June 13-17, 2014; San Francisco, CA – Incretin-Based Therapies – Draft

Executive Highlights

There were plenty of updates and new data on GLP-1 agonists this year, focusing on better drug delivery and on promising combinations with other drug classes, especially basal insulin. The field is growing in complexity and there are ever more big questions to consider. We saw results from a phase 2b study of Sanofi’s LixiLan, a fixed-ratio combination of the short-acting GLP-1 agonist Lyxumia (lixisenatide) and the market-leading basal insulin Lantus (insulin glargine). The results showed significant postprandial improvements with LixiLan compared to Lantus, but similar A1c reductions (due to a stronger-than-expected showing from the Lantus arm, possibly a study effect). One-year follow-up data from the DUAL I trial on Novo Nordisk’s IDegLira (liraglutide/insulin degludec) presented by Dr. Stephen Gough (University of Oxford, UK) showed that the substantial A1c reductions, weight benefit (vs. insulin), and hypoglycemia benefit (vs. insulin) seen after 26 weeks were preserved through to 52 weeks. It is hard to overstate the promise presented by GLP-1 agonist/basal insulin combinations – conversely, it is disappointing that both IDegLira and LixiLan’s timelines will be pushed back by regulatory delays.

We saw extensive data on Lilly’s once-weekly GLP-1 dulaglutide, the only once-weekly option on or near the market that comes as a ready-to-use suspension and does not require reconstitution. A poster on the usability of the dulaglutide single-use pen showed that it was generally easy to use and reduced patients’ fear of injection. Interestingly, two of the phase 3 trials we saw on dulaglutide compared it to basal insulin, with dulaglutide emerging with A1c, weight, and hypoglycemia benefits. Although there is much to still learn about dulaglutide, it may well stand to be a relatively beginner-friendly injectable that could perhaps grow the entire class. Novo Nordisk’s once-daily GLP-1 Victoza marketing is quite strong though! We also saw clinical data on TransTech’s oral GLP-1 agonist program, which distinguishes itself from other oral GLP-1 agonists in development by using small molecule agonists rather than encapsulated polypeptides. A potentially transformative development in GLP-1 agonist delivery is Intarcia’s implantable exenatide mini-pump ITCA-650; we saw a poster on the candidate, as well as a demo of the quick and simple implantation and removal protocol (just a few minutes each). There are a lot of questions about IP, similar to mounting questions that are emerging about biosimilars.  

Questions about incretin safety, namely the potential association of incretins and pancreatitis and DPP-4 inhibitors and heart failure, were on the forefront of many people’s minds coming into ADA and mostly the reactions to the questions seemed to be pretty reassuring. Dr. John Buse (University of North Carolina, Durham, NC) attempted to allay some of the concerns during a Meet the Experts session, suggesting that heart failure was probably a spurious signal or at worst a modest one. Cardiovascular outcomes trials received their own full dedicated symposium, with in-depth presentations on SAVOR (for AZ’s Onglyza) and EXAMINE (for Takeda’s Nesina) – this topic is going to be increasingly important this year, with a big FDA meeting coming up. We also saw a theatrical presentation on the challenges and misconceptions about injectable therapies for diabetes, similar to one presented at IDF last year in Melbourne, courtesy of a Novo Nordisk corporate symposium. This session was packed to the brim, and we feel that HCPs walked away with some valuable learning.

Below you’ll find detailed reports on all of these topics and more. Presentation titles highlighted in blue were not previously published in our daily highlight reports during ADA. We’ve highlighted in yellow presentations we found particularly notable.

 

Incretin-Based Therapies

Banting Medal for Scientific Achievement Award Lecture

Deciphering Metabolic Messages from the Gut Drives Therapeutic Innovation

Daniel Drucker, MD (Lunenfeld Tanenbaum Research Institute, University of Toronto, Canada)

Dr. Dan Drucker, recipient of this year’s Banting Medal, is a truly unparalleled mind in the realm of gut hormone-related therapeutic innovations. Dr. Drucker opened by noting he was originally supposed to be a thyroid hormone specialist, but serendipitously ended up being assigned to work on the glucagon gene instead. He’s worked on proglucagon-derived peptides from the very beginning, since the first cDNAs and genes had just been cloned and no one knew what any of those peptides did. In the early days, Dr. Drucker and colleagues discovered that one fragment of the GLP-1 peptide was a potent regulator of insulin gene expression, cAMP production and beta cell secretion – it seemed trivial to him at the time, but his mentor Joel Habener filed a patent in 1986, which is the patent that has laid the foundation for GLP-1 as a therapy. Since then, Dr. Drucker and his team have extensively characterized the pharmacologic and physiologic actions of GLP-1, including characterizing GLP-1’s potential beta cell preservation and proliferation effect in mice, GLP-1’s numerous actions outside of glucose regulation, and delineating DPP-4 inhibitors’ mechanism of action. He also touched on the hot topics of pancreatic safety and potential cardioprotective effects. Notably, Dr. Drucker gave reasons not to sound the alarm over GLP-1’s consistently demonstrated effect on increasing pancreas mass – he has evidence from mice that increased pancreas mass is not due to edema, inflammation, or increased cellular proliferation. In fact, he has shown that it is due to increased protein synthesis, possibly reflecting the communication between the gut and the pancreas to increase pancreas protein synthesis following meal ingestion, however the mechanism is not fully understood. The thousands of audience members gave Dr. Drucker a thunderous standing ovation at the conclusion of his presentation.

• Dr. Drucker described his early work in the 1980s first characterizing peptides derived from the proglucagon gene, which led to the discovery and patenting of GLP-1 as a glucose regulator. From a self-described “unimaginative” experiment that involved “dumping” several glucagon-like peptides on “as many cell cultures as we could,” Dr. Drucker and his colleagues observed that the 7-37 fragment of GLP-1 was a potent regulator of insulin gene expression, cAMP production, and beta cell secretion. At the time Dr. Drucker did not think much of the finding, but his mentor, Joel Habener, filed a patent for the molecule on May 5, 1986, which is the patent that has laid the foundation for GLP-1 agonist therapies. It was at this point, said Dr. Drucker, that he was introduced to the concept of science forming the foundation for new therapeutics, which he has since gone on to do in spades. He noted at the end of his presentation that the proglucagon gene has given rise to more drugs for the treatment of human disease than any other gene in the human genome.
  
  • Dr. Drucker noted that we’re still interested in new clinical ways to activate the GLP-1 receptor signaling pathway. The well known methods currently used are (i) inhibiting the inhibitor of GLP-1 by using DPP-4 inhibitors, and (ii) pharmacologically activating the GLP-1 receptor using analogs. Ongoing work remains in potentially developing GLP-1 secretagogues or neutraceuticals/functional foods that activate GLP-1 secretion from the gut.
• In addition to the pharmacological effects of GLP-1, Dr. Drucker has also worked extensively on characterizing the role of endogenous GLP-1 using GLP-1 receptor knockout mice (Glp1r ^-/-).
  
  • GLP-1 is not only secreted after meals, but throughout the entire day: Unexpectedly,  Glp1r ^-/- mice had fasting hyperglycemia in addition to glucose intolerance, which led to the finding that there is not only postprandial secretion of GLP-1, but also some basal level of GLP-1 activation that helps control fasting glucose.
  • Endogenous actions other than stimulating insulin secretion include enhancing beta cell preservation and proliferation: Dr. Drucker and colleagues were also among the first to characterize GLP-1’s potential effect on beta cell preservation and proliferation. In an experiment where mice were treated with exendin-4 (exenatide’s precursor) for seven days, and given STZ to injure their beta cells, then exendin-4 treatment was stopped, three weeks later the animals that had received exendin-4 treatment had higher plasma insulin levels than those who had not and lower blood glucose levels. Dr. Drucker and colleagues were able to demonstrate that GLP-1 receptor activation was inhibiting beta cell apoptosis in mice as a direct effect of GLP-1 receptor activation on the beta cells. Furthermore, as demonstration that this was also an effect of endogenous GLP-1, not just pharmacologic GLP-1, Dr. Drucker has shown that mice with no GLP-1 receptor activity are more sensitive to STZ-induced apoptosis compared to wildtype mice. With regards to proliferation, Dr. Drucker’s lab also demonstrated that incretin receptors are necessary to for increased insulin production in response to high-fat diet-induced insulin resistance.
• Dr. Drucker remarked that the evidence thus far presented a seeming paradox: GLP-1 could both increase insulin secretion while also preserving beta cell function (whereas other insulin secretagogues seemed to wear down beta cell function). Normally, increased protein production (in this case insulin) would upregulate endoplasmic reticulum (ER) protein synthesis, and at a certain point start causing ER stress. Dr. Drucker’s colleagues reconciled this conundrum by finding that incretin receptors directly engage several arms of the ER stress response, allowing the upregulation of insulin biosynthesis while simultaneously preserving cell survival. Dr. Drucker noted that “incretin secretion is uniquely positioned to enhance insulin secretion and prolong beta cell survival,” in contrast to other insulin secretagogues – of course the positive effect on beta cells has only been convincingly shown in mice, and human data has been sparse to date.
• Dr. Drucker has also characterized where GLP-1 acts outside of the beta cell, including the brain. Native GLP-1 (which is a relatively small peptide) has direct central nervous system effects, and years ago it was not known whether synthetic high-molecular weight GLP-1 agonists would also be able to interact with the brain (since they would be too large to penetrate the blood-brain barrier). Dr. Drucker’s group compared exendin-4 (small peptide) to albiglutide (large peptide) and found that they produced about the same extent of central nervous system (CNS) activation, and had the same ability to inhibit food intake and reduce gastric emptying. Thus, they learned that GLP-1 does not have to directly penetrate the CNS to activate the classical actions of GLP-1 receptor signaling in the brain – Dr. Drucker noted that this finding informed the decision to move forward with development of high-molecular weight, longer-acting GLP-1 receptor agonists (e.g., Lilly’s dulaglutide and GSK’s albiglutide).
• Dr. Drucker’s work on glucagon-derived hormones also led to a better characterization of DPP-4 inhibitors’ mechanism of action. With the DPP-4 enzyme’s dozens of substrates, it at first was not clear which ones were truly important for its effect on glucose metabolism. Dr. Drucker’s group showed that both GLP-1 and GIP receptor activation was necessary for DPP-4 inhibitors to exert their effect.
• In working with GLP-1’s sister peptide, GLP-2, Dr. Drucker also discovered that GLP-2 stimulates small bowel growth, which led to its development as a treatment for small bowel syndrome.
• Finally, Dr. Drucker explored the clinical relevance of some of the non-glycemic actions of GLP-1 in the intestine, pancreas, and cardiovascular system, highlighting that we still have much to learn.
  
  • Intestinal safety: Dr. Drucker noted that many have questioned why GLP-1 is made in the distal gut if its role is to stimulate insulin secretion after we eat (nutrients don’t reach the distal gut for several minutes or even hours after food being ingested). However, GLP-1, like GLP-2, is a potent bowel growth factor, and Dr. Drucker’s group has found that GLP-1 activation increases growth of intestinal polyps and tumors when activated in the distal bowel of a rodent cancer model. When GLP-1 receptors are removed in this model, tumor size and number significantly decrease. Dr. Drucker implied that we may need to more closely monitor the potential for inappropriate intestinal growths in treating patients with GLP-1 agonists.
  • Pancreatic safety: GLP-1 has been consistently found to increase the mass of the mouse pancreas by about 10%, but Dr. Drucker gave reasons not to sound the alarm over potential tumor formation – he noted that “what we have failed to address, as a community, is why the pancreas is bigger.” Dr. Drucker’s team has shown that the increased pancreas size is not due to increased inflammation, edema (water and edema actually decreases in mice given exendin-4), or cellular proliferation. The reason he has pinpointed is that it GLP-1 stimulates the pancreas to make more protein in response to meal intake. We believe we heard Dr. Drucker say that his team has identified which proteins are selectively modulated by GLP-1 signaling in the mouse pancreas, but he did not disclose what those were. The takeaway here is increased pancreatic mass on its own is no reason to jump to conclusions about potential for pancreatic cancer – however, he noted that we do not completely understand the mechanisms through which GLP-1 receptor signaling modifies pancreatic protein synthesis.
  • Cardiovascular effects: GLP-1’s cardioprotective effects on mice have been well established, and Dr. Drucker noted that for years we assumed it was due to direct activation of GLP-1 receptors on ventricular cardiomyocytes (which are the cells most directly involved in CV events like heart failure or myocardial infarction). However, Dr. Drucker upended this thinking by showing that the receptor is not actually expressed in the ventricular cardiomyoctyes. Instead, it has been found in the atrium. Dr. Drucker, furthermore, has shown that direct GLP-1 receptor activation in the heart is not even necessary for GLP-1 to exert its cardioprotective effects: a mouse model with no GLP-1 receptor expression in the heart was no different than a wildtype mouse with full GLP-1 receptor expression when responding to ischemia (blood supply shortage). Therefore, Dr. Drucker concluded that GLP-1 does not act directly on the heart to exert its potential cardioprotective effects, but likely acts through some other unknown indirect mechanism. So the obvious next question is why there are GLP-1 receptors in the atria in the first place – Dr. Drucker demonstrated that these receptors were actually important for heart rate regulation rather than playing a role in cardioprotection. Dr. Ducker gave a presentation on this topic at the Keystone Symposium on Diabetes Complications earlier this year.
• Looking to the future, Dr. Drucker outlined a slew of potential new roles for GLP-1 agonists: as potential treatments for obesity, prediabetes, type 1 diabetes, children with type 2 or type 1 diabetes, neuroprotection and neurodegeneration, anti-inflammation, fatty liver disease, cardiovascular indications, and microvascular disease.

Oral Presentations: GLP-1 Agonists

Benefits of a Fixed-Ratio Formulation of Once-Daily Insulin Glargine/Lixisenatide (LixiLan) vs. Glargine in Type 2 DM Inadequately Controlled on Metformin Monotherapy (332-OR)

Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)

Dr. Julio Rosenstock presented results of a 24-week proof of concept study demonstrating that the combination of the lixisenatide and Lantus (Sanofi’s LixiLan GLP-1 agonist/basal insulin fixed-ratio combination product) has advantages over Lantus alone. This study randomized 323 people with type 2 diabetes on background metformin (relatively early-stage type 2 diabetes), to LixiLan or Lantus. LixiLan dose was adjusted according only to Lantus basal insulin requirements. Both arms achieved similar and striking A1c reductions (1.8% reduction on LixiLan compared to 1.6% on Lantus from 8% baseline) to a final A1c of 6.3% with LixiLan that was statistically superior to the 6.5% achieved with Lantus as LixiLan blunted postprandial glucose excursions substantially more so than Lantus (LixiLan reduced excursions by 70 mg/dl compared to 12 mg/dl on Lantus; p<0.001). A striking 84% of patients on LixiLan achieved an A1c goal of <7% (although a surprisingly high 78% of Lantus patients also achieved this goal); extraordinarily, 72% on LixiLan reached an A1c goal of ≤6.5% compared to 65% of Lantus patients (again, still pretty high for Lantus, probably indicating the investigators’ skill at titrating dose). Moreover, LixiLan produced a -1.2 kg [-2.6 lb] weight change over the 24 weeks compared to a 0.4 kg weight gain [0.9 lb] on Lantus. Documented symptomatic hypoglycemia (≤70 mg/dl) was similar between the two groups at 22-23%. The study also examined several composite efficacy endpoints of interest as outlined in the table below in which LixiLan was consistently better than Lantus. Frequency of nausea and vomiting with LixiLan (7.5% and 2.5%, respectively) was less in this trial compared to what has been reported for other GLP-1 agonists likely due to the slow titration determined by the insulin adjustments so that for each increment of two units of insulin glargine there was a lixisenatide increase of only 1 μg. In all, the data are very impressive – yet another testament to the strength of the GLP-1 agonist/basal insulin combination that we think bodes very well to future therapeutic approaches and combinations. In the introduction to his talk, Dr. Rosenstock positioned LixiLan as a better alternative for basal insulin intensification compared to adding on prandial insulin.

Composite Endpoint	LixiLan (n=161)	Lantus (n=162)
A1c ≤7% and No Weight Gain	56%	37%
A1c≤7% and No Symptomatic Hypoglycemia	64%	57%
A1c≤7% and No Weight Gain and No Symptomatic Hypoglycemia	46%	29%

Efficacy and Safety of Once-Weekly Dulaglutide vs. Insulin Glargine in Combination with Metformin and Glimepiride in Type 2 Diabetes Patients (AWARD-2) (330-OR)

Francesco Giorgino, MD, PhD (University of Bari Aldo Moro, Bari, Italy)

Dr. Francesco Giorgino presented the results of the AWARD-2 trial, which compared Lilly’s once-weekly GLP-1 agonist dulaglutide against Sanofi’s basal insulin Lantus (insulin glargine) added on to maximally tolerated doses of metformin and a sulfonylurea in type 2 diabetes patients for 78 weeks. At week 78, dulaglutide 1.5 mg (the highest of the two doses tested) led to a superior reduction in A1c from baseline (-0.90%) than insulin glargine (-0.59%), while dulaglutide 0.75 mg provided a non-inferior mean A1c reduction (-0.62%) relative to insulin glargine. Dulaglutide 1.5 mg led to weight loss of 2 kg (~5 lbs) at week 78, while the insulin glargine group gained over 1 kg (~3 lbs) on average. The incidence of total hypoglycemia was ~60% higher with insulin glargine than dulaglutide, and the incidence of nocturnal hypoglycemia was more than double the incidence with dulaglutide. As expected, the incidence of nausea was higher in the dulaglutide arms (15% and 8% for dulaglutide 1.5 mg and 0.75 mg, respectively) than the insulin glargine arm (2%). These results serve as evidence that GLP-1 agonism can be a more beginner-friendly initiator injectable for patients not at goal on oral medications, especially those that cause hypoglycemia. However, the fact that investigators may have held back in up-titrating insulin due to fears about hypoglycemia should be considered when discussing the relative clinical efficacy of dulaglutide and insulin glargine.

Harmony 3 Year 3 Results: Albiglutide vs. Sitagliptin and Glimepiride in Patients with T2DM on Metformin (329-OR)

Molly Carr, MD (GSK, King of Prussia, PA)

GSK’s Dr. Molly Carr presented the results of the phase 3 Harmony 3 study for the once-weekly GLP-1 agonist Tanzeum/Eperzan (albiglutide). As with other studies in the Harmony program, Harmony 3 ran for three years, quite a long duration for a phase 3 program – we think it is fantastic when studies can run (and be funded) this long. Dr. Carr’s team analyzed the trial’s results in two ways: the first analysis excluded data from patients who needed hyperglycemia rescue from the point the rescue occurred, consistent with the way that phase 3 efficacy data is generally presented. In this analysis, at the two year primary endpoint, albiglutide demonstrated a -0.91% placebo-adjusted reduction in A1c from a baseline of 8.1%, which was 0.35% greater than the reduction seen with sitagliptin and 0.27% greater than the reduction seen with glimepiride (2 – 4 mg). The differences in A1c were still visible but less pronounced at year three. Notably, in Harmony 3, patients who required hyperglycemia rescue continued to receive their randomized therapy. Taking advantage of this design element, Dr. Carr also presented an analysis of efficacy in an intent-to-treat population, including those who required rescue. In this analysis, albiglutide still demonstrate significantly greater placebo-adjusted A1c lowering from baseline at year three (-0.68%) than sitagliptin (-0.27%) or glimepiride (-0.41%). Notably, albiglutide did not provide better weight loss than placebo or sitagliptin in the long term, but was also associated with a relatively low rate of GI side effects compared to other GLP-1 agonists. Seeing evidence of sustained efficacy out to three years was reassuring, but it remains to be seen how the seemingly modest weight loss but also a low incidence of GI side effects will factor into providers’ and patients’ perspectives on this agent.

• Study design: The randomized, double-blind, placebo and active-controlled, parallel-group phase 3 study randomized 1012 type 2 diabetes patients in a 3:3:3:1 fashion to albiglutide 30 mg -> 50 mg, sitagliptin 100 mg, glimepiride 2 mg -> 4 mg, or placebo. A notable aspect of the study design, which Dr. Carr repeatedly emphasized, was that patients that underwent hyperglycemia rescue (as per FDA requirements) continued receiving study medication in a blinded fashion after rescue. Although this protocol added some extra complexity to the results, we also believe it added real-world relevance, given that diabetes is a progressive disease that for most patients requires occasional intensification of treatment. At baseline, patients’ mean age was ~55 years, mean BMI was 33 kg/m², and mean A1c was ~8.1%.
• Dr. Carr first presented the primary endpoint analysis of A1c change through week 104. Albiglutide provided a statistically superior reduction in A1c from baseline relative to sitagliptin, glimepiride, and placebo. Placebo-adjusted reductions in A1c for each group were -0.91% for albiglutide, -0.64% for glimepiride, and -0.56% for sitagliptin (mean baseline A1c = 8.1%). The curves for albiglutide and glimepiride were comparable for the first six months, and subsequently the effect of glimepiride began to wear off while albiglutide’s efficacy largely remained. At week 104, 39% of patients in the albiglutide group achieved an A1c below 7% compared to 31% in the glimepiride group, 32% in the sitagliptin group, and 16% in the placebo group. Given that less than half of patients in the albiglutide group had not reached a sub-seven A1c, we were surprised that only 53% of patients in the albiglutide group had been uptitrated to the higher 50 mg dose by week 104.
• Dr. Carr next presented three-year data in the population of patients that did not require hyperglycemia rescue. Albiglutide still provided the greatest reduction in A1c, although the difference was more modest at year three: albiglutide provided a -0.42% placebo-adjusted reduction in A1c from baseline, compared to -0.13% with glimepiride and -0.10% with sitagliptin. However, it also bears mentioning that the number of patients who were still in the study at year three and did not require hyperglycemia rescue was very small – only 16 of the 94 patients on placebo made it from study initiation made it to week 156, and perhaps as a result, the placebo group saw a -0.46% A1c reduction from baseline at week 156. Albiglutide also led to a modest reduction in fasting plasma glucose at week 156, on the order of -22 mg/dl (the slide did not indicate whether the difference was statistically significant).
• Because patients that required hyperglycemia rescue continued taking their randomized therapy, Dr. Carr was able to present the results of an intent-to-treat analysis. Significantly fewer patients randomized to albiglutide required hyperglycemia rescue (29%) by year three, relative to 38% with sitagliptin, 34% with glimepiride, and 49% with placebo. In this patient population (which included more patients than the per-protocol 156-week pool), albiglutide led to a placebo-adjusted reduction in A1c of -0.68%, compared to -0.41% with glimepiride and -0.27% with sitagliptin.
• Unusually for a GLP-1 agonist, albiglutide was not associated with a long-term weight benefit relative to placebo or sitagliptin. While there might have been a slight advantage for the first half year, from then onwards out to year three, the three curves tracked roughly in line with one another. Interestingly, the three groups held steady at ~1 kg (~2 lbs) weight loss for the entire study period, rather than the upward drift we would have expected with placebo and perhaps sitagliptin for such a long time period. The lack of weight loss with albiglutide was brought up during Q&A, where Dr. Carr acknowledged the likelihood that albiglutide’s large molecular size prevents it from crossing the blood-brain barrier and interacting with satiety-regulating hypothalamic nuclei. However, she also noted that this phenomenon could explain the low rates of nausea seen with the drug (see below).
• Generally, relatively low weight loss would be negative, but it appears that the mechanism behind that also leads to very low nausea rates. Indeed, in in this trial, albiglutide was associated with a relatively low incidence of nausea and vomiting. The respective incidences of nausea/vomiting were 12%/7% with albiglutide relative to 7%/5% with sitagliptin, 8%/4% with glimepiride, and 13%/1% with placebo. The three-year duration of the study explains the slightly elevated incidence of GI side effects across the board. Given that nausea is one of the most challenging tolerability issues that patients experience with GLP-1 agonists, this profile might portray albiglutide as a more beginner-friendly option.
  
  • There were two cases of definite or probable pancreatitis in the trial, both in the albiglutide group. The incidence of injection site reactions was somewhat elevated in the albiglutide group (18%). The numbers of adverse events that led to withdrawal of active treatment were perhaps slightly higher in the albiglutide group (8%) than with sitagliptin (4%) or glimepiride (6%), but the overall number of events was relatively small for a three-year trial.

Questions and Answers

Q: It was puzzling that there was no weight loss with this GLP-1 agonist – it appeared that sitagliptin caused just as much weight loss. Dr. Michael Nauck theorized two years ago that albiglutide might not show weight loss because it does not cross the blood-brain barrier. Did you examine that?

A: I would agree with Dr. Nauck’s hypothesis – albiglutide is a large 73 kilo-Dalton peptide, which is unlikely to have much passage through the blood-brain barrier to gain access to the hypothalamic nuclei. Those nuclei that regulate satiety and food intake are close to the centers that regulate nausea, which could be the reason that we saw low rates of nausea and vomiting. But we do not have data yet specifically on blood-brain barrier penetration.

Efficacy and Safety of Liraglutide vs. Placebo When Added to Basal Insulin Analogs in Patients with Type 2 Diabetes (LIRA-ADD2BASAL) (331-OR)

Andrew Ahmann (Oregon Health and Science University, Portland, OR)

Dr. Andrew Ahmann described a 26-week randomized controlled trial of liraglutide 1.8 mg/day vs. placebo in patients with poorly controlled type 2 diabetes using basal insulin, with or without metformin (n=550). Mean baseline data in the liraglutide and placebo groups were as follows for A1c (8.2% vs. 8.3%), BMI (32.3 vs. 32.2 kg/m²), diabetes duration (12.1 vs. 12.1 years), and stable dose of insulin analog dose (48.3 vs. 45.9 U/day). Insulin dosage could not be increased following randomization; during Q&A Dr. Ahmann said that this rule was made to clearly show liraglutide’s effect on A1c. At 26 weeks, liraglutide was statistically significantly superior to placebo with respect to A1c decrease (1.30% vs. 0.11%), FPG decrease (1.44 vs. 0.16 mmol/l [25.9 vs. 2.9 mg/dl]), weight loss (3.54 kg vs. 0.42 kg [7.9 lbs vs. 0.9 lbs]), percentage of patients achieving A1c <7.0% (59% vs. 14%), and percentage of patients achieving A1c <7.0% without weight gain or hypoglycemia (42% vs. 9%). Liraglutide-treated patients also used a significantly lower ratio of their initial basal insulin dose (0.87 vs. 0.98). The liraglutide group had more documented symptomatic hypoglycemia (30.7% vs. 20.4%) and more asymptomatic hypoglycemia (31.6% vs. 27.6%). Adverse events occurring in at least 5% of patients were more common with liraglutide (69% vs. 58%), due largely to gastrointestinal side effects such as nausea (22% vs. 3%), vomiting (9% vs. 1%), and decreased appetite (10% vs. 2%). No known pancreatitis occurred in either group.

Questions and Answer

Dr. Richard Bergenstal (International Diabetes Center, Minneapolis, MN): Were there any seven-point glucose profiles? I’m trying to get a sense of fasting and postprandial.

A: Seven-point profiles were done three times during the trial. Fasting glucose started at roughly 145 mg/dl. In the liraglutide group fasting glucose decreased by 26 mg/dl. Postprandial glucose was significantly different; the delta was about 18 mg/dl. The mean values for the seven-point profiles were consistent with the A1c changes.

Q: If the control group could have kept adjusting their basal insulin, they probably would have had better A1c and maybe more hypoglycemia. How did you decide to design the trial to prevent up-titration of insulin?

A: The intention was to focus on A1c in part because of regulatory guidance trying to make that the point.

Q: Were the decreases in systolic blood pressure seen in all patients, or only those patients starting with higher systolic blood pressure?

A: I don’t know exactly; the blood pressure was not exceptionally high as a whole. In this particular trial we have not looked at that yet. In other trials, there appears to be more effect with higher baseline SBP.

Q: The cynic in me thinks that if you make someone feel sick, whatever drug you give them, they tend to get better. Was A1c different in the patients with nausea?

A: In other trials, significant benefits on A1c and weight were seen even without nausea. It was not separated out in this study.

Dr. Bergenstal: Thank you for using composite indexes. I think these are valuable and we need to decide which to use.

Liraglutide and the Preservation of Beta-Cell Function in Early Type 2 Diabetes: A Randomized, Controlled Trial (328-OR)

Ravi Retnakaran, MD (University of Toronto, Canada)

Dr. Ravi Retnakaran of Bernard Zinman’s group presented results suggesting that beta cell function is preserved if not enhanced in people on liraglutide who did not have glucotoxicity at baseline. Dr. Retnakaran suggested that this finding warrants further investigation into the long-term clinical effects of early liraglutide use on the progression of type 2 diabetes. During Q&A, however, several attendees objected to the use of a placebo instead of an active comparator. Due to this decision it is difficult to determine if the difference in beta cell function between the two groups at the end of the study was because of the glucotoxicity the control group likely experienced. Had an active comparator (e.g., IIT) been used it might be easier to conclude the direct impact liraglutide had on beta cell preservation. That said, comparing the liraglutide group’s beta cell function at the end of the treatment period against that at baseline, does suggest the therapy preserved or enhanced beta cell function. 

• Dr. Retnakaran critiqued other studies of anti-diabetes drugs’ effects on beta cell function for not addressing the confounding effect of glucotoxicity. Studies evaluating the effects of anti-diabetes therapies on beta cell function are typically confounded by glucotoxicity at baseline and its alleviation by the therapy under study. As a result, improvements in beta cell function attributed to a drug could partly reflect the removal of glucotoxicity as opposed to a direct effect of the therapy on the beta cells. Thus, elimination of glucotoxicity is needed for the objective assessment of the capacity of a therapy to directly preserve or improve beta cell function.
• To address this confounding variable, the researchers placed participants (n=63) on four weeks of intensive insulin therapy (IIT) to eliminate glucotoxicity before randomizing them to either liraglutide or placebo. To determine if glucotoxicity had been removed the investigators tested if a person’s fasting venous glucose level was less than 126 mg/dl a day after ending the IIT – in this way they saw if a person’s endogenous beta cell function could keep his/her FPG in the euglycemic range. People were only randomized to treatment if they met this threshold. Of the 61 people initially enrolled, 51 were randomized to either liraglutide or placebo. These participants were then followed for 48 weeks.
• At the time of randomization, 60% of participants were male, 70% were white, and they had an average age of 58 years. The average diabetes duration was slightly different between the liraglutide (three years) and control (1.5 years) groups. The average A1c was similar between the two groups at 6.4% in the liraglutide arm and 6.2% in the placebo arm. The measure of beta cell function utilized was ISSI-2; at randomization the liraglutide group’s was 193 and the control’s was 220 (for context, an ISSI-2 associated with NGT is >800). Dr. Retnakaran did not seem concerned about the difference in ISSI-2 between the two groups.
• The liraglutide arm’s ISSI-2 was enhanced by more than 50% (from 193 to ~350) in the first 12-weeks post-randomization and was preserved thereafter. In contrast, the placebo arm’s ISSI-2 stayed flat at roughly 250. Similarly, the researchers identified significant improvements in OGTT insulin, glucose, and C-peptide response curves in the liraglutide arm relative to the control. This conferred better glycemic control in the liraglutide arm, with significantly more people in the treatment group than in the control achieving an A1c <6% at each point in time. No significant difference in insulin sensitivity was observed, though the liraglutide group did lose weight.
• The improvement in ISSI-2 did not persist after a washout period. The liraglutide group’s ISSI-2 dropped to 192 and the control’s continued at 238.

Questions and Answers

Dr. Julio Rosenstock (University of Texas Southwestern Medical School, Dallas, TX): Beautiful study. That is a great concept to assume that in the hyper-milieu you probably wont see the effects of beta cell preservation. I would have kept the basal insulin so that way you would have had an active control. 

A: Absolutely, thank you for that point. We have eliminated glucotoxicity at the outset; however, the two meds do have differing glucose lowering effects subsequently. It could be that with an active comparator we would address that part of the design.

Q: At the end of these 48 weeks glucose control was worse in the placebo arm. How can you exclude that the difference in these effects were due to the difference in glucose control? You might have seen the effects of glucotoxicity.

A: It needs to be recognized that ISSI-2 is a measure of beta cell function, not glucose control. Your concern is – how do we know that this is the direct effect of liraglutide on beta cell function at the end of the study given the lack of glucose control in the placebo. That is right. What we can say is that glucotoxicity was not a confounder at the outset. At the end there could be some effect of glucotoxicity.

Comment: Then it is difficult to conclude that liraglutide has this protective effect after 48 weeks, because this might be due to the difference in glucose control over the 48 weeks.

A: The justification of the statement of preservation is that at the outset they were the same and then when we gave this drug we enhanced beta cell function and maintained that.

Q: I love the concept of intervening to reverse glucose toxicity, but I cannot tell from this study how much of that occurred. At the end you had 250 when normal was 800; so you only had 30% of beta cell function.

A: The reason is that we are still in the non-normal range is that these people still have diabetes. We have only addressed the glucotoxicity.

Comment: You did not improve ISSI-2 so you probably did not have to do the IIT at the start.

A: We would not know that the ISSI-2 would not improve until we have done it.

Comparison of Glycemic Control and Beta-Cell Function in Newly Diagnosed Type 2 Diabetes Patients Treated with Exenatide, Insulin, or Pioglitazone: A Multicentre, Randomized, Parallel-Group Trial (CONFIDENCE) (327-OR)

Wen Xu, MD (Yat-sen University, Guangzhou, China)

Dr. Wen Xu shared 48-week data from a randomized comparison of AstraZeneca’s Byetta (exenatide), pre-mix insulin, and Takeda’s TZD Actos (pioglitazone) – three therapies that have been associated with improved beta-cell function. The Lilly-funded trial enrolled 416 Chinese adults with newly diagnosed type 2 diabetes and mean baseline A1c ~8.0%, age ~50, and weight ~70 kg (~155 lbs). In the trial’s primary endpoint, exenatide was shown non-inferior to pre-mix insulin and pioglitazone in 48-week A1c decline (1.8% vs. 1.74% vs. 1.47%); the difference between exenatide and pioglitazone was statistically significant. Exenatide caused weight loss (3.25 kg [7.15 lbs]), pre-mix insulin caused weight gain (1.0 kg [2.2 lbs]), and pioglitazone was weight-neutral.  As for beta-cell function, all three treatments significantly improved acute insulin response, insulin/proinsulin ratio, and disposition index, though none improved HOMA-B. The improvement in disposition index was numerically largest with exenatide (statistics not given). Dr. Xu did not comment about how much of exenatide’s effects on disposition index could be directly attributed to weight loss.  

• The CONFIDENCE trial enrolled patients with newly diagnosed type 2 diabetes, no previous exposure to antihyperglycemic drugs, A1c between 7.0% and 10.0%, and BMI between 20 and 35 kg/m². The study was conducted at 25 national-university-affiliated hospitals in China. Patients were randomized to receive exenatide (n=142), premix insulin (n=138), or pioglitazone (n=136) for 48o weeks; the number of completers in each group was 110, 114, and 118, respectively. In the premix insulin group, dosage was titrated in order to maintain blood glucose targets; the average daily dose 26 units.  
• An A1c below 7.0% was achieved by more than three-quarters of the patients in each treatment group: 84% with exenatide, 78% with pre-mix insulin, and 76% with pioglitazone. The percentage of patients achieving A1c below 6.5% was statistically significantly highest in the exenatide group.
• All three treatments had beneficial effects on one or more markers of cardiovascular risk, but these changes seemed to be most promising in the exenatide group. Relative to baseline, the exenatide group had lower systolic blood pressure (4 mm Hg), lower diastolic blood pressure (3 mm Hg), and better lipid profile.
• Rates of symptomatic hypoglycemia <70 mg/dl with exenatide, premix insulin, and pioglitazone were 9.2%, 13.0%, and 3.8%, respectively. Dr. Xu noted that six exenatide-treated patients reduced their dose due to frequent confirmed hypoglycemia; excluding these patients, the rate of hypoglycemia with exenatide was 4.9%. The most common side effects with exenatide were gastrointestinal; with pioglitazone the most common side effect was edema.

Questions and Answers

Dr. Richard Bergenstal (International Diabetes Center, Minneapolis, MN): What do you think is more important for beta-cell function: lowering glucose, or something about a particular agent?

A: We are sure that glucose toxicity is one of the things that makes beta cell function decline. All three drugs are non-inferior in beta cell function. Still, we see different impact on beta-cell function. Insulin/proinsulin ratio and acute insulin response improved similarly; disposition index improved most in exenatide.

Q: Can you test patients again in a study extension?

A: We have an extension phase. Hopefully we can check them again in five years.

Q: Was insulin titrated in the study to a certain target?

A: Yes, we had specific recommendations. We did not have a specific glycemic target, but we did ask investigators to increase doses if fasting or after-dinner glucose rose above specific thresholds.

Q: Was control similar in all three groups?

A: Yes.

Q: What type of insulin was used? What was the average insulin dose used?

A: All the insulin was pre-mixed. The average dose was roughly 26 U/day.

Q: Did you find patients early enough that no metformin had been introduced, or is it not necessarily given to everyone early like it might be in US?

A: No, no one had used metformin. That was one of the inclusion criteria.

Q: How soon after diagnosis were these patients?

A: The patients had been just diagnosed.

Exenatide Affects the Distribution of Cerebral Postprandial GLucose Uptake: A Double-Blind, Randomized Clinical Trial (325-OR)

Guiseppe Daniele, MD, PhD (University of Texas, Health Science Center, San Antonio, TX)

Dr. Guiseppe Daniele presented new data on the effects of the GLP-1 agonist exenatide on cerebral glucose uptake. Though exenatide’s effects on the pancreas and the GI tract have been studied relatively extensively, little is known about its potential impact on glucose metabolism in the brain. This double-blind study involved 15 male subjects with impaired glucose tolerance (IGT) or new-onset type 2 diabetes (with an average A1c of 5.7%) who were randomly assigned to receive an injection of either exenatide or placebo prior to undergoing an oral glucose tolerance test (OGTT). The results demonstrated that the rate of glucose uptake in several brain regions implicated in food intake and/or glucose regulation was significantly higher with exenatide. Interestingly, the rate of glucose uptake was actually lower in the hypothalamus. Other results confirmed previously known metabolic effects of GLP-1 agonists, including lower plasma glucose and reduced gastric emptying. The researchers found that in the relevant brain regions, the increased glucose uptake was strongly correlated with the reduction in gastric emptying but was not correlated with suppression of endogenous glucose production (EGP). Based on these results, Dr. Daniele concluded that exenatide has a postprandial effect on cerebral glucose disposal and maintains glucose homeostasis in part by regulating the rate of gastric emptying and thus the rate of entry of ingested glucose into the bloodstream.

• The goal of this study was to evaluate exenatide’s postprandial effects on cerebral and peripheral glucose metabolism. GLP-1 agonists like exenatide are increasingly becoming part of the treatment paradigm for type 2 diabetes and their effects on appetite suppression and insulin and glucagon secretion are widely known, but little was previously known about whether they have an effect on glucose metabolism in the brain.
• The double-blind study enrolled 15 male subjects with IGT (n=12) or new-onset type 2 diabetes (n=3). The average BMI of the subjects was 29 kg/m², their average A1c was 5.7%, and their average age was 56.
• Subjects were randomly assigned to receive a subcutaneous injection of exenatide (5 mcg) or placebo 30 minutes before undergoing an OGTT. PET scans were used to measure brain glucose uptake. All subjects underwent the procedure under both the exenatide and placebo conditions 2-3 weeks apart.
• Exenatide increased glucose uptake in a variety of brain regions involved in food intake and glucose regulation but decreased glucose uptake in the hypothalamus. Treatment with exenatide led to a significant increase in glucose uptake in total gray matter and total cortex, as well as in the frontal, temporal, and occipital lobes, though not in the parietal lobe. Among regions that have been shown to be involved in glucose regulation, uptake was significantly increased in the insula and the putamen with exenatide; rates were comparable between the groups in the nucleus tractus solitarius (NTS), brainstem, caudate, and amygdala, and surprisingly, there was a significant decrease in uptake in the hypothalamus. Among regions known to be involved in regulation of food intake, there was a significant increase in glucose uptake in the orbitofrontal cortex, thalamus, posterior cingulate, and putamen with exenatide, but rates were comparable between the groups in the anterior cingulate, caudate, and amygdala.
• Other results from this study confirm the previously studied effects of GLP-1 agonists on glucose metabolism. The area under the curve for plasma glucose was significantly lower (1231 mg/dl) with exenatide than with placebo (1594 mg/dl) for the first hour after the beginning of the OGTT. Somewhat unexpectedly, the area under the curve for plasma insulin was also significantly lower (45 mU/l) with exenatide than with placebo (63 mU/l) during the same time period – we would speculate that this might have been due to a substantial slowdown in gastric emptying. Glucagon levels and endogenous glucose production (EGP) were lower with exenatide, as was the rate of appearance of oral glucose, an indication of reduced gastric emptying. Glucose clearance was comparable between the two groups.
• An analysis of this data found that increased cerebral glucose uptake was correlated with reduced gastric emptying and was not correlated with EGP suppression. In the brain regions implicated in glucose control that displayed increased glucose uptake with exenatide, there was no correlation between the rate of uptake and the rate of EGP, but there was an inverse correlation between the rate of uptake and the rate of appearance of oral glucose.

Questions and Answers

Q: This is fascinating and amazing data; it’s really exciting. You saw a remarkable increase in uptake despite lower plasma glucose with exenatide. If you just gave exenatide and measured glucose uptake without the glucose load, would you get the same effect?

A: We haven’t done that experiment. Another group did a study using fMRI with subjects in a fasting condition and found that exenatide increased connectivity between the hypothalamus and the rest of the brain, but no one has measured glucose uptake.

Comment: That would be interesting. I would wonder whether hepatic glucose production compensates and glucose is redistributed from the brain.

Q: Did you ask the participants about GI side effects, e.g. nausea? If so, you would need a nausea control group.

A: That’s an important question. We asked subjects to evaluate their level of GI effects but we didn’t observe any GI effects, so we couldn’t have a nausea control group.

Q: I was struck by the marked decrease in uptake in the hypothalamus. Are there any implications of that?

A: I can only speculate since we can’t study that directly, but I can speculate that the reduction is related to the decrease in appetite and regulation of food intake. This is something that’s been shown with GLP-1, where researchers infused GLP-1 in healthy subjects with no OGTT and observed the same thing. But that was native GLP-1, so it could be different.

Oral Presentations: Basal Insulin Therapy

One-Year Efficacy and Safety of IDegLira in Patients with Type 2 Diabetes (65-OR)

Stephen Gough, MD (University of Oxford, Oxford, UK)

Dr. Stephen Gough presented findings from a 26-week extension of the original 26-week DUAL I trial on Novo Nordisk’s IDegLira, the fixed-ratio combination of Novo Nordisk’s ultra-long-acting basal insulin Tresiba (insulin degludec) and GLP-1 agonist Victoza (liraglutide).  The 52-week results were remarkably consistent with the results of the original 26-week study, which were first presented at last year’s ADA (read our coverage). From a baseline of ~8.3%, patients in the IDegLira arm achieved a mean final A1c at 52 weeks of 6.5% (reduction of 1.8% from baseline), a statistically significant improvement over insulin degludec’s final A1c of 6.9% (reduction of 1.4%) and liraglutide’s 7.1% (-1.2%). The theme of conserved results also applied to fasting plasma glucose (IDegLira was significantly better than liraglutide but not insulin degludec), hypoglycemia (IDegLira was associated with 37% less confirmed hypoglycemia than insulin degludec monotherapy), and body weight (IDegLira was fairly weight neutral and fell squarely between the weight gain of insulin degludec and weight loss of liraglutide). The constancy of efficacy and safety results from the original 26-week results was reassuring for a few reasons – it reduces the likelihood that the 26-week findings were due to chance, and also demonstrates that the combination product’s efficacy is not only strong, but also fairly durable (patients’ mean IDegLira dose was flat from week 26 to week 52).   

• Following the 26-week trial DUAL I study, the investigators began an additional 26-week long extension study. Attrition rates were approximately equal among the three arms. Out of the 1,442 patients that completed the 26-week DUAL I study, 84% completed the extension phase. Notably, the mean daily dose of IDegLira remained steady during the full 26-week follow-up, while the average dose in the insulin degludec group rose slightly.
• Results from the extension study showed that IDegLira’s A1c-lowering efficacy was stable through 52 weeks – overall many of the efficacy values were remarkably similar from the 26-week results. IDegLira yielded a final absolute A1c reduction of -1.8%, versus insulin degludec (-1.4%) and liraglutide (-1.2%) from an average baseline of 8.3% (p<0.0001 for both comparisons). Percentages of patients who met A1c targets also remained stable: IDegLira users continued to achieve A1c targets of 7% and 6.5% (78.2% and 66.9% of patients, respectively) significantly more than insulin degludec users (62.5% and 49.2%) and liraglutide users (56.5% and 38.2%).
• Compared to insulin degludec, IDegLira still yielded significantly fewer episodes of confirmed hypoglycemia, showed decreased glycemic variability, and resulted in no weight gain. At 52 weeks, IDegLira users experienced only 63% of the hypoglycemia rate of insulin degludec users, a significant difference (p<0.0001). Hypoglycemia rate ratios remained relatively stable from 26 weeks to 52 weeks. Post-prandial glucose excursions were significantly smaller for IDegLira users compared to insulin degludec users for every meal. IDegLira also resulted in slight weight loss (0.4 kg, ~1 lb), compared to insulin degludec’s 3 kg (~5 lb) weight gain and liraglutide’s 3 kg (~7 lb) weight loss, all of which were relatively stable after the first 26 weeks.
• Compared to liraglutide, IDegLira showed significantly greater reductions in fasting plasma glucose as well as fewer GI adverse events. After 52 weeks, fasting plasma glucose in the IDegLira arm (103 mg/dl) was comparable to that in the insulin degludec arm (108 mg/dl), but still significantly lower than that in liraglutide users (132 mg/dl) (p<0.0001 for the IDegLira – liraglutide difference). Percentage of subjects with nausea remained stable after the initial 26 weeks, with IDegLira users reporting more nausea than insulin degludec but less than liraglutide (overall incidence was very low compared to the first few weeks of the trial). Adverse GI events associated with liraglutide usage were also mitigated in IDegLira. Events included diarrhea (10.2% of IDegLira users, compared to 6.8% for insulin degludec users and 16.3% for liraglutide users), the common cold (13.9%, 12.6%, 13.3%), headache (12.8%, 10.9%, 14.6%), nausea (10.3%, 3.9%, 22.3%), increased lipase (5.8%, 4.4%, 8.5%), vomiting (5%, 2.4, 9.2%), and decreased appetite (2.7%, 0.5%, 7.3%).
  • In terms of serious adverse events, four major adverse cardiovascular events occurred in the IDegLira group, and one each occurred in the insulin degludec and liraglutide groups (note that the IDegLira arm was randomized 2:1:1). Total adverse events still did not differ significantly after 52 weeks: 71.2% IDegLira users experienced adverse events, compared to 70.6% insulin degludec users and 77.2% liraglutide users. Rates of serious adverse events remained low across the board. After 52 weeks, 4.6% IDegLira users, 5.3% insulin degludec, and 5.8% liraglutide users experienced serious adverse events.

Questions and Answers

Q: I wonder about the ratio between insulin and liraglutide. The average dose of liraglutide in IDegLira was 1.4 mg. What about patients who used 20 to 30 units of insulin in the combination product, because they would have received liraglutide less than 0.6 mg, and far less than 1.2 mg, the effective dose of liraglutide. Can you speak about the distribution of doses, and how subgroups compared with high doses versus low doses for each of the drugs?

A: This is a fixed ratio of degludec and liraglutide. The question is: what ratio should you have to suit the most people? We know that 40% of the patients did get the max dose and 70% achieved the target A1c. There are patients who could benefit from a little more insulin or a little more liraglutide, but on the whole a great portion of patients responded and a large portion reached the target of 7%. Obviously some may benefit from free mixing but this combination seemed to work pretty well.

Comment: I was wondering if patients using less than 30 units of insulin did better on the combination, or would there be no difference between IDegLira and degludec?

A: I don’t have those analyses with me.

Q: The hypoglycemia data is very encouraging, but I was wondering whether it was reduced calorie intake or decreased gastric emptying.

A: I’m not sure we know the exact answer to that, but we know that liraglutide has very little, if any, effect in terms of gastric emptying in the long term, at least relative to the shorter-acting GLP-1 receptor agonists.

Impact of BMI on HbA1c Reduction, Hypoglycemia Rates, and Insulin Requirements in Response to IDegLira in Patients with Type 2 Diabetes (T2D) (66-OR)

John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)

In this packed room, over a thousand attendees watched the legendary Dr. John Buse take us through a post-hoc analysis of Novo Nordisk’s DUAL I and DUAL II studies. These studies were an investigation of the effectiveness of IDegLira (Xultophy) – a combination of the GLP-1 agonist Victoza (liraglutide) and ultra-long-acting basal insulin Tresiba (insulin degludec) – compared to each its two components (insulin degludec and liraglutide). Dr. Buse showed that regardless of baseline BMI, IDegLira lowered A1c more or less by the same amount, and there was a reduction in hypoglycemia with increasing BMI in the DUAL I study. By and large, IDegLira demonstrated larger A1c reductions than insulin degludec alone, with less hypoglycemia. Meanwhile, insulin use increased with BMI, as might be expected.

• Dr. Buse presented the results of a post-hoc analysis of the DUAL data, stratifying A1c reduction and hypoglycemia by baseline BMI, and demonstrated that there is no significant difference in IDegLira’s efficacy with increasing BMI and only a slight decrease in hypoglycemia with increasing BMI. In DUAL I, the A1c reduction with IDegLira was around 1.9% from baseline, which was constant across four BMI cohorts and superior to insulin degludec or liraglutide alone. In DUAL II there was a bit more variation with BMI, but it was probably because it was a smaller trial. Turning to severe hypoglycemia, the DUAL I data suggested that hypoglycemia is consistently lower with IDegLira than insulin degludec, regardless of BMI, and that hypoglycemia incidence halved going from BMI <25 kg/m² to BMI >35 kg/m².where it was in the range of one event per patient year. Again the DUAL II data was less clear, this time because of outliers.
• Finally, in DUAL I, insulin requirements increased with increasing BMI across the four cohorts, (as might be expected) and the IDegLira group used consistently less insulin than the insulin degludec group, regardless of BMI. DUAL II was less clear because there was a cap on insulin dose, which most patients reached.
• Last year’s presentation of the original DUAL I results (by none other than Dr. Buse) was one of the most exciting happenings of ADA 2013 – read our coverage.

Questions and Answers

Q: Did any of the patients have impaired renal function, and how do you use this drug in this patient group?

A: If I remember correctly, theses studies did not include patients with impaired renal function. The drug is only available in trials, but we know that liraglutide is metabolized in circulation. However, there is a higher risk of hypoglycemia with these patients, so I would apply it cautiously.

Q: The studies started with quite a high IDegLira dose. What was the incidence of nausea?

A: In DUAL II, we started with the equivalent of the 0.6mg dose of liraglutide. But rates of nausea were quite low; 2-3% at maximum at any point. But remember that the trial was blinded and patients had not been told to expect nausea. So starting with a lower dose creates less nausea, not telling patients lessens nausea, and so does slow titration.

IDegLira Is Efficacious Across the Range of Disease Progression in Type 2 Diabetes (T2D) (67-OR)

Helena Rodbard MD, FACE, MACE (Rockville, MD)

Dr. Helena Rodbard continued the analysis of Novo Nordisk’s DUAL I and DUAL II trials by demonstrating that regardless of baseline A1c, duration of diabetes or prior diabetes medications, IDegLira (Xultophy, Novo Nordisk’s combination of the GLP-1 agonist Victoza [liraglutide] and the ultra-long-acting basal insulin Tresiba [insulin degludec]) lowers A1c better than liraglutide or insulin degludec alone, with lower rates of hypoglycemia than insulin degludec. As might have been expected, A1c reduction was proportional to A1c at baseline. None of Dr. Rodbard’s post-hoc analyses gave us reason to suggest that IDegLira might be meaningfully less effective in any major patient subgroups.

• IDegLira is a fixed-ratio combination of liraglutide and insulin degludec that delivers one unit of insulin degludec for every 0.036 mg of liraglutide.
• IDegLira was compared to its individual components in the DUAL I trial, which was one of the most striking presentations of last year’s ADA (read our coverage). DUAL II compared IDegLira to insulin degludec only. DUAL I was a 52-week open label study of over 1,600 insulin naïve patients who were failing oral therapy. The three arms were IDegLira, insulin degludec alone and liraglutide alone. At baseline, participants were middle aged with BMI around 31 kg/m², duration of diabetes about 7 years and A1c around 8.5%. DUAL II was designed for a specific regulatory purpose – to study the impact of the liraglutide component compared to insulin degludec alone. DUAL II was a 26-week study of nearly 400 patients, who were uncontrolled on basal insulin and oral drugs. At baseline, the participants were taking 20-40 units of basal insulin daily, had BMI of 34 kg/m², duration of diabetes 10-11 years, and baseline A1c of 8.7%.
• Dr. Rodbard showed that as expected, the A1c reduction obtained with IDegLira increases with increasing baseline A1c; however regardless of baseline A1c, iDegLira was more effective than either insulin degludec or liraglutide alone. In DUAL I, the A1c reduction for IDegLira ranged from 2.5% at A1c > 9% down to 1.2% at A1c <7.5%. The results of the DUAL II analysis were broadly similar, although reductions were not quite as large because of the trial design.
• Turning to hypoglycemia, in DUAL I, IDegLira demonstrated consistently less hypoglycemia than insulin degludec alone, regardless of baseline A1c. Hypoglycemia for IDegLira declined slightly with increasing baseline A1c, in the region of two events per patient-year. In DUAL II there was no real difference between iDegLira and insulin degludec in the incidence of hypoglycemia, (except in the 8.5%-9.0% group which was driven by two outlier patients).
• A1c reduction was independent of diabetes duration and more or less the same regardless of prior diabetes medications. Scatter plots showed no significant relationship between duration of diabetes and A1c reduction for IDegLira, insulin degludec or liraglutide even out to patients with >35 years duration. In DUAL I, participants were formerly taking metformin or metformin and pioglitazone. In both cases, iDegLira delivered a strong A1c reduction, with only small (but statistically significant) differences (slightly better reduction in the metformin/pioglitazone group). In DUAL II, the reduction was the same regardless of pre-trial insulin dose and similar for the different pre-trial oral therapies (metformin or metformin/sulfonylurea/glinide).

Questions and Answers

Q: The average hypoglycemia event rate is not so meaningful since the distribution is highly skewed, and it has affected both yours and John Buse’s presentations. Shouldn’t we use the percentage of participants affected instead? Do you have this data?

A: I don’t think that this was done, but thanks for the suggestion.

Oral Presentations: Oral Incretin-Based Therapies

TTP273, an Orally-Available Glucagon-like Peptide-1 (GLP-1) Agonist, Notably Reduces Glycemia in Subjects with Type 2 Diabetes Mellitus (155-OR)

Stephanie Gustavson, PhD (Trans Tech Pharma, High Point, NC)

Dr. Gustavson presented data from a dose-ranging study of TTP273, Trans Tech’s second-generation oral GLP-1 agonist, in patients with type 2 diabetes (n=112). The objective of this trial was to evaluate the safety, tolerability, and PK/PD profile of TTP273. Dr. Gustavson commented that this second-generation oral GLP-1 agonist demonstrated increased potency compared to Trans Tech’s first-generation oral GLP-1 agonist, TTP054. In terms of efficacy, dose-responsive decreases in fasting plasma glucose and mean daily glucose were observed (39 mg/dl and 42 mg/dl, respectively, at the 75 mg BID dose). In addition, there were very few GI-related adverse events, with only four patients in the entire study exhibiting any nausea. However, given that this was a dose-ranging study and many patients received low doses of TTP273, we look forward to longer-term trials with therapeutic doses of TTP273 to better understand the adverse event profile and GI-related side effects.

• Trans Tech conducted a 14-day inpatient clinical trial of TTP273 in type 2 diabetes patients on stable doses of metformin. Patients were checked into a clinical research facility for three weeks – arriving five days prior to the first dose and remaining until day 16. The purpose of the inpatient design was to ensure adherence and standardize diets, in order to isolate the glycemic effects of TTP273. The study included a 23-point mean daily glucose assessment and a mixed meal tolerance test (MMTT) on days -1 and 14. The trial investigated a broad range of dosing options, with 10 dose cohorts (25-450 mg QD, 25-150 mg BID, and an alternative dosing of 75 mg QPM).
• Treatment with TTP273 was associated with dose-responsive decreases in mean daily glucose and fasting glucose. At baseline, the mean A1c was 8.1% (8.5% in placebo and 8.0% in active). TTP273 was quickly absorbed, with a t_max of two hours and a half-life of six hours. The 24-hour glucose profile showed maximal reduction in glycemic control at the 150 mg BID and 450 mg QD doses; however, the BID and QPM regimens resulted in greater glucose lowering compared to the QD regimens. For mean daily glucose, TTP273 resulted in a 42 mg/dl reduction (75 mg BID), which was significantly greater than the 11 mg/dl reduction observed in the placebo group. TTP273 also significantly reduced fasting glucose, with patients in the 75 mg BID arm experiencing a 39 mg/dl reduction in FPG compared to 11 mg/dl in the placebo group.
• All adverse events were characterized as mild, with diarrhea being the most common GI-related adverse event. There were no serious adverse events or incidences of hypoglycemia. While diarrhea was the most frequent GI adverse event, Dr. Gustavson noted that there was no clear dose response relationship for this adverse event and that it often occurred on meal test days when patients were required to consume meals in a certain period of time.
• While this study was not designed to assess changes in secondary parameters, there were favorable trends in metabolic and cardiovascular markers. While specific data on secondary markers were not disclosed, Dr. Gustavson commented that there was a trend toward reduced body weight (up to 2 kg) and improvements in triglycerides, systolic blood pressure, and diastolic blood pressure.

Questions and Answers

Q: Could you say more about the chemical that is being administered and how it mimics and acts on GLP-1 receptor?

A: This compound is an allosteric agonist of the receptor. We’ve shown that exendin (9-37) competes with functional activity and we don't activate glucagon or GIP. What’s really interesting is that it may be more physiological in terms of cell signaling and receptor bias activation. Our compound does not activate ERK pathway, unlike current GLP-1 agonists; it just activates the cAMP pathway, so there may be a lower risk of cell proliferation.

Q: So it is acting on a different site on the receptor?

A: Yes.

TTP054, a Novel, Orally-Available Glucagon-like Peptide-1 Agonist, Lowers HbA1c in Subjects with Type 2 Diabetes Mellitus (156-OR)

Stephanie Gustavson, PhD (Trans Tech Pharma, High Point, NC)

In back-to-back presentations, Dr. Gustavson provided results from a 12-week trial of Trans Tech Pharma’s first-generation oral GLP-1 agonist, TTP054. In the trial, subjects with type 2 diabetes on stable metformin were randomized to receive 200 mg QD (n=19), 400 mg QD (n=28), or 800 mg QD (n=35) TTP054 or placebo (n=31) for 12 weeks. Results indicated placebo-corrected A1c declines of 0.9% (baseline 9.1%), 1.0% (baseline 9.0%), and 0.6% (baseline 8.8%) with the 200, 400, and 800 mg dose groups, respectively – similar to the values estimated from phase 1 data at ADA 2013. Weight loss was non-significant across the groups, at 0.1 kg (0.2 lbs), 0.4 kg (0.9 lbs), and 0.7 kg (1.5 lbs) in the 200, 400, and 800 mg dose groups, respectively, though Dr. Gustavson noted weight loss became significant when patients who discontinued sulfonylureas at baseline were excluded from the analysis; she also noted that weights at baseline were relatively low for diabetes trials (82-87 kg; 181-192 lbs). Rates of GI adverse events were 4%, 4%, and 16% in the 200, 400, and 800 mg dose groups, respectively, and 10% in the placebo group. Dr. Gustavson suggested the second-generation agonist, TTP273, has shown increased potency in early studies, though we will be interested to see how this plays out in clinical trials. As a reminder, there has increasing interest in oral formulations of GLP-1 as of late, with numerous candidates in clinical trials, including Novo Nordisk’s NN9924 (phase 2), NN9928, NN9926, and NN9927, Oramed’s ORMD-0901 (phase 2), and Zydus’s ZYOG1 (phase 1).

• In this double-blind trial, subjects with type 2 diabetes on stable metformin were randomized to receive 200 mg QD (n=19), 400 mg QD (n=28), or 800 mg QD (n=35) TTP054 or placebo (n=31) for 12 weeks. Patients on sulfonylureas at baseline stopped use with a wash out period prior to initiation in the trial. Baseline weights were 83 kg (182 lbs), 82 kg (181 lbs), and 87 kg (192 lbs) in the 200, 400, and 800 mg dose groups, respectively, and 84 kg (185 lbs) in the placebo group.
• Results indicated placebo-corrected A1c declines of 0.9% (baseline 9.1%), 1.0% (baseline 9.0%), and 0.6% (baseline 8.8%) with the 200, 400, and 800 mg dose groups, respectively, with no clear dose response (p<0.01). Weight loss, however, increased with increased dose, a 0.1 kg (0.2 lbs), 0.4 kg (0.9 lbs), and 0.7 kg (1.5 lbs) in the 200, 400, and 800 mg dose groups, respectively, though results were not significant. Dr. Gustavson noted that when patients who discontinued sulfonylureas at the beginning of the trial were excluded from the analysis, weight loss became significant across the groups. She posited this may gave been due to shifting weights at baseline in this population.
• Rates of GI adverse events were 4%, 4%, and 16% in the 200, 400, and 800 mg dose groups, respectively, and 10% in the placebo group. There were no episodes of hypoglycemia during the study. Dr. Gustavson indicated that two patients in the 800 mg dose group experienced serious adverse events with regards to elevated liver function test levels, though when scrutinized both occurred with contributing factors and resolved. She suggested this was not a major concern for the company given there was no increase in median liver function tests over the other dose groups and elevated levels were never seen in other clinical studies of the drug.

Questions and Answers

Dr. Zachary Bloomgarden (Mt. Sinai, New York, NY): Is the newer agent more potent for fasting blood glucose when corrected for baseline?

A: We compared earlier studies with this compound. Our second-generation compound does seem to lower more than our leading compound.

Q: Does the drug reach the brain?

A: They do not – we feel it is neural signaling in the gut that acts in the brain.

Q: Did you look at the population that did not respond at all?

A: We did. We were unable to identify why that could be. But I think it’s similar to what we see with the peptides with response rates.

Q: What about heart rate?

A: This wasn’t designed to pick that up. We did see minor fluctuations but didn’t see any major increases in heart rate. I think we need long-range studies to definitively answer that.

Incretin Therapy and Risk of Acute Pancreatitis: A Nationwide Population-based Case-Control Study (154-OR)

Reimar Thomsen, MD, PhD (Aarhus University, Aarhus, Denmark)

Dr. Thomsen presented the results of a population-based case-control study investigating the association between incretin use and the risk of acute pancreatitis. Using the Danish national patient registry, 12,868 patients with first-time hospitalization of acute pancreatitis were identified and matched with 128,680 control patients. Nationwide prescription data was then used to identify ever incretin use of 0.69% in pancreatitis patients versus 0.53% in controls. When adjusted for common risk factors, there was no significant increase in the risk of pancreatitis amongst incretin users (RR 0.95; 95% CI 0.75-1.21), in line with meta-analyses from clinical trials and FDA/EMA’s recent conclusions. Intriguingly, Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX) stepped out in the Q&A to critique the use of population-based studies to assess the risk of pancreatitis associated with incretin therapies – due to the lack of prospective design and the need for risk factor adjustment, he suggested “the answer will only come from randomized controlled trials.”

• Using the Danish national patient registry, 12,868 patients with first-time hospitalization of acute pancreatitis were identified and matched for age, gender, index date, and residence with 128,680 control patients from 2005-2012. Nationwide prescription data was then used to identify 8.5% ever use of glucose lowering drugs in the pancreatitis patients versus 6.1% use in the controls. Overall, ever incretin use was 0.69% in pancreatitis patients versus 0.53% in controls. Other known risk factors for pancreatitis identified included gallstone disease (16.8% vs. 4.0%), obesity (7.4% vs. 3.1%), and heavy alcohol use (15.4% vs. 4.4%).
• When adjusted for common risk factors (gallstones, alcohol use, obesity, inflammatory bowel disease, cancer), there was no significant increase in the risk of pancreatitis amongst incretin users (RR 0.95; 95% CI 0.75-1.21). This remained non-significant when specified for current GLP-1 use (RR 0.84; 95% CI 0.53-1.34) and current DPP-4 use (RR 0.78; 95% CI 0.53-1.16).
• Dr. Thomsen concluded by noting the relative strengths and weaknesses of the study design. The population-based design, he suggested, reduced the risk of selection and referral biases. However, he acknowledged that these studies are dependent on the choice of confounders used for adjustments as well as other potential unknown confounders affecting the data.

Questions and Answers

Dr. Zachary Bloomgarden (Mt. Sinai, New York, NY): This was interesting – I think most studies like this use diabetes diagnosis to identify patients – you didn’t use diabetes itself as a diagnosis but rather glucose-lowering drug use as a proxy. It seems in other studies, diabetes itself is a strong predictor of pancreatitis risk. Do you have any comment?

A: Yes, I think it worked out. We tried our best to match our cases and our controls.

Q: There are other known common drugs associated with pancreatitis. Have you been able to put these in the model?

A: That is a good recommendation – we could.

Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX): Very nice presentation, with very cleanly presented data and in transparent fashion noting the limitations. One of the problems these days with all these reports from population databases is that none of them are prospectively designed to look at pharmacovigilance. The problem with these data is that you precisely do not need to do the adjustments that are required – it is these populations that may be at the increased risk. In reality, those are the patients exposed – those that drink, that are obese, that have gallstones. It’s a very nice exercise; I applaud you for that, but the answer will only come from randomized controlled trials.

A: Thank you for the comment. We hope to improve this model.

DPP-4 Is Expressed in Human Pancreatic Islets and Its Inhibition Improves the Function and Survival of Type 2 Diabetic Beta Cells (149-OR)

Marco Bugliani PhD, PharmD (University of Pisa, Pisa, Italy)

Dr. Marco Bugliani’s talk focused on a novel inter-islet regulatory pathway in the pancreas. Since it is understood that there is an active GLP-1 response system in the islet cell, Dr. Bugliani set out to investigate the presence and role of DPP-4 in human islets. He tested alpha and beta cells, and found that DPP-4 was indeed present in islets, mostly in alpha cells, in both non-diabetic individuals and (to a lesser extent) in type 2 diabetes patients. Exposing cultured islets to a DPP-4 inhibitor protected the beta cells from both glucotoxicity and lipotoxicity, and also increased GLP-1 levels in the culture medium. Given the reduction in DPP-4 expression in type 2 diabetes patients, these protective effects would likely be hard to elucidate in the real world – no major clinical trials have provided conclusive evidence of a protective effect. If the protective action seen in this preclinical trial is indeed real, the long-term data from the longer DPP-4 inhibitor cardiovascular outcomes trials stand the best chance of providing corroborating evidence. We await the results …

• This work was designed to explore the presence and role of DPP-4 in human islet cells, since it is known that GLP-1 acts in the islet. Alpha and beta cells were isolated from 17 non-diabetic individuals and type 2 diabetes patients. Isolated islets were cultured for 24 hours in the presence of a DPP-4 inhibitor (MK-0626) and then observed in gluco- and lipotoxic conditions (using glucose and palmitate respectively). 
• DPP-4 could indeed be observed in pancreatic tissue and islets, and it was localized primarily to a subset of alpha cells. DPP-4 expression was reduced by roughly two thirds in the type 2 beta cells compared to non-diabetic cells.
• In cultured islets, the DPP-4 inhibitor MK-0626 improved insulin secretion, accompanied by a partial restoration of the volume density of insulin granules. DPP-4 inhibition increased insulin secretion more in the non-diabetic islets compared to the islets from type 2 diabetes patients, perhaps due to the reduced islet DPP-4 expression in type 2 diabetes. MK-0626 was also able to partially prevent beta cell apoptosis via the exposure to palmitate. In the presence of DPP-4, higher concentrations of GLP-1 were observed in the culture medium.

Questions and Answers

Q: Other peptides can be degraded or activated by DPP-4, so how do you know that these effects on the beta cell are mediated via GLP-1?

A: This is a very good point. We are testing other compounds that might be implicated, although we are relatively confident in our results.

Q: This work suggests that the effect on the beta cells is indirectly coming via a subset of alpha cells. What do you know about these cells?

A: We know that from a morphological point of view, DPP-4 is present in a subset of alpha cells, but we don’t currently know anything about the characteristics of these alpha cells versus the others.

Oral Glucose Lowering with Linagliptin Plus Metformin Is a Viable Initial Treatment Strategy in Patients with Newly Diagnosed Type 2 Diabetes and Marked Hyperglycemia (150-OR)

Stuart Ross, MD (University of Calgary, Alberta, Canada)

Dr. Ross presented the results of a pre-specified subgroup analysis from a 24-week clinical trial comparing linagliptin+metformin to linagliptin alone in newly diagnosed type 2 diabetes patients with marked hyperglycemia (mean baseline A1c of 9.8%). This sub-analysis examined A1c reductions in various subgroups, including patients with extreme hyperglycemia (≥9.5% A1c at baseline). In this subgroup, patients on the linagliptin+metformin combination experienced robust A1c reductions of 3.4% after 24 weeks, compared to a 2.5% reduction in the linagliptin alone group (from a high baseline A1c of 10.5%). In the overall study population, 61% of patients achieved a target A1c of <7% in the linagliptin+metformin group, and 40% of patients achieved target A1c in the linagliptin alone group. Dr. Ross acknowledged he was not expecting such a robust A1c reduction with linagliptin alone or in combination. As a result, he challenged the commonly held belief that insulin initiation is required to achieve target A1c levels in newly diagnosed patients with marked hyperglycemia. During Q&A, Dr. Zachary Bloomgarden hypothesized that newly diagnosed patients may be uniquely responsive to glycemic control interventions, citing data from the UKPDS study that showed similarly impressive A1c reductions during a three-month diet-based run-in period. Dr. Ross noted that diet and exercise did not appear to have played a major role in the A1c reductions achieved by linagliptin with or without metformin.

• The 24-week randomized trial compared linagliptin+metformin vs. linagliptin in drug-naïve type 2 diabetes patients within 12 months of diagnosis who had marked hyperglycemia. In this study, the linagliptin+metformin combination was associated with a 2.8% reduction in A1c, compared to 2.0% reduction in the linagliptin arm (from a mean baseline A1c of 9.7%). In the full-analysis set, patients on linagliptin+metformin experienced an A1c reduction of 2.7% compared to 1.7% for patients on linagliptin alone (from a mean baseline A1c of 9.8%).
• Notably, the majority of patients achieved an A1c <7% after 24 weeks of treatment with linagliptin+metformin. For patients with a baseline A1c <9.5%, the linagliptin+metformin group experienced an A1c reduction of 2.0%, which was significantly greater than the 1.4% reduction in the linagliptin alone group (mean baseline A1c of 8.7%). For the cohort of patients with a baseline A1c ≥9.5%, the linagliptin+metformin combination was associated with an impressive 3.4% reduction in A1c, compared to a 2.5% reduction in the linagliptin alone group (mean baseline A1c of 10.5%). These reductions in A1c were consistent across all major subgroups, including age, BMI, renal function, race, and ethnicity.

Questions and Answers

Dr. Zachary Bloomgarden, MD (Mount Sinai Hospital, New York, NY): Congratulations on getting 300 treatment-naïve patients recruited into your study. That is quite an accomplishment. This is reminiscent of the UKPDS cohort, where patients entered the trial with an A1c of 9%, had a three-month diet run-in and on average went to 7% with diet alone, suggesting this may indeed be a group of people who are uniquely able to respond to all sorts of interventions. So it’s fascinating that linagliptin alone was not bad.

A: It was a little bit of a surprise to us. We raised the question ourselves of diet and exercise. In the linagliptin alone group, there was no weight loss and in the linagliptin+metformin combination group, there was 1 kg weight loss. It’s interesting how we’ve always been led to insulin being the right way to bring A1c down in this patient population.

Q: Did response rates differ by race or ethnicity?

A: We wondered about that because there has been a lot of interest in this, especially with international clinical trials. There appears to be differences in some other treatments, so we did look for bias. We didn't have a large range of ethnicities (Hispanic, Asian, and Caucasian); however, we saw no difference at all among these racial subgroups. That does not mean there is no difference, we just did not find any evidence of a difference.

Q: Did you exclude ketonuria?

A: There were no patients with ketonuria. We were worried we’d be seeing type 1 diabetes instead of type 2 diabetes, so ketones were assessed, but nothing suggested they had ketonuria.

Posters

Efficacy and Tolerability of ITCA 650 (Continuous Subcutaneous Exenatide in Poorly Controlled Type 2 Diabetes with Baseline A1c >10% (114-LB)

RR Henry, J Rosenstock, and MA Baron

Dr. Robert Henry and colleagues report six-month data from an open-label trial of Intarcia Therapeutics’ ITCA 650 (continuous subcutaneous exenatide infusion) in 60 type 2 patients with baseline A1c >10% (FREEDOM-1HBL). The participants first received the three-month, low dose (20 mcg/day) ITCA 650 mini-pump for 13 weeks followed by the six-month high dose (60 mcg/day) mini-pump for 26 weeks. Background anti-diabetic medications were maintained for the treatment period. This initial interim analysis included data from the patients who had completed treatment up to 13 weeks (n=50), 19 weeks (n=39), or 26 weeks (25). Increasing reductions in A1c were observed at each time point: -2.5% at 13 weeks, -2.9% at 19 weeks, and -3.2% at 26 weeks. Furthermore, an impressive proportion of these patients achieved A1c reductions of ≥2% (78%), ≥3% (50%), ≥4% (22%), and ≥5% (10%). Of the cohort, 30% achieved the A1c target of ≤7% and only two patients were classified as non-responders (i.e., A1c reduction <0.05% at the time of the interim analysis). Lastly, a mean weight loss of 2.4 lbs (1.1. kg) was observed at 26 weeks. Based on these data, the authors conclude that ITCA 650 has the potential to markedly improve glycemic control in patents with severe hyperglycemia and longstanding diabetes.

• This study enrolled 60 type 2 patients whose high A1c level (>10%) made them ineligible to participate in the main double-blind placebo-controlled trial (FREEDOM 1). These patients met all of the other inclusion criteria for FREEDOM 1. At baseline, the participants had a mean age of 52 years, BMI of 32 kg/m², A1c of 10.7%, fasting plasma glucose of 248 mg/dl, and duration of diabetes 9 years. Sixty-nine percent of the cohort also used oral anti-diabetic medications and 33% were male.
• The figure below gives mean baseline A1c and mean A1c reduction for participants completing treatment periods of 13, 19, and 26 weeks:

	13 weeks     (n=50)	19 weeks    (n=39)	26 weeks   (n=25)
Mean baseline A1c	10.8%	10.7%	10.9%
Mean A1c at time point	8.3%	7.8%	7.7%
Mean change in A1c	-2.5%	-2.9%	-3.2%

• The authors note that adverse events were consistent with previous trials with ITCA 650 (data not provided).

Efficacy and Safety of Once Weekly Dulaglutide vs. Once Daily Liraglutide in Type 2 Diabetes (AWARD-6) (110-LB)

KM Dungan, ST Povedano, T Forst, JGG González, C Atisso, W Sealls, JL Fahrbach

This poster presented the results of the long-awaited AWARD-6 trial, which found that Lilly’s once-weekly GLP-1 agonist dulaglutide provided non-inferior A1c lowering relative to Novo Nordisk’s once-daily Victoza (liraglutide). The open-label study randomized 599 type 2 diabetes patients on metformin. Head-to-head studies can sometimes use fairly wide non-inferiority margins (we’ve seen as large as 0.4%), so even though the topline results announced that dulaglutide achieved non-inferiority, there were plenty of potential surprises in the full data. However, the two drugs had similar glycemic effects – dulaglutide led to a mean A1c reduction of 1.42%, while liraglutide 1.8 mg led to a mean reduction of 1.36% (p < 0.001, baseline A1c = 8.1%). Approximately 68% of both groups achieved a final A1c of less than 7%, and seven-point SMBG profiles were effectively superimposable. The slight differences between groups emerged in the weight and hypoglycemia categories. Patients in the liraglutide arm lost an average of 3.6 kg (~8 lbs), while patients in the dulaglutide arm lost an average of 2.9 kg (~6 lbs) (p = 0.01) – we wonder if a difference that small will be perceived as clinically meaningful by HCPs. The incidence of hypoglycemia was slightly higher in the liraglutide arm (0.52 events/patient/year) than the dulaglutide arm (0.34 events/patient/year), but the number of events was so small that the difference is likely not very clinically meaningful. On the whole, the results of the study demonstrate that dulaglutide has a comparable clinical profile to liraglutide, and sets the stage for the two to compete on other points like pricing, device design, and patient preferences on does frequency.  

• The incidence of hypoglycemia in both groups was very low, but appeared very slightly higher in the liraglutide arm. The incidence of hypoglycemia (defined as blood sugar at or below 70 mg/dl with or without symptoms) was 0.34 events/patient/year in the dulaglutide arm and 0.52 events/patient/year in the liraglutide arm. The incidence in both groups was so low that the difference may not be clinically meaningful, whether or not it is statistically significant (which was not mentioned). 
• Liraglutide came out ahead with regards to weight loss, but only slightly. From a mean baseline of 94 kg (~210 lbs), patients in the dulaglutide arm lost 2.9 kg (~6 lbs), while patients in the liraglutide arm lost 3.6 kg (~8 lbs). The difference was statistically significant (p = 0.01), but given that both groups achieved weight loss of ~3kg, the difference may not be highly clinically significant. Novo Nordisk management has speculated that Victoza would come out ahead on weight during previous quarterly updates, primarily because liraglutide is a smaller molecule that is believed to cross the blood-brain barrier to a greater extent and act at neural appetite regulation centers.
• The incidence of nausea was similar between arms – we have heard in the past that longer-acting GLP-1 agonists have less of an effect on GI motility and, as a result, generally cause less nausea. We might have therefore expected a slight advantage for dulaglutide, but of course other characteristics of the molecule beyond PK/PD could impact GI tolerability. Approximately 19% of patients in both arms experienced nausea, while ~7-8% experienced vomiting.
• The results of AWARD-6 make dulaglutide the only GLP-1 agonist to achieve non-inferiority to liraglutide in a phase 3 trial.

 

Better Glycemic Control and Less Weight Gain with Once Weekly Dulaglutide versus Once Daily Insulin Glargine, Both Combined with Pre-Meal Insulin Lispro in Type 2 Diabetes Patients (AWARD-4) (962-P)

J Jendle, J Rosenstock, L Blonde, V Woo, J Gross, H Jiang, Z Milicevic

This phase 3, open-label, 52-week study (n=884 with type 2 diabetes) compared Lilly’s once-weekly GLP-1 agonist dulaglutide to the basal insulin Lantus (once-daily insulin glargine), both in combination with the mealtime insulin lispro (Lilly’s Humalog). The idea that a GLP-1 agonist could actually replace a basal insulin is a pretty novel concept, and the authors of the poster note that AWARD-4 is the first study exploring use of a GLP-1 agonist with mealtime insulin. Impressively, results of this trial show that (as in AWARD-2) both the 0.75 mg and 1.5 mg doses of dulaglutide showed statistically greater A1c reductions at 26 and 52 weeks compared to insulin glargine (see table below). At 52 weeks, statistically more patients on dulaglutide 1.5 mg achieved an A1c goal of <7% (59%) compared to glargine (49%). The difference between dulaglutide 0.75 mg (56%) and glargine was not significant. At 52 weeks, there was no statistically significant difference between arms for achieving A1c ≤6.5%. Consistent with the other phase 3 results for dulaglutide presented at ADA, dulaglutide showed very modest weight changes (but still better than insulin glargine; see table below). Total hypoglycemia in events/patient/year was lower on dulaglutide 1.5 mg compared to glargine (44 vs. 63), but similar between dulaglutide 0.75 mg and glargine (53 vs. 63). Percentage of patients modest weight and hypoglycemia benefit of dulaglutide vs. glargine in this trial is likely explained by the background insulin lispro therapy. Patients at baseline were 59 years old, had mean A1c of 8.5%, mean BMI of 32.5 kg/m², mean insulin dose of 56 U/day, and mean diabetes duration of 12-13 years.

	Dulaglutide 1.5 mg (n=295)	Dulaglutide 0.75 mg (n=293)	Insulin glargine (n=296)
Primary Endpoint: 26 weeks
A1c change	-1.64%	-1.59%	-1.41%
Patients with A1c <7%	68%	69%	57%
Weight change	-0.9 kg (-1.9 lb)	-0.2 kg (-0.4 lb)	2.3 kg (5.1 lb)
Final Endpoint: 52 weeks
A1c change	-1.48%	-1.42%	-1.23%
Patients with A1c <7%	59%	56%	49%
Weight change	-0.4 kg (-0.8 lb)	0.9 kg (1.9 lb)	2.9 kg (6.4 lb)

Safe and Effective Use of the Single-Use Pen for Injection of Once Weekly Dulaglutide in Injection-Naïve Patients with Type 2 Diabetes (122-LB)

G Matfin, A Zimmermann, K Van Brunt, R Threlkeld, D Ignaut

This poster presented results from an open-label, four-week outpatient study investigating the usability of the single-use pen (SUP) designed to administer 0.5 ml of Eli Lilly’s dulaglutide in injection-naïve individuals with type 2 diabetes, as assessed by the injection success rate during the final of four weekly injections of placebo using the SUP. Study participants (n=211) were on average 61 years old, with diabetes duration of 7.7 years, and BMI of 31.7 kg/m² at baseline (36% of participants only had a high school education or less). All but two of the 211 participants successfully injected placebo using the SUP during their final (fourth) injection, for a success rate of over 99%. The injection success rate for the initial injection was 97.2%, suggesting ease of use without much practice. Participants reported experiencing very little injection pain, rating the pain an average across injections of 1.0 on a 0-10 scale. In addition, participants reported a significant reduction in fear of self-injecting, as assessed by the change in their average modified D-FISQ Fear of Injecting Subscale Score. The vast majority of participants found the pen easy to use, and said they would be willing to use the pen if it were available.

Effect of Saxagliptin on Renal Outcomes (544-P)

O Mosenzon, D Bhatt, L Litwak, M Shestakova, G Liebowitz, B Hirshberg, A Parker, N Iqbal, B Scirica, R Ma, I Raz

This poster presented renal outcomes results from SAVOR-TIMI 53, the cardiovascular outcomes study for BMS/AZ’s saxagliptin (Onglyza). As a reminder, SAVOR randomized 16,452 patients with type 2 diabetes and established cardiovascular disease or multiple risk factors to saxagliptin or placebo for a median follow-up of 2.1 years (presented initially at ESC 2013; stratification of results by baseline renal function presented at ACC 2014). As noted in the primary analysis, patients treated with saxagliptin demonstrated more improvement in albumin to creatinine ratio (ACR; 11% vs. 9%; p<0.01) and less worsening in ACR (13% vs. 16%; p <0.01) versus placebo-treated patients, with greatest benefit observed in patients with known baseline microalbuminuria (31.3% returned to normal albuminuria vs. 25.7%; p<0.0001). Interestingly, this effect appeared independent of glucose control, with improvement in ACR similar in patients with A1c decline of >0.5% at one year versus those without. However, this benefit to ACR did not translate to significant differences in predetermined renal outcomes with saxagliptin, including doubling of serum creatinine (HR 1.04; 95% CI 0.83-1.30), initiation of chronic dialysis, renal transplant, or serum creatinine >6.0 mg/dl (HR 0.90; 95% DI 0.61-1.32), or composite end point of death and all of the above (HR 1.08; 95% CI 0.96-1.22).

Medication Compliance Rates of Weekly Albiglutide vs. Daily Oral Comparators in Phase III Trials (994-P)

LA Leiter, RA Scott, J Ye, MC Carr

This study compared the rates of compliance between GSK’s once-weekly GLP-1 agonist albiglutide (now Tanzeum following its recent US regulatory approval) and three once-daily oral comparators (glimepiride, pioglitazone, and sitagliptin) in HARMONY trials 3, 5, and 8. Overall compliance was consistently higher in both the albiglutide and albiglutide matching placebo groups than in any of the oral comparator groups. Low compliance was defined as ≤ 80% compliance – many providers would probably love to get long-term adherence of 80%. Low adherence was more frequent in the oral comparator groups (7.5% to 14.9%) than in the albiglutide groups (1.6% to 2.3%). Compliance was measured at each visit using pen and/or pill counts. While the results bode well for patient compliance on albiglutide, it will be important to conduct follow-up studies in real-world clinical settings. Device design has a major impact on adherence for GLP-1 agonists – see our GSK exhibit hall coverage (from today as well) for an overview of how the administration process works.

Effect of Lixisenatide vs. Liraglutide on Glycemic Control, Gastric Emptying, and Safety Parameters in Optimized Insulin Glargine T2DM ± Metformin (1017-P)

JJ Meier, J Rosenstock, A Hincelin-Mery, C Roy-Duval, A Delfolie, HV Coester, T Forst, C Kapitza

This study compared the effect of Sanofi’s Lyxumia (lixisenatide) and Novo Nordisk’s Victoza (liraglutide) on postprandial glucose in patients with type 2 diabetes ± metformin after optimal insulin glargine titration. In an 8-week, open-label trial, patients were randomized to three treatment arms: lixisenatide 20 µg (n=46), low-dose Victoza (liraglutide 1.2 mg; n=44), and high-dose Victoza (liraglutide 1.8 mg; n=46). Lixisenatide showed a benefit over both liraglutide doses in lowering postprandial glucose and delaying gastric emptying. All arms benefited from decreased A1c and body weight, with liraglutide 1.8 mg arm seeing the greatest decrease in body weight. Symptomatic hypoglycemia was slightly more frequent in the lixisenatide arm (14 events vs. 9 and 10 events in the liraglutide arms), whereas more GI side effects were noted in the liraglutide treatment arms (17 in lixisenatide vs. 21 and 22 events in the liraglutide arms). One case of severe symptomatic hypoglycemia was noted in the lixisenatide arm. Overall, both lixisenatide and liraglutide provided improved glycemic control, with lixisenatide offering a greater effect on postprandial glucose and gastric emptying and liraglutide providing a slightly better safety profile. This finding is not surprising given our understanding of short-acting

AUC PPG (h)(mg)/dl	lixisenatide 20µg	liraglutide 1.2 mg	liraglutide 1.8mg
Baseline mean ± SD	282.2 ± 120.9	280.1 ± 99.9	307.0 ± 103.2
Week 8 mean ± SD	63.6 ± 117.9	171.7 ± 95.2	156.7 ± 62.2
LS mean change from baseline ± SD	-240.2 ± 20.0	-131.8 ± 20.2	-157.1 ± 21.0

Relationship between Changes in Postprandial Glucagon, Patient Characteristics, and Response to Lixisenatide as Add-On to Oral Antidiabetics (971-P)

M Nauck, S Azar, L Blonde, D Dicker, MP Domingo, FG Eliaschewitz, E Nikonova, r Roussel, K Sakaguchi, L Sauque-Reyna, C Bailey

This poster presented an analysis of the predictors and consequences of glucagon changes in response to treatment with lixisenatide, Sanofi’s once-daily “short-acting” GLP-1 agonist, as an add-on to oral therapy for type 2 diabetes. A total of 423 patients drawn from the GetGoal-M and –S trials were divided into two groups (“Greater Change” and “Smaller Change”) based on the magnitude of their change in two-hour postprandial glucagon levels over the course of the 24-week study. The authors found that patients who experienced larger reductions in postprandial glucagon also displayed significantly greater improvements in a variety of efficacy and safety parameters (see table below), suggesting that lixisenatide’s effects on glucagon suppression are an essential part of its overall therapeutic impact. The authors also determined that patients with newer-onset diabetes who had spent less time on their baseline oral medication regimen were more likely to end up in the Greater Change group, suggesting that lixisenatide treatment is most effective when begun early in the progression of type 2 diabetes.

Table: Differences in glycemic control and other parameters based on change in postprandial glucagon

	Greater glucagon change	Smaller glucagon change
A1c reduction (average)	1.1%	0.67%
Fasting plasma glucose reduction (average)	25.2 mg/dl	9.3 mg/dl
Postprandial glucose reduction (average)	129.4 mg/dl	78.22 mg/dl
Weight loss (average)	2.3 kg	1.2 kg
Percent achieving A1c<7%	46.5%	32.4%
Preprandial glucose reduction	31.9 mg/dl	16 mg/dl
Fasting glucagon reduction	17 mg/dl	5.6 mg/dl
Percent experiencing symptomatic hypoglycemia	6.1%	12.9%

*All differences listed in the table were statistically significant

• The goals of this analysis were to determine: (i) which baseline characteristics best predicted the magnitude of postprandial glucagon reduction with lixisenatide; and (ii) whether patients who experienced greater postprandial glucagon reduction displayed differences in other efficacy and safety outcomes. The outcomes assessed included (i) changes in A1c, fasting plasma glucose (FPG), postprandial glucose (PPG), and body weight; (ii) the percentage of patients who achieved glycemic targets; (iii) indicators of beta-cell function; and (iv) frequency of hypoglycemia.
• The analysis involved 423 patients with type 2 diabetes on oral medications who were randomly assigned to receive once-daily injections of either lixisenatide or placebo. The patients analyzed were participants in the GetGoal-M and GetGoal-S studies evaluating the effects of lixisenatide added to oral therapy in the treatment of type 2 diabetes. The patients in the GetGoal-M study were receiving metformin monotherapy and the patients in the GetGoal-S study were receiving either sulfonylurea monotherapy or sulfonylurea and metformin combination therapy. All patients had been diagnosed with type 2 diabetes for at least 1 year and had a baseline A1c of 7-10%.
• Patients receiving lixisenatide were divided into two cohorts based on their change in 2-hour postprandial glucagon levels over the course of the 24-week study. The Greater Change cohort (n=213) consisted of patients with a median change of >23.57 ng/l and the Smaller Change cohort (n=210) consisted of patients with a median change of £23.57 ng/l.
• Short duration of diagnosed diabetes and less time on oral medications were associated with greater reductions in postprandial glucagon with lixisenatide. Patients in the Greater Change cohort had an average diabetes duration of 7.3 years, compared to 9 years in the Smaller Change cohort. Patients in the Greater Change cohort had been treated with oral medications for an average of 4.5 years, compared to 5.7 years in the Smaller Change cohort. Multivariate regression analysis found that older patients and males were more likely to see a greater change in glucagon. In our minds, it was curious and somewhat contradictory that older age and shorter diabetes duration were both correlated with a greater change in glucagon.
• Greater reductions in postprandial glucagon were associated with greater improvements in efficacy parameters over the course of the study.
  
  • The average A1c reduction was 1.10% for the Greater Change cohort compared to 0.67% for the Smaller Change cohort. The average reduction in FPG was 25.2 mg/dl for the Greater Change cohort compared to 9.3 mg/dl for the Smaller Change cohort. The average PPG reduction was 129.4 mg/dl for the Greater Change cohort compared to 78.22 mg/dl for the Smaller Change cohort. All else being equal, it is not surprising that greater improvements in glucagon levels led to improved glycemic control.
  • Patients in the Greater Change group lost an average of 2.3 kg (~5 lbs), while patients in the Smaller Change group lost an average of 1.2 kg (~3 lbs).
  • Approximately 47% of patients in the Greater Change cohort achieved an A1c <7% by the end of the trial compared to 32% of patients in the Smaller Change cohort.
  • Beta-cell function: Patients in the Greater Change cohort showed greater improvements in beta-cell function as demonstrated by a greater reduction in preprandial glucose (31.9 mg/dl compared to 16 mg/dl) and fasting glucagon levels (17 mg/dl compared to 5.6 mg/dl). The Greater Change cohort also experienced a significant increase in the HOMA-b index, while the Smaller Change cohort did not.

Greater reductions in postprandial glucagon were also associated with lower rates of hypoglycemia. No patients in either group experienced severe hypoglycemia, but only 6.1% of the patients in the Greater Change cohort experienced symptomatic hypoglycemia, while 12.9% of the patients in the Smaller Change group did. This was a somewhat counterintuitive finding, as a greater change in glucagon (i.e.: less glucagon secretion) could be seen as a predictor of more hypoglycemia, not less. This phenomenon suggests that the differences in the changes in glucagon might be a manifestation of more sweeping changes in metabolic health occurring as a result of lixisenatide treatment.

Meet-the-Expert Session: Incretin-Based Drugs

Incretin-Based Drugs

John Buse, MD, PhD (University of North Carolina, Durham, NC)

Incretin expert Dr. John Buse led an engaging discussion in front of hundreds of attendees during this meet-the-expert session on incretin-based therapies (DPP-4 inhibitors and GLP-1 agonists). Several recurrent themes emerged in the discussion:

• A major question on many people’s minds is how “real” the heart failure signal is with DPP-4 inhibitors. As a reminder, Onglyza’s cardiovascular outcomes trial, SAVOR, unexpectedly found a 27% relative increased risk of heart failure compared to placebo. Dr. Buse has not significantly changed his prescribing patterns, and his opinion is that if any real risk exists, it would be quite moderate in the real-world DPP-4 population; SAVOR was heavily enriched for people at high risk of CVD, whereas most people prescribed DPP-4 inhibitors in the real world are much earlier in the disease progression. Said Dr. Buse, “Yes, there is a finger being pointed, and there’s always a finger being pointed, but I’d say nine times out of 10 the relationship is spurious. My guess is at the end of the day, 20 years from now, there will not be a major issue with DPP-4 inhibitors being agents that cause heart failure in the routine management of type 2 diabetes.”
• With regard to the potential for incretins to show cardioprotection Dr. Buse is not terribly optimistic: “I think it’s almost asking too much in these relatively short-term trials […]. I think it’s a bit much to expect [CV risk reduction] out of a diabetes drug. From day one, and I don’t know if Galen felt this way or the Ancient Egyptians that first described honeyed urine, but from day one glucose management has been focused primarily on microvascular complications.” He noted that the EXSCEL trial, Bydureon’s cardiovascular outcomes trial, is the only one he is aware of that was primarily designed as a superiority study (the others were designed with the primary endpoint of CV safety to satisfy the FDA’s CV safety requirements).
• Dr. Buse was also fairly lukewarm about the prospect of incretins for other indications outside of type 2 diabetes, such as type 1 diabetes or obesity: Dr. Buse remarked, “My personal experience with my patients who have type 1 diabetes has not been overwhelmingly positive.” With regards to obesity, he noted that the data for liraglutide 3.0 mg has yet to be fully disclosed, so it would be premature to use GLP-1 agonists to treat people with obesity and not diabetes. He pointed to SGLT-2 inhibitors as additional promising agents for both type 1 diabetes and obesity.
• Other notable quotes from the session included:
  
  • “With regard to whether there are specific ethnicities that might respond better [to GLP-1 agonists], I don’t believe we have strong data in that regard. But I  can’t tell you with absolute certainty. There is a report, for instance, and I just read the title this morning, that metformin after 50 years on the marketplace is more effective in African Americans than Caucasian Americans. It’s stunning to me that this would just come out now in 2014. So certainly to answer a question like the ones you’ve raised requires a very specific kind of study, and I’m not aware of that having been done.”
  • “I think SFUs are certainly a legitimate choice for managing diabetes. From my perspective, what I personal avoid doing is using high doses. Particularly, a little tiny dose of SFU can provide a lot of efficacy and relatively low risk for hypoglycemia […]. When you start increasing the dose of an SFU because A1c is inadequate, that’s when you have risk of trouble. If you find a patient on maximum doses of SFU, that person should be on another drug and on a half-maximal or lower dose of SFU.”

“I personally think the data [for beta cell regeneration with incretin-based drugs] is pretty weak. The strongest data come from animal models, especially young animals. My personal belief is if the appropriate long-term study is done, if there is an effect, it will be quite modest.”

Symposium: Cardiovascular Outcomes in Recent Diabetes Trials

Saxagliptin (SAVOR-TIMI 53) Trial

Benjamin Scirica, MD, MPH (Harvard Medical School, Boston, MA)

Dr. Benjamin Scirica reviewed the results of SAVOR-TIMI 53, the cardiovascular outcomes study for BMS/AZ’s saxagliptin (Onglyza). As a reminder, SAVOR’s primary results (presented initially at ESC 2013 Day #1) demonstrated non-inferiority on cardiovascular safety with saxagliptin compared to placebo in 16,452 patients with type 2 diabetes at high risk for cardiovascular disease, though with a slightly greater risk of hospitalization due to heart failure in the saxagliptin group. Subgroup analyses of these patients at AHA 2013 failed to identify a subpopulation for which the relative risk of heart failure was particularly high or low with saxagliptin versus placebo; further subgroup analyses at ACC 2014 indicated similar outcomes with saxagliptin when patients were stratified by baseline renal function. In addition to these results, Dr. Scirica reviewed a recently published analysis (Raz et al., Diabetes Care 2014) that reiterated similar risk for pancreatitis between the treatment arms (HR 1.09; 95% CI 0.86-1.79), which held true following adjudication of events for any pancreatitis (0.29% in the saxagliptin group vs. 0.26% with placebo; HR 1.13; 95% CI 0.63-2.06), definite acute pancreatitis (0.2% vs. 0.1%; HR 1.88; 95% CI 0.86-4.41), definite plus possible pancreatitis (HR 1.36; 95% CI 0.72-2.64), and chronic pancreatitis (HR 0.33; 95% CI 0.05-1.44). Dr. Scirica noted that the distribution of definite and possible acute pancreatitis and chronic pancreatitis events was similar between the groups, suggesting that events were spontaneous rather than drug-induced. He closed by reinforcing that few agents in diabetes have now been studied as extensively as saxagliptin, emphasizing the benefit to microvascular outcomes without adverse macrovascular outcomes.

Questions and Answers

Dr. Vivian Fonseca (Tulane University, New Orleans, LA): I believe dose adjustment was required for the renal patients. How well was that adhered to?

A: It was very well adhered to. The patients were getting yearly central labs as well as local labs. Instructions for dose adjustments were complied with.

Q: Do you think the dose should be reduced further?

A: I again see consistency in results regardless of eGFR. I think given the neutrality with CV outcomes and effects on hyper- and hypoglycemia that dose reduction was appropriate.

Q: Did you check your hospitalization from heart failure in patients with prior coronary disease?

A: Patients with prior MI did have a higher risk. It was a moderate correlate behind history of heart failure, chronic renal insufficiency, and microalbuminuria. It wasn’t a strong predictor, but it was certainly.

Q: Can you tell us a bit more about what investigators were instructed to do with regard to improvement in hyperglycemia?

A: We gave instructions that providers should follow their local practice guidelines for the management of glucose control. We did not mandate any treatment algorithm or control. The only thing that was prohibited was open-label incretin therapy. There were very small drop-ins of incretin therapies and of TZDs.

Alogliptin (EXAMINE) Trial

William White, MD (University of Connecticut, Farmington, CT)

Dr. William White reviewed results of EXAMINE, the cardiovascular outcomes trial for Takeda’s DPP-4 inhibitor Nesina (alogliptin). For coverage of these results when they were first presented, see our reports from ESC 2013 Congress at and ACC 2014 Scientific Sessions. During Q&A, Dr. White noted that blood levels of NT-proBNP (a marker of heart failure) decreased from baseline in both groups. However, he said the decrease was larger in the alogliptin group. These data were from a subanalysis of roughly 1,000 patients that has not yet been formally presented. Dr. White added that the researchers were continuing to explore this finding. Other questioners asked about the increased rate of heart failure seen in SAVOR-TIMI 53, the CVOT for BMS/AZ’s DPP-4 inhibitor Onglyza (saxagliptin), which was not seen in EXAMINE. Dr. White said that it is “too early” to say whether heart-failure risk is a class effect, and that he thinks the question will remain unresolved even if a slight risk signal is seen in TECOS, the ongoing CVOT for Merck’s Januvia (sitagliptin).

Questions and Answers

Q: Did BNP change?

A: These data have not been formally presented. The change was not in BNP but in NT-proBNP, which fell significantly in a group of roughly 1,000 patients evaluated at six months. Although levels fell in both groups, there was a greater fall with alogliptin and placebo. We are furthering research in this area at this time.

Q: Can you comment on the difference in heart failure between EXAMINE and SAVOR-TIMI 53?

A: The differences relate to CV morbidity. SAVOR had fairly high-risk patients, with a 7% event rate. But the proportion of patients with baseline disease was higher in EXAMINE. It’s reassuring that alogliptin did not increase cardiovascular events, including heart failure, in this population. I cannot speculate why there was a difference in heart failure alone between the studies. It is important to see if there was confounding by death; we did have a nominal reduction in death in EXAMINE, and I do not believe this was observed in SAVOR.

Q: A couple of these DPP-4 inhibitors have been shown to have more tendency to develop CHF in primary coronary artery disease. Am I to conclude that this is a class effect?

A: Everyone in EXAMINE had coronary artery disease, and they did not develop a greater risk of heart failure when treated with alogliptin. It is too early to say that this is a class effect; I would not make that statement. Even if TECOS sees a small signal, I still don’t know if I’d call that an increased risk. Patients with heart failure had more renal disease; these patients were sicker. Patients on insulin might have higher risk, as might those with other comorbidities or longer duration of diabetes. We must be careful, especially because there was no clear-cut mechanistic reason for why DPP-4 inhibitors would increase the risk of heart failure.

Symposium: Initial Treatment of Type 2 Diabetes – New and Not-So-New Ideas

GLP-1 Receptor Agonists

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

Dr. Richard Pratley provided an overview of the efficacy and safety of GLP-1 agonists, focusing on their potential use as a first line treatment of early stage type 2 diabetes. He began by discussing the pathophysiology of type 2 diabetes, drawing on Ralph DeFronzo’s “ominous octet” to highlight the many organ systems affected by hyperglycemia and arguing that the primary defects of insulin resistance and beta cell dysfunction are apparent even before diabetes is diagnosed. He described his ideal anti-hyperglycemic agent as one that is effective, well-tolerated, and addresses multiple metabolic abnormalities, among other more wishful criteria. He claimed that out of the many treatment options now available for type 2 diabetes, incretin-based therapies like GLP-1 agonists come closest to meeting those criteria. He presented evidence from several studies demonstrating GLP-1 agonists’ high glucose-lowering efficacy, low risk of hypoglycemia, and weight loss, which he said his patients were very enthusiastic about. Ultimately, Dr. Pratley presented a compelling case for GLP-1 agonists as an appealing treatment option for certain patients with early stage type 2 diabetes, though he did not address the issue of affordability in depth or make substantive comparisons with many of the other available drug classes. The development of once-weekly GLP-1 agonists and better administration devices should help grow the class and make it more “beginner-friendly.”

• In Dr. Pratley’s opinion, the appearance of multiple metabolic abnormalities early in the progression of type 2 diabetes supports the use of incretin therapy as a first line treatment. He was careful to note as a disclaimer that GLP-1 agonists are not recommended as a first-line therapy by current guidelines, but said that “we can still have a scientific discussion” about the possibility of first-line GLP-1 agonist therapy. He discussed the advantages of selecting treatment options like GLP-1 agonists that more proactively deal with multiple elements of type 2 diabetes pathophysiology rather than beginning with metformin and inevitably adding more medications later.
• Dr. Pratley presented an overview of data on the efficacy and safety of currently available GLP-1 agonists and concluded that they meet many of his criteria for an ideal type 2 diabetes therapy. Clinical studies of already-approved GLP-1 agonists have shown A1c reductions of 0.7% to 1.5% that in many cases were superior to other diabetes drug classes, and GLP-1 agonist therapy generally also led to at least a small amount of weight loss. Importantly, the risk of hypoglycemia is very low with this drug class, as its effects on both insulin and glucagon are diminished when blood glucose levels are low.
• Dr. Pratley admitted that a slight risk of pancreatitis has been reported and that more information is needed about cardiovascular risk, but he claimed that neither of those issues presents a serious concern at this time. The main downsides to this drug class in his mind are the GI side effects and the fact that there is no oral formulation currently available.
• Because of their high glucose-lowering efficacy, acceptable safety profile, and beneficial effects on body weight, Dr. Pratley believes GLP-1 agonists could be a good first line treatment for certain patients with early type 2 diabetes. The ideal candidates for initial GLP-1 therapy would be people who can’t tolerate metformin, are overweight or at high risk of hypoglycemia, and don’t mind injections. The additional issue of affordability came up during Q&A: Dr. Pratley humorously added “well-insured and independently wealthy” as one of his criteria for the ideal patient for initial GLP-1 agonist therapy.

Questions and Answers

Q: Is there a difference in gastric emptying between long-acting and short-acting GLP-1 agonists? What about targeting fasting plasma glucose vs. postprandial?

A: It looks like the longer-acting GLP-1 agonists have less of an effect on gastric emptying long-term, although they do at first. Possibly as a consequence, they also have less of an effect on postprandial glucose. The best options for controlling postprandial glucose are exenatide and lixisenatide.

Q: What do you think about DPP-4 inhibitors as a first line therapy in early type 2 diabetes?

A: I didn’t have time to address that class today, but many of the same reasons would apply. We have monotherapy studies on DPP-4 inhibitors showing that they’re well-tolerated, safe, and effective, and they would work well for the same type of patients that would do well on GLP-1 agonists.

Q: I really enjoyed your talk, but affordability can be a stumbling block for this class because these drugs are so expensive.

A: Yes, I should have said that the ideal patient is also well-insured and independently wealthy.

Symposium: Can We Limit the Long-term Decline of Beta Cells in Type 2 Diabetes?

Can Gastrointestinal Hormones Limit the Long-Term Decline of Beta Cells in Type 2 Diabetes?

Patricia Brubaker, PhD (University of Toronto, Toronto, Canada)

Dr. Patricia Brubaker reviewed that GLP-1 receptor agonist therapy increases beta-cell mass and/or function in type 2 diabetes. She emphasized that scientists still do not understand this process clearly, because GLP-1’s effects seem to be age-and-species dependent, and because “we know extremely little about human islets, unfortunately.” Incretin therapy stimulates beta-cell proliferation in some rodent models of diabetes. However, Dr. Brubaker does not think that current evidence strongly supports this theory in humans (especially adults, in whom beta-cell replication seems minimal). The more validated mechanism in humans is prevention of apoptosis, as seen in some experiments with isolated human islet cells (Farilla et al., Endocrinology 2003; Buteau et al., Diabetologia 2004). In clinical studies the benefits of GLP-1 receptor agonists on beta cells appear durable for at least three years, but these benefits seem to disappear or diminish shortly after treatment is stopped (Bunck et al., Diabetes Care 2011), and researchers do not know whether the effects are on beta-cell mass, beta-cell function, or both. In the last several minutes of her talk Dr. Brubaker discussed other gastrointestinal hormones, which could potentially be combined with each other or GLP-1 to benefit beta cells.

• In rats with diabetes, treatment with GLP-1 enhances beta-cell growth and decreases apoptosis (Xu et al., Diabetes 1999; Farilla et al., Endocrinology 2002; Perfetti et al., Endocrinology 2000). Similar effects have been seen in young mice, but old mice do not respond as well, indicating that GLP-1’s effects on the beta cell are species- and age-dependent (Tschen et al., Diabetes 2009; Rankin and Kushner, Diabetes 2009). Dr. Brubaker said that she continues to think that rodent beta cells are an appropriate model for people. However, she hopes that we learn much more about inter-species similarities and differences. She suggested that someday scientists might use such knowledge to create a humanized rodent-cell model.  
• After spending most of her presentation on GLP-1, Dr. Brubaker briefly reviewed several other gastrointestinal hormones with possible therapeutic effects on beta cells. Therapy with gastrin “doesn’t seem to do much by itself,” Dr.
  Brubaker said, but it does increase beta-cell mass in mice when given with either TGF-alpha or EGF. In vitro data with human cells suggests that gastrin-plus-EGF increases beta-cell number (Suarez-Pinzon et al., J Clin Endocrinol Metab 2005), and Zealand Pharma has performed promising pre-clinical experiments with the gastrin/GLP-1 dual agonist ZP3022 (Fosgerau et al., Diabetes Obes Metab 2013). Ghrelin therapy seems beneficial in rats, but human data are not available. Therapy with gastric inhibitory peptide (GIP) seems to help in streptozotocin-treated rats, but not streptozotocin-treated mice; data are not yet available in humans. Therapy with cholecystokinin (CCK) seems not to help in mice or humans. 

Questions and Answers

Q: So many people a few years ago thought that absolute mass matters. But in humans it looks like we see little improvement in mass but a big improvement in function. Is this your understanding?

A: We don’t yet know if it’s increasing function, mass, or both in humans. Evidence shows that GLP-1 therapy does improve ability to lower blood glucose, whether by beta-cell function or mass.

Comment: Given what you said about how beta-cell replication seems to slow down in adults, maybe we’ll learn that these drugs have special effects in teenagers with diabetes.

Corporate Symposium: Update on GLP-1 based Therapies – Effects on Exocrine and Endocrine Pancreas (Supported by an Unrestricted Educational Grant from Merck)

Incretin Effects on Human and Rodent Beta Cells

Colin Leech, PhD (SUNY Upstate Medical University, Syracuse, NY)

Dr. Colin Leech presented data comparing the effects of incretins (GLP-1 and GIP) on pancreatic islets in rodents and humans. Both rodents and humans have GLP-1 receptor signaling pathways, notably involving the “new player” SAD-A kinase (which represents a nexus point between glucose signaling and GLP-1 signaling). However, one notable difference is that insulin secretion from human islets is dependent on protein kinase A (PKA) activity; this is not required for rodent insulin secretion. The second half of the presentation explored the effects of pancreatic beta cell GLP-1 receptors and neuronal GLP-1 receptors on regulation of insulin secretion. Dr. Leech made the point that a rat can lose either the pancreatic GLP-1 receptor OR the neuronal GLP-1 receptor and still maintain most insulin secretion, although losing both types of GLP-1 receptors impairs secretion greatly. Additionally, administering a GLP-1 receptor agonist to the portal vein disrupted glucose homeostasis, but no effect when it was the jugular vein, suggesting that the portal vein has a critical neuronal GLP-1 receptor. This seems physiologically very possible, as endogenous GLP-1 from the gut is first transported through the portal circulation. Overall, Dr. Leech stressed that incretin hormone pathways are highly complicated and involve GLP-1 receptors in the brain, liver, stomach, and of course the pancreas.

Inconvenient Truths – Clinical Data Informing the Safety of Incretin-Based Therapies

Jacqueline Koehler, PhD (Samuel Lunenfeld Research Institute, Toronto, Canada)

In front of an overflowing audience, Dr. Jacqueline Koehler reviewed the current preclinical and clinical data surrounding the risk of incretins and pancreatitis/pancreatic cancer. While there was no new data in the presentation, she synthesized the current state of affairs very cogently: much of the debate over incretins and pancreatic safety has been fueled by a few publications of preclinical and clinical data that have not been reproducible. The majority of the available clinical data has come from retrospective database and case-controlled observational studies, which are subject to numerous biases and limitations. In particular, she explored the possibility for over-diagnosis based on elevated pancreatic enzyme levels (a marker of pancreatitis that is not, in itself, sufficient for diagnosis). Dr. Koehler suggested that the highest quality clinical data on this issue will come from the large cardiovascular outcomes trials (CVOTs) ongoing for incretin-based therapies – she found the neutral pancreatic findings from SAVOR and EXAMINE “promising” and remarked that they demonstrated that if any risk exists, it is so low that it was not even detected with a 16,000+ person trial (SAVOR). She noted that we will have to wait for more data from the outcomes studies to draw better conclusions on the benefit/risk profiles for incretin-based drugs.

• Retrospective, observational studies are plagued by a number of limitations and biases, including the potential for over-diagnosis of pancreatitis based solely on elevated lipase levels. About 10-20% of people with type 2 diabetes exhibit elevated baseline lipase levels with no other symptoms for pancreatitis, independent of incretin treatment (Steinberg et al., Gastroenterology 2012). GLP-1 agonist treatment can increase median lipase activity ~5-10 U/L (remaining within the normal range, but persistent until treatment discontinuation), as shown in phase 3 trials of Novo Nordisk’s Victoza (liraglutide 1.8 mg), liraglutide 3 mg for obesity, and Lilly’s dulaglutide. The majority were unaccompanied by pancreatitis events, but the overall elevations of lipase levels in this population makes an accurate diagnosis of acute pancreatitis more challenging – clinicians who are not as thorough as to use imaging to confirm the diagnosis may over-diagnose based on lipase levels alone. Dr. Koehler, thus, emphasized the need for formalized procedures to assess these adverse events (e.g., in randomized-controlled studies).
• Dr. Koehler highlighted all of the CVOTs for incretin-based therapies that are ongoing, or recently completed, saying that the neutral pancreatitis findings in SAVOR and EXAMINE were “promising” and suggest that any risk of pancreatitis is very low (0.3-0.4% chance over median follow ups of 1.5-2 years in these two trials).
• Finally, Dr. Koehler reviewed the FDA and EMA’s independent assessment (published in NEJM February 2014 – see our report here). She characterized this undertaking as extremely thorough, noting that the agencies evaluated all preclinical and clinical data, including more than 250 toxicology studies in over 15,000 rodents and almost 2,500 non-rodents, 120 pancreatic histopathology slides, their own commissioned pancreatic toxicology studies with exenatide, all clinical safety databases to date including more than 200 trials, and results from the recent SAVOR and EXAMINE outcomes trials.

Corporate Symposium: Getting Straight to the Point – A Theatrical Play Exposing the Misconceptions Around Injections and Tackling the Barriers They Create (sponsored by Novo Nordisk)

Steven Edelman (UCSD, San Diego, CA); Stephen Brunton, MD (University of North Carolina, Chapel Hill, NC); Melissa Magwire, RN, CDE (Shawnee Mission, KS)

Introduction

Moderator Ms. Melissa Magwire opened the session by explaining its innovative and unconventional format. A trio of short plays would explore the particular anxieties and challenges facing patients as they considered moving to injectable therapies. Each act would be followed by a short panel discussion. Novo Nordisk previously staged a version of this show – written and directed by English playwright Mr. Tim Gomersall – at last year’s IDF in Melbourne, but this iteration benefited immensely from the presence of Dr. Stephen Brunton and Dr. Steve Edelman (University of San Diego, San Diego, CA). The two panelists were able to speak both as healthcare providers and as patients; Dr. Edelman has type 1 diabetes and is the founder of Taking Control of Your Diabetes (TCOYD), while Dr. Brunton has type 2 diabetes and is the father of a child with type 1 diabetes. This session was packed to the brim, and we feel that HCPs walked away with some valuable learning.

Act One: “The Injection Barrier”

The first act of the play spotlighted how doctors and patients could come away from the same consultation equally frustrated, albeit for very different reasons. A doctor and a nurse discussed their difficulties; the former complains of a “whirlwind” patient who assumed that her internet research was comparable to his carefully considered recommendation that she begin injectable therapy, while the nurse explained her patient clammed up at the first mention of injectables, probably out of fear of needles. On the other side of a dividing wall, those same patients gave their side of the story. Fiery Isabel explained that she sought out other options because she considered injectables a sign of personal failure, while timid Paul said he simply couldn’t understand what the nurse was trying to tell him about his treatment! Eventually, the wall between them was removed, giving each pair another chance to communicate more effectively. What follows are some particularly incisive lines from the scene:

• Paul: “I’m not good with my change. I have my routines. It was hard enough adding all those pills into my life, now they want to add an injection into my life.”
• Isabel: “It’s more a matter of a pride. It was like he was saying I was at the end of the road, and that wasn’t fair to me.”
• Paul: “I was pretty sure you told me that I needed more medicine, but I was so busy trying to understand that much that I didn’t have time to understand why.”
• Doctor: “It’s not necessarily your fault if you can’t manage your diabetes through orals and a healthy lifestyle alone… Diabetes is a progressive disease.”

 

Act One Panel Discussion

To begin the discussion, Ms. Magwire asked the audience, “What do you think is the biggest reason that patients are hesitant to switch from orals to injectables?” Fourteen percent attributed this to “feelings of guilt, shame, or failure,” 41% to “lack of understanding about disease progression,” 6% to “concerns about possible side effects,” and 39% to “fear of needles/pain associated with injection.” During their discussion, the panel referred to several findings from Novo Nordisk’s DAWN2 trial.

Ms. Magwire: What you do you think about the answers to the audience response questions?

Dr. Brunton: I think all of those things are correct, and the answer will vary between different patients. We as providers make a lot of the issue of fear with needles and injections, but needles are so thin now, and people don’t have the same kind of fear they used to have.

Dr. Edelman: The option I picked was “the lack of understanding around disease progression.” I’m a big fan of patient education. The more you educate people about the natural history of diabetes and the pros and cons of different medicines and show what it's going to do for them, then the better the buy-in and adherence is. Education combats a lot of the fear and the anxiety that patients deal with. This act of the play brought up of those issues, and the patient and their understanding is where the rubber meets the road, so to speak.

[Screens displayed Novo Nordisk data (on file) indicating that 80% of patients are “open to” or “comfortable with” the idea of self-injection.]

Ms. Magwire: Studies have shown that the majority of patients are willing to at least consider injectable therapy.

Dr. Edelman: I don't think there's a fear among patients, many physicians, caregivers, nurse practioners, whatever – they’re afraid of starting insulin because of the time commitment, they’re hesitant to approach the patient, just the hassles involved. I think all of us in general, no matter what we do as a profession, we tend to take the path of least resistance.

[Screens displayed data (Nakar et al., J Diabetes Complications 2007) showing that 12% of patients feared the pain of injections, but 48% of providers thought their patients feared the pain of injections.]

Ms. Magwire: As we can see here, providers often overestimate patients’ fear of injectables.

Dr. Edelman: Yeah, absolutely, I’m not surprised by this at all. I’ll just provide one 15-second story: Many years ago, I was recruiting a patient for a study, I believe it was GLP-1, and I went through this long, 10-minute monologue about injections and how it really is fairly painless, and, at the end, they just said: “Okay.” And I said, “What do you mean, ‘Okay’?” They said, “I have no problem with it.” I said, “Why didn’t you stop me from this whole 10-minute explanation, could have saved me 10 minutes!” And I’ll always remember that because it really shocked me that, hey, this patient wasn’t against injections when you go through the explanation of why it’s going to help them and how it’s going to help them.

Dr. Brunton: The real concern many patients have is that initiating injectable therapies means that they have failed. We need to have open-ended discussion with our patients to see what the issue is. It may not be what we think it is. We think it might be a fear of pain, when really it's a fear of failure.

Dr. Edelman: From now until the end of time, starting a patient on an injectable is going to be a challenge.

[Screens displayed data from the Diabetes Attitudes Wishes and Needs 2 Trial (DAWN2), indicating that many healthcare professionals wanted to receive more training on diabetes care.]

Dr. Brunton: One universal thing we do not receive in our education is background on motivational interviewing. If we can remove the wall between us and our patients, and understand not only what our patients are thinking but also how to motivate them better, it will drive us towards better treatment.

Dr. Edelman: The DAWN2 study was excellent because it brought in the family factor. If you don’t address the education and motivation of patients’ family support networks, you’re missing a big part of the diabetes care puzzle.  

Dr. Brunton: There’s nothing better for learning about a disease than having the disease yourself. It really makes you understand the process! It's interesting for me, having the role both as a patient and a practitioner, recognizing how other practitioners speak to me. And it's such a crucial idea that even though there's this overall disease, diabetes, it's really one disease that one person has at one time. Part of the communication is finding out what diabetes means to the individual patient. What's your understanding of it and what troubles you the most about your diabetes? That way we can develop a very individualized approach.

Dr. Edelman: The individualization of care can feel new with the ADA's recent move in that direction, but we've needed to individualize care since the beginning of medicine! It's not a novel concept at all. Every patient is different, and we have to approach them in terms of their education, their motivation. I think our role is to motivate patients to put diabetes higher on their priority list.

Act Two: “The Trial of Mrs. Annabel Jenkins”

This high-concept scene literalized the judgment that patients often experience in the form of an actual trial, as Annabel Jenkins, a middle-aged woman whose attempts to improve her diet and lifestyle continuously failed, was forced to defend her resistance to initiating injectable therapy. The prosecuting attorney was merciless, calling a series of witnesses who spoke to Mrs. Jenkins’ inability to keep her promises to improve her lifestyle. Ultimately, Mrs. Jenkins and her doctor were able to reach more of an understanding, as both confronted the fact that her need to switch to injectables was about more than any personal failings in treatment. Some of our favorite quotes from the scene include:

• The presiding judge: “This trial, investigating Annabelle Jenkins’ poor diabetes management, is hereby convened.”
• Mrs. Annabel Jenkins: “My reluctance to start on injectables is not a matter of self-neglect – it’s a matter of self-preservation! I’ve read how insulin can cause side effects like weight gain, which can’t be good for me. I’m sure I can control my blood sugar with diet and exercise alone.
• The personification of the Internet: “I’ve found some great blogs for you, on how insulin makes you gain weight, gives you regular hypoglycemia, and even a story about a grandmother on insulin who lost her leg. Scientific evidence? Where’s the fun in that?”

Act Two Panel Discussion

To begin the discussion, Ms. Magwire polled the audience: “Which area do you feel needs the most improvement when treating people with diabetes?” Twenty-nine percent said “ensure a greater understanding of disease progression,” 20% said “improve communication skills,” 13% said “better understanding of the injection barrier,” and 39% said “provide resources and education for patients and caregivers.”

Ms. Magwire: That act may have seemed a little bit extreme, but maybe not. We do find there is a lot of guilt and a lot of judgment, unfortunately, involved sometimes. 

Dr. Edelman: The play wasn’t so far off reality in many situations. We label our patients, and I think we're all guilty to some degree, as "non-compliant." You get someone who has type 2 who is older and heavier, they have to change their lifestyle. They've suddenly got 100 things to do in terms of lifestyle: pills, injectable, seeing the doctor, seeing the eye doctor, seeing the foot doctor, washing the feet every night - there is a lot of things that we ask our patients to do. Many of those things we probably wouldn't be so great at doing ourselves! And then they come back to the clinic and they haven't done them, and you just think, "That person doesn't care at all about their own health." It's really an attitude issue, and I think we're all guilty to some degree. It gets hard to see patients one after the other in the clinic, who don’t bring their logbook, don’t achieve weight loss, and that can be frustrating as a caregiver. And then that attitude starts to build up.

Dr. Brunton: What I appreciated about the play - obviously it was very dramatically done - but that idea of criminalizing the patient. I think we do that a lot. We ask patients to do so much, in all diseases but particularly in diabetes, which is perceived by both patients and providers as a lifestyle disease. So therefore, it's your fault: You're overweight, you don't exercise, etc. We ask patients to make a lot of changes when it's difficult for us to make even one change. I did an experiment with some residents in which they chose one lifestyle and tried to change it for a month. We did this for ten years, and one of the things the residents picked was that they weren't going to have cookies for a month. At the end, out of 70 residents, only two people were able to make the changes! Back to the play, you look at the fear that Annabel had about taking injections. Once again, there are people telling her that she's at fault. The problem is that a lot of providers think the same thing. As we've seen, diabetes is a progressive disease; it's going to eventually happen. That's why I talk to patients very early on and tell them that they will probably eventually have to have an injectable, and that it's a natural kind of therapy, replacing what is naturally wrong. And then it's not a guilt thing. It's just part of the disease itself.

Dr. Edelman: You probably have to say that more than one, so that it sinks in! We have great tools, including orals and injectables, but we have to go beyond that. We’re limited in the time we have with our patients, both in the US and around the world.

Dr. Brunton: Education is power. One of the things about having diabetes for many patients is a loss of control. So you provide resources for the patient's education, particularly with regards to the disease progression or even what the disease is, then the patient is able to take more control and feel better about themselves.

Dr. Edelman: The other thing that I try to do with newly diagnosed type 2 diabetes is to re-frame the issue. The fact is that if you are diagnosed with type 2 diabetes, you stand to live a longer and healthier life, because now you’ll pay more attention to your health, start looking at cholesterol, blood pressure, and all the things you may have ignored before you got the diagnosis. I try and turn it around and make it a positive, because I’m a glass-half-full kind of guy.

Dr. Magwire: Patients and providers also come out of consultations with very different memories of how the consultation went, and what was discussed.

Dr. Brunton: We need to go beyond asking, “How are you doing?” That is just a social question; a patient’s leg may be falling off, and they would say that they are doing well in response to that question. We have to really ask deeper questions.

Dr. Edelman: The discrepancy stems from a lack of proper communication, and a lack of understanding of where patients and providers are each coming from.

Ms. Magwire: Do you think that education is the biggest barrier to initiation on injectables?

Dr. Edelman: I think it is key. You have to bring out and show them the new needles. I show my patients the 32-gauge 4 mm needles, and insert it in their arm with their eyes closed. Most of the time they don’t say they feel it until I tell them I actually did it!

Act Three: “It’s Complicated”

The final act of the play focused on Michael, an overworked businessman who has been on injectable therapy for some time. His heartless boss sends him on open-ended business trips to Japan on a moment’s notice, his wife worries and accuses him of not taking good enough care of his diabetes, and his doctor insists that he needs to get more serious about his therapy. As he tries to juggle all the demands on his life, he soon realizes just how much he has lost control. Some key lines follow:

• Michael: “I’m just struggling to stay on top, and failing.”
• Michael’s wife: “I’ve lost count of the number of times I’ve come home to find you asleep, but your insulin pen is just as full as the night before.”
• Michael: “If I have more medicine, aren’t there going to be complications like weight gain and hypogly-whatchamacallit?”

Act Three Panel Discussion

Ms. Magwire once again polled the audience, asking “Which do you feel is the biggest area of concern for your patients living with diabetes?” Nine percent said “lack of caregiver involvement/support,” 44% said “day-to-day stress/feeling overwhelmed,” 13% said “feeling discriminated because of their condition,” and 35% said “daily diabetes management at home. Ms. Magwire closed the panel by asking one final audience question: “As a result of my participation in this program, I intend to _____.” Thirty-two percent said “engage in more effective communication with my patients, 25% said better address the psychosocial impact diabetes can have in my patients, 24% said “more effectively incorporate family members into the diabetes management plan,” and 19% said “make no changes as this program validated my current practice.”

Dr. Brunton: The issue is that Michael cannot communicate his problems, due to a mix of embarrassment and shame about his diabetes. It's not just a personal or even a family disease; it involves everyone from his boss to his physician.

Dr. Edelman: The other point that I'd like to make is the "diabetic police wife." It all comes from a place of love, but the way that she communicates with him puts him on the defensive. Family members have to be educated to communicate in a constructive way that doesn't turn off their partner.

Dr. Brunton: Part of the reason why the wife is the police is because she has fears of her own. She's frightened that he will die or lose a foot. She becomes overly protective and makes his life even more miserable than ever before.

Dr. Edelman: Diabetes is a 24/7 commitment, and that brings up issues of self-management, because you can't follow your patients around 24/7. That's where education becomes so important, and the more information they have, the less stress they'll have. That's true for patients and for caregivers as well.

Ms. Magwire: One of the issues that came up in the play was that the patient was hesitant to tell his boss what was going on.

Dr. Edelman: I think there's real discrimination out there. At least in the United States, it's become less and less prevalent out there, because so many people have diabetes now. I think the whole thing is communication and telling the people that you have tell, and then more people who know will understand. Certainly that includes family, although I've seen patients hide things from their family members. If you work, you've got to tell some people at work. It comes to just education and information and just not being fearful of what might happen.

Dr. Brunton: There is such a lack of understanding within the public in terms diabetes is. If someone sees you taking insulin, god help you, it must be a very serious disease. There's this issue of communicating with the public. Too often, your disease can come to define you.

Dr. Edelman: There are a lot of people who wrongly think that every person with type 2 diabetes ate themselves into their disease.

Ms. Magwire: In your type 2 diabetes practice, how do you impress upon patients the importance of self-management?

Dr. Brunton: I'm a family physician, so we manage many different kinds of diseases. Really, the patient owns the disease. I serve as consultant to help them do that. But I think part of the issue is that we're asking people to do a lot. The behavior change is challenging anyway. So the key is choosing one behavior that they think that they can manage, and get some success with that before they have to change everything.

Dr. Edelman: One thing I do that helps is to give patients a 30-day challenge. Patients will try basal insulin for 30 days, and at the end of that time, if the injections are too painful, or if they don’t see improvements, or if they simply want to stop for any reason, they can stop. They look at me in disbelief when I tell them this idea. I never saw a patient who improved on basal insulin in the 30-day period who decided to go off it.

Dr. Brunton: When you've had high blood sugar for a very long time, that's just the way you feel. So when patients start on an injectable, one great thing that happens is that their blood sugars go back to normal. They feel better. It's like a new lease on life.

Ms. Magwire: For a busy practitioner, what is the key factor to address first?

Dr. Brunton: We've talked generically about the issue of education. For me, it's about addressing it very early and not talking about it as a punishment. You just say that an injectable is simply about the natural progression of the disease. I think for a clinician who doesn't already have his or her team in the office, it's about developing a team. Have someone in the office who can handle the education aspects for you. It's about reinforcement for the patients, staying in touch with them and addressing their issues.

Ms. Magwire: What is your pearl of wisdom for overcoming the injection barrier?

Dr. Edelman: You need to ask truly open-ended questions, to prompt patients to tell you what their biggest concern is, and you need to listen closely. If you ask good open-ended questions, you will pick up a lot of what is stopping the patient from reaching their glycemic goals, and then you can address the problem.

Question and Answer Session

Q: How do you deal with patients’ travel?

Dr. Edelman: I have worked on publications showing that, depending on the magnitude of the time zone change, there are ways to advance basal insulin administration from nighttime in California to nighttime in France, for example. It is a complicated answer.

In terms of individualizing diabetes education, what is your goal to creating a successful plan for each patient?

Dr. Brunton: What we're starting to understand is that patients have different levels of health literacy. It's really about trying to understand where they're coming from so that I know where to take them. I start by asking them, "What is your understanding about diabetes?" The answer to that can develop an entire curriculum. Most people know that it's something about blood sugar. It depends on their necessity, their urgency, and what are their biggest fears. If I can deal with all that up front, I think the rest of it follows. I work closely with a diabetes educator so that that person can spend a lot more time with patients and is very skilled in handling all that. It's also important to be open at any time to that education, and just to understand where the patient is coming from.

Dr. Edelman: Use your diabetes educators. They have the luxury of spending an hour with your patients when you only have 15 minutes, during which you have to deal with all the other things you need to discuss with them.

Q: Do you approach different injectable therapies differently?

Dr. Edelman: Starting a basal insulin is different than starting a GLP-1 agonist – each has its own pros and cons. I think overcoming the fear of injections is an overlap, but there are differences in terms of what each drug class will do to patients.

Dr. Brunton: As a family physician, it is easier for me to initiate a GLP-1 agonist, as there are fewer concerns about hypoglycemia. Patients also seem to have a particular bias against insulin, and GLP-1 agonists don’t seem to have the same stigma. We’ve seen tremendous adoption of both injectable classes.

Q: How can we better support patients who start injectables?

Dr. Edelman: There is nothing like peer influence – it can do more than a provider who only gets 15 minutes with a patient. You get a whole group of patients who have succeeded at taking injections. I think that's way more powerful than a doctor trying to talk someone into it in 15 minutes. And we see that at shared medical appointments that we do at the university. It's quite helpful.

Dr. Brunton: And actually I was going to say the same thing. There's a big movement in the US now to be very efficient. Bring six or eight patients together, and they talk amongst themselves, so they can share best practices and give them support that they don't feel right asking for, and then you as a practitioner can take an individual patient into a room and deal with what needs to be done. But that group support thing is a way of alleviating distress. We saw that in the first play. In dealing with some of the concerns that the patients had, other patients had more credibility than doctors.

Q: Some final pearls of wisdom: What are some best practices when initiating discussion of injectable therapy?

Dr. Brunton: I think that you have to overcome what's traditionally being done in many places, which is saying back in the day, when the patients were children, people would say, "Behave, or the Doctor's going to give you a shot!" So, now there's this thought, if you don't behave i.e. not speak to your doctor or not take care of your diabetes, you're going to have to get a shot. You're going to have to get insulin. So my big thing to patients is that, at a certain point in time, you're going to have injectable therapy: What are your thoughts? It's very open-ended. And that way I can really address their big concerns.

Dr. Edelman: Yeah, I agree, Steve. Even though we talk about it, it's hard to get someone who is relatively early in their natural history to talk about injections, maybe even give them a sample. Tell them, "You don't need it now, you may or may not need it in the future, but you most likely will need an injectable." So, you don't have to come back to it for years, but at least that fear is out of their minds. And the other pearl is that 30-day challenge. That really does work. If they don't get better, if the insulin or GLP-1 injections are too painful, or they just don't want to keep taking it, we'll stop it. They like that fact that it's not the rest of their life. It's always going to be a challenge. I don't care what you're taking, it's always going to be harder to take an injection than to swallow a pill. That's for sure.

Product Theaters

The Critical Role GLP-1 Receptor Agonists Play in Addressing the Treatment of Type 2 Diabetes (Sponsored by AstraZeneca)

Zachary Bloomgarden, MD (Mount Sinai Medical Center, New York, NY), Susan LaRue, CDE (Amylin Pharmaceuticals, San Diego, CA)

In this presentation, Dr. Zachary Bloomgarden reviewed some of the basic science behind GLP-1 receptor agonists and described the efficacy and side effects of AstraZeneca’s once-weekly Bydureon (exenatide). Bydureon achieves steady and continuous release in the bloodstream via degradation of microspheres, which are made from the same polymers as surgical sutures and orthopedic implants. Dr. Bloomgarden next presented data on Bydureon’s efficacy. Results from the phase 3 DURATION-5 study, which compared Bydureon with AZ’s Byetta (once-daily exenatide), demonstrated Bydureon’s superiority in both reducing A1c (1.5% reduction versus 0.9% with Byetta) and fostering weight loss (5 pounds vs. 3 pounds with Byetta). With regards to adverse events, Dr. Bloomgarden stressed several times that hypoglycemia was only a problem when Bydureon was taken concurrently with sulfonylureas. GI effects were quite prevalent, although Dr. Bloomgarden noted that they were “part of the baggage” for GLP-1 agonists. He also mentioned that patients who have or may have pancreatitis or renal impairments should not use Bydureon. Afterwards, he invited Ms. Susan LaRue, a renowned certified diabetes educator, to speak about AZ’s efforts in patient education. The presentation concluded with a demonstration of Bydureon’s single dose tray – although AZ recently received approval for a new dual-chambered pen that greatly improves the reconstitution and administration process from a patient perspective, the pen will only be launched later this year, which is why the demonstration used the single-dose tray. 

• Dr. Zachary Bloomgarden presented data from the DURATION-5 study, which compared efficacy and safety of once-weekly Bydureon against once-daily Byetta; results showed that Bydureon was generally superior. For more details, read our coverage of the topline DURATION-5 data from 2009.
• There was a strong focus on patient education – certified diabetes educator Ms. Susan LaRue talked about AZ’s education programs and demonstrated how to mix and inject Bydureon. Ms. LaRue described AZ’s SteadySTART Educator Network as the largest diabetes educator network in the US. SteadySTART’s team of 84 full-time clinical educators and 400 on-demand educators train office staff, retail pharmacists, and patients themselves on how to use Bydureon. Ms. LaRue also talked briefly about another program that helped patients develop healthy eating and exercising habits. For the finale, she stood in front of the audience and demonstrated, step-by-step, how a patient should administer Bydureon (using the old single-dose tray, because the recently-approved dual-chambered pen will likely not be launched until later this year). According to Ms. LaRue, 88% of a group of type 2 diabetes patients (n=102, 78% insulin-naïve) were able to use the single dose tray successfully on the first try without hands-on help. Regardless, we think the new Bydureon pen will be much easier. 

Questions and Answers

Q: I’m concerned about the 15 to 20% nausea and problems with diarrhea in this prep. Also, shouldn’t 2 mg of exenatide at once cause more GI effects compared to the smaller doses of Byetta?

Dr. Bloomgarden: When Bydureon first became available, that was exactly my thought. I thought we could start everyone on Byetta, get them to accept that, and then use Bydureon. That turns out to be incorrect, probably because of fluctuations in the blood level after immediate release. The likelihood of developing GI side effects initially seems to be higher, maybe not with diarrhea, which is interesting and suggests a slightly different mechanism. With nausea, though, you don’t reach a steady state level until six weeks have gone by. This is actually a gentler way of initiating treatment, compared with Byetta. Starting Bydureon at 2 mg is actually better tolerated than Byetta.

Q: A patient of mine was on basal bolus with Levemir and NovoRapid, and I suggested she lose some weight with Bydureon. It was her first time taking a GLP-1 agonist. She was fine for six months, but then she had a severe hypertensive crisis where she had to go to the emergency room. We thought it was an isolated event. Then there was another hypertensive crisis. I don’t know what to do now. Should I take her off Bydureon? Is it related to the crises?

Dr. Bloomgarden: At the present time, Bydureon is not recommended for use in conjunction with insulin. I’m acting on behalf of AstraZeneca, so we can only say that that’s off-label use. It may or may not be related to the hypertensive process.

Q: What if she were just on Bydureon, with no insulin?

Dr. Bloomgarden: There’s no reason to think any GLP-1 agonist should increase blood pressure. I would evaluate her as with anyone having a hypertensive crisis.

Q: There was not much explanation given about the microsphere technology. Would that information be available online?

Dr. Bloomgarden: I’m going to ask you to direct that question to the AstraZeneca people here to get full details on the composition of the polymer. I don’t actually personally know that.

Q: One more quick question. If we calculate 10 micrograms exenatide twice per day, which is the Byetta dosage, that’s 140 micrograms, or 1.4 mg, per week. Bydureon is 2 mg per week. Why the difference?

Dr. Bloomgarden: There’s a tremendous difference in 24-hour exposure comparing quick release Byetta and slow release Bydureon. There’s a very rapid increase and decrease in concentration of exenatide after the injection of Bydureon. Almost certainly there is some degree of degradation brought about by its microsphere formulation. After one develops an agent, we must find out what’s the most effective dose. The 2 mg dose seems to be a good balance between efficacy and side effects with the once-weekly drug, whereas the once-daily drug works well with 140 micrograms per week.

-- by Eric Chang, Hannah Deming, Jessica Dong, Emily Regier, Katherine Sanders, Joe Shivers, Sanjay Trehan, Manu Venkat, Alasdair Wilkins, Rebecca Xu, John and Kelly Close