical and unacceptable for cost to be a barrier for access to a lifesaving drug, and he certainly had a chorus of support among the audience. One audience member even invoked the Declaration of Independence in arguing that affordable insulin should be a right rather than a privilege. This issue is far from black-and-white: Lilly Diabetes President Mr. Enrique Conterno noted during the company’s Diabetes Business Update that net Humalog prices have been stable over the past several years, with rising list prices and simultaneously rising rebates to PBMs. It appears to be cash-paying patients who lose out, and we hope to see providers, patients, advocacy groups, foundations, professional associations like the ADA, and industry collaboratively work toward a more clear-cut approach that makes pricing and profitability less of a black box.

Talk titles highlighted in yellow were among our favorites from ADA 2015; those highlighted in blue are new or expanded full report additions from our daily coverage.

Detailed Discussion and Commentary

Oral Presentations: Basal Insulin Analogs — New Evidence

Basal Insulin Peglispro (BIL) Is Superior to Insulin Glargine (GL) in Reducing HbA1c at 52 Wks in Insulin-Naïve T2D Patients (Pts) Treated with Oral Antihyperglycemic Medications (OAMs): IMAGINE 2 (93-OR)

Melanie Davies, MD (University of Leicester, Leicester, UK)

Dr. Melanie Davies presented full results of the IMAGINE 2 trial, a phase 3 randomized controlled trial comparing Lilly’s basal insulin peglispro (BIL) to Sanofi’s Lantus (insulin glargine) in insulin-naïve people with type 2 diabetes. The topline results of this trial had been announced all the way back in May 2014. Impressively, BIL actually demonstrated statistical superiority in A1c reduction (by 0.3% after 52 weeks) over market-leading glargine. Consistent with BIL’s liver-selective effects (and, thus, reduced peripheral effects), BIL treatment resulted in less nocturnal hypoglycemia, less weight gain, but higher serum triglyceride levels (11 mg/dl difference) and higher liver ALT levels (6 IU/L difference), which are a marker for potential liver damage. As a reminder, Lilly announced earlier this year that it plans to delay BIL submission for at least two years – presumably because of these consistent liver safety signals.

• IMAGINE 2 was a phase 3 trial comparing Lilly’s basal insulin peglispro (BIL) to Sanofi’s Lantus (insulin glargine) in people with type 2 diabetes who had never previously been treated with insulin. The primary endpoint of the trial was non-inferiority for A1c change after 52 weeks, and some key secondary endpoints were statistical superiority in A1c change after 52 weeks (if non-inferiority was met), total hypoglycemia, nocturnal hypoglycemia, patients achieving A1c <7%, and patients achieving A1c <7% without nocturnal hypoglycemia.
• IMAGINE 2 was a double-blind study (neither the patients nor physicians knew which drug the patient was taking), which is a challenging feat to pull off in the world of insulin trials. It was a treat-to-target study with 1,538 patients randomized 2:1 to BIL or glargine for 52 weeks. A prespecified cohort of 920 of the original 1,538 patients were also followed out to 78 weeks (keeping the same 2:1 randomization). In addition, liver fat content was examined via MRI in a small subgroup of 168 patients.
• At baseline, patients had an A1c of 8.5% and BMI of 32 kg/m². Over 96% were on background metformin therapy, 83% on background sulfonylurea therapy, and just over 20% were on three oral antidiabetic agents.
• BIL achieved a statistically superior A1c reduction compared to insulin glargine. After 52 weeks, BIL reduced mean A1c from 8.5% to 6.9% (for a mean reduction of 1.6%) compared to a reduction from 8.5% to 7.2% with glargine (mean reduction of 1.3%) (difference of 0.3% between BIL and glargine; p<0.001). This difference was still statistically significantly different at 78 weeks, although the sample size was substantially smaller (920 vs. 1,538 patients). Significantly more patients on BIL achieved an A1c <7%, and significantly more patients on BIL did so without nocturnal hypoglycemia. This relationship held true at 26, 52, and 78 weeks. After 52 weeks of treatment, 58% of BIL patients had achieved A1c <7% compared to 43% of glargine patients. Twenty six percent of BIL patients achieved A1c <7% without nocturnal hypoglycemia compared to 15% of glargine patients after 52 weeks.
• BIL resulted in less nocturnal hypoglycemia compared to glargine; meanwhile, total and severe hypoglycemia were similar between the two insulins. Specifically, the RR for cumulative nocturnal hypoglycemia was 0.73 (95% CI: 0.59, 0.91) for BIL compared to glargine.
• BIL also demonstrated a weight benefit compared to glargine. While patients on glargine gained 2.6 kg (5.7 lb) over 52 weeks, patients on BIL gained 2.1 kg (4.6 lb), representing a 0.5 kg (1.1 lb) weight benefit for BIL – we don’t see this as a meaningful advantage, but it is going the right way.
• However, BIL had unfavorable effects on liver enzyme levels and patients’ lipid profile. After 52 weeks, patients on BIL had a statistically significant 11 mg/dl triglyceride elevation compared to patients on glargine. This effect persisted to 78 weeks when the difference grew to an 18 mg/dl difference. LDL and HDL cholesterol remained unchanged. After 52 weeks, ALT levels, a marker of liver damage, rose from a baseline of ~29 IU/L to 34 IU/L in patients on BIL compared to a reduction from ~28 IU/L to 27 IU/L in patients on glargine (p<0.001). Significantly more patients in the BIL arm experienced ALT levels three times the upper limit of normal (3X ULN): 2.3% of BIL patients compared to 0.6% of glargine patients (p<0.05). No patient met the criteria for Hy’s Law, which is the set of criteria used to suggest that a drug has a high risk of causing liver injury.
• A subset of patients (n=168) had their liver fat content analyzed by MRI, showing that patients on BIL had more fat in their livers than patients on glargine (this is consistent with BIL’s liver-targeted actions) than patients. At 52 weeks, BIL patients had 12.6% liver fat compared to 10% in glargine patients (p<0.01). Dr. Davies noted that the liver fat discrepancy resulted from a decrease in baseline in the glargine group with no change from baseline in the BIL group.

Questions and Answers

Q:  What treat-to-target algorithm was used?

A: We used a fairly conventional algorithm. The target was an A1c <7% and fasting glucose of 3.9-7.2 mmol/L [70-130 mg/dl]. We used the 2-4-6-8 approach to increasing glargine and BIL, which was consistent with the Riddle algorithm that has been previously published.

Q: What is a possible explanation for the impact on weight?

A: With previous insulins we had hoped that reducing nocturnal hypoglycemia may have an impact on weight, but that hasn’t always been case. Here we know BIL does have a reduced effect on the periphery and that may result in increased lipolysis and reduced fat storage. So that may be well part of the difference we see in weight.

Q: Congratulations for proving it is possible to do a double-blind insulin study, which no one does anymore. Do you think, with the liver issues, there is just a slight increase of transaminases or do we have a real problem?

A: That’s a good question. We did look at liver fats in this study, and we didn’t see an increase in liver fats in the BIL arm, but a reduction with glargine. This effect has been seen in glargine trials before and to the same extent that we see here. There is a poster that extensively talks about the ALT and liver changes across the IMAGINE program that you can refer to. This may well be a result of hepatic adaptation. That might be one of the explanations. But obviously we should continue to look at longer-term follow up data.

Greater HBA1c Reduction with Basal Insulin Peglispro (BIL) vs. Insulin Glargine (GL) in an Open-Label, Randomized Study in T1D Patients (pts): IMAGINE 1 (95-OR)

Satish Garg, MD (University of Colorado, Aurora, CO)

Dr. Satish Garg presented the IMAGINE 1 study in type 1 diabetes patients. The results show plenty of upside but also a sizable list of the safety signals that were seen elsewhere in the IMAGINE phase 3 program. We walked away from this talk slightly less than positive, not because any of the individual potential red flags are insurmountable, but because there are fairly many of them for a phase 3 candidate that we believe will dampen overall enthusiasm. However the positives – a significant 0.37% A1c benefit, a 2 kg (~4lb) weight benefit, and 36% nocturnal hypoglycemia reduction – still make this a unique and compelling candidate. Lilly has delayed peglispro’s timeline to better understand changes in liver fat, and at this point it is far from certain that peglispro will reach the market, although we believe Lilly and the peglispro investigators have made a compelling case in favor of liver-selective insulin.

• Following a two-week lead in, patients were randomized to peglispro or insulin glargine for a 26-week primary endpoint analysis followed by a final treatment endpoint at 78 weeks. Patients had an average age of 39 years, average BMI of 25 kg/m², average A1c of 7.9%, and average diabetes duration of 15-18 years. The majority were on insulin glargine at baseline (~70%).
• Efficacy: Peglispro led to a 0.69% A1c reduction from baseline after 26 weeks compared to -0.33% with insulin glargine, for a statistically significant difference of 0.37%. The difference was largely preserved out to 78 weeks, with glycemic control deteriorating slightly in both groups between weeks 26 and 78. There was a significant 22 mg/dl difference in fasting glucose at week 26, and a significant (p=0.019) though not enormous reduction in between-day FPG variability.
• Hypoglycemia: At 26 weeks, there was a significant 36% reduction in nocturnal hypoglycemia. However, there was a 29% significant increase in total hypoglycemia and a significant imbalance in severe hypoglycemia (15% vs. 8% out to 78 weeks). This drew some worry during Q&A, and it is hard to believe as strongly in the efficacy benefit with increases in both total and severe hypoglycemia – we think this would be considered a major negative since there are other alternatives that do not increase severe hypoglycemia.
• Safety: There were definite increases in triglycerides (~20 mg/dl), liver enzymes (around six times more cases of ALT rising to more than three times the normal upper limit), and liver fat, though Dr. Garg provided some cautious reassurance that the differences are not highly dangerous at the magnitudes seen. Importantly, there were no cases of Hy’s Law. There were no changes in HDL or LDL cholesterol. There was an imbalance in injection site reactions not favoring peglispro.

Questions and Answers:

Q: It looks like the increase in daytime hypoglycemia may have been due to more aggressive increases in BIL than glargine, as there were differences in glucose and A1c?

A: Yes this was an open label study, but IMAGINE 3 was a double blind randomized trial and the data there is nearly identical. The A1c lowering in that trial was in fact a shade better. By the way, during the day when we saw more hypoglycemia, it was not related to the basal insulin – it was related to the prandial insulin. Most hypoglycemia episodes occurred within three or four hours of taking prandial insulin.

Q [Dr. Stephanie Amiel (King’s College London, London, UK)]: We’ve all been waiting for hepato-selective insulin, but these results were a bit disappointing. You can’t describe it as better glucose control if there is an increase in control with increased severe hypoglycemia. To have “better control” you need to improve both. I also take issue with the idea that the difference in daytime hypoglycemia was only due to bolus insulin, because the only difference in the regimen was the basal insulin. The previous speaker [Dr. Tim Heise] showed that insulin glargine doesn’t provide 24-hour coverage. With very long acting insulin, patients can’t be flexible with dosing around changes in their activity. I’m wondering if you could compare against Levemir twice daily, which has full 24-hour coverage.

A: Those are good points, and I wish we could have used twice-daily glargine in our protocol. You are right that there was an increase in severe hypoglycemia if you look at 78 weeks. It’s a marginal increase, and if you combine the results from IMAGINE 3 and IMAGINE 1 there was no increase in severe hypoglycemia. If you hypothesis is correct that the increase was related to basal insulin, we would have seen no difference, or an increase, in nocturnal hypoglycemia.

Dr. Amiel: It depends on when the patients were taking their once daily glargine. If you take it at night, you obviously get higher action at night than you do later in the day. I’m commenting on increased severe hypoglycemia during the day, which I think is a worry for our patients.

A: I think some of this can also be answered by another poster where we gave insulin flexibly, from a range between eight and 48 hours.

Q: Given the increase in liver fat, might there be an increased long-term risk of steatosis?

A: Clearly there was an increase in liver fat. I would remind you that this insulin is more specifically targeted to the liver. Up to 78 weeks, you see that liver fat barely goes above the normal range, which is 5.5, and at most here we went up to 5.8 or 6. Liver fat that causes hepatic steatosis or insulin resistance is in the hundreds or thousands. My wife is a radiologist and has done lots of work in this area. I am not highly concerned about the liver fat changes with this insulin.

Q: Did you look at patient satisfaction?

A: I don’t know how many patients fill in those questionnaires. No, this was not part of this study.

Q: The company has delayed the submission of this insulin by two years, according to a press release. What will the company do during that time?

A: I do not work for the company, as you know. I work for the University of Colorado. I’m sorry but I don’t think I’d be able to answer that exactly. All I know is that they’re looking into future studies to explain whether the changes in liver fat will have any significance down the road. 

Reduced Intra-subject Variability of Basal Insulin Peglispro (BIL) Compared with Insulin Glargine (GL) in Patients with Type 1 Diabetes Mellitus (T1DM) (94-OR)

Tim Heise, MD (Profil, Neuss, Germany)

Dr. Tim Heise presented the results of a randomized, open-label study comparing the variability of the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of Lilly’s basal insulin peglispro (BIL) and Sanofi’s Lantus (insulin glargine). 75 patients with type 1 diabetes were randomized to receive a daily 0.5 U/kg dose of either peglispro or Lantus; blood samples were collected on days 8, 11, and 14 to assess the PK profiles of the two insulins, while 24-hour automated euglycemic clamps were performed to assess the PD profiles. Overall, the results suggested that peglispro had a flatter time-action profile than Lantus with a more even distribution of the glucose-lowering effect; the daily variability of both PK and PD profiles was statistically significantly lower for peglispro than for glargine. Dr. Heise concluded that this may have contributed to the superior A1c-lowering efficacy and reduced nocturnal hypoglycemia seen with peglispro vs. Lantus in other studies. These findings are potentially notable, as we see “time in zone” (and particularly avoiding severe hypoglycemia) as an important issue for patients that is too often overlooked by the medical and regulatory communities (to some extent this is understandable since less variability hasn’t been linked definitively with fewer complications). However, several attendees expressed skepticism about the results during Q&A due to limitations in the study design, and it remains to be seen to what extent they will be clinically meaningful.

Questions and Answers

Dr. Geremia Bolli (University of Perugia, Perugia, Italy): I want to point out some limitations of your investigation. You’re talking about PK, but you can’t really measure PK because the concentration of BIL that you report is not the free, biologically active insulin, but the total insulin, i.e. lispro bound to PEG which is not active. The total BIL insulin cannot be interpreted as “plasma insulin concentration” the way we traditionally use this parameter for example after NPH or glargine injection. So, your PK analysis for BIL is not valid, it is however for glargine. You also gave an unusually high dose of basal insulin, 0.5 U/kg for more than 1 weeks and this excess of basal insulin I am sure had to be compensated by reduction of prandial insulin dose and frequent snacking to prevent hypoglycemia. So, subjects were studied in metabolic conditions far from real life. Last, the total glucose infused over 24 h in response to same dose of insulin was much less with BIL as compared to glargine as to suggest that 1 unit of BIL is much less active than 1 unit of glargine, despite 1 unit of BIL contains 9 mmol of insulin which 50% more as compared to the 6 mmol in 1 unit of insulin glargine. Thus, the present formulation of BIL is not bioequivalent to glargine.

A: Your talk was nearly longer than mine! PK is not completely meaningful, but the comparison in variability may be meaningful even though the absolute levels are different. I agree that PD is more important, and PD was very much in line with PK. The 0.5 U/kg dose was higher than the dose patients used, which was around 0.3-0.4 U/kg because you need a higher dose to get a glucose infusion rate during the clamp, but we didn’t have lots of hypoglycemia.

Dr. Bolli: Thanks for agreeing that we can forget about the variability in PK, which wasn’t meaningful. You gave 0.5 U/kg of glargine, which resulted in high glucose utilization, higher than what people in real life need to regulate glucose metabolism in a post-absorptive state. My real point is that what you showed here is the difference in variability or potency of one unit of glargine vs. one unit of BIL. BIL is concentrated to 9 nM/ml and glargine is 6 nM/ml. Yet one unit of BIL was less effective than one unit of glargine.

A: I disagree. This is what patients will experience using equal units. It’s a fair comparison. This is the variability they will experience. There are limitations in all studies, but there’s not doubt that glargine’s variability is substantially higher with regard to both PK and PD. I think it’s very meaningful.

Q: Do you think we should use insulin glargine twice daily rather than once?

A: That’s a good point. Many type 1 diabetes patients do. It’s a very sensible thing to do, it’s just against the label.

Q: If I used BIL every other day, the variability would probably exceed the variability of glargine. It’s the ratio of frequency and half-life that matters. Was this study necessary, because it should be obvious? With a three-day half life, this should be expected. If it’s used less frequently, variability would go up.

A: I agree that the longer half-life should have advantages in variability. Glargine has a good time-action profile, but there are issues because it precipitates whereas others stay in solution.

New Insulin Glargine 300 U/mL Provides Sustained Glycemic Control and Reduced Hypoglycemia over 12 Months Compared with Glargine 100 U/mL in Japanese (98-OR)

Yasuo Terauchi, MD, PhD (Yokohama City University, Yokohama, Japan)

Dr. Yasuo Terauchi presented full-year results from the EDITION JP 2 study, which randomized 241 type 2 diabetes patients on basal insulin plus oral drugs to either Toujeo (insulin glargine U300) or Lantus (insulin glargine U100). At one year, both groups experienced comparable A1c reductions from baseline of around 0.3% from a baseline of 8%. The average daily dose of Toujeo was around 20% higher (0.36 U/kg/day vs. 0.30 U/kg/day), and the annualized rate of confirmed or severe hypoglycemia was significantly lower with Toujeo: 36% less (95% CI: 6%-56% less) at any time of the day, and 59% less (95% CI: 8%-82% less) nocturnally. Though the confidence intervals were wide, from the Kaplan-Meier curves there definitely did seem to be a benefit, particularly at night. Toujeo performed particularly well in this population from a body weight perspective, with 0.7 kg (~1.5 lbs) mean weight loss vs. 0.5 kg (~1 lb) weight gain with Lantus – seeing weight loss (as opposed to less weight gain) is unusual for a clinical trial with insulin, and the weight loss was seen regardless of whether patients were on a sulfonylurea at baseline, suggesting a reduction in sulfonylurea dose was not the culprit. All in all, we see EDITION JP 2 as contributing to the real differentiation for Toujeo vs. Lantus, although it is hard to get a great handle on the true degree of the hypoglycemia benefit due to the post-hoc slicing and dicing of those data. We see different factors resulting in success commercially for Toujeo including an intensive focus on access by Sanofi, increased attention on increasing adherence through COACH, and an easier-to-use pen (partly stemming from lower injection volume per unit). 

Safety and Efficacy of Insulin Glargine 300 U/ml (Gla-300) Compared with Other Basal Insulin Therapies in Patients with Type 2 Diabetes Mellitus (T2DM)—A Network Meta-analysis (NMA) (99-OR)

Hongwei Wang, PhD (Sanofi, Bridgewater, NJ)

Dr. Hongwei Wang presented a network meta-analysis of trials to indirectly compare Sanofi’s Toujeo (U-300 glargine formulation) with other basal insulins. Currently there are no head-to-head comparisons for U-300 against NPH, Tresiba, Levemir, or pre-mixed insulins. The network meta-analysis is a statistical tool used to integrate both direct and indirect evidence to make comparisons of U-300 glargine to these other insulins. We’ve seen more network meta-analyses at meetings as of late; for example, Lilly’s presented a network meta-analysis for Trulicity (dulaglutide) at EASD last year. The Toujeo analysis showed no difference in A1c change from baseline with U-300 glargine vs. comparators. However, rates of nocturnal hypoglycemia were significantly lower compared to U-100 glargine (Lantus), NPH, and pre-mixed insulin, as expected. Documented symptomatic hypoglycemia was also numerically lower on Toujeo compared to other insulins. Limitations of the study include that it utilized only study-level results, and the study populations and design characteristics might not be accounted for in the analyses. We do not believe these data add much new to the understanding of the safety and efficacy of Toujeo, but we imagine that Sanofi is interested in bolstering claims for Toujeo’s nocturnal hypoglycemia benefit since it was not able to include this claim in the label.

Improved Glucose Control Without Increased Hypoglycemia Risk at Any Level of HbA1c Reduction with Insulin Glargine/Lixisenatide Fixed-Ratio Combination (LixiLan) vs. Insulin Glargine Alone (169-OR)

Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Julio Rosenstock presented a post-hoc phase 2 analysis on Sanofi’s LixiLan (lixisenatide/insulin glargine) that found no correlation between A1c levels achieved with LixiLan and hypoglycemia risk. The 24-week study (n=323), presented at last year’s ADA, demonstrated striking A1c reductions in both the LixiLan and Lantus (insulin glargine) groups, with a slight but statistically significant advantage (1.8% vs. 1.6%) for LixiLan. While there was no difference between the groups in incidence of documented symptomatic hypoglycemia (≤70 mg/dl), the primary results did not indicate whether participants who achieved tighter control or larger A1c reductions were at increased risk of hypoglycemia. This analysis divided patients into subgroups based on their A1c at the end of the study (<6%, 6-6.5%, 6.5-7%, or >7%) and magnitude of A1c reduction from baseline (<1%, 1-1.5%, 1.5-2%, or >2%). Results showed no significant relationship between these parameters and rates of documented symptomatic hypoglycemia, challenging the traditional conventional wisdom that tighter control raises the risk of hypoglycemia – this of course has been seen in older outcomes trials like DCCT and UKPDS when far less stable insulins were used. The finding is not as surprising for LixiLan, as GLP-1 agonist/basal insulin combinations appear to come with a relatively low risk of hypoglycemia compared with insulin alone. It is definitely more surprising for the Lantus comparator arm, as more intensive control with insulin usually does mean more hypoglycemia. The lack of an increase in hypoglycemia with larger A1c reductions may speak to the skill of the study investigators – for now we would not necessarily assume that these findings are generalizable to less optimal settings although we do think that a more stable product like LixiLan would be associated with less hypoglcyemia.

Questions and Answers

Q: A number of observational studies have shown no association with hypoglycemia and baseline A1c, and large studies have been done recently. We think the lower we go, the more hypoglycemia we get. Why are we at that stage now?

A: I don’t know. We showed the same thing in ORIGIN. Regardless of baseline A1c, even if it’s 7.5% or 7%, that doesn’t mean people will have more hypoglycemia. If you drop 2%, it doesn’t mean you get more hypoglycemia. It’s very interesting. It may be a marker of other things.

Q: Were both groups pretty similar?

A: These are small numbers; when you split into so many groups you have 25-30 people per group, but that’s why they did all these trend analyses. They were very specific. Baseline A1c was a good predictor of subsequent A1c. You always say if you start at a higher A1c you get a bigger drop. Regardless of the drop, you eventually have a delta of 0.317.

Q: Are you sure the PK profiles of both are preserved or does glargine precipitate?

A: We have the PK/PD data and it’s pretty consistent. The formulation doesn’t affect PK.

Q: It looked like the insulin dose was the same. You didn’t save any insulin?

A: There was a little less insulin with LixiLan but not much. This was a very specific homogeneous population with early type 2 diabetes, which is why you saw that kind of response. We have other studies where we’ll see whether the difference is greater.

Unique Profile of the Weekly Insulin HM12470: Very Slow Onset of Action, Rapid Off-Rate Similar to Insulin, and Absence of Insulin Receptor Downregulation (96-OR)

Nina Wronkowitz (German Diabetes Center, Düsseldorf, Germany)

Dr. Nina Wronkowitz presented on the mechanistic profile of Hanmi’s novel basal insulin analog, HM12470, which has potential for once-weekly dosing given its long half-life (expected to be 132 hrs in humans). The candidate was recently advanced into phase 1 under the new name LAPSInsulin-115. Investigators in this study sought to characterize HM12470’s action at the insulin receptor, especially to allay any fears of mitogenic (cancer-inducing) activity due to HM12740’s very long half-life and the insulin receptor’s dual role in stimulating glucose uptake and in cellular proliferation. HM12470 showed a similar receptor dissociation rate compared to regular human insulin in a rat cardiomyoctye (heart cell) line overexpressing the human insulin receptor. HM12470 also had similar mitogenic activity and metabolic activity compared to human insulin. Uniquely, Dr. Wronkowitz reported that while regular insulin is known to cause downregulation of the insulin receptor in the chronic setting (>24 hrs), HM12470 does not induce insulin receptor downregulation, which suggests that each unit of HM12470 may have a more prolonged effect than each unit of regular insulin.

Questions and Answers

Q: What could be a possible mechanism for the lack of downregulation of the insulin receptor after exposure to this agent?

A: We have preliminary data showing that HM12470 is not internalized together with the insulin receptor after binding, so that’s the reason why the insulin receptor stays at the membrane and is not internalized and degraded. This could also be a reason for the very long half-life of HM12470.

PE0139, the First Recombinant Fully Human Monomeric Super-Long-Acting Basal Insulin to Display a Sustained Nearly Peakless Insulin Profile Following a Single Subcutaneous Dose in Subjects with T2DM Supporting Weekly Dosing (100-OR)

Poul Strange, MD, PhD (PhaseBio Pharmaceuticals, Malvern, PA)

Dr. Poul Strange outlined the results of a phase 1 single ascending dose trial (n=37; ClinicalTrials.gov Identifier: NCT01835730) of PhaseBio’s ultra-long-acting basal insulin PE0139 in patients with type 2 diabetes. PE1039 consists of native human insulin fused at the DNA level to an elastin-like peptide (ELP) polymer that allows for more gradual release and a longer duration of action. Participants were randomized to receive a single subcutaneous injection of either placebo or one of four doses (0.05-1.35 mg/kg) of PE0139 and were followed for 28 days to evaluate safety and tolerability. The trial also included secondary endpoints related to pharmacokinetics (PK) and glycemic control. Results showed that PE0139 was well tolerated at the doses tested, with mild injection site reactions the only notable adverse event identified. There were no concerning signals related to cardiovascular safety (such as increases in heart rate or blood pressure) and no indication of changes in liver enzymes. PK results showed that PE0139 was released at a relatively constant rate over the course of a week and produced significant reductions in fatty acids and fasting glucose. While Dr. Strange acknowledged that the study was too small to identify a clear dose-response curve, he stated that there were “real differences” between treatment groups and that the investigators were optimistic for future trials.

• PhaseBio plans to initiate a multiple-dose study of PE1039 in 3Q15 and is conducting preclinical experiments of the compound in combination with a once weekly GLP-1 agonist. The company announced in March that it had raised $40 million in Series C financing, which is expected to cover costs until the end of 2016. We assume that the potential GLP-1 agonist combination would involve PhaseBio’s once-weekly candidate PB1023, which was placed on hold as a monotherapy after failing to achieve non-inferiority vs. Novo Nordisk’s Victoza (liraglutide) in a phase 2b trial – we imagine that such a once-weekly GLP-1 agonist/basal insulin combination would be a very appealing option for many patients.

Questions and Answers

Q: How do you metabolize and excrete the biopolymer formulation of the microspheres? Do they break down subcutaneously or are they absorbed in the circulation?

A: They are self-aggregates that are slowly released but intact and then broken down. It might be a substrate for elastase. We haven’t done careful studies yet.

Q: Are they broken down in the circulation?

A: There or in the tissues. It stays around everywhere and gets excreted by the kidneys.

The In Vitro and In Vivo Pharmacology of AB101, A Potential Once-Weekly Basal Subcutaneous Insulin (97-OR)

Brian Roberts, MD (Mills-Peninsula Health Services, Emeryville, CA)

Dr. Brian Roberts presented preclinical results for AntriaBio’s once-weekly insulin AB101, a microsphere formulation of PEGylated human recombinant insulin. The formulation does not involve any modifications to the native human insulin structure, which Dr. Roberts highlighted as a potential safety advantage. In vitro studies of AB101 confirmed the expected binding kinetics at the insulin and IGF-1 receptors and demonstrated a pharmacokinetic (PK) and pharmacodynamic (PD) profile comparable to that of native human insulin. Dr. Roberts presented the results of a 14-day trial in rats (n=6 per group; 37.5 mg/kg AB101 or vehicle control) and dogs (n=3 per group; 10 mg/kg or 37.5 mg/kg of AB101) evaluating the effects of a single subcutaneous dose on insulin and glucose levels. Results showed a very flat effect on insulin and glucose levels over the first 24 hours after administration (the typical duration of action for current basal insulins) and then a gradual, sustained increase in insulin levels over approximately one week associated with a reduction in glucose; hypoglycemia was only present at the highest dose level for dogs. Dr. Roberts concluded that this data supports once-weekly administration of AB101 in humans at clinically relevant doses and that the slow onset should lead to improved insulin and glucose levels without the risk of hypoglycemia associated with an acute release of insulin. AntriaBio believes the smaller size of the AB101 PEG group should help AB101 avoid the degree of liver effects seen with Lilly’s peglispro (phase 3 data presented in this same session) – still, we imagine the company will be looking at liver safety and lipids very closely in clinical development given that it has created meaningful issues for Lilly.

• AntriaBio is currently conducting IND-enabling studies for AB101 and plans to submit an IND application in the near future. The company announced in January that it had raised $7 million in a private placement transaction that would enable initiation of a phase 1 trial in type 1 diabetes in 2H15, assuming the IND filing is successful. If all goes well, the company anticipates an approval by 2022.

Questions and Answers

Q: What are the key differences between AB101 and other approved basal insulins?

A: The key point is that AB101 is a formulated product and the extended duration is achieved through slow release. The PEGylation group is small, about 5 kD, and it has increased solubility in the polymer, allowing it to be injected and slowly released. It’s an elegant formulation that doesn’t require modification to the native hormone.

Q: In the non-diabetic animals, did you measure insulin levels at baseline?

A: The baseline was shown. The scale on the x-axis was hard to see, but the baseline levels were measured and were on the figures.

Oral Presentations: Assessing and Improving Adherence to Insulin Therapy

Does Insulin Adherence Decline With More Injections?

Ian Blumer, MD, (University of Toronto, Ajax, Ontario)

A provocative presentation from the charismatic Dr. Ian Blumer sought to demystify a thought-provoking question: Does insulin adherence decline with more frequent injections? Turning to geography for a lighthearted analogy, he suggested that the question may not be as straightforward as it appears, just as Mount Everest is not the world’s tallest mountain (that would be Mauna Kea in Hawaii, as Mount Everest is the world’s “highest” mountain). Similarly, Dr. Blumer suggested that there is more nuance to this debate than a yes or no answer. Taking on a behavioral view, Dr. Blumer suggested that there are other salient factors beyond injection frequency – such as patient-level motivation – that are at play when looking at adherence rates with injections. Indeed, in his view, it has not been definitely established that insulin adherence declines with more frequent injections (“though it probably does”). As a result, he advocated for providers to keep an open mind in thinking about the lurking variables (e.g., discomfort, inconvenience) that may drive lesser adherence. Ultimately, we appreciated this patient-oriented spirit from Dr. Blumer and applaud his effort to generate greater conversation about the psychosocial aspects of diabetes management. We are interested in HCP feedback to other questions about pens, like, if a pen is easier to use (less force), does his make a meaningful impact for patients? This seems to be the case for Toujeo and we’d love to understand any commercial benefit. We’d also love to better understand the degree to which oral drugs are delaying MDI – we certainly think they are but it’s hard to accurately forecast the degree to which this is happening.

Questions and Answers

Q: Does this question even make sense to begin with?

A: I think it does. I believe that we, as diabetes health care providers, often take it as a given that more frequent insulin injections in and of themselves increase the likelihood of missed doses without us first doing our due diligence and looking for –and addressing – other, modifiable factors that might be leading to missed doses; factors such as inconvenience or embarrassment giving insulin at work or school, injection discomfort, fear of hypoglycemia, and so on.

Q: Multiple injections are often synonymous with better control. However, can you argue that maybe MDI is not the best regimen?

A: I think that for our patients with type 1 diabetes, CSII or multiple daily insulin injections (MDI) are indeed far more likely to achieve better – and safer – control than using split-dose, mixed insulin therapy. For our patients with type 2 diabetes who require more than one insulin injection per day, MDI is also typically preferred over split-dose, mixed insulin. There is, however, a large subset of patients with type 2 diabetes who are on huge doses of insulin because of extreme insulin resistance – taking hundreds of units of insulin per day. For these patients I think it is far less important to tease out and fine tune the theoretical, minute benefits of one insulin regimen versus another and far more important to make sure the patients are getting enough insulin, however it is given. As I jokingly say, just pull up the dump truck and pour in the insulin!

Q: I do think that perhaps the number of injections is trumped by convenience and flexibility? Do you think we’re doing enough to help patients with diabetes?

A: Absolutely yes; many patients on MDI find it onerous to take the number of injections we ask them to and that they, ideally, ought to. I think that there are many patients on MDI who would be far better served by CSII and, in particular, would find it much more convenient to give boluses – including correction boluses – if they were on a pump. And even at that, using a pump is very labor-intensive and demands a great degree of hands-on patient effort in order to maximally benefit from it. As health care providers we ask so very much of our patients living with diabetes – all our patients with diabetes - and I think we have to be more sensitive to the demands we place on our patients and, moreover, we need to be more aware of the incredible work involved by the very fact of living with diabetes. So many patients are referred to me and within minutes of walking into the office for the first time they are in tears because they feel so incredibly burdened by an unremitting and pervasive feeling that their entire life revolves around their diabetes and its management. I can see the cloud lift as I tell them “we are going to change all that” and that “we will manage their diabetes around their life, not their life around their diabetes.” Better – and more convenient – therapies will go a long way to help us do this. I can’t wait for the artificial (bionic) pancreas to become routinely available. I believe this will be the single most life-changing and life-enhancing therapy for our type 1 patients (and many insulin-treated type 2 patients eventually) since the discovery of insulin.

Oral Presentations: Combining Basal Insulin and GLP-1 Agonists

Insulin Degludec/Liraglutide (IDegLira) is Superior to Insulin Glargine (IG) in A1c Reduction, Risk of Hypoglycemia, and Weight Change: DUAL V Study (166-OR)

John Buse, MD, PhD (UNC, Chapel Hill, NC)

Two years after taking the podium at ADA to present the strong results from the DUAL I study on Novo Nordisk’s GLP-1 agonist/basal insulin combination Xultophy (IDegLira; insulin degludec/liraglutide), Dr. John Buse returned to the podium to present the first phase 3 trial comparing Xultophy and class-leading basal insulin Lantus (insulin glargine). The study randomized 557 patients with type 2 diabetes already on Lantus + metformin to either intensify their Lantus therapy or switch to Xultophy. The results this time around were just as impressive as for DUAL I: after 26 weeks, Xultophy led to a 1.8% A1c decrease from a baseline of 8.4% to a striking final A1c of 6.6%; Lantus intensification led to a 1.1% reduction in A1c from 8.2% to 7.1%; the treatment difference was 0.6% and was statistically significant (p<0.001). Those who know the DUAL I data will know that the benefits do not stop there. Xultophy boasted a more than 3kg (~7lb) weight benefit vs. Lantus (-1.5kg [~3lb] absolute weight loss from baseline). Xultophy caused 57% fewer episodes of confirmed hypoglycemia (p<0.001) and a stunning 83% reduction in nocturnal hypoglycemia (p<0.001). There were also increases in certain quality of life metrics and 5.5 times more patients with Xultophy who achieved an A1c below 7% without hypoglycemia and weight gain. Incidence of nausea was below 4% throughout the trial; there were more subjects (58% vs. 51%) with adverse events but fewer severe adverse events with Xultophy. When compared beside new basal insulins that are struggling to show benefits vs. Lantus, these and other DUAL program results look quite compelling. We learned during Novo Nordisk’s analyst event at ADA (see our ADA Exhibit Hall & Corporate Updates Report) that the company will hold off on submitting Xultophy in the US until later this year, even though it has already resubmitted Tresiba (insulin degludec). This means that Xultophy is unlikely to become available in the US until late 2016 at the earliest.

• Q&A Highlights: Dr. Philip Home (University of Newcastle, Newcastle Upon Tyne, UK) and Dr. Naveed Sattar (University of Glasgow, Glasgow, UK) questioned whether DUAL V tested a fair comparison. Dr. Sattar noted that it was essentially a test of two drugs vs. one, although Dr. Buse made the good counterargument that it was a test of one injection vs. one injection. Dr. Home pointed out the potential for biased responses because DUAL V was open label – Dr. Buse pointed to DUAL II, a blinded trial in which Xultophy had similar efficacy. In response to a question of what to do in the sizable percent of patients that reached the maximum Xultophy dose, Dr. Buse speculated (after multiple disclaimers that what he was about to say involved very off-label use) that “creative” clinicians might double-dip from the same pen to achieve a higher maximum dose, especially because a >1.8 mg dose of liraglutide (Saxenda) has been approved.
• Study Design: DUAL V was an open label, randomized, phase 2b trial enrolling 557 type 2 diabetes patients for 26 weeks of treatment. Previous trials like DUAL I and DUAL II have compared Xultophy against one or both of its component drugs, whereas this trial was intended to shape clinical decision-making for providers of the many patients on Lantus that need improved glycemic control. Patients were randomized to either stay on Lantus, intensifying treatment as per a treat-to-target titration protocol, or to switch to Xultophy. The starting dose of Xultophy was pre-specified at 16 dose steps (16 U insulin degludec, 0.6 mg liraglutide) – as a result, a secondary goal of the trial was to confirm that switching patients from Lantus to Xultophy could occur smoothly and without greatly diminished glycemic control.
• Baseline Characteristics: Average age was around 60 years, average BMI was 32 kg/m², mean diabetes duration of 11-12 years, and mean A1c of 8.3%. All patients were on insulin glargine + metformin at baseline, with a mean pre-trial insulin dose of 31-32 U. 
• Efficacy Results:
  
  • A1c: From a baseline of 8.4%, the Xultophy group experienced a mean A1c reduction of 1.8%, reaching a strikingly low mean final A1c of 6.6%. By comparison, the group continuing and intensifying their Lantus therapy saw a change of -1.1% from a baseline of 8.2% to a final A1c of 7.1%. The difference in the A1c reduction was 0.6% in favor of Xultophy.
  • Fasting Glucose: There were no significant differences in fasting glucose over the course of the trial. If anything, at early points it seemed that the Xultophy group had a slightly lower mean FPG. The significance here is that patients were able to maintain glycemic control even when switching over to a 16 unit dose of Xultophy from their previous Lantus dose.
• Body Weight: Not only did Xultophy hold a 3 kg (~7 lb) weight advantage in terms of weight gain reduction over Lantus, patients on Xultophy actually lost weight (-1.4 kg [~3 lbs]) from baseline.
• Hypoglycemia: Patients on Xultophy had a statistically significant 57% lower risk of confirmed hypoglycemia than patients on Lantus (p<0.001). Even more positively for Xultophy, the combination led to a massive 83% reduction in nocturnal confirmed hypoglycemia (p<0.001) based on a smaller but still considerable number of events (195).
• Composite endpoints: In presentations of DUAL data, investigators have done a good job of showcasing Xultophy’s comprehensive benefits by presenting comparisons of the percentage of patients who achieve target A1c without hypoglycemia or weight gain. In this trial, 39% of patients achieved A1c targets with Xultophy vs. 12% with Lantus (p<0.001), for an odds ratio of 5.5.  
• Insulin dose: Patients in the Xultophy group leveled off at a mean dose of 41 dose units, whereas patients in the Lantus group experienced a continued climb, ending at 66 units at the end of the trial.
• Quality of life: Across the board in an SF-36 health-related quality of life questionnaire taken at the end of the study, Xultophy scored higher (or at least trended higher) than Lantus. The summary of physical quality of life showed a statistically significant difference in Xultophy’s favor, while the mental quality of life composite was a non-significant trend in Xultophy’s favor. More detailed quality of life data from DUAL V was published independently as a publish-only abstract (2550-PO).
• Adverse events: The rate of patients experiencing adverse events over the trial was higher with Xultophy than with Lantus (58% vs. 51%). Beyond noting that nausea was higher in the Xultophy group (though notably always below 4% - quite good given the GLP-1 agonist component), we did not get to see what else contributed to the imbalance. In contrast, the imbalance in serious adverse events tipped in Xultophy’s favor (3.9 vs. 6.7 SAEs per 100 patient-years).
  
  • In a qualitative description of adverse events, we learned that: (i) CV events were balanced between groups, with one stroke with IDegLira and one CV death with Lantus; (ii) There were no confirmed events of acute pancreatitis; (iii) There were two confirmed malignant neoplasm events with Xultophy and one treatment emergent confirmed event of metastatic pancreatic carcinoma in a subject previously treated with Xultophy; and (iv) there were no confirmed medullary thyroid carcinoma cases.

Questions and Answers:

Q: This seems to be a comparison of two drugs vs. one. Wouldn’t it be fairer to study IDegLira vs. insulin glargine plus liraglutide given separately, the way you have to give them currently?

A: There are other studies that have compared basal insulin + GLP-1 vs. basal plus bolus insulin. The difference in A1c in those trials was less, but the relative benefit for hypoglycemia was greater. I think this is a fair fight because we’re comparing one injection vs. one injection. The commonly used approach for type 2 diabetes is to just keep pushing the one injection. But yes, there is lots of room for many more studies.

Comment (Dr. Philip Home [University of Newcastle, Newcastle Upon Tyne, UK]): Few of us would treat patients failing glargine alone with glargine alone. It seems to be an irrelevant comparator. Isn’t there also a scientific problem with an open label study where you take some people on insulin glargine and move them to a new therapy? This could have impacted hypoglycemia and especially the quality of life questionnaire results.

A: There is a blinded study, DUAL II, where the insulin dose was capped and the primary goal was to examine the contribution of liraglutide. The results were similar in some ways, giving us reassurance that there can be meaningful results even in blinded situations. Secondly, the titration was conducted with equipoise and at the end of the trials the fasting glucose levels were essentially identical. Finally, in endocrine practices in the US and around the world, for patients with A1cs around the mid 8% range, the standard practice is to continue titrating insulin. I think this is a relevant comparison. That said, there is definitely room for further studies to examine other relative effects. Comparative effectiveness is going to be an important area for many years to come.

Q: In terms of patients at the maximum dose reached in treat-to-target, what options are there to keep pushing further with IDegLira?

A: The on-label use in this product, which is available in Europe, is that you would need to add something else. That could be an oral agent, but we don’t have many studies with SGLT-2 inhibitors combined with GLP-1 agonists, and certainly no studies of GLP-1 agonists, SGLT-2 inhibitors, and insulin combined on background metformin. Another possibility would be to add bolus insulin or more basal insulin. That decision would be based on patient characteristics. The off-label thing that one could … hallucinate, since GLP-1 doses higher than 1.8 mg are approved for obesity … one could have a very high-order hallucination about taking another dip on the same pen, continuing to increase the dose of the GLP-1 analog and basal insulin. But we have zero evidence on that. I know creative clinicians will find all kinds of things to do when a product is available.

Assessment of Glycemic Control by CGM in Patients with T2D Treated with IDegLira (170-OR)

Allen King, MD (Diabetes Care Center, Salinas, CA)

Dr. King presented the results of a post-hoc analysis of a DUAL I extension substudy examining changes in glycemic fluctuations over 52 weeks in insulin-naïve patients with type 2 diabetes treated with Xultophy (IDegLira; insulin degludec/liraglutide) (n=131) versus insulin degludec (n=64) or liraglutide (n=65) alone. 72-hour continuous glucose monitoring was performed at baseline and at 52 weeks, which showed that IDegLira treatment was associated with a greater reduction in mean interstitial glucose (IG) than liraglutide (p<0.0001), a greater reduction in postprandial IG versus insulin degludec (p=0.0288), and a greater reduction in time out of range versus liraglutide (p=0.0072). Dr. King commented that these observations may have contributed to the greater A1c reductions seen with IDegLira than with either component medication in the DUAL I study. For detailed information about DUAL I baseline characteristics and methodology, please see our coverage of the initial 26-week results presented at ADA 2013.

• IDegLira treatment was associated with a greater reduction in mean interstitial glucose (IG) than liraglutide (p<0.0001), a greater reduction in postprandial IG versus insulin degludec (p=0.0288), and a greater reduction in time out of range versus liraglutide (p=0.0072). Mean IG decreased 63.1 mg/dl, 64.9 mg/dl, and 45.0 mg/dl from baselines of 180-184 mg/dl with IDegLira, insulin degludec, and liraglutide treatment, respectively. Postprandial IG changed an average of -9.0 mg/dl, 3.6 mg/dl, and -3.6 mg/dl from baselines of 25-27 mg/dl with IDegLira, insulin degludec, and liraglutide treatment, respectively. Time outside of the IG target range (70-162 mg/dl) at the end of the study were 3.2 hours, 3.8 hours, and 5.6 hours from a baseline of 14-15 hours with IDegLira, insulin degludec, and liraglutide treatment, respectively.

Questions and Answers:

Dr. Philip Home (Newcastle University, Newcastle, United Kingdom): Nice study, and nice data. I just want to make a plea. These are supposed to be scientific sessions. There are things called standard deviations, confidence intervals, [etc.,] that would allow me to understand your data. Can we ask that that these have conventional measures of dispersion to go with the mean?

A: Some of the data was statistically analyzed, but the duration of the talk did not allow me to discuss them.

Superior Effects with Combination of Insulin Degludec (IDeg) and Liraglutide (Lira) (IDeg+Lira) Compared with Basal-Bolus Insulin Therapy (BB) in Hemodialysis (HD) Patients with Poorly Controlled Type 2 Diabetes (T2D): An Assessment by Continuous Glucose (171-OR)

Satoshi Funakoshi, MD, PhD (Jikei University, Tokyo, Japan)

Dr. Satoshi Funakoshi presented a unique study investigating the effects of GLP-1/basal insulin combination therapy on glycemic variability and control in 12 dialysis patients. For background, dialysis presents a challenge for glucose management because it can cause hypoglycemia. A potential mechanism to explain this effect is that glucose is cleared more quickly through the hemodialysis membrane than is insulin, so patients undergoing dialysis experience a temporary hyperinsulinemic state. Dr. Funakoshi’s study sought to compare the efficacy of basal insulin + GLP-1 agonist therapy (Tresiba + Victoza) compared to basal-bolus insulin therapy (Tresiba + Humalog) for controlling fasting plasma glucose and glucose variability in type 2 diabetes patients on dialysis. In this study, patients started on basal-bolus therapy and then transitioned to GLP-1/basal therapy. Glycemic variability was measured by CGM. As shown in the table below, during the basal-bolus portion of the study, patients experienced worse glycemic variability on days where they got dialysis (p<0.05 for mean amplitude of glucose excursions [MAGE] off vs. on). However, transitioning to GLP-1/basal therapy cut MAGE in half for both on and off dialysis days (p<0.05 for basal-bolus compared to GLP-1/basal), and the difference between on and off dialysis days was no longer significant. The GLP-1/basal combination also improved FPG. In conclusion, this small study suggests that the combination of insulin degludec and liraglutide can both improve glycemic control and glycemic variability in dialysis patients. This further bolsters GLP-1 agonists’ utility in patients with renal impairment, who may not be able to use therapies like SGLT-2 inhibitors or even metformin.

Table: Glucose variability (MAGE) and fasting plasma glucose (FPG)

	Off-dialysis days	On-dialysis days
Basal-bolus	MAGE = 108 mg/dL FPG = 166 mg/dL	MAGE = 133 mg/dL FPG = 145 mg/dL
GLP-1/basal	MAGE = 55 mg/dL FPG = 131 mg/dL	MAGE = 75 mg/dL FPG = 118 mg/dL

Questions and Answers

Q: The GLP-1 agonist label says not to use these drugs in people with renal failure. What is the PK of liraglutide in people on dialysis?

A: Insulin degludec and liraglutide are not removed by dialysis, and that is the point. The PK profile is not affected, as published last year.

Q: Did you look at the proportion of patients experiencing hypoglycemia both on and off dialysis?

A: We did not see any symptomatic hypoglycemia. During hemodialysis, the glucose drops not only because of the insulin issue, but also removing toxins improves insulin resistance peripherally. Removal of fluid improves over-hydration, which improves insulin resistance. pH goes up, which encourages glucose to go into cells. So all the factors push down glucose at the end of hemodialysis, but for some reason we did not experience symptomatic hypo.

Least Glucose Variability and Hypoglycemia Is Observed with the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study) (167-OR)

Harpreet Bajaj, MD, MPH (LMC Diabetes and Endocrinology, Toronto, Canada)

Dr. Harpreet Bajaj provided interest-piquing if not completely surprising evidence that the combination of a basal insulin and a GLP-1 receptor agonist (RA) provides the least glycemic variability among several commonly used insulin regimens. The study enrolled 150 subjects (ages 18-80) with A1cs ≤7.5% who were on one of four stable diabetes regimens containing insulin for six months prior to the study (basal insulin + oral agent, basal insulin + GLP-1 RA, premixed insulin, MDI basal bolus regimen). In the six-day protocol, subjects continued their existing lifestyle and treatment regimens and were monitored with masked CGM as well as SMBG (≥4 times daily). A combination of a basal insulin + a GLP-1 RA resulted in significantly lower daily standard deviation of glucose than alternate regimens (SD = ~31 mg/dl vs. ~34 mg/dl with basal + oral agent, ~36 mg/dl with premixed, and ~38 mg/dl with basal-bolus MDI). Both the basal insulin + oral agent and basal insulin + GLP-1 RA regimens resulted in significantly lower self-reported hypoglycemia than the premixed or MDI regimens (basal + oral agent = 20% hypo rate, basal + GLP-1Ra = 17%, premixed = 35%, basal-bolus = 57%). Overall, the authors concluded that a combination of basal insulin + GLP-1 RA provides the least variability versus three commonly prescribed insulin regimens. While the difference in standard deviation was perhaps slightly more modest than we might have expected vs. MDI, but a ~20% improvement is still highly meaningful and could mean substantially less time at extreme ranges.

Synergistic Action of PE0139, a Super-Long-Acting Basal Insulin, and PB1023 a Weekly GLP-1 Receptor Agonist (168-OR)

Jim Ballance, PhD (PhaseBio Pharmaceuticals, Malvern, PA)

Dr. Jim Ballance presented pre-clinical data suggesting that PhaseBio’s long-acting basal insulin, PE0139, and weekly GLP-1 agonist, PB1023, could have synergistic effects when combined. For background, both agents use PhaseBio’s ELP biopolymer technology to prolong half-life. The GLP-1 agonist (PB) is in phase 2 and the insulin (PE) in phase 1. This db/db mouse study found that low doses of PE and PB were inadequate as monotherapy for bringing glucose levels within control in response to an intraperitoneal glucose tolerance test. However, the combination of the two products normalized glucose control in a greater-than-additive fashion, even with the same low doses of each individual component that were ineffective in the monotherapy arms. Synergistic (more than additive) efficacy has not been seen in the largest clinical trials of GLP-1 agonist/basal insulin combinations, although it is far from certain whether these preclinical results can be duplicated in humans. Dr. Ballance remarked that PhaseBio plans to commence a six-week phase 2 multiple ascending dose study with basal insulin PE in 2H15 with a PE/PB combination study to follow.

• For background, PE0139 and PB1023 use PhaseBio’s elastin-like polypeptide technology (ELP) to extend half-life. The ELP is a set of repeating five amino acid sequences (VPGXG where X is any amino acid except proline). The ELP polymer, when fused to a peptide of interest, confers a longer half-life to the peptide of interest by allowing the fusion product to undergo the process of “coacervation” under specific temperature and solvent conditions. Coacervation is a liquid-liquid phase separation, rendering the drug either available or not available to be absorbed. By varying the number of repeats in the ELP, the concentration of the protein, the concentration of salts in the solvent, and the hydrophilicity of the protein, one can control at what temperature the phase separation occurs and, thus, control the temperature at which the drug essentially becomes available to be absorbed. Thus, one mechanism by which ELP prolongs a drug’s half-life is via this slow, controlled release. The other mechanism is that ELP prolongs the protein’s circulatory half-life by reducing clearance from circulation.

Questions and Answers:

Q: Yesterday we learned [with Lilly’s basal insulin peglispro] that if you have a large hydrodynamic range, you get liver specificity with unwanted side effects. Did you test any of that with these insulins?

A: We haven’t studied it or seen anything yet but it’s something we will look out for.

Q: What happens to absorption if body temperature goes up or down [given that the effect of ELP is dependent on temperature]?

A: From a safety perspective, if the patient has an elevated temperature what will happen is the depot will be more stable. If you have someone plunging into an ice bath then that’s something one would have to look at. What we have studied so far is a prelude to longer study – we looked at what would happen if someone took the product directly from the fridge and injected it. There was no difference in PK there. It doesn’t matter if it’s cold when you inject it as long as it gets to the right temperature in your body.

Q: In the phase 2 study of your GLP-1 agonist, what did you see in terms of weight loss? I ask because the proportion of active moiety seems pretty small.

A: We didn’t see a big change in weight, but we also had liraglutide as a control arm, and we didn’t see weight loss in that group either. In any case, based on the protein’s structure, one would expect similar weight effects as dulaglutide or albiglutide.

Q: Have you looked into temperature variability systematically?

A: We have done one single ascending dose study so far. In the presentation yesterday, the error bars were very small so at least in that small group, it didn’t seem to be very variable, but we’ll obviously have to look at that going forward. The multiple ascending dose study is our next study.

Once-Weekly Combination of GLP-1R Agonist and Insulin (HM14220) Offers Improved Glycemic Control and Reduced Weight Gain Risk (172-OR)

Michael Trautmann, MD (Profil Institute for Clinical Research, San Diego, CA)

Dr. Michael Trautmann presented promising results from a series of early explorations of a novel once-weekly GLP-1/insulin combination from Hanmi Pharmaceuticals. Developed via the LAPSCOVERY platform, the compound is a combination of ^LAPS insulin 115 (phase 1 in the US), and efpeglenitide (HM11260C; an exendin-4 analog, phase 2b), which both have ultra long acting profiles suitable for weekly dosing. A combination of these compounds has shown similar PK/PD profiles to those of each product alone. When administered as a co-formulated once weekly product to diabetic rodents, the combination of ^LAPS insulin 115 resulted in greater A1c reductions than either product alone. Additionally, in a mild type 2 diabetes animal model, the weight gain seen with ^LAPS insulin 115 was neutralized by the combination product. Notably, in switching studies, switching diabetic mice to treatment with the ^LAPS combo after an initial 14 days of treatment with glargine resulted in significantly greater A1c decreases at six weeks versus either staying on glargine or switching to ^LAPS insulin 115. Similar results were seen in studies where mice were initially treated with liraglutide rather than glargine. These initial results are promising, as we feel a once weekly combination product could indeed improve adherence. We look forward to data from human studies on the topic, particularly to better understand how a once weekly product fares in face of every day glucose variations.

Posters

Liver Enzyme Results from 7 Basal Insulin Peglispro (BIL) Clinical Trials in Type 1 Diabetes and Type 2 Diabetes (989-P)

ML Hartman, S Zhang, E Bastyr III, AM Chang, SJ Jacober, and MJ Prince

This poster integrated liver enzyme data from phase 2 and 3 trials of Lilly’s basal insulin peglispro (BIL) where glargine was used as a comparator. As a reminder, liver enzyme elevation had been observed in BIL’s phase 2 program and was a cause for concern given the drug’s relative hepato-selectivity compared to other insulins. This study found consistent elevation of the enzyme ALT in both people with type 1 and type 2 diabetes at 26, 52, and 78 weeks. For background, ALT is a marker of liver inflammation and damage; it is a normal liver enzyme that can leak into the blood when liver cells are damaged. ALT elevation was evident within the first few weeks of treatment and persisted stably for the duration of treatment; it then trended back towards baseline after treatment discontinuation. In the type 1 diabetes trials, ALT hovered around 23 IU/L in the glargine arm compared to ~30 IU/L in the BIL arm. In the type 2 diabetes trials, ALT ranged from ~25-27 IU/L in the glargine arm compared to ~33-34 IU/L in the BIL arm. The investigators concluded that the ALT reversion towards baseline and the lack of cases of Hy’s Law (a criterion for more severe liver injury) suggests that there was no acute drug-induced liver injury. Generally the magnitude of ALT elevation was not egregiously large in the grand scheme of things. However we can see why investigators wanted to look into this further, as drug-induced liver injury is a serious and potentially fatal adverse drug effect and it isn’t clear the benefit is worth the uncertainty on a slew of questions. As such, we can understand why Lilly decided to further study peglispro’s liver effects and delay submission until at least 2017.

• For background, Lilly’s peglispro (BIL) is a basal insulin analog with relatively greater liver-selectivity than other insulins (which have relatively greater peripheral action), a flatter PK/PD, and a prolonged half-life (2-3 days). In phase 3 trials also presented in full at ADA, it showed superior A1c reductions compared to insulin glargine along with less weight gain. However, in both phase 2 and 3 trials, mean elevations in liver enzymes ALT and AST were also observed, suggesting the drug could be adversely affecting the liver.
• The analysis presented in this poster pools together liver enzyme data from seven trials of BIL vs. glargine. Three of the trials were conducted in patients with type 1 diabetes (one phase 2 and two phase 3 trials; n=1028 BIL and n=678 glargine) and four trials in patients with type 2 diabetes (one phase 2 and three phase 3 trials; n=2194 BIL and n=1464 glargine). Patients’ ALT, AST, alkaline phosphatase, and total bilirubin were measured at weeks 0, 4, 8, 12, 16, 26, 52, 65, and 78 as well as 4 weeks after drug discontinuation. Liver fat content was also measured by MRI in a subset of patients at weeks 0, 26, and 52.
  
  • For background on what each of these markers means: ALT and AST are normal liver enzymes that can leak into the blood stream when liver cells are damaged. Alkaline phosphatase is an enzyme normally found in bile canaliculi between liver cells that can back up into the blood stream if something is impeding bile flow from liver cells or out of the bile duct. Bilirubin is a normal byproduct of red blood cell turnover; it can back up if the liver is damaged and cause jaundice. Liver fat content is another marker for liver damage – when liver cells are damaged and lose the ability to oxidize fat for energy, fat can build up in liver cells.
• In patients with type 2 diabetes, BIL caused a slight increase in both ALT and AST. Mean baseline ALT was 28 IU/L and mean baseline AST was 24 IU/L. By week 78 on drug, ALT had risen to 34 IU/L in the BIL group compared to essentially no change in the glargine group (p<0.001), and AST had risen to 28 IU/L in the BIL group compared to no change in the glargine group (p<0.001). These elevations began soon after patients started taking the drug and persisted throughout treatment. The poster shows only ALT data for four weeks post-drug discontinuation, where mean ALT had come down to 30 IU/L.
• In patients with type 1 diabetes, BIL increased ALT but not AST. From a baseline ALT of 22 IU/L, patients on BIL rose to 29 IU/L after 78 weeks, whereas there was no change for patients on glargine (p<0.001). Again, the rise occurred soon after starting the drug and persisted throughout treatment. Four weeks after BIL discontinuation, ALT returned to ~24 IU/L.
• The authors suggest that the ALT reversion towards baseline suggests that the drug did not cause acute liver injury. Indeed, 100% of BIL-treated type 1 diabetes patients who experienced an ALT ≥ 3X the upper limit of normal (ULN) either returned to baseline or had a ≥20% decrease in ALT after discontinuing the drug. The corresponding figure for the type 2 diabetes population was 91%.
• The subset of patients who had liver fat content analyzed by MRI showed a roughly 1.5-2 fold increase of liver fat content between glargine and BIL (3% vs. 6% in type 1 diabetes, ~9% vs. 12% in insulin-naïve type 2 diabetes, and ~9% vs. 15% in type 2 diabetes patients previously treated with insulin).
• No patients met the criteria for Hy’s Law (ALT ≥3X the upper limit of normal plus total bilirubin ≥2X the upper limit of normal). Hy’s Law is a rule of thumb that predicts that a drug is at high risk of causing fatal drug-induced liver injury.

Lipid Changes During 26-Wk Treatment with the Novel Basal Insulin Peglispro (BIL) vs. Insulin glargine (GL) or Insulin NPH in 6 IMAGINE Trials (990-P)

H Ginsberg, B Cariou, T Orchard, L Chen, J Luo, E Bastyr III, J Bue-Valleskey, A Change, T Ivanyi, S Jacober, J Jacobson, B Hoogwerf

This analysis pooled data from 5,583 patients in six of the phase 3 IMAGINE trials (four in type 2 diabetes and two in type 1 diabetes) to examine the effect of Lilly’s basal insulin peglispro compared to insulin glargine (Sanofi’s Lantus) and NPH on lipid profiles. Individual phase 2/3 trials of peglispro have found potentially worrisome elevations in triglycerides (in addition to potential liver safety signals), prompting this analysis to more fully characterize patients’ lipid profiles. The authors compared the changes in apolipoprotein A-I, apolipoprotein B, free fatty acids, HDL and LDL cholesterol, and triglycerides after 26 weeks of treatment with the three types of insulin.  They found significantly elevated triglyceride levels with peglispro compared to insulin glargine and NPH, which varied depending on whether patients were insulin-naïve or not. In insulin-naïve type 2 diabetes patients (n=2,179), triglyceride levels decreased with insulin glargine and NPH but did not change with peglispro. In type 1 and type 2 diabetes patients (n=3,404) previously exposed to insulin, triglyceride levels were unchanged with glargine but increased 15-25% with peglispro. There were no significant differences in other lipid parameters examined (HDL and LDL cholesterol, apolipoproteins A-I and B). The results were not surprising, as elevated triglycerides have emerged as one of several potential safety concerns with peglispro as the IMAGINE trials have reported results. We see this as just one aspect of peglispro’s overall high-risk/high-reward profile and wonder whether the additional safety studies Lilly plans to conduct in lieu of a submission this year will investigate this signal  in addition to the concerns about liver toxicity. 

• The authors propose that the differences in lipid profiles could be tied to peglispro’s hepato-preferential properties. The authors suggest that the release of free fatty acids from adipose tissue, decreased lipoprotein lipase activity in adipose tissue, or increased hepatic de novo lipogenesis could contribute (separately or jointly) to the differences in triglyceride levels.

Efficacy and Safety of Technosphere Inhaled Insulin: Systematic Review and Meta-Analysis (96-LB)

G Westcott, E Balk, A Pittas

This systematic review and meta-analysis analyzed the efficacy, safety, and patient acceptability of Sanofi/MannKind’s recently launched inhaled insulin Afrezza. The analysis included 12 randomized controlled trials that met eligibility criteria (n=5,273). However, many trials were designed to demonstrate non-inferiority, which could lead to bias, and most were 24 weeks or less in duration, limiting the ability to draw conclusions about long-term effects. In adult patients with type 1 diabetes or insulin-requiring type 2 diabetes, the analysis found that Afrezza was slightly less effective than subcutaneous insulin at improving glycemia (net difference 0.16%; 95% CI 0.06-0.25%). However, Afrezza was associated with less weight gain (net difference 1.6 kg; 95% CI 2.1-1.6 kg) and severe hypoglycemia (odds ratio 0.61; 95% CI 0.35-0.92) compared to subcutaneous insulin. In patients treated with Afrezza, there was an increased risk of a mild, transient, dry cough (odds ratio 7.82; 95% CI 6.14-10.15) and a greater decline in FEV1 (a measure of lung function) (net difference 0.038 liters; 95% CI 0.049-0.026). Finally, those treated with Afrezza were more likely to discontinue participation than those treated with an active comparator. The study authors concluded that long-term safety data is needed and that subcutaneous insulin continues to be a better option for patients who can tolerate needles. While long-term data is clearly important, we do feel that the clinical appeal of Afrezza’s faster action profile, hypoglycemia and weight advantages, and ease of administration should not be underestimated. As of MannKind’s 1Q15 update in May, sales of Afrezza had gotten off to a relatively slow start, which the company attributed mainly to administrative issues like doctor appointment lags, spirometry scheduling, and prior authorizations. The product has generally had a very positive reception on social media since its launch, and we continue to believe it holds significant potential for a wide range of patients.

Improved Postprandial Glycemic Control with Faster-Acting Insulin Aspart in Subjects with Type 1 Diabetes Using CSII (994-P)

B Bode, L Hyveled, SC Tamer, P Ybanez, M Demissie

Dr. Bruce Bode et al. conducted a randomized controlled trial that evaluated the effects of Novo Nordisk’s faster-acting insulin aspart and standard NovoLog (insulin aspart) delivered via continuous subcutaneous insulin infusion (CSII). Over 14 days, this study measured two-hour postprandial glucose responses in 43 adult patients with type 1 diabetes. Following two hours, the Faster Aspart group had a significantly greater reduction in plasma glucose levels than the insulin aspart group in a direct comparison (a mean of -18 mg/dl, n=43, p<0.05). There was a trend towards a benefit in one hour post-administration as well (roughly -9 mg/dl), though it was not statistically significant. The preliminary indications of superiority in plasma glucose reduction and hypoglycemic duration complement positive data we’ve seen already and have led to phase 3 trials that are currently underway for evaluations of efficacy and safety in a larger sample population.

• The phase 1, double-blind randomized controlled trial compared changes in 2-hour postprandial glucose response in the faster aspart (n=43) and insulin aspart (n=42) groups via CSII. Their secondary objective evaluated the two formulations of aspart with regard to efficacy, safety, and pump-related endpoints after the 14-day trial period. The test study group had baseline and demographic characteristics with a mean age of 48, BMI of 27.0 kg/m², a 24-year duration of type 1 diabetes, and a starting A1c of 7.5%. Both groups were given a standardized meal and their mean plasma glucose levels were assessed continuously from 60 minutes prior to the meal to 240 minutes after the meal.
• The faster aspart group had a significantly greater glucose lowering effect than insulin aspart two hours after the standardized meal in a direct comparison (roughly -18 mg/dl, p<0.05). The secondary endpoint supported this finding at the 1-hour interval although this difference was not statistically significant (-9 mg/dl, p>0.05). Regarding safety profiles, the duration in hours of hypoglycemia was slightly greater in the insulin aspart group, although the difference was not significant at the <3.0 mmol/L level. In addition, no new safety issues occurred in both treatment groups.

Current Issues: Are They Really Worth It? Debating the Value of New Insulins in the Management of Type 2 Diabetes

New Insulins are Worth It

Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN)

Dr. Richard Bergenstal argued in favor of the value of new insulins. After showing data indicating that on a national level patients on insulin are not achieving desired glycemic goals he argued that we can’t keep using the same insulins in the same ways if we want better glycemic outcomes. Following this, he provided an overview of some novel basal insulins (Novo Nordisk’s Tresiba [insulin degludec], Sanofi’s Toujeo [insulin glargine U300], and Lilly’s peglispro [BIL]) and bolus insulins (Sanofi’s Afrezza, Novo Nordisk’s Faster-acting Aspart) and what potential they have shown in PK/PD and phase 3 studies. Specifically, he highlighted how Tresiba and Toujeo provide similar A1c reductions vs. insulin glargine but have benefits in terms of hypoglycemia and flexible dosing. As noted multiple times in this report, we also believe there are additional benefits to Toujeo like better focus on access, the COACH behavioral program, and an easier-to-use pen, and we expect to see greater other benefits with Tresiba. Peglispro is associated with superior A1c reductions compared to Lantus, as well as less nocturnal hypoglycemia (see above for data we learned today on peglispro). Dr. Bergenstal ultimately argued that novel insulins should meet a triple aim of quality (based on A1c without hypoglycemia), patient experience, and cost. Dr. Bergenstal highlighted that CGM data may help us judge quality (via identifying lows, time in range, etc.) and also noted that we will need to make efforts to curtail the costs of insulin (via guidelines for selective prescribing, biosimilars, etc.) if current efforts don’t make needed insulins available.

• Dr. Bergenstal argued that we can’t keep doing the same thing with insulins if we want better results. Based on NHANES data, the percent of people with A1cs <7% hasn’t markedly improved over the last one to two decades among those with insulin. We thus need better insulin management – but questions remain about when to start, and how to adjust it, and deliver it.
• New basal and bolus insulins have potential for clinical value based on PK/PD profiles and phase 3 data, although ultimately they will need to be proven in the real world. For example, Tresiba has a long half-life, a flat profile, and four fold less variability than glargine.  Notably, although A1cs are similar with Lantus vs. Tresiba, the latter is associated with less nocturnal hypoglycemia and is compatible with flexible dosing. Toujeo is more concentrated than Lantus and has a significantly flatter profile. Like Tresiba, it causes similar A1c reductions vs. Lantus, but is associated with both less nocturnal and overall hypoglycemia. Peglispro is long acting with a flat profile, is associated with superior A1c reductions compared to glargine, and results in less nocturnal hypoglycemia (although total hypoglycemia was not reduced). Meanwhile, Afrezza and Faster Aspart have shown promise in PK/PD studies for their fast onset of action.
• Dr. Bergenstal suggested that new insulins (and in fact all novel drugs) fit a triple aim for healthcare delivery. This triple aim consists of: (i) Quality (based on A1c without hypoglycemia), (ii) patient experience (including safety, minimal side effects, and flexibility with regards to daily life activities), and (iii) acceptable costs. He noted that while we wait for more precise markers to guide diabetes therapy, CGM can help judge a patient’s response to a particular drug (i.e. how much time a patient is low each day, what percent of values is in range). The FDA should not shy away from CGM – it should in fact insist on it. In terms of cost, he noted that if new insulins cost more, they may end up being limited to high risk hypoglycemia. Other efforts to moderate the costs of insulins  (i.e. guidelines for selective prescribing, expansion of biosimilars, healthcare reform to improve coverage) may be needed if current efforts don’t make insulins available.

New Insulins are Not Worth It

David Nathan, MD (Massachusetts General Hospital, Boston, Massachusetts)

Dr. Nathan argued that the current enthusiasm for new(er) insulin analogs for use in type 2 diabetes represents a triumph of advertising over substance, as the promise of effective and safer insulins for type 2 diabetes has not been demonstrated and costs continue to escalate with no end in sight. This is not the first time we’ve heard Dr. Nathan voice a conservative opinion on the value of today’s new drug options, making him a great fit to take on this side of the debate. Though Dr. Nathan recognized that insulin analogs have PK profiles that more closely mimic human physiology than older insulins, he emphasized that the clinical evidence of the benefits of insulin analogs for type 2 diabetes has been limited. In various meta-analyses, insulin analogs have not shown a glucose-lowering benefit or reduced risk of severe hypoglycemia versus regular or NPH insulin according to Dr. Nathan – we do not believe that most trials resemble “real life” exactly and certainly believe there is a benefit away from NPH for certain subgroups in particular. Dr. Nathan commented that the main benefit of newer basal insulin analogs appears to be a reduction in nocturnal or nonsevere hypoglycemia; as such, he questioned the appropriateness of their use for broad swaths of the type 2 diabetes population, given the high costs of such analogs – Dr. Irl Hirsch (University of Washington, Seattle, WA) had a lot to say about the high costs of insulins on the first day of the meeting. We certainly do not believe that “one size fits all” and that less expensive insulins may well be adequate for some patients though some will not be able to deal with the relative lack of stability.

• Dr. Nathan posited that though the PK profiles of rapid-acting and long-acting insulin analogs mimic physiology more closely, they have not demonstrated significant clinical benefits in efficacy or reductions in hypoglycemia beyond older insulins in patients with type 2 diabetes. In a meta-analysis of 13 randomized controlled trials, rapid-acting insulin analogs only had an average A1c reduction of 0.09% beyond regular human insulin; severe hypoglycemia was rare and the difference in incidence was not statistically significant between the two insulin types (Monami et al., Diabetes Obesity Metabolism 2009). In a meta-analysis of 12 randomized controlled trials, there was no significant difference in A1c lowering or severe hypoglycemia between NPH insulin and long-acting insulin analogs (Monami et al., Diab Res Clin Pract 2008). Another meta-analysis found no clinically relevant differences between long-acting insulin analogs and NPH insulin (Horvath et al., Cochrane 2007). Dr. Nathan pointed out that there is no difference in overall hypoglycemia or severe hypoglycemia between insulin degludec and insulin glargine (Diabetes Care 2012). However in both meta-analyses of long-acting insulin analogs versus NPH insulins, long-acting insulin analogs were associated with a lower risk of nocturnal hypoglycemia – we see this as a benefit that is highly meaningful to patients.
• Though Dr. Nathan acknowledged that Sanofi’s inhaled insulin Afrezza has a better PK profile than insulin lispro, he concluded that it does not confer any significant clinical benefits beyond injected rapid-acting insulin analogs. Dr. Nathan highlighted that in clinical trials for Afrezza, the inhaled insulin was at best non-inferior to injected rapid-acting insulin, and it only managed to bring a small minority of study participants to goal (an A1c of ≤7%). He mentioned that analysts are skeptical that Sanofi can turn around the Afrezza launch – arguably it’s too early to assess the success of Afrezza’s launch – but noted there may still be a chance yet as direct-to-consumer advertisements are coming. From our view, the ability to get more patients and more HCPs to try more insulin is a positive.
• Dr. Nathan emphasized that the introduction of new insulin analogs has not driven costs down; on the contrary, insulin analogs experienced some of the biggest prices hikes of any drugs in recent history. This was the second major presentation we covered at ADA to address explicitly with the high cost of insulin – the first was Dr. Irl Hirsch’s presentation on the topic on Day #1. According to a FiercePharma analysis, the price of Lantus and the price of Levemir each increased 29.9% in 2015. Over the past five years, Levemir increased 169% in price, and Lantus increased 168%. A now well-known and much-cited Bloomberg piece noted that these price increases were in all-but-identical increments – when the price of Lantus went up, the price of Levemir followed shortly thereafter. Unfortunately, Dr. Nathan’s talk did not address the changes made in rebates by companies to pharmacy benefit organizations. As such, Dr. Nathan asserted that the idea that competition is going to lower prices does not seem to be working – we had heard that idea related to biosimilars, and we think it’s early to know – presumably insulin prices will certainly be reduced by it’s hard to know by how much. Dr. Nathan commented that pharmaceutical companies do not appear to be struggling financially – their profit margins are comparable to those of banks (~20%), which is more than the profit margins of carmakers, oil/gas companies, and companies in media. There is no question from our view that there is great variability across the board in this measure.  

Rebuttal

Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN)

Dr. Richard Bergenstal said that both he and Dr. Nathan are in agreement about the need for good glucose control and affordability. He said that the field has made good advances in bringing down hypoglycemia considerably. However, it needs to take a broader patient centered view to help patients live the way they want. The field also needs to do better in terms of costs. He argued that companies could afford to keep innovating if they had a higher cost at the beginning that later comes down.

Panel Discussion

Q: If cost were not an issue, would there be a role for analogs in type 2 diabetes?

Dr. Nathan: It would be much easier to swallow; I’m offended by the price that goes along with them. I do want more tools to manage patients with diabetes, and there may be specific patients with schedules and lifestyles that require different insulin. I use and appreciate the variety, but it’s just that the hard data doesn’t support the costs. If they were to cost the same, I would be much happier.

Dr. Bergenstal: At the moment, they are looking at the right patients but there do seem to be benefits. If costs were equal, their market share would go up.

Q: It seems like with the human insulins, at least in DCCT and UKPDS, the patients treated more intensively had cardiovascular benefits. Do you know whether trials with analog insulins have shown cardiovascular benefits on scale with older insulins? Do you think analog insulins can be trusted for safety?

Dr. Nathan: Glycemia is very important, but glycemia achieved by drug X will have the same results as drug Y. The studies you mentioned were done with non-analog insulins. You would probably get the same results with analog insulins, but in terms of direct data, those were with older insulins.

Q: Have they been tested adequately for safety? We saw the first Lantus cancer issue many years ago. I think that testing of insulins has been adequate.

Dr. Bergenstal: Lantus had a large trial with ORIGIN. Degludec is in midst of large CV trial.

Q: I’m a nurse practitioner in a hospital setting and I’ve recognized that prices of insulin go up every year. I do have contracts with certain companies for both basal and prandial. In last couple of years, I’ve recognized the increased cost in insulin, and this year I got tired of it, and pushed hard, such that if I didn’t get pricing wanted, I would switch to a different company. What are we doing as a larger healthcare community in US to get prices down? Some patients to pay $500 per vial of glargine, some pay $300 per vial.

Dr. Bergenstal: I don’t think we’re speaking as one voice yet as a community. David mentioned the cancer community. There was a Sloan-Kettering group of oncologists saying that they were not paying for more expensive oncology drug, and the price was reduced. I think speaking as one voice, requesting insulins be provided at an affordable cost or copay so those who can benefit have adequate access to these important medications, will make a difference.

Dr. Nathan: Bill Harman is better suited to answer question than we are. The argument is that patients are insulated from the real price of the drug. Someone is paying for this stuff; with all deference for international visitors, the US pays for it because EMA and Canada negotiate. We have been very ineffective in pushing this agenda, and I think do need to be more effective.

Q: The reason why drug companies charge is because they can. There is absence of a regulatory environment that prevents them from doing so. Why hasn’t ADA as an organization pushed harder? What can the organization do? It isn’t doing much because there is a lot of drug company money that supports this meeting, but it seems like it should take a stand as an organization.

Dr. Nathan: Right on target. That’s why we’re not on leadership currently.

Dr. Bergenstal: The ADA, while not specifically advocating for lower drug costs,  has been pushing very hard for healthcare reform policies that are a great benefit to people with diabetes and in many case provide access to decent insurance coverage.

Q: I am a visitor from Saudi Arabia. Are there differences between traditional insulin and newer insulins in terms of effects other than hypoglycemia?

Dr. Nathan: There is a weight difference. When these results were first reported, detemir was shown to have less weight gain pretty consistently. In terms of site injection reactions, more concentrated insulins give more local site inflammation. I’m not aware of major other differences other than that.

Dr. Bergenstal: There are a few differences in the weight moderation, hypoglycemia, and schedule and life flexibility.

Q: Branded human NPH insulins have increased in price. Excluding Wal-Mart’s ReliOn, did the slide looking at price increases include NPH?

Dr. Bergenstal: Yes, human insulins have gone up as well.

Q: Have pharmaceutical companies provided reason as to why human insulin is more expensive?

Dr. Nathan: It’s the same human NPH insulin – manufacturing hasn’t changed one iota. In terms of rationale, I don’t remember children asking for rationale when asking for more money.

Dr. Bergenstal:  There is no generic or biosimilar. There was a period of time when you got into development, just like metformin, which was expensive in its day but not for long.

Q: I have a hypothesis for the reason that pricing is out of control: there are enough patients to go around for everybody. It’s a plot of net profit growing vs. people.

Moderator: He doesn’t have an answer.

Q: This is a comment for Dr. Bergenstal. Despite the anecdotal nature of some of the posters, if you go look at some of the posters addressing prediction of hypoglycemia, some of those directly address issues raised by Dr. Bergenstal. One issue is regarding new basal insulin, which is the only reason why there was a small but significant difference in nocturnal glucose. This has been published and advertised by companies. Fasting glucose is designated to be < 100 mg/dl in studies. Many patients who have insulin don’t need fasting insulin < 100 most patients see in clinic don’t need glucose of 90 fasting. By doing that in the studies you put the patients deliberately at risk to have hypoglycemia that they would not have otherwise. This is the question of how studies are designed.

Dr. Nathan: I agree; if it were designed to lower fasting glucose, we would be pushing harder on NPH night before. You’re going to either achieve that goal or you won’t and it raises the issue of whether you’re going to have more hypo overnight.

Dr. Bergenstal: Some of the recent targets in some of the Type 2 studies have been more 80-130 versus 90, which we have a hard time achieving in anyone.

Q: We’re lucky to have human insulin since the new analogs more expensive. Still today in type 2 diabetes, I think SMBG is the most important. In Germany it’s not so expensive; every German has to be insured. If you make less than 5000 euros per month, you have to have social public assistance. In Germany, the manufacturer has to pay back to social insurance so that new insulin is not more expensive than human insulin (aside from Tresiba). That is a strong position for the patients.

Dr. Nathan: We both agree that cost control is critical.

Q: Dr. Bergenstal has said that one of the ways to moderate costs is to have guidelines that would restrict it from patients where it is likely to be a cost deficit. Dr. Nathan’s talk suggested those types of guidelines are not going to be effective. Instead of not listing the drug, maybe professionals should restrict its use to a smaller group of patients, the same as the choosing wisely movement.

Dr. Bergenstal: I wouldn’t say the guidelines aren’t effective. They haven’t been written. Who are the high-risk patients and who is identifying them? It is incumbent upon them to identify who are good candidates.

Q: Is there a consumer demand for insulins? What has been the role for direct consumer marketing?

Dr. Nathan: Without disempowering the consumer from choosing medications that he or she may benefit by, one has to wonder whether TV advertisements or printed advertisements are the way to do that. You should discuss pluses and minuses with a healthcare provider, come to a solution, one that both patient and physician can live with in terms of their choice. The TV advertisements tend to be problematic.

Dr. Bergenstal: We need informed discussions with good material and shared decision-making. Let’s sit down with pros and cons.

Q: I’m from India. I think we have been extremely unfair to insulin-making companies in the world. When we go back to any scientific lectures, hypoglycemia is the biggest limiting factor in starting insulin. We are painting 76% reductions in nocturnal as completely irrelevant to this debate. We are painting the pharmaceutical industry as a villain. They cannot increase the price. If you took a bottle of milk so many years ago, it was a few cents, and now it’s a few dollars. They can increase the price. Every other industry can increase cost, but somehow we don’t take the cost of production into consideration when we say should insulin should cost less for poor people. We are criticizing insulin manufacturers as if they are the villain, even though they’re bringing new products which make life better. I think it’s a very unfair criticism of industry. Scientific issues we discuss like reduction in hypoglycemia, flexible administration, and good quality of life are important, so if the price comes at a premium, we have to accept it. We ask pharmaceutical companies to donate to conferences and research. Where will the money come from?

Dr. Nathan: I don’t work for pharma. I’m a physician and a researcher, and my goal is to provide the best possible care to my patients. Both of us agree it has to be accessible and affordable. My job is not to argue for the profit-making pharma industry. I don’t accept honoraria, and want to be able to speak unfettered for patients. Uncontrolled insulin pricing is unacceptable, and someone needs to speak out against it. I count many people who work in or with pharma as my friends, but I cannot abide by their pricing. Some people who need insulin to survive may not afford it.

Dr. Bergenstal: I hope you heard me emphasize three-fourths of my presentation on the benefits of newer agents in hypoglycemia risk and quality of life. But they have to be accessible. It can be done at a cost that’s reasonable.

Q: I work at the FDA and want to understand more what you mean by the phrase “added benefit.” For new insulins, what added benefits do you anticipate?

Dr. Bergenstal: I think less hypoglycemia is probably the biggest benefit. You want A1c to come down – it’s a tried a true marker, even though it’s derided now. You want good A1c lowering with less hypoglycemia. Can these new analogs provide those, and improve quality of life? The FDA could evaluate this more precisely by doing some continuous glucose monitoring in these studies, and sort out the amount of hypoglycemia that is severe or moderate. The problem with these trials is that the people who need these therapies the most aren’t in the initial trials. People at high risk often haven’t made it into the trial, and only get access later after drugs are approved.

Symposium: Costs of Medications for Diabetes

Changing Costs of Insulin Therapy in the US

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

Dr. Irl Hirsch took the stage to tackle the tough but very timely topic of the increase in insulin prices over the past decade. We heard him speak passionately on this subject at Keystone last year. He views the current scenario of skyrocketing copays or completely unaffordable out-of-pocket costs for insulin as unacceptable, especially given that prices have risen so sharply in the past decade and that three of the six drugs that have had the sharpest price increases in the past five years are insulins. Patient-level solutions include Walmart and Costco insulin for those paying cash and manufacturers’ support programs; he mentioned but did not endorse online international pharmacies. As bigger-picture solutions, he listed: (i) clinical guidelines that incorporate cost-benefit analyses, (ii) value-based pricing based on panel decisions (though he wouldn’t want providers who work with insulin companies to be excluded), (iii) allowing importation (which he recognized as unrealistic, and probably not in patients’ best interest anyways), (iv) educating more providers about human insulin, and (v) advocacy. On the latter point, he characterized the ADA and JDRF for arguably not doing enough direct advocacy work on insulin prices and access – former ADA President Dr. Mayer Davidson noted during Q&A that he tried to get the ADA to take on the issue 15 years ago but was turned down. Continuing to speak frankly, he shared results of an Access to Medicine ranking of the companies that best provide drugs to developing countries, noting that Novo Nordisk is high (#2) on the list, with Sanofi at #8 and Lilly near the bottom at #17. We applaud Dr. Hirsch for repeatedly taking on a topic that is so controversial and tricky to discuss comprehensively. We were not surprised that he received a few rounds of applause during his talk and Q&A. 

• During Q&A, Dr. Hirsch expressed a sense of disillusionment with coupon programs for new drugs. He noted that these programs help drugs “infiltrate” the market and lead to pent up demand for products that may or may not have the best clinical benefit, to the point that payers have a hard time saying no to price increases. He characterized it as a strategy that he refuses to buy into anymore. Also during Q&A, the conversation took on a more philosophical tone when an audience member quoted the Declaration of Independence that every American deserves life (in addition to liberty and the pursuit of happiness). He suggested that unbearably high insulin costs are potentially unconstitutional, in addition to being immoral.
• Dr. Hirsch began with an overview of the history of insulin pricing. Setting the stage with Drs. Banting and Best’s altruistic sale of their insulin patent for $1, he noted how insulin prices stayed fairly low for decades before starting to climb in the 1990s and early 2000s. In his view, however, nobody could have predicted the tremendous rise in insulin prices that followed from 2005 to the present.
• In an attempt to better understand the cost trends over the past decade, Dr. Hirsch drew a distinction between the different metrics for insulin pricing. He downplayed the significance of AWP list prices (the “ain’t what’s paid” price) due to its vulnerability to “fraudulent” manipulation. Even wholesaler prices have increased far more rapidly than the medical consumer price index. The “usual and customary” price paid at the consumer level is often unreasonable and may be rising even faster than list prices, with a disproportionate impact on uninsured patients who pay out of pocket.
• Digging deeper into the theme of insulin sticker shock, Dr. Hirsch noted that out of the 30 name brand drugs that have doubled in price over the past five years, three of the top six were insulins. Humulin U500 – which Dr. Hirsch has selected as a target before – was second on the list. Novo Nordisk’s Levemir (insulin detemir) and Sanofi’s Lantus (insulin glargine) were #5 and #6 on the list, respectively. Using goodrx.com price data, he cited a 508% increase in Humulin U500 between 2005 and 2015, along with sizable price increases in the same time period for Lilly’s Humalog (insulin lispro), NovoLog (insulin aspart), Lantus, and Levemir).
  
  • Just as worrying as the increase in price, in Dr. Hirsch’s view, is the way those increases have happened. He cited a Bloomberg article from earlier this year that received a great deal of attention on the parallel identical increases in price for Lantus and Levemir. He noted that these parallel increases occurred 13 times. However, when asked during Q&A whether this pattern should trigger anti-trust litigation, he did not comment one way or another. 
• Dr. Hirsch noted that insulin prices vary greatly across different geographies. He characterized this as a problem not just for the US, but also for manufacturers in terms of their reliance on one market for a large share of income.
• As an imperfect but necessary solution, Dr. Hirsch argued in favor of better training for new physicians on human insulin for type 2 diabetes – he did, however, stand more strongly by analog insulin for type 1. From his observations, many young residents have no experience with NPH or regular human insulin for type 2 diabetes. However, Dr. Hirsch suggested that for many type 2 diabetes patients, regular human insulin works just as well.   
• Dr. Hirsch did not voice confidence that the introduction of biosimilar insulins will be a true game changer for insulin prices. Although he acknowledged that they will attenuate some of the growth in prices, he noted that discounts vs. existing options are not expected to be very significant and that Sanofi and Lilly will both be entering the biosimilar field to recapture some of the share they might lose to the biosimilars.
• In addition to prices, Dr. Hirsch called out some of the more ridiculous practices he has seen from insurers regarding insulin. These include Medicaid’s resistance to paying for an insulin pen (vs. vial and syringe) for a patient who lost an arm to a sarcoma as well as strictly monitored one-at-a-time insulin vial dispensation, even if a patient is traveling. These practices, as well as skyrocketing out of pocket costs, are forcing patients to use regular human insulin in pumps and in some cases are even causing patients to ration their carbohydrate intake.

Questions and Answers (Expanded):

Dr. Mayer Davidson (UCLA, Los Angeles, CA): About fifteen years ago, a bunch of us became concerned about insulin costs. We approached the ADA to put that on their agenda – to go to congress on this. They turned me down and said that they had more important issues to deal with. As one potential source of optimism, in Germany insulin glargine is not so expensive because the government simply refused to pay. Now there are some pharmacies like Express Scripts that are negotiating and not paying what’s demanded, which may cause a small improvement.

A: The reason why Kaiser and Group Health have been so successful is by just saying no. For the most part we haven’t said no to the manufacturers. With coupon programs, new drugs infiltrate the patient population, leading to pent up demand that makes it harder for the payers to say no. It’s not a strategy I’m going to buy into anymore.

Q: We have a tremendous number of people on Medicare that we are taking back to NPH. We also recommend the Walmart ReliOn insulin. Most of our Medicare patients don’t realize that when they’re in the donut hole, they can fill out the low income subsidy form and, if they qualify, they can get scripts for $3 to $6. If they don’t qualify, they can get the letter of denial and apply for pharma assistance. But they have to fill out the form. Especially with U500, what is going on is absolutely shameful.

A: You’re absolutely right about the Walmart ReliOn insulin.

Q: When we worked together on the first articles we wrote in Clinical Diabetes, we predicted that new analog insulin would vastly increase the cost of insulin. The situation is getting much worse. In Georgia, we were telling patients to go to Walgreens and through the buyer’s club they could get regular human insulin cheaper than at Walmart. The Feds discovered it and then said that Medicare patients can’t use the out-of-pocket service. Now they have to put their purchases through Medicare Part D. The problem is that with high deductible insurances, this is going to become more widespread. Do you think that the rise of PBMs such as Express Scripts may buffer that?

A: I don’t really have any direct contact with Express Scripts or any of the PBMs, so I can’t even speculate about that.

Q: Do pharma companies lose money when they market and sell to countries in the EU where they sell at lower prices? You showed the graph with the price increases – it looks suspiciously like price fixing. Do you have any idea if there is potential for antitrust legislation kicking in?

A: I never wanted to be a lawyer or work with one, so I can’t comment on the second question. It will be interesting to see how prices change when biosimilars come to bear. We also don’t have patients screaming about the costs of strips like they were five years ago. When the government got involved, everyone started generally paying less for strips. Something like that may happen here. And I’m not sure if insulin companies make money when they charge less. There is no transparency there. [Editor’s note – we would like to better understand rebates in this argument.]

Q: We are all responsible for the lives of the patients we see. In the 18^th Century when our country was coming together, the Declaration of Independence called for life, liberty, and the pursuit of happiness. The lives of Americans, and people around the world, are now dependent on money for a product they need to save their lives. This is immoral, illegal, and should never be practiced. [applause]

A: Thank you for your comments.

Biosimilar Insulins – How Will They Be Regulated and Marketed?

Lutz Heinemann, PhD (Science & Co., Düsseldorf, Germany)

Dr. Lutz Heinemann spoke comprehensively about biosimilar insulins, which stand to shake things up following years of a stable insulin market. Starting with regulatory topics, he argued in favor of harmonizing biosimilar regulations around the world, as currently there is a great deal of variation (including many countries with no laws on the books about biosimilars). He cited his group’s recent article surveying the biosimilar regulatory landscape. On the key issue of how biosimilars will be priced, he collected and averaged different forecasts for biosimilar insulin price reductions, coming up with ~35%. However, 35% off the estimated $32 billion insulin market in 2019 would be $11 billion, and Dr. Heinemann expressed uncertainty whether manufacturers would tolerate such a step down in revenue. From our view, presumably next-gen insulins and basal insulin/GLP-1 combinations would not go down in price. In a review of different stakeholders’ views on biosimilar insulins, he cited a common lack of comprehensive understanding on the part of patients and prescribers. Both groups may feel hesitant to embrace switches to biosimilars without being at least consulted because the move would be for cost savings rather than clinical benefit. New pens or dosing practices with biosimilars may lead to confusion, and if patients have a bad experience with a biosimilar it may undermine their trust in both biosimilars in general and in their caregivers. Clearly, a high-stakes game!

• One of the most illuminating portions of the presentation, in our view, was a review of perspectives on biosimilar insulins across a range of stakeholders:

Patients	Love-hate relationship with “their” insulins Limited understanding of the topic – why switch? Wary of moves to save money that don’t involve them or at least consult them Risk of confusion: new product names, new pens (dosing errors) Bad experience could mean lost trust in physician and/or healthcare system
Physicians	Limited understanding of the topic – why switch? Longstanding cooperation with insulin manufacturers – most have had good experiences Wary of moves to save money without involving them Risk of confusion with new names and pens Potential safety concerns?
Insurers	With recent increase in costs, even small reductions in price could mean large savings They have experience with saving money on strips, so why not insulin? Could this lead to a race to the bottom? Will they force switches? Low prices may look attractive at first glance, but how will manufacturers invest in new research?
Manufacturers	Not willing to reduce biosimilar price much due to high investments in regulatory approval, more costly manufacturing process vs. generics Established manufacturers will reduce prices to maintain share If the decreases in prices are too great, some manufacturers may withdraw Will the increase in the global market counterbalance the price reduction?

• Cost savings from the price of biosimilar insulins may be counterbalanced by other factors. Dr. Heinemann noted that biosimilars my drive greater usage of pens for insulin administration, which are likely to be more costly per unit than vial and syringe insulin. Efforts to educate patients and physicians about biosimilar insulins and potentially new pens/devices will come at some cost. Patient confusion (potentially leading to inaccurate dosing) has its own cost. If biosimilars are not properly quality checked, decline in metabolic control or side effects from subpar products would further chip away at costs savings.
• In line with Dr. Irl Hirsch, who spoke before him, Dr. Heinemann does not believe that biosimilars will overtake the market, at least not unless governments take big steps to help them. He wondered aloud whether insulins could be subjected to a bidding process like CMS competitive bidding for test strips – he did not come out strongly one way or another, but noted to “be careful what you wish for.”
• Dr. Heinemann issued a call for action regarding the regulatory approach for biosimilar insulins. Currently, different regulatory approaches mean different levels of safety between countries. He thinks harmonization is needed to ensure that people across geographies have access to safe insulins. Furthermore, he is not sure that today’s guidelines for biosimilars answer the full range of clinically relevant topics – he would advocate for clinical trials with head-to-head comparisons. Finally, Dr. Heinemann would like to see registries to help evaluate biosimilar insulins once they are on the market.
• Dr. Heinemann discussed the status of biosimilar insulins in a few geographies where they are more available:
  
  • India: Insulin copies have been on the market for years from a number of companies, though there have been scandals due to bad quality products. Because of these scandals, patients have relatively little trust in manufacturers and insulin copies have been slow to enter the market. Price differences between branded and copied insulins are minimal due to low pressure from payers, although the baseline for branded insulin prices is lower in India.
  • Latin America: Here, governments buy insulin in tenders, meaning that insulin access changes every few months. In Mexico, an insulin glargine copy marketed by Gan Lee is available.

Global Pattern of Cost of Branded and Generic Drugs

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

During his presentation, Dr. Pratley compared the costs of branded and generic diabetes medications across countries and examined how local regulations can impact drug pricing. He explained that European countries are more able than the United States to control drug pricing, because they have centralized regulatory authorities in place to tend to this matter. As a result, diabetes medication costs only accounted for 5.4% of direct medical expenditures related to diabetes in the United Kingdom, whereas they accounted for 12.9% of direct medical expenditures related to diabetes in the United States (The Economist 2007). In closing, Dr. Pratley stated that pharmaceutical pricing is highly complex, with many key stakeholders and little transparency; as such, prices are lower where there is clear regulatory oversight.

• Dr. Pratley explained that the average wholesale price (AWP) can be thought of as a list price or sticker price that can be used as a starting point for bargaining. A benchmark that has been used for more than 40 years, the AWP is a price set by the manufacturer in collaboration with publishers. It is not defined by the government, and does not include discounts or rebates, which can reduce the price significantly.

Questions and Answers

Q: What’s the answer to this problem? Is it generic formularies? Is it better negotiations with pharma?

A: It’s pretty clear a market-based approach like we follow in the US is not the optimal approach to deliver high quality medications to our patients. We pay more money for our medications than any other country in the world, perhaps unfairly. Increasingly there are going to be pricing pressures coming through different channels, including employers. They’re going to demand generic medications, step care as they already do, and an explanation of the value of more costly and brand medications – what the value proposition is for a drug that costs 10 times that of a generic.

Regulation and the Economics of Drug Development

Joseph DiMasi, PhD (Tufts University, Boston, MA)

During his presentation, Dr. Joseph DiMasi discussed drug development and regulatory approval time trends, FDA review division productivity, and biopharmaceutical R&D costs. He noted that diabetes compounds approved from 2000 to 2014 got to market quicker, on average, than new drugs in general, but that the development times and number of subjects in clinical trials for diabetes medications has been increasing (largely due to the 2008 cardiovascular risk guidance, though he did not stress this point too heavily). In his analysis of FDA review division productivity, Dr. DiMasi found that productivity was only slightly below average for the metabolism and endocrinology division. Dr. DiMasi presented data showing that R&D costs have increased each decade since the 1970s, which he found to be due largely to increased clinical development costs, and to a lesser extent, due to a recent drop in the success rate of drug development (from 1995 to 2007, only ~12% of drugs that entered clinical development gained FDA approval).

• The average time required for clinical development of diabetes medications increased 1.6 years following the 2008 cardiovascular risk guidance. For the eight diabetes medications approved by the FDA from 2000 to 2008, clinical development took an average of 4.7 years, whereas for the nine diabetes medications approved from 2009 to 2014, clinical development took an average of 6.3 years. Dr. DiMasi noted that for drugs approved between 2000 and 2014, clinical development of diabetes medications took less time on average than drugs for other therapeutic areas – 5.7 years versus 6.8 years overall.
• For FDA drug approvals between 2000 and 2014, regulatory review took slightly longer for diabetes medications than for other therapeutics (16.9 months versus 15.2 months overall). Notably, he highlighted that none of the 17 diabetes medications approved between 2000 and 2014 received FDA priority review status, whereas more than half of all antineoplastic, AIDS, endocrine (excluding diabetes), and anti-infective therapies received priority review during this time period.  

Questions and Answers

Q: I have a question about the clinical development costs. It seems like that’s the major contributor to increased cost of drug development. It seems to be driven by the number of subjects primarily. Is that related to the new regulation for cardiovascular outcomes assessment, or what seems to be driving that?

A: In part. The results of other data you can look at show that clinical trial complexity has increased over this period of time, more is being done, more procedures in particular, and more protocol amendments. Another major driver of increase in cost actually is the high failure rates for drugs entering the clinical pipeline. You now have more failures per approval.

Q: If I asked you to look in your crystal ball, what do you see in the future? Are there any trends developing that may bend some of these cost curves?

A: I think in the short term costs will probably increase. There is potential for significant change in the future called personalized medicine, which may play a bigger role in drug development where science reaches the point that we can have good predictors of who will respond. If you’re able to get a good idea of who is going to respond on a per compound basis, it can certainly reduce the cost.

Comment: I was astonished by the lack of priority reviews for type 2 diabetes therapeutics. I think people need to understand diabetes kills people. The number of years lost in total for diabetes is pretty similar or even higher than years lost for cancer. That should be mentioned to people to understand that issue.

A: I absolutely agree that the burden of disease is quite high.

Q: When you look at the growth of cost in R&D in the pharma industry, have you compared it to R&D costs in other industries? What’s unique about the pharma industry?

A: What is maybe unique is that it is the most heavily regulated industry. I’m not saying it shouldn’t be, but that’s just the fact of life. There are enormous health and safety regulations, as well as economic regulation (mostly abroad). Also, it’s just a very, very long and risky process. I’m not sure there is any other industry with all those elements together.

Symposium: Effect of Intensive Insulin Therapy on Patients with Newly Diagnosed Type 2 Diabetes

Effect of Intensive Insulin Therapy on Patients with Newly Diagnosed Type 2 Diabetes

Longyi Zeng, MD, PhD (Sun Yat-Sen University, Guangzhou, China)

This presentation reviewed several studies demonstrating the beneficial effects of short-term intensive insulin (STII) therapy on patients with newly diagnosed type 2 diabetes. Previous studies led by investigators in China and elsewhere in East Asia have shown that, when implemented early in the course of type 2 diabetes mellitus, treatment with intensive insulin therapy for two to three weeks can induce a glycemic remission, wherein patients are able to maintain normoglycemia without any anti-diabetic medication. In a 2014 meta-analysis published by the journal Lancet, the proportion of participants in drug-free remission was about 66% after 3 months of follow-up, about 59% after 6 months, about 46% after 12 months, and about 42% after 24 months.

• China Expert Consensus STII Therapy Guidelines recommend that newly diagnosed patients with type 2 diabetes, who have an A1c of >9% or a FPG>11.1 mmol/L participate in short term insulin therapy. STII therapy could take the form of basal plus prandial insulin, continuous subcutaneous insulin infusion (CSII), or premixed insulin taken two or three times a day. There is still no clear consensus about the most appropriate endpoints for initiating treatment and how long to maintain STII therapy after normalization of glycemia.
• There are still several unanswered questions and challenges: Notably, there are barriers to implementing this program to primary care settings. Although endocrinologists are often the most comfortable initiating STII treatment, they are not likely to make the initial type 2 diabetes diagnosis. As a result, systems need to be put into place training primary care physicians and key support staff to initiate this treatment. Additionally, it will be exciting to see whether STII will reduce overall health cost by improving long-term glycemic control and thereby reduce the overall microvascular complications.
• Since STII is a relatively new option for patients with type 2 diabetes, more efforts are needed to educate practitioners and patients about the potential risks and benefits of the treatment.

Questions and Answers

Q: The shortage of diabetes educators limits the universality of this program in China. Would it be the nurses or doctors who implement this program?

A: I think that diabetes education is not only the responsibility of doctors or nurses. We have to share the responsibility of diabetes education. The other thing is that it is very busy in the offices of doctors and nurses, so we have to use some newer technologies such as web apps.

Q: How early should you start STII?

A: Open to investigation.

Symposium: The Impacts of Hypoglycemia in Diabetes

Common Mistakes in Using Insulin: Hypoglycemia Risk and A1c

Geremia Bolli, MD (University of Perugia, Perugia, Italy)

Dr. Geremia Bolli began his lecture by discussing the challenges of insulin therapy, which he believes is “more of an art than a science.” He reviewed several current limitations, including the narrow time window in which insulin should be delivered and the non-physiologic nature of subcutaneous delivery. Dr. Bolli highlighted the relationship between A1c, severe hypoglycemia and complications seen in the DCCT, arguing that sometimes providers might need to set a more ambitious A1c goal to prevent complications but other times they may need to allow a higher A1c value in order to prevent hypoglycemia. He focused the remainder of his talk on insulin mistakes, referencing research that attributes 9.2 percent of emergency department visits to insulin-related hypoglycemia and errors (Geller et al., JAMA Intern Med, 2014).  Dr. Bolli listed clinician errors, self-administration errors (including injection in lipo-hypertrophic areas), using the wrong insulin, self-monitoring errors, and miscalculations as just a few of many errors with life-threatening consequences. Dr. Bolli concluded with strong recommendations to reconcile the current limitations of insulin therapy with A1c goals while preventing mistakes. He urged providers to individualize glycemic targets and argued that we should devote more resources to education than to new technologies and insulin preparations; he believes education and time spent with patients are among the most important factors in remedying this problem.

Corporate Symposium: Addressing Postprandial Glucose Excursions in T2DM with Inhaled Insulin (Supported by Sanofi)

Current Thinking: Glucose Control and Postprandial Hyperglycemia

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

Dr. Irl Hirsch discussed the important contributions of postprandial hyperglycemia to diabetes pathology, which he argued are somewhat overlooked in current guidelines. He explained that it would theoretically make sense to target postprandial glucose earlier in the type 2 diabetes treatment algorithm given the strong association with cardiovascular morbidity and mortality in past studies. Additionally, there are already significant postprandial excursions that occur by the time fasting glucose is elevated. However, he then reviewed the evidence that led to the establishment of basal-only regimens as the standard way to initiate insulin therapy in type 2 diabetes – namely, the significant hypoglycemia that occurs with current rapid-acting insulins. He also referred to results from the HEART 2D study that challenged the connection between postprandial hyperglycemia and adverse outcomes by showing no difference in CV risk with prandial vs. basal insulin, though he noted that the difference in postprandial control between the two groups was quite small. Based on this somewhat conflicting evidence, Dr. Hirsch suggested that the field can either abandon the theory that addressing postprandial hyperglycemia improves outcomes or find better tools that do not cause hypoglycemia – not surprisingly, he would prefer the latter approach. Dr. Hirsch has taken a leading role in collecting better data on the independent effects of glycemic variability in diabetes, including the FLAT-SUGAR trial presented at this very meeting.

• During his talk, Dr. Hirsch also highlighted an unpublished ACCORD analysis of mortality risk with various medications. The analysis was originally performed in response to the rosiglitazone (GSK’s Avandia) scare, and it did not find any association between either rosiglitazone or pioglitazone (Takeda’s Actos) and increased mortality. However, it did find a significant ~25% increase in mortality with prandial and premixed insulin, supporting Dr. Hirsch’s hypothesis that the excess hypoglycemia produced by existing rapid-acting insulins may lead to negative long-term outcomes. On a more positive note, the analysis also found a significant reduction in mortality risk with exenatide – an intriguing signal that begs further investigation in a long-term prospective trial (as we understand it, most ongoing CVOTs of GLP-1 agonists are likely not powered to detect such a benefit). Of course, a major caveat is that these results came from a post-hoc analysis that (according to Dr. Hirsch) the investigators concluded was not robust enough to publish. Patients treated with insulin, for example, are likely to have been at poorer control or have more longstanding diabetes, on average, which could explain the increase in mortality seen. However, analyses like these do raise some important questions about the potential impact of various type 2 diabetes drug classes on long-term outcomes.

Management of Postprandial Hyperglycemia with Insulin

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

Dr. Bruce Bode discussed the potential of Sanofi/MannKind’s inhaled insulin Afrezza to address the need for more therapies to treat postprandial hyperglycemia. Echoing the sentiments from Dr. Irl Hirsch’s talk in the same symposium, Dr. Bode explained that the risks of hypoglycemia and weight gain, the inconvenience of multiple daily injections, and the stigma associated with insulin are all major challenges with current rapid-acting insulins, and there is a clear need for more effective options. He downplayed the past concerns about Pfizer’s less-than-successful previous inhaled insulin Exubera to some extent, suggesting that the primary issue was flawed marketing. Dr. Bode then reviewed clinical trial data showing a fast-on, fast-off profile, strong glucose-lowering efficacy, and improvements in weight and hypoglycemia with Afrezza. He characterized the product as safe and well tolerated, suggesting that the transient cough at the beginning of treatment is the main issue for patients and stressing that pulmonologists are “not concerned” about any effects on pulmonary function. Overall, Dr. Bode believes Afrezza should hold great appeal for many patients, particularly those who dread insulin injections. He also suggested that Afrezza could be particularly appealing in combination with an ultra-long-acting basal insulin like Sanofi’s Toujeo (insulin glargine U300) or Novo Nordisk’s Tresiba (insulin degludec). Uptake of Afrezza has been modest since its launch in February, and this appears to be largely due to administrative and logistical issues like spirometry scheduling and prior authorizations, and we believe the future potential is still quite high.

Panel Discussion

Richard Pratley, MD (Sanford-Burnham Translational Research Institute, Orlando, FL), Irl Hirsch, MD (University of Washington, Seattle, WA), and Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA)

Q: I have a patient who is 77 years old who was diagnosed at the age of 60. His C-peptide is undetectable, and he has a BMI of 23 kg/m². So he’s non-obese and has beta cell dysfunction. He was using an insulin pump, but he needed to switch since he has severe dementia. There is a clear pattern – his sugar goes up to almost 300 mg/dl 2-2.5 hours after a meal, then goes really low before the next meal, despite dropping the Levemir down to 2 and 6 units. I’m suspicious there may be an issue with gastric emptying – he has rapid gastric emptying. I’m labeling him as having type 1 diabetes, and treating as if he has type 1 diabetes. What do I do? Do I add GLP-1? Acarbose? Inhaled insulin?

Dr. Hirsch: First of all, you have to be very careful about gastric emptying studies. The nature of the study is that it has to do with glucose levels at the time. It can be extremely misleading. The other thing is that your patient most likely has type 1 diabetes. JDRF now estimates that half of people with type 1 diabetes are diagnosed as adults. If you wait too long, you’re not going to find antibodies. You can have type 1 diabetes for decades and still have a bit of C-peptide. It’s not as discriminatory as you think in terms of sensitivity or specificity. The real challenge is with timing of the prandial insulin. If there were no cognition issues, I would get the patient on the sensor and tighten his control. The reason it is so tough is that the dose of insulin is important, but the timing of prandial insulin is as important if not more important. That’s really the issue.

Dr. Bode: The benefit of inhaled insulin is that it doesn’t cause that much hypoglycemia – it’s fast in and fast out. Could this person do this? You’d have to try it and see what happens. If it works in your clinic, he can go home and try it. Right now, he’s going low and high and he’s a mess. You’re looking at assisted living for him. This guy has type 1 diabetes. Acarbose or GLP-1 would certainly suppress glucagon, but for someone like that, you still have to take rapid-acting insulin.

Q: If you were in my shoes, would you try giving him a GLP-1?

Dr. Bode: Because his BMI is 23 kg/m², no. If he had a BMI of 35 kg/m², I’d try it.

Q: If a patient inhaled insulin and then coughed, within how many seconds can you see that the dose is OK and does not need to be repeated?

Dr. Bode: With inhaled insulin, once it’s inhaled it goes into the deep tissue in two to four minutes. You might cough some out, but typically it’s an irritation you feel and later dry cough. It’s not persistent. There’s irritation of some particles in the back. Most people tolerate it and get over it in three to five days. It does cause people, especially those with type 1 diabetes who have been injecting all the time, to not want to do this any more after trying it. 

Q: Because the inhaled insulin has a quick out, what have you seen in postprandial glucose with a fatty meal?

Dr. Bode: In general in our type 1 trial, we saw a 35 mg/dl difference in plasma glucose, favoring inhaled insulin. However, when we looked at glucose during the day, the next pre-meal was higher, and the post-meal didn’t change. Our problem was that we didn’t have good enough basal during the day, because a fatty meal is going to absorb in three to four hours. This insulin is gone in 2.5 to three hours. You might have to inhale 90 minutes after you’re high. You can read blogs like afrezzauser.com and they’ll tell you how to do it. For example, it might be something like, “For cereal, inhale once. For pizza, take two fours and one four afterwards.”

Q: Does it stack?

Dr. Bode: It doesn’t stack because it is so quick.

Q: Do you use it as a correction insulin?

Dr. Bode: I was with Anne Peters today. She was telling me that for some people with type 1 diabetes, inhaled insulin is the best correction dose she has ever seen. It quickly gets it down, with no hypoglycemia. The reason why patients like it is because they can take it without getting hypoglycemia. In trials, we told people to take a correction dose after 90 minutes if they were above 180 mg/dl. Only 20% ever did. One of my patients, who always participates in my trials, usually comes in with an A1c of 9-10% and usually gets down to about 8.1-8.4%. With Afrezza, he exited the trial at 6.4%. I asked him what the heck he was doing. He said, “You don’t get it doc. I can take it and get my glucose down without crashing.” 

Q: Is there any effect on taste?

Dr. Bode: It’s mixed. Some say it has a little metallic taste. One said it tasted like lemon drops. People have different perceptions. In general, most people didn’t comment.

Dr. Pratley: All this inhaling doesn’t give you the munchies?

Dr. Bode: It’s fast in fast out, with a reduction in weight relative to traditional prandial insulins.

Dr. Pratley: Here’s a question I think it’s worth talking about. What can you say about Afrezza and lung cancer?

Dr. Bode: In their’s [MannKind’s], Pfizer’s, Lilly’s, and Novo’s [inhaled insulin] programs, there was no signal of increased lung cancer risk. However, there were some that got lung cancer. There were four lung cancers in the MannKind development program. Some occurred very early. How do you get lung cancer in 70 days? Others occurred 380 days post being on it. Two were smokers and two were non-smokers. Lung experts/oncologists think that this is pretty normal for the population, but the FDA mandated a long-term five-year 8,000 patient trial, including those at high risk (e.g., smokers, older people) to see what happens.

Corporate Symposium: Insulin-Based Options – Current Treatment Strategies and the Potential Impact of Emerging Options on Patient Outcomes (Supported by Novo Nordisk)

Where Are We Going from Here? Advances in Insulin-Based Treatment

Chantal Mathieu, MD, PhD (KU Leuven, Leuven, Belgium)

After explaining the need for new basal insulins, Dr. Mathieu provided an overview of Novo Nordisk’s Tresiba (insulin degludec), Sanofi’s Toujeo (U-300 insulin glargine), and Lilly’s peglispro. Throughout her presentation, she emphasized longer duration of action (>24-hour half-life) and reduced risk of nocturnal hypoglycemia as the main advantages of these new basal insulins. For insulin degludec specifically, she highlighted flexible dosing as another advantage.  

• Dr. Mathieu explained the need for new basal insulins. She commented that current basal insulins (by which she meant Lantus [insulin glargine U100] and Levemir [insulin detemir]) have still too much variability in their glucose-lowering effect, must be administered the same time every day, do not always last 24 hours, and cannot be mixed with other products.
• Subsequently, she provided an overview of Tresiba, Toujeo, and peglispro:
  
  • Tresiba: Dr. Mathieu emphasized that Tresiba reduces nocturnal hypoglycemia for both patients with type 1 diabetes and patients with type 2 diabetes. She mentioned that there is flexibility in time of dosing with insulin degludec – the medication does not lose its efficacy or safety when dosed flexibly (8-40 hours between doses) instead of at a fixed time each day (Meneghini et al., Diabetes Care 2013, Mathieu et al., JCEM 2013). In addition, Dr. Mathieu explained that Tresiba and insulin aspart (Ryzodeg) can be successfully co-formulated while retaining their individual action profiles.
  • Peglispro: After highlighting insulin peglispro’s liver-selective activity, Dr. Mathieu she discussed some of the medication’s benefits and risks. In clinical trials, insulin peglispro has been shown to reduce nocturnal hypoglycemia risk, and cause less weight gain than other insulins (though the mechanism remains unknown). However, increases in triglycerides, AST, and ALT were observed in clinical trials for insulin peglispro; as a result, Eli Lilly delayed its regulatory submission.
  • Toujeo: Dr. Mathieu stated that though Toujeo is associated with less nocturnal hypoglycemia than Lantus, higher doses of insulin are required to achieve the same glucose-lowering efficacy. In addition, Dr. Mathieu mentioned that in trials, Toujeo caused less weight gain than Lantus; however, there are no explanations for this observation at this moment in time.
• Dr. Mathieu discussed the synergies achieved by combining insulin and GLP-1 therapies, focusing her discussion on Novo Nordisk’s Xultophy (IDegLira; insulin degludec/liraglutide). In DUAL I, Xultophy treatment led to substantially better A1c control than either component treatment alone, caused less hypoglycemia and less weight gain than insulin degludec alone, and caused less nausea than liraglutide alone.

Insulin as a First-Line Therapy

Richard Pratley, MD (Florida Hospital Diabetes Institute, Orlando, Florida)

Dr. Richard Pratley addressed a less-than-filled ballroom in this corporate symposium to discuss the advantages of insulin as a first-line therapy for patients with type 2 diabetes. He first explained the rationale behind initializing insulin therapy, then discussed the process of starting and intensifying the therapy, and concluded with a review on the barriers to insulin therapy. His presentation challenged the existing paradigm of waiting until the rest of the type 2 diabetes therapeutic toolbox has been exhausted before moving to insulin. In his view, first-line insulin therapy could be a useful option in the context of individualized therapy.

• Dr. Pratley rationalized the introduction of initial insulin therapy by citing data from the UKPDS study. This study indicated that despite the common conception that metformin alone should be the primary line of treatment, the addition of insulin may provide relatively higher levels of glycemic control. At six years after initial diagnosis, more than 50% of patients needed insulin to reach their fasting glucose targets.  These results then translated to a consideration of insulin as a primary line of treatment for severe hyperglycemia.
• Dr. Pratley reviewed the various types of insulin and their activity profiles, then discussed the benefits and downsides of the progression from basal insulin, to basal plus prandial insulin, to premixed insulin. The most important takeaway in terms of benefits was that the emergence of analogs has provided marked increases in glycemic control as well as reduction in hypoglycemic events. He noted that MDI more closely mimics the physiological mechanism of action for insulin. Despite the benefits of progressive insulin therapy, more intensive therapy increases the risk of hypoglycemic events, which themselves have their own set of complications. We see the theoretical value of this argument though believe that PCPs do not like to prescribe mealtime insulin, broadly speaker.
• For each barrier to insulin therapy, Dr. Pratley recommended strategies to address their concerns. On the patient side, there may be frustration due to how long therapy takes as well as the fear of injections. However, he highlighted that the underlying concern comes from the fear of failing to meet the goals and endpoints towards managing glycemic levels. This fear has a prohibitive effect that delays the initiation of insulin therapy. Despite these barriers, Dr. Pratley asserted that insulin works and provides the most individualizable approach of all the existing therapies – we agree with this but think the barriers are many, particularly now that there are much easier to use and easier to prescribe orals. We do still think insulin will be very relevant however as type 2 patients are living longer and the need to individualize medicine for them is eventually very important.

Product Theaters

Afrezza – An Alternate Insulin Delivery (Sponsored by Sanofi)

Timothy Gilbert, MD (Imperial Health, Lake, Charles, LA)

We got to attend one of the first product theaters for Sanofi’s Afrezza. It didn’t include all the benefits we hear from patients, though it of course was boxed in by whatever was (and wasn’t) included by the FDA in the product’s prescribing information – the “wasn’t” includes hypoglycemia, ultra-rapid-acting, and weight benefits. Fortunately, the Q&A did answer some of the more critical questions on pulmonary function testing hassles and patient experiences. As for the presentation, ideally we would have loved a more targeted review at those (i) who don’t know the drug at all; and (ii) who are skeptical that the benefits are worth it vs. current insulins. The presentation started broadly with a discussion of the fraction of patients not at target, but did not discuss barriers to injection therapy (e.g., fear of needles) or postprandial hypoglycemia. Speaker Dr. Tim Gilbert focused on use of Afrezza in type 2 diabetes (type 1 was first mentioned 36 minutes in), though he did acknowledge in Q&A that most of his 12 Afrezza patient starts have been type 1s (this is also where the drug has seen a lot of early adopters to date). The two case studies provided a valuable window into how Sanofi is positioning the drug: (i) a type 2 not at goal maxed out on metformin and a DPP-4 (i.e., failing orals); and (ii) a type 2 not at goal on basal insulin. Indeed, Afrezza was positioned as a valuable tool for doctors to help basal insulin users with high A1cs but in-target fasting glucose levels (i.e., for whom increasing the basal insulin dose won’t correct the underlying problem). Overall, we do believe that Afrezza is a meaningful advance, though uptake will take some time to accelerate due to restrictions (lung function testing) and CME.

Toujeo — A Long Action Insulin Option (Sponsored by Sanofi)

John Anderson, MD (The First Clinic, Nashville, TN)

Dr. John Anderson took to the product theatre to explain why clinicians should prescribe Toujeo (U300 insulin glargine) to some of their patients instead of Lantus (U100 insulin glargine). Due to the FDA’s decision to exclude Toujeo’s nocturnal hypoglycemia data from the agent’s label, Dr. Anderson was restricted to describing the drug’s non-inferior efficacy (though at a higher dosage) as compared to Lantus, and not its improvement in nocturnal hypoglycemia. Fortunately, during Q&A an attendee specifically asked for a comparison of the two drugs’ hypoglycemia rates, enabling Dr. Anderson to highlight – with an emphasized and repeated acknowledgement that this data is off label – that in type 2 diabetes Toujeo demonstrated a statistically significant reduction in nocturnal hypoglycemia, and that in type 1 diabetes Toujeo had a statistically significant advantage in nocturnal hypoglycemia during the titration period (though not during the full trial). Though we had heard some early skepticism about the degree of Toujeo’s hypoglycemia benefit, more recent data (including the EDITION JP 2 study presented at this meeting) does seem to back it up and we think Sanofi’s ambitious set of upcoming real-world studies could make an even more convincing case. Dr. Anderson was then asked why he would prescribe Toujeo instead of Lantus; he highlighted that Toujeo is cheaper than Lantus thanks to Sanofi’s copay card for the agent and its lower nocturnal hypoglycemia rate, though he noted he will be able to provide a more nuanced answer after using it with his patients for a year. We have heard other doctors say that the pen is easier to use and we believe the COACH program is also quite valuable as it gives patients another connection point.

Questions and Answers

Q: Can you compare the hypoglycemia rate of Lantus vs. Toujeo?

A: First, the FDA considers it off-label to discuss the hypoglycemia data even though it was a secondary endpoint.  That said, in type 2 diabetes nocturnal hypoglycemia rate was significantly lower with Toujeo than with Lantus. In type 1 diabetes, it was not significantly different overall, though it was improved during the titration phase.

Q: What has your clinical experience with the drug been?

A: I am using it a lot more now. My patients are not coming back with hypoglycemia, in general. It is an easy pen to use. I haven’t gotten much three month or six month data with it since it is still new. I can’t say if I am seeing a difference between Lantus and other insulins.

Q: Why prescribe Toujeo over Lantus?

A: First, there is the lower rate of nocturnal hypoglycemia. Additionally, for many of my patients insulin has become very expensive. The copay card for Toujeo helps. I can’t fault anyone for considering staying with the same therapy. When we have new products on the market we have to get familiar with. I will be able to answer this question better in a year.

Q: Why do people need higher doses of Toujeo?

A: The most popular theory is that because Toujeo’s micro-precipitate is in the subcutaneous space for a long time you get more degradation as it sits there so you probably need a little more of it. To put this higher dose perspective, you have a patient on 35 U with Lantus they are looking at being on 38 or 39 U. So it’s not a big difference.

Q: Is Toujeo’s metabolite the same as Lantus?

A: It is. Its degradation is the same. However, it has a different PK/PD profile due to its concentration and how it acts in the subcutaneous space.

 

--by Hannah Deming, Jessica Dong, Samiul Haque, Varun Iyengar, Emily Regier, Mallika Tamboli, Lisa Vance, Manu Venkat, Vincent Wu, and Kelly Close