This year’s meeting was a big one for GLP-1 agonists, with the first cardiovascular outcomes trial (CVOT) results for the class as well as an excellent look at the future of the class beyond existing agents.
The long-awaited results from the ELIXA CVOT for Sanofi’s Lyxumia (lixisenatide) were resoundingly neutral (as one of our associates says, quite persuasively, we think – “yeah. That’s what they are all going to be. Neutral. All. Neutral.”), with Kaplan-Meier curves for the primary and secondary cardiovascular endpoints that were essentially superimposable and showed no hint of a benefit emerging towards the end. While reassuring in terms of safety, the results from ELIXA and similarly neutral results from other CVOTs prompt broader questions about the value of these trials as they are currently designed. ELIXA was large enough to detect some level of cardiovascular superiority, but its fairly short duration made the chances of demonstrating a benefit fairly slim. Discussant Dr. Silvio Inzucchi (Yale University, New Haven, CT) raised larger questions about whether these studies are enrolling the right patients, running for long enough, and asking and answering the most relevant clinical questions. These are especially important questions to consider for GLP-1 agonists given that these CVOTs add considerably to the cost of drug development and GLP-1 agonists are already perceived as an expensive drug class. We are of course so glad to have had this data ahead of time.
On the more positive side, the future for GLP-1 agonists looks bright based on other new data we saw at ADA. We are especially excited about the potential for combination with basal insulin along with innovative new delivery devices. We were very impressed with the results from the DUAL V study, which compared Novo Nordisk’s GLP-1/basal insulin combo Xultophy (insulin degludec/liraglutide) and Sanofi’s Lantus (insulin glargine). The results after 26 weeks showed a mean A1c reduction of 1.8% from a baseline of 8.4% with Xultophy vs. a reduction of 1.1% from a baseline of 8.2% with continued Lantus therapy in type 2 diabetes patients also on metformin. Xultophy also boasted a more than 3 kg (~7 lb) weight benefit vs. Lantus, 57% fewer episodes of confirmed hypoglycemia (p<0.001), and a stunning 83% reduction in nocturnal hypoglycemia (p<0.001). Whoa. We’re also looking forward to seeing topline phase 3 data for Sanofi’s LixiLan, expected in 3Q15. In terms of strong efficacy and well-balanced side effects, the results from GLP-1 agonist/basal insulin combinations have been perhaps the best out there – particularly because once a patient goes on such a therapy, they might be able to stay on it quite awhile.
We finally got to see the pivotal phase 3 data on Intarcia’s implantable exenatide mini-pump ITCA-650. Mean A1c reductions were around 1.4% for the whole group from baseline, with placebo-adjusted efficacy that looked to be around 1.1%. This is roughly in line with what we’ve seen from other GLP-1 agonists, though efficacy was found to be even better in patients not taking a sulfonylurea. Keeping with expectations for a GLP-1 agonist, ITCA-650 led to weight loss and nausea around the time of dose escalation. We thought the results were solid, though the company will need to work to manage expectations after an explosively positive past year in the news cycle that has built up a fair amount of hype (external forces are driving this). We see both GLP-1/basal insulin combos and new delivery devices like ITCA-650 (and looking further ahead, potentially GLP-1 agonists in pill form) as a great set of options for the individualization of therapy using this drug class, which has plenty of room for growth in the coming decade, from a variety of companies.
Talk titles highlighted in yellow were among our favorites from ADA 2015; those highlighted in blue are new or expanded full report additions from our daily coverage.
- Executive Highlights
- Detailed Discussion and Commentary
- Oral Presentations: The Evaluation of Lixisenatide in Acute Coronary Syndrome – The Results of ELIXA
- ELIXA Design and Baseline
- ELIXA in Perspective
- Panel Discussion
- Press Conference: ELIXA
- Oral Presentations: Combining Basal Insulin and GLP-1 Agonists
- Insulin Degludec/Liraglutide (IDegLira) is Superior to Insulin Glargine (IG) in A1c Reduction, Risk of Hypoglycemia, and Weight Change: DUAL V Study (166-OR)
- Assessment of Glycemic Control by CGM in Patients with T2D Treated with IDegLira (170-OR)
- Superior Effects with Combination of Insulin Degludec (IDeg) and Liraglutide (Lira) (IDeg+Lira) Compared with Basal-Bolus Insulin Therapy (BB) in Hemodialysis (HD) Patients with Poorly Controlled Type 2 Diabetes (T2D): An Assessment by Continuous Glucose (171-OR)
- Least Glucose Variability and Hypoglycemia Is Observed with the Combination of a GLP-1 Receptor Agonist and Basal Insulin (VARIATION Study) (167-OR)
- Synergistic Action of PE0139, a Super-Long-Acting Basal Insulin, and PB1023 a Weekly GLP-1 Receptor Agonist (168-OR)
- Once-Weekly Combination of GLP-1R Agonist and Insulin (HM14220) Offers Improved Glycemic Control and Reduced Weight Gain Risk (172-OR)
- Oral Presentations: Update on GLP-1 Receptor Agonists
- Clinical Impact of ITCA 650 in Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, 39-Week Trial (276-OR)
- Efficacy and Safety of Liraglutide Added to Insulin in Type 1 Diabetes: The LIRA-1 Trial (277-OR)
- Twelve Weeks Treatment with Liraglutide as Add-on to Insulin in Normal-Weight Poorly Controlled Patients with Type 1 Diabetes (279-OR)
- Dose-Response Improvements in Glycemic Control and Body Weight Reductions With Hm11260c, A Once-Weekly GLP-1 Receptor Agonist with Liraglutide as Reference, in Type 2 Diabetes (T2DM) (278-OR)
- Efficacy and Safety of Once-Weekly Dulaglutide vs. Insulin Glargine in Combination with Metformin and/or a Sulfonylurea in Predominantly Asian Patients with Type 2 Diabetes (280-OR)
- Mechanisms of Action of the Glucose-Lowering Effect of Lixisenatide in Combination with Insulin Glargine (281-OR)
- The Influence of GLP-1 Receptor Agonists on the Heart Rate Using Holter Electrocardiography and Power Spectrum Analysis of Heart Rate Variability (282-OR)
- Oral Presentations: ADA Presidents Oral Session
- IDegLira in Insulin-Naïve Patients with Type 2 Diabetes (T2D) Inadequately Controlled on Sulfonylureas (SU) Alone or in Combination with Metformin: The DUAL IV Study (1003-P)
- Efficacy and Safety of Liraglutide vs. Sulfonylurea Both in Combination with Metformin during Ramadan in Subjects with Type 2 Diabetes (LIRA-Ramadan): A Randomized Trial (1121-P)
- Insulin Degludec/Liraglutide (IDegLira) Improves Patient-Reported Impacts in Subjects with Type 2 Diabetes (T2D) Inadequately Controlled on Insulin Glargine (IG) plus Metformin (Met): Dual V Study (2550-PO)
- Efficacy and Tolerability of 39 Weeks of ITCA 650 (Continuous Subcutaneous Exenatide) in Poorly Controlled T2DM with High Baseline A1c (>10%) (1107-P)
- Symposium: New Developments with GLP-1 Receptor Agonists
- Differentiating Current and Emerging GLP-1 RAs
- GLP-1 Receptor Agonists in Combination with Basal Insulin
- GLP-1: To Use or Not to Use? Safety is the Question
- GLP-1 Receptor Agonists as Adjunctive Treatment in Type 1 Diabetes
- GLP-1 Receptor Agonists for the Treatment of Obesity
- Panel Discussion
- Corporate Symposium: Complementary Treatments to Enhance Insulin Efficacy: Theory and Strategies (Supported by Joslin and Sanofi)
- Basal Insulin and Complementary Treatments: Summary of Pathophysiology and Pharmacology
- Basal Insulin and Complementary Treatments: Basal Insulin Plus GLP-1 Agonists
- Joslin Needs Assessment Data: Exploring Some “Disconnects”
- Basal Insulin and Complementary Treatments: Overcoming Barriers and Developing Patient-Centric Treatments
- Selected Q&A/Panel Discussion
- Corporate Symposium: Clinical Issues in Type 2 Diabetes: Discussions and Debates Around GLP-1 Receptor Agonists (Supported by AZ)
- Product Theaters
- Non-Adherence and Glycemic Control – A Real-World Look at the Issues and Challenges We Face (Sponsored By Intarcia)
- A Case Study in Treating Adult Patients with Type 2 Diabetes (Sponsored by Lilly)
- The Effect of a Once-Weekly Therapy on A1C and Weight Over 3 Years (Sponsored by AstraZeneca)
- Oral Presentations: The Evaluation of Lixisenatide in Acute Coronary Syndrome – The Results of ELIXA
Detailed Discussion and Commentary
Oral Presentations: The Evaluation of Lixisenatide in Acute Coronary Syndrome – The Results of ELIXA
Rafael Diaz, MD (Estudios Cardiológicos Latinoamérica, Rosario, Argentina)
Dr. Rafael Diaz provided some context for the ELIXA results by discussing the enormous burden of diabetes and the associated excess risk of cardiovascular disease and mortality. He emphasized the complexity of the factors that contribute to CV risk and the need for a treatment approach that addresses multiple risk factors, including blood glucose. Notably, he focused specifically on the potential for cardioprotection with GLP-1 agonists, saying that ELIXA was designed to assess the potential beneficial effects of lixisenatide as well as its safety profile. This is somewhat surprising to us, as we might have expected speakers to emphasize the study’s primary objective of non-inferiority in order to discourage an overly negative interpretation of the results.
ELIXA Design and Baseline
Eldrin Lewis, MD (Brigham and Women’s Hospital, Boston, MA)
This double blind study randomized 6,068 patients with type 2 diabetes 1:1 to the short-acting prandial GLP-1 agonist Lyxumia (lixisenatide) or matching placebo. Patients were started on an initial dose of 10 ug/day lixisenatide that was down- or up-titrated to a maximum of 20 ug/day during a seven-day run-in period. All patients were within 180 days of an acute coronary syndrome event. The study’s primary composite endpoints were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina. Secondary endpoints included all-cause death, the percent change in urinary albumin/creatinine ratio from baseline to 108 weeks, the incidence of a primary endpoint + hospitalization for heart failure, and the incidence of a primary endpoints + hospitalization for heart failure + coronary revascularization. In terms of baseline characteristics, there were no significant differences between the groups’ lipid profiles, other cardiovascular risk factors, or baseline medications. For perspective, the international trial included 49 countries and 782 sites: 32% of patients were enrolled in Lain America, 26% in Central and Eastern Europe, 12-13% in North America, Northern and Southern Europe, and Asia Pacific, and 5% in Asia and Africa.
Matthew Riddle, MD (OHSU, Portland, OR) and Marc Pfeffer, MD, PhD (Brigham and Women’s Hospital, Boston, MA)
Results from the ELIXA CVOT for Sanofi’s Lyxumia (lixisenatide) were resoundingly neutral. The hazard ratio for MACE was 1.02 (95% CI: 0.89-1.17), and the hazard ratios were also neutral for the expanded composite (MACE + unstable angina; HR 1.02 [0.89-1.17]), heart failure hospitalization (HR: 0.96 [0.75-1.23]), and all-cause death (HR: 0.94 [0.78-1.13]). No cardiovascular subgroup analyses deviated from neutrality and the Kaplan-Meier curves were fairly superimposable. Unfortunately, there was not even a hint of cardioprotection emerging towards the end of the trial. There were very modest average reductions in weight (0.7 kg [~2 lbs]) and systolic blood pressure (0.8 mmHg) with Lyxumia, with no effect on heart rate for most of the trial following a transitory 1 BPM increase over the first few weeks. Interestingly there was a slight attenuation in the usual rise in albuminuria over time (24% increase over two years with lixisenatide vs 34% with placebo; p<0.01), although it was far from a conclusive signal and there was no significant change in eGFR. Nausea and vomiting were increased roughly 3x but comparable with other lixisenatide trials, with discontinuation in just under 5% of lixisenatide patients due to GI side effects – this drove a very modest imbalance in overall adverse events (odds ratio: 1.3; 95% CI [1.1-1.5]), though severe adverse events were balanced (odds ratio: 0.9; 95% CI [0.8-1.0]). We were glad to see that there was no increase in pancreatitis or pancreatic cancer (neoplasms were actually imbalanced in lixisenatide’s favor).
- Primary outcome: There was no significant difference in the primary endpoints of MACE + unstable angina: 13.4% (lixisenatide) vs. 13.2% (control). The hazard ratio was 1.02 (95% CI: 0.89-1.17; p<0.001). No subgroup analyses showed significant differences either: (i) cardiovascular morality was 5.2% (lixisenatide) vs. 5.1% (control); (ii) fatal/non-fatal myocardial infarction was 8.6% (lixisenatide) vs. 8.9% (control); (iii) fatal/non-fatal stroke was 2.0% (lixisenatide) vs. 2.2% (control), and unstable angina was 0.3% (lixisenatide) vs. 0.4% (control). Hazard ratios were 0.98 (95% CI: 0.78-1.22) for cardiovascular morality, 1.03 (087-1.22) for fatal/non-fatal myocardial infarction, 1.12 (0.79-1.58) for fatal/non-fatal stroke, and 1.11 (0.47-2.62) for unstable angina. No subgroup analyses (gender, race, racial category, or region) caused any heterogeneity for the primary MACE+ outcome.
- Secondary outcomes: Hazard ratios were also neutral for the expanded composite: MACE + unstable angina + heart failure hospitalization (HR 0.97 [0.85-1.10]); MACE + unstable angina + heart failure hospitalization + coronary revascularization (HR 1.00 [0.90-1.11]); heart failure hospitalization (HR: 0.96 [0.75-1.23]), cardiovascular mortality + heart failure hospitalization (HR: 0.97: 0.82-1.16) and all-cause death (HR: 0.94 [0.78-1.13]).
- Other outcomes: Stratification by history of heart failure did not deviate from neutrality either. For heart failure hospitalization, hazard ratios were 0.93 (0.66-1.30) for patients with a history of heart failure and 0.97 (0.67-1.40) for patients without a history of heart failure – heart failure received slightly more attention due to recent theories of effects on heart failure with DPP-4 inhibitors, the other major type of incretin-based drug. For cardiovascular mortality + heart failure + hospitalization, hazard ratios were 0.97 (0.75-1.24) for patients with a history of heart failure and 0.96 (0.75-1.23) for patients without a history of heart failure.
- Glycemic control: There was a marginal improvement in A1c of 0.3% with Lyxumia that followed a “Nike swoosh” pattern, falling immediately after treatment initiation but then rising with time. The same relationship over time was seen with fasting plasma glucose, which dropped an average of ~5 mg/dl. Despite these improvements, the rate of hypoglycemia (28 per 100 patient-years) and severe hypoglycemia (0.3 per 100 patient-years) in lixisenatide patients was not elevated relative to placebo (26 per 100 patient-years and 0.6 per 100 patient-years, respectively).
- Cardiovascular risk factors: There were marginal improvements in weight (0.7 kg [~2 lbs]) and systolic blood pressure (0.8 mmHg), with no effect on heart rate (+0.4 beats/minute). There was a slight attenuation in the rise in albuminuria over time (24% increase over two years with lixisenatide vs. 34% with placebo; p<0.01) highlighted in the presentation – there is no clear cause and this could be a chance finding, but we hope it spurs at least some degree of further study.
- Non-cardiovascular side effects: Rates of diarrhea did not differ between the two arms though nausea and vomiting were increased roughly 3x (odds ratio: 8.4; 95% CI [4.8-15.9]) – this increase is comparable with other lixisenatide trials. There was a slight increase in the number of events leading to discontinuation of treatment (odds ratio: 1.7; 95% CI [1.4-2.9]) driven largely by GI side effects on lixisenatide patients (odds ratio: 4.2; 95% CI [2.9-6.2]). We were glad to see that there was no concern of systemic allergies associated with lixisenatide (5 events in each arm). Overall on-study malignancy showed no concerning signals as well with 89 diagnoses in lixisenatide patients vs. 78 in placebo. Sub-group analysis suggested no specific cancer rates were elevated either.
- Notably, there was also no significant increase in pancreatitis (8 events vs. 5 events), although the number of events was small. We hear it increasingly acknowledged that acute pancreatitis may be a real side effect with incretin-based therapies, although if it is the risk appears to be acceptably small.
- Changes in medications: There was an increase in the use of insulin, metformin, and SFUs in patients on placebo and a slight decrease in patients on Lyxumia.
ELIXA in Perspective
Hertzel Gerstein, MD (McMaster University, Hamilton, Ontario, Canada)
Though not particularly adventurous in terms of speculation or hypothesizing, we thought Dr. Hertzel Gerstein’s presentation did a very valuable job contextualizing the results from ELIXA. At multiple points, he put a positive spin on findings that could otherwise be perceived as neutral. For example, although the primary finding of cardiovascular neutrality perhaps fell short of the most optimistic expectations, Dr. Gerstein reminded the audience that glucose lowering is a proven and important goal in and of itself due to the impact on microvascular complications. He also characterized the modest 0.3% A1c difference between groups as a positive for lixisenatide; after all, investigators were using other agents in the placebo group to try and achieve the same targets and lixisenatide still came out ahead in terms of A1c. Dr. Gerstein noted that the unique study population (very high risk post-ACS patients) impacts how the findings can be generalized – other GLP-1 agonist CVOTs, he noted, do not enroll patients at the same level of risk.
Silvio Inzucchi, MD (Yale School of Medicine, New Haven, Connecticut)
Dr. Silvio Inzucchi offered a very astute take on the implications of the ELIXA results for the broader questions surrounding type 2 diabetes drugs and cardiovascular disease. He began with a strong endorsement of the trial’s rigor and assured clinicians that it had convincingly answered the important question of whether lixisenatide is associated with excess cardiovascular risk. He then reviewed the existing data on the relationship between glycemic control and cardiovascular disease, concluding that sustained glucose reduction appears to provide a benefit but that it accrues over a very long time period (certainly longer than the duration of ELIXA and other CVOTs) and is likely attenuated in patients with existing cardiovascular disease. With regard to the effects of specific drugs, Dr. Inzucchi discussed the limited data available and emphasized the challenges of distinguishing the effects of specific agents from the impact of glucose-lowering itself. Overall, he predicted that ongoing CVOTs for diabetes drugs are unlikely to demonstrate cardioprotection unless a drug has dramatic off-target cardiovascular effect, which is unlikely. He raised several important broad questions about whether these trials are being designed in the best way possible and whether they are worth the enormous cost. However, he ended on a tantalizing note with a picture of a theoretical future ADA/EASD treatment algorithm in which the long current list of second-line therapies was simply replaced with a “drug X” that had achieved the “holy grail” of demonstrating CV benefit.
Q: This was a very well done study telling us a lot of important messages. However, as a clinical endocrinologist looking into aspects of hypoglycemia, it might be of interest to see what the change in insulin dose was. We’ve been told that the same number of people were on insulin in both groups, and the same with sulfonylureas, yet the protocol asked for a reduction.
Dr. Pfeffer: This was the first presentation and the data just went to the academic group for analysis. I can tell you the numbers but I don’t have granularity at this point.
Dr. Riddle: It’s a good question. We have access to the data but it hasn’t been analyzed, which we hope to get to soon enough. It will be interesting to know exactly how the doctors at the sites did manipulate the dose and what relationship the changes had to any outcomes.
Q: I noticed that there were regional differences in different parts of the world. What was the result in the Asian subgroup? Was it better than in the rest of world?
A: At this moment, I can’t tell you about the subgroups. We’re working on that analysis. Quite naturally, some groups are going to be on one side or the other. No group was out far enough that it caught our eye. Notably, North America was in the right direction. We still have to figure out the numbers.
Press Conference: ELIXA
ELIXA Press Conference – Selected Q&A
Matthew Riddle, MD (OHSU, Portland, OR) & Dr. Marc Pfeffer, MD, PhD (Brigham and Women’s Hospital, Boston, MA)
Q: If there is no benefit, why take this drug and subject patients to adverse events?
Dr. Riddle: This was not a glucose control comparison trial. This was a trial designed to see if there was any risk with this drug compared to other forms of treatment used. There was the possibility that the drug itself, independent of glucose control, could have favorable or unfavorable effects. In clinical practice, all diabetes drugs are used sequentially and in combination, with the goal of attaining the best possible glucose control without undue side effects, namely hypoglycemia. In another setting than this trial design, it seems rather likely that GLP-1 agonists could be used to improve glucose control, thereby reducing microvascular complications. Long term data from trials like DCCT/EDIC and UGDP show that glucose control can protect against cardiovascular disease. There is no reason from these results not to use GLP-1 agonists as another tool in the toolbox to maintain good glucose control.
Q: When GLP-1 agonists were first introduced, there was a hope that they would improve cardiovascular disease. Now these studies are coming out neutral. Are we content with these safety trials?
Dr. Pfeffer: It depends what you mean by working. They work by lowering A1c, and that can be proven with 200 patients. This safety issue is another elusive story, and we’re giving you the first installment. It’s my understanding that there are four other trials with different designs looking at cardiovascular end points. None will have 15-year follow up, so we’re all looking for short-term benefit, which in our case was not there, nor was there any short-term harm.
Q: Are your results transposable to other GLP-1 agonists, especially the longer-acting ones?
Dr. Riddle: The results are probably generalizable to broad populations since we had such a diverse collection of patients enrolled, but the generalizability of these findings for an individual GLP-1 agonists to the entire class is less certain. Especially vs. the longer-acting agents, the effective duration of action is very different. Whether this has an effect on cardiovascular risk or not is completely unknown. We know it has an effect on the best concurrent therapies. We advised investigators on the use of insulin and sulfonylureas during the daytime to protect against daytime hypoglycemia. Fortunately, as you know, there are other long-term safety trials being done with other long-acting GLP-1 agonists.
Q: You mentioned side effects like nausea. If the hope of benefit is only after 20 years of treatment, does this mean that we should not use this drug for patients over age 60 who may not reach another 20 years?
Dr. Pfeffer: From a cardiovascular point of view, we’ve always felt that concentrating on known conventional risk factors like lipids and blood pressure is what we should really be doing. But there is a focus on A1c not just for cardiovascular reasons. To treat the whole patient, we can’t ignore the other effects of glycemia. Nausea and vomiting are true side effects, but when you look at severe adverse events there was no difference vs. placebo. If a patient has trouble tolerating the agent, they of course should not be taking it, but most patients did not have serious trouble. Then it’s a question of how you can best control a person’s glucose over their lifetime.
Dr. Riddle: A sixty-year-old patients who is reasonably healthy at that age has upwards of twenty years life expectancy, which is plenty of time to accrue microvascular complications like retinopathy and neuropathy, which affect quality of life. There is some reason to predict that intervention at that age will make a difference for some patients, even if there is no effect on cardiovascular disease. Another point is that other agents we might use to treat glucose have other significant side effects. Insulin has hypoglycemia risk. This class has nausea in the range of 3-5% of patients who find it unacceptable. The proportion is about the same for metformin. Everyone is apparently enthusiastic about metformin, but about 5% of people can’t tolerate it.
Q: When you and your team designed ELIXA, was it clear from the beginning that this would only be a trial to rule out excess risk, or did you think it had the potential to show superiority?
A: In the design phase of this trial, the executive committee wanted the resources to do a superiority trial, which we did. We had enough events to be able to say that in this patient population, we did not see a benefit. We could have simply met the FDA guidance with a simpler and smaller study. We met the FDA guidance, we are safe by that rule, and we are comfortable telling you that we could not find a cardiovascular benefit.
Q: Is there any plan for a passive follow-up of this cohort to see if a benefit could emerge later on?
A: That is not happening, but what we will be able to do is further probe this data with biomarkers, dissecting out the population for risk based on novel biomarkers and conventional biomarkers.
Q: In terms of the amount of information that clinicians are getting out of these cardiovascular safety trials, is it panning out to be worthwhile, or could these resources be better used to do outcomes studies that would compare different regimens in a way that might show a benefit of one regimen over another?
Dr. Pfeffer: This question has nothing to do with our trial but with the climate in general. In 2008 when the question was raised whether these drugs were helping or hurting patients, the response was what you’re seeing. There are 140,000 human beings randomized into trials like others. This is the issue we have when an approval process is based on a surrogate, be it blood pressure, LDL, or hemoglobin A1c. You can get approved by doing something nice to the surrogate, but always in the back of your mind you’ll have that question. So, where should resources be spent? I feel very comfortable providing reassurance in this high-risk patient population, but in the absence of that we were dealing with a vacuum.
Oral Presentations: Combining Basal Insulin and GLP-1 Agonists
John Buse, MD, PhD (UNC, Chapel Hill, NC)
Two years after taking the podium at ADA to present the strong results from the DUAL I study on Novo Nordisk’s GLP-1 agonist/basal insulin combination Xultophy (IDegLira; insulin degludec/liraglutide), Dr. John Buse returned to the podium to present the first phase 3 trial comparing Xultophy and class-leading basal insulin Lantus (insulin glargine). The study randomized 557 patients with type 2 diabetes already on Lantus + metformin to either intensify their Lantus therapy or switch to Xultophy. The results this time around were just as impressive as for DUAL I: after 26 weeks, Xultophy led to a 1.8% A1c decrease from a baseline of 8.4% to a striking final A1c of 6.6%; Lantus intensification led to a 1.1% reduction in A1c from 8.2% to 7.1%; the treatment difference was 0.6% and was statistically significant (p<0.001). Those who know the DUAL I data will know that the benefits do not stop there. Xultophy boasted a more than 3kg (~7lb) weight benefit vs. Lantus (-1.5kg [~3lb] absolute weight loss from baseline). Xultophy caused 57% fewer episodes of confirmed hypoglycemia (p<0.001) and a stunning 83% reduction in nocturnal hypoglycemia (p<0.001). There were also increases in certain quality of life metrics and 5.5 times more patients with Xultophy who achieved an A1c below 7% without hypoglycemia and weight gain. Incidence of nausea was below 4% throughout the trial; there were more subjects (58% vs. 51%) with adverse events but fewer severe adverse events with Xultophy. When compared beside new basal insulins that are struggling to show benefits vs. Lantus, these and other DUAL program results look quite compelling. We learned during Novo Nordisk’s analyst event at ADA (see our ADA Exhibit Hall and Corporate Updates Report) that the company will hold off on submitting Xultophy in the US until later this year, even though it has already resubmitted Tresiba (insulin degludec). This means that Xultophy is unlikely to become available in the US until late 2016 at the earliest.
- Q&A Highlights: Dr. Philip Home (University of Newcastle, Newcastle Upon Tyne, UK) and Dr. Naveed Sattar (University of Glasgow, Glasgow, UK) questioned whether DUAL V tested a fair comparison. Dr. Sattar noted that it was essentially a test of two drugs vs. one, although Dr. Buse made the good counterargument that it was a test of one injection vs. one injection. Dr. Home pointed out the potential for biased responses because DUAL V was open label – Dr. Buse pointed to DUAL II, a blinded trial in which Xultophy had similar efficacy. In response to a question of what to do in the sizable percent of patients that reached the maximum Xultophy dose, Dr. Buse speculated (after multiple disclaimers that what he was about to say involved very off-label use) that “creative” clinicians might double-dip from the same pen to achieve a higher maximum dose, especially because a >1.8 mg dose of liraglutide (Saxenda) has been approved.
- Study Design: DUAL V was an open label, randomized, phase 2b trial enrolling 557 type 2 diabetes patients for 26 weeks of treatment. Previous trials like DUAL I and DUAL II have compared Xultophy against one or both of its component drugs, whereas this trial was intended to shape clinical decision-making for providers of the many patients on Lantus that need improved glycemic control. Patients were randomized to either stay on Lantus, intensifying treatment as per a treat-to-target titration protocol, or to switch to Xultophy. The starting dose of Xultophy was pre-specified at 16 dose steps (16 U insulin degludec, 0.6 mg liraglutide) – as a result, a secondary goal of the trial was to confirm that switching patients from Lantus to Xultophy could occur smoothly and without greatly diminished glycemic control.
- Baseline Characteristics: Average age was around 60 years, average BMI was 32 kg/m2, mean diabetes duration of 11-12 years, and mean A1c of 8.3%. All patients were on insulin glargine + metformin at baseline, with a mean pre-trial insulin dose of 31-32 U.
- Efficacy Results:
- A1c: From a baseline of 8.4%, the Xultophy group experienced a mean A1c reduction of 1.8%, reaching a strikingly low mean final A1c of 6.6%. By comparison, the group continuing and intensifying their Lantus therapy saw a change of -1.1% from a baseline of 8.2% to a final A1c of 7.1%. The difference in the A1c reduction was 0.6% in favor of Xultophy.
- Fasting Glucose: There were no significant differences in fasting glucose over the course of the trial. If anything, at early points it seemed that the Xultophy group had a slightly lower mean FPG. The significance here is that patients were able to maintain glycemic control even when switching over to a 16 unit dose of Xultophy from their previous Lantus dose.
- Body Weight: Not only did Xultophy hold a 3 kg (~7 lb) weight advantage in terms of weight gain reduction over Lantus, patients on Xultophy actually lost weight (-1.4 kg [~3 lbs]) from baseline.
- Hypoglycemia: Patients on Xultophy had a statistically significant 57% lower risk of confirmed hypoglycemia than patients on Lantus (p<0.001). Even more positively for Xultophy, the combination led to a massive 83% reduction in nocturnal confirmed hypoglycemia (p<0.001) based on a smaller but still considerable number of events (195).
- Composite endpoints: In presentations of DUAL data, investigators have done a good job of showcasing Xultophy’s comprehensive benefits by presenting comparisons of the percentage of patients who achieve target A1c without hypoglycemia or weight gain. In this trial, 39% of patients achieved A1c targets with Xultophy vs. 12% with Lantus (p<0.001), for an odds ratio of 5.5.
- Insulin dose: Patients in the Xultophy group leveled off at a mean dose of 41 dose units, whereas patients in the Lantus group experienced a continued climb, ending at 66 units at the end of the trial.
- Quality of life: Across the board in an SF-36 health-related quality of life questionnaire taken at the end of the study, Xultophy scored higher (or at least trended higher) than Lantus. The summary of physical quality of life showed a statistically significant difference in Xultophy’s favor, while the mental quality of life composite was a non-significant trend in Xultophy’s favor. More detailed quality of life data from DUAL V was published independently as a publish-only abstract (2550-PO).
- Adverse events: The rate of patients experiencing adverse events over the trial was higher with Xultophy than with Lantus (58% vs. 51%). Beyond noting that nausea was higher in the Xultophy group (though notably always below 4% - quite good given the GLP-1 agonist component), we did not get to see what else contributed to the imbalance. In contrast, the imbalance in serious adverse events tipped in Xultophy’s favor (3.9 vs. 6.7 SAEs per 100 patient-years).
- In a qualitative description of adverse events, we learned that: (i) CV events were balanced between groups, with one stroke with IDegLira and one CV death with Lantus; (ii) There were no confirmed events of acute pancreatitis; (iii) There were two confirmed malignant neoplasm events with Xultophy and one treatment emergent confirmed event of metastatic pancreatic carcinoma in a subject previously treated with Xultophy; and (iv) there were no confirmed medullary thyroid carcinoma cases.
Questions and Answers:
Q: This seems to be a comparison of two drugs vs. one. Wouldn’t it be fairer to study IDegLira vs. insulin glargine plus liraglutide given separately, the way you have to give them currently?
A: There are other studies that have compared basal insulin + GLP-1 vs. basal plus bolus insulin. The difference in A1c in those trials was less, but the relative benefit for hypoglycemia was greater. I think this is a fair fight because we’re comparing one injection vs. one injection. The commonly used approach for type 2 diabetes is to just keep pushing the one injection. But yes, there is lots of room for many more studies.
Comment (Dr. Philip Home [University of Newcastle, Newcastle Upon Tyne, UK]): Few of us would treat patients failing glargine alone with glargine alone. It seems to be an irrelevant comparator. Isn’t there also a scientific problem with an open label study where you take some people on insulin glargine and move them to a new therapy? This could have impacted hypoglycemia and especially the quality of life questionnaire results.
A: There is a blinded study, DUAL II, where the insulin dose was capped and the primary goal was to examine the contribution of liraglutide. The results were similar in some ways, giving us reassurance that there can be meaningful results even in blinded situations. Secondly, the titration was conducted with equipoise and at the end of the trials the fasting glucose levels were essentially identical. Finally, in endocrine practices in the US and around the world, for patients with A1cs around the mid 8% range, the standard practice is to continue titrating insulin. I think this is a relevant comparison. That said, there is definitely room for further studies to examine other relative effects. Comparative effectiveness is going to be an important area for many years to come.
Q: In terms of patients at the maximum dose reached in treat-to-target, what options are there to keep pushing further with IDegLira?
A: The on-label use in this product, which is available in Europe, is that you would need to add something else. That could be an oral agent, but we don’t have many studies with SGLT-2 inhibitors combined with GLP-1 agonists, and certainly no studies of GLP-1 agonists, SGLT-2 inhibitors, and insulin combined on background metformin. Another possibility would be to add bolus insulin or more basal insulin. That decision would be based on patient characteristics. The off-label thing that one could … hallucinate, since GLP-1 doses higher than 1.8 mg are approved for obesity … one could have a very high-order hallucination about taking another dip on the same pen, continuing to increase the dose of the GLP-1 analog and basal insulin. But we have zero evidence on that. I know creative clinicians will find all kinds of things to do when a product is available.
Assessment of Glycemic Control by CGM in Patients with T2D Treated with IDegLira (170-OR)
Allen King, MD (Diabetes Care Center, Salinas, CA)
Dr. King presented the results of a post-hoc analysis of a DUAL I extension substudy examining changes in glycemic fluctuations over 52 weeks in insulin-naïve patients with type 2 diabetes treated with Xultophy (IDegLira; insulin degludec/liraglutide) (n=131) versus insulin degludec (n=64) or liraglutide (n=65) alone. 72-hour continuous glucose monitoring was performed at baseline and at 52 weeks, which showed that IDegLira treatment was associated with a greater reduction in mean interstitial glucose (IG) than liraglutide (p<0.0001), a greater reduction in postprandial IG versus insulin degludec (p=0.0288), and a greater reduction in time out of range versus liraglutide (p=0.0072). Dr. King commented that these observations may have contributed to the greater A1c reductions seen with IDegLira than with either component medication in the DUAL I study. For detailed information about DUAL I baseline characteristics and methodology, please see our coverage of the initial 26-week results presented at ADA 2013.
- IDegLira treatment was associated with a greater reduction in mean interstitial glucose (IG) than liraglutide (p<0.0001), a greater reduction in postprandial IG versus insulin degludec (p=0.0288), and a greater reduction in time out of range versus liraglutide (p=0.0072). Mean IG decreased 63.1 mg/dl, 64.9 mg/dl, and 45.0 mg/dl from baselines of 180-184 mg/dl with IDegLira, insulin degludec, and liraglutide treatment, respectively. Postprandial IG changed an average of -9.0 mg/dl, 3.6 mg/dl, and -3.6 mg/dl from baselines of 25-27 mg/dl with IDegLira, insulin degludec, and liraglutide treatment, respectively. Time outside of the IG target range (70-162 mg/dl) at the end of the study were 3.2 hours, 3.8 hours, and 5.6 hours from a baseline of 14-15 hours with IDegLira, insulin degludec, and liraglutide treatment, respectively.
Questions and Answers:
Dr. Philip Home (Newcastle University, Newcastle, United Kingdom): Nice study, and nice data. I just want to make a plea. These are supposed to be scientific sessions. There are things called standard deviations, confidence intervals, [etc.,] that would allow me to understand your data. Can we ask that that these have conventional measures of dispersion to go with the mean?
A: Some of the data was statistically analyzed, but the duration of the talk did not allow me to discuss them.
Satoshi Funakoshi, MD, PhD (Jikei University, Tokyo, Japan)
Dr. Satoshi Funakoshi presented a unique study investigating the effects of GLP-1/basal insulin combination therapy on glycemic variability and control in 12 dialysis patients. For background, dialysis presents a challenge for glucose management because it can cause hypoglycemia. A potential mechanism to explain this effect is that glucose is cleared more quickly through the hemodialysis membrane than is insulin, so patients undergoing dialysis experience a temporary hyperinsulinemic state. Dr. Funakoshi’s study sought to compare the efficacy of basal insulin + GLP-1 agonist therapy (Tresiba + Victoza) compared to basal-bolus insulin therapy (Tresiba + Humalog) for controlling fasting plasma glucose and glucose variability in type 2 diabetes patients on dialysis. In this study, patients started on basal-bolus therapy and then transitioned to GLP-1/basal therapy. Glycemic variability was measured by CGM. As shown in the table below, during the basal-bolus portion of the study, patients experienced worse glycemic variability on days where they got dialysis (p<0.05 for mean amplitude of glucose excursions [MAGE] off vs. on). However, transitioning to GLP-1/basal therapy cut MAGE in half for both on and off dialysis days (p<0.05 for basal-bolus compared to GLP-1/basal), and the difference between on and off dialysis days was no longer significant. The GLP-1/basal combination also improved FPG. In conclusion, this small study suggests that the combination of insulin degludec and liraglutide can both improve glycemic control and glycemic variability in dialysis patients. This further bolsters GLP-1 agonists’ utility in patients with renal impairment, who may not be able to use therapies like SGLT-2 inhibitors or even metformin.
Table: Glucose variability (MAGE) and fasting plasma glucose (FPG)
MAGE = 108 mg/dL
FPG = 166 mg/dL
MAGE = 133 mg/dL
FPG = 145 mg/dL
MAGE = 55 mg/dL
FPG = 131 mg/dL
MAGE = 75 mg/dL
FPG = 118 mg/dL
Questions and Answers
Q: The GLP-1 agonist label says not to use these drugs in people with renal failure. What is the PK of liraglutide in people on dialysis?
A: Insulin degludec and liraglutide are not removed by dialysis, and that is the point. The PK profile is not affected, as published last year.
Q: Did you look at the proportion of patients experiencing hypoglycemia both on and off dialysis?
A: We did not see any symptomatic hypoglycemia. During hemodialysis, the glucose drops not only because of the insulin issue, but also removing toxins improves insulin resistance peripherally. Removal of fluid improves over-hydration, which improves insulin resistance. pH goes up, which encourages glucose to go into cells. So all the factors push down glucose at the end of hemodialysis, but for some reason we did not experience symptomatic hypo.
Harpreet Bajaj, MD, MPH (LMC Diabetes and Endocrinology, Toronto, Canada)
Dr. Harpreet Bajaj provided interest-piquing if not completely surprising evidence that the combination of a basal insulin and a GLP-1 receptor agonist (RA) provides the least glycemic variability among several commonly used insulin regimens. The study enrolled 150 subjects (ages 18-80) with A1cs ≤7.5% who were on one of four stable diabetes regimens containing insulin for six months prior to the study (basal insulin + oral agent, basal insulin + GLP-1 RA, premixed insulin, MDI basal bolus regimen). In the six-day protocol, subjects continued their existing lifestyle and treatment regimens and were monitored with masked CGM as well as SMBG (≥4 times daily). A combination of a basal insulin + a GLP-1 RA resulted in significantly lower daily standard deviation of glucose than alternate regimens (SD = ~31 mg/dl vs. ~34 mg/dl with basal + oral agent, ~36 mg/dl with premixed, and ~38 mg/dl with basal-bolus MDI). Both the basal insulin + oral agent and basal insulin + GLP-1 RA regimens resulted in significantly lower self-reported hypoglycemia than the premixed or MDI regimens (basal + oral agent = 20% hypo rate, basal + GLP-1Ra = 17%, premixed = 35%, basal-bolus = 57%). Overall, the authors concluded that a combination of basal insulin + GLP-1 RA provides the least variability versus three commonly prescribed insulin regimens. While the difference in standard deviation was perhaps slightly more modest than we might have expected vs. MDI, but a ~20% improvement is still highly meaningful and could mean substantially less time at extreme ranges.
Jim Ballance, PhD (PhaseBio Pharmaceuticals, Malvern, PA)
Dr. Jim Ballance presented pre-clinical data suggesting that PhaseBio’s long-acting basal insulin, PE0139, and weekly GLP-1 agonist, PB1023, could have synergistic effects when combined. For background, both agents use PhaseBio’s ELP biopolymer technology to prolong half-life. The GLP-1 agonist (PB) is in phase 2 and the insulin (PE) in phase 1. This db/db mouse study found that both PE and PB were inadequate as monotherapy for bringing glucose levels within control in response to an intraperitoneal glucose tolerance test. However, the combination of the two products normalized glucose control in a greater-than-additive fashion, even when lower doses of each individual component were used compared to the doses used in the monotherapy arms. Synergistic (more than additive) efficacy has not been seen in the largest clinical trials of GLP-1 agonist/basal insulin combinations, although it is far from certain whether these preclinical results can be duplicated in humans. Dr. Ballance remarked that PhaseBio plans to commence a six-week phase 2 multiple ascending dose study with basal insulin PE in 2H15 with a PE/PB combination study to follow.
- For background, PE0139 and PB1023 use PhaseBio’s elastin-like polypeptide technology (ELP) to extend half-life. The ELP is a set of repeating five amino acid sequences (VPGXG where X is any amino acid except proline). The ELP polymer, when fused to a peptide of interest, confers a longer half-life to the peptide of interest by allowing the fusion product to undergo the process of “coacervation” under specific temperature and solvent conditions. Coacervation is a liquid-liquid phase separation, rendering the drug either available or not available to be absorbed. By varying the number of repeats in the ELP, the concentration of the protein, the concentration of salts in the solvent, and the hydrophilicity of the protein, one can control at what temperature the phase separation occurs and, thus, control the temperature at which the drug essentially becomes available to be absorbed. Thus, one mechanism by which ELP prolongs a drug’s half-life is via this slow, controlled release. The other mechanism is that ELP prolongs the protein’s circulatory half-life by reducing clearance from circulation.
Questions and Answers:
Q: Yesterday we learned [with Lilly’s basal insulin peglispro] that if you have a large hydrodynamic range, you get liver specificity with unwanted side effects. Did you test any of that with these insulins?
A: We haven’t studied it or seen anything yet but it’s something we will look out for.
Q: What happens to absorption if body temperature goes up or down [given that the effect of ELP is dependent on temperature]?
A: From a safety perspective, if the patient has an elevated temperature what will happen is the depot will be more stable. If you have someone plunging into an ice bath then that’s something one would have to look at. What we have studied so far is a prelude to longer study – we looked at what would happen if someone took the product directly from the fridge and injected it. There was no difference in PK there. It doesn’t matter if it’s cold when you inject it as long as it gets to the right temperature in your body.
Q: In the phase 2 study of your GLP-1 agonist, what did you see in terms of weight loss? I ask because the proportion of active moiety seems pretty small.
A: We didn’t see a big change in weight, but we also had liraglutide as a control arm, and we didn’t see weight loss in that group either. In any case, based on the protein’s structure, one would expect similar weight effects as dulaglutide or albiglutide.
Q: Have you looked into temperature variability systematically?
A: We have done one single ascending dose study so far. In the presentation yesterday, the error bars were very small so at least in that small group, it didn’t seem to be very variable, but we’ll obviously have to look at that going forward. The multiple ascending dose study is our next study.
Michael Trautmann, MD (Profil Institute for Clinical Research, San Diego, CA)
Dr. Michael Trautmann presented promising results from a series of early explorations of a novel once-weekly GLP-1/insulin combination from Hanmi Pharmaceuticals. Developed via the LAPSCOVERY platform, the compound is a combination of LAPS insulin 115 (phase 1 in the US), and efpeglenitide (HM11260C; an exendin-4 analog, phase 2b), which both have ultra long acting profiles suitable for weekly dosing. A combination of these compounds has shown similar PK/PD profiles to those of each product alone. When administered as a co-formulated once weekly product to diabetic rodents, the combination of LAPS insulin 115 resulted in greater A1c reductions than either product alone. Additionally, in a mild type 2 diabetes animal model, the weight gain seen with LAPS insulin 115 was neutralized by the combination product. Notably, in switching studies, switching diabetic mice to treatment with the LAPS combo after an initial 14 days of treatment with glargine resulted in significantly greater A1c decreases at six weeks versus either staying on glargine or switching to LAPS insulin 115. Similar results were seen in studies where mice were initially treated with liraglutide rather than glargine. These initial results are promising, as we feel a once weekly combination product could indeed improve adherence. We look forward to data from human studies on the topic, particularly to better understand how a once weekly product fares in face of every day glucose variations.
Oral Presentations: Update on GLP-1 Receptor Agonists
Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Results from Intarcia’s pivotal phase 3 FREEDOM-1 trial for the implantable exenatide mini-pump ITCA-650 were fairly strong, and even better in a pre-specified subgroup analysis. In FREEDOM-1 (n=460), the mean A1c reduction for the overall ITCA-650 group was 1.4% at the end of the trial (mITT analysis), and from the graph we would expect the placebo-adjusted efficacy to be around 1.1%. Notably, a pre-specified secondary analysis of efficacy by concomitant therapy found that patients not on a sulfonylurea did far better in terms of A1c reduction from baseline to week 39 (1.7% from baseline; we estimate ~1.4% placebo-adjusted) than those on a sulfonylurea (1.2% from baseline; we estimate ~0.9% placebo-adjusted). It looked to us like the SFU group was beginning to see the deterioration of glycemic control that is characteristic of the drug class, with an upswing in A1c towards the end of the trial. Especially because it was prespecified, we see these stronger results in non-SFU-taking patients (likely to be earlier-stage diabetes patients on average) as pretty persuasive. In terms of efficacy, the higher 60 mcg/day dose appeared to barely beat out the 40 mcg/day dose without much of a safety/tolerability sacrifice. ITCA-650 drove 2% placebo-adjusted weight loss from baseline at the higher dose, and from the abstract it looks like weight was still decreasing at the end of the trial. Composite outcome analyses showed that ITCA-650 helped more patients achieve a 1% or greater A1c reduction plus a >5% decrease in weight (21% and 17% with the two ITCA-650 doses vs. 6% with placebo).
- We were surprised that there was absolutely no hypoglycemia data presented – we hope to see those results soon, and would expect to see the results here to be worse in SFU users as well.
- ITCA-650 was associated with GI tolerability issues for some patients, although most of the risk was right around initiation and dose increases. Around 30% of patients on ITCA-650 40 mcg/day and 31% of patients on the 60 mcg/day dose experienced nausea vs. 10% on placebo; 19%-24% of ITCA-650 patients experienced vomiting vs. 2% on placebo. These issues were the primary drivers behind an imbalance in adverse events leading to discontinuation between the ITCA-650 group (9%-12%) vs. placebo (4%) – keep in mind that “discontinuation” means device removal in this case, not just the cessation of taking a pill or injection. Providing some reassurance, presenter Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas TX) did display data indicating that the vast majority of nausea cases occurred during initiation or dose escalation, returning to much lower background levels (<5%) afterwards. This fact should make the issue manageable, though we wish there was some way to more gradually step up the dose as can be done with some injectable GLP-1 agonists.
- Importantly for the patient experience, administration site events (bruising, irritation) were generally mild and transient. Intarcia has gone to great lengths to focus on the patient experience, including totally reworking the insertion procedure to make it much quicker and easier, a push that appears to have paid off.
Efficacy and Safety of Liraglutide Added to Insulin in Type 1 Diabetes: The LIRA-1 Trial (277-OR)
Thomas Dejgaard, MD (Steno Diabetes Center, Gentofte, Denmark)
This study, out of the prestigious Steno Diabetes Center, randomized poorly controlled, overweight type 1s to liraglutide 1.8 mg + insulin (n=50) vs. insulin alone (n=50). At 12 weeks, A1c declined 0.6% in the insulin+liraglutide group and 0.2% in the insulin-only group (p=0.001; baseline: 8.8%), but the placebo group had caught up by 26 weeks (-0.6% vs. -0.4%; p=0.15). [This was consistent with some anecdotal reports that the effect of liraglutide may “wear off” in some type 1s over time, perhaps necessitating cycling on and off it – we look forward to seeing Novo Nordisk’s longer-term type 1 data to address questions like this.] Liraglutide did cause very significant reductions in body weight at 26 weeks (-6 kg vs. +0.23 kg; p=0.015), much less need for additional insulin (+4 units vs. +14 units; p=0.02), and a non-significant trend towards less hypoglycemia. It was surprising to see that more insulin was needed in the liraglutide arm, but that probably speaks to the poorly controlled population and how aggressively the trial titrated patients’ insulin - certainly, an additional 4 vs. 14 units is 70% less additional insulin, which is what we would expect with liraglutide in type 1. The protocol of this trial is published in BMJ Open.
- This study was notable for a few reasons: (i) a randomized trial of liraglutide in type 1 (these have been single arm to date); (ii) studied in poorly controlled patients, a challenging and very important population to study; and (iii) included CGM (Medtronic iPro 2 with Enlite sensors).
- Two phase 3 trials investigating Victoza as an adjunct to insulin in type 1 diabetes (ADJUNCT ONE and ADJUNCT TWO) are scheduled to report within the next two to five months, per Novo Nordisk’s call in April.
Christian Frandsen, MD (Hvidovre Hospital, Hvidovre, Denmark)
In tandem with 277-OR (see above), the 40 patients in this second trial (still poorly controlled with a baseline A1c of 8.9%, but normal weight) had consistent results directionally on A1c (-0.5% with liraglutide vs. -0.6% with insulin alone; p=0.78), weight (-3 kg vs. +1 kg; p<0.01), and bolus insulin dose (-4 units vs. +0; p=0.02). There was no significant difference in time-in-range, hypoglycemia, or variability. Again, the results were a bit less positive than we would have expected, though it’s very difficult to draw broader conclusions about liraglutide in type 1 due to these studies’ small size and very strong results in the treat-to-target insulin-only group – we’re not sure either study had very real-world control groups.
Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Dr. Julio Rosenstock presented promising phase 2 data on Hanmi Pharmaceutical’s novel ultra-long-acting GLP-1 agonist candidate efpeglenatide (HM11260C), developed using Hanmi’s Long Acting Peptide/Protein DISCOVERY Technology (LAPSCOVERY). The 12-week long study randomized 254 adults with type 2 diabetes to HM11260C doses between 0.3 mg to 4 mg, placebo, or liraglutide 1.8 mg (although Dr. Rosenstock emphasized that this arm was used only for reference and not for statistical comparison). The findings showed that at week 13, HM11260C produced a dose-dependent reduction in A1c, fasting plasma glucose (FPG), and 7-point daily glucose. Specifically, from a baseline A1c of ~8%, the 3 mg and 4 mg doses saw fairly impressive mean A1c reductions of 1.4% and 1.6% respectively; the placebo and liraglutide arms respectively achieved A1c reductions of 0.4% and 1.4%. The proportion of participants reaching the A1c target of <7% was 86% (4 mg), 83% (3 mg), 23% (placebo), and 57% (liraglutide). On the weight loss front, reductions for the 3 mg and 4 mg doses of HM11260C were 3.0 kg vs. 0.2 kg with placebo and 2.6 kg with liraglutide. Regarding safety and tolerability, the profile of HM11260C was similar to that of liraglutide, with the most frequent adverse events being GI side effects. The heart rate increases also seemed to be less than those of liraglutide (though we wouldn’t read too far into this with a study of this size) and no neutralizing antibodies were found with HM11260C. Overall, Dr. Rosenstock noted that the 3 mg dose of HM11260C is fairly similar to liraglutide, with the 4 mg dose being slightly better than liraglutide. In conclusion, he highlighted that this data supports further investigation and clinical development of HM11260C alone as well as in combination with a weekly insulin.
Questions and Answers:
Q: I noticed that the lower doses had minimal nausea and vomiting. Would you recommend starting at the lower dose and titrating up?
A: Yes, the 3 mg to 4 mg doses had more nausea and vomiting. But they showed very robust reductions in A1c and weight. Whenever phase 3 comes, my own recommendation would be to do some gradual escalation.
Q: Looking at A1c, the two higher doses did not yet reach a plateau so they may have further reductions. I would recommend that if the study design were to be repeated, the primary endpoint should go on until there is a plateau, because it’s possible that the lower dose may catch up to the higher dose.
A: That point is well taken. This is just phase 2 to determine an idea of the doses. I’m personally skeptical that a 1 mg to 2 mg dose would make it, but it’s an interesting point.
Q: Is the PK/PD profile affected by renal function?
A: These are very large molecules so they don’t get absorbed in the kidney.
Jun Yang, MD (Lilly Suzhou Pharmaceuticals Co. Ltd, Shanghai, China)
Dr. Jun Yang presented a study showing superiority of Lilly’s once-weekly Trulicity (dulaglutide) over Lantus (insulin glargine) in type 2 diabetes patients predominantly in Asia. In a 26-week study of predominantly Asian participants with type 2 diabetes (n=165), participants were randomized to either Trulicity or Lantus in combination with metformin and/or a sulfonylurea. The findings showed that Trulicity led to greater reductions in A1c with weight loss and less hypoglycemia. Specifically, A1c reductions from a baseline A1c of 8.4% were 1.7% for the 1.5 mg dose of Trulicity, 1.3% for the 0.75 mg dose of Trulicity, and 1.2% for Lantus. The proportion of patients who reached target A1c levels (<7%) were 65%, 54%, and 41% for Trulicity 1.5 mg, Trulicity 0.75 mg, and Lantus, respectively. In addition, Trulicity was associated with greater weight loss from a mean baseline of 78 kg, with the 1.5 mg and 0.75 mg doses losing a mean of 1.5 kg (~3 lbs) and 0.9 kg (~2 lbs), respectively; the Lantus group, on the other hand, gained 1.0 kg (~2 lbs). On the safety front, Trulicity appeared to have a lower hypoglycemia risk, with the proportion of patients with hypoglycemia being 18% for the Trulicity doses vs. 29% for Lantus (this would have been even lower without the SFU usage). Trulicity was relatively well tolerated, with the exception of having more GI side effects compared to Lantus – 9% of Trulicity 1.5 mg and 5% of Trulicity 0.75 mg experienced nausea compared to 1% of Lantus. Lilly has worked hard to compare Trulicity to Lantus in a variety of applications (see AWARD-2 and AWARD-4), and the benefits definitely appear to be there for A1c, hypoglycemia, and weight.
Questions and Answers:
Q: So this was a predominantly Asian study. So the BMI was lower at 27 or 28. Did you look at the correlation of baseline BMI and A1c reduction? Did you check drug exposure in smaller patients?
A: We thought about GLP-1 exposure and BMI, which is why we conducted in lower-BMI patients. Before we decided this dosage, we did a simulation of this exposure in lower BMIs. There was about a 20%-30% increase of exposure due to dulaglutide in these kinds of BMI patients. We also have other PK trials in these same patients.
Juris Meier, MD (St. Josef Hospital, Bochum, Germany)
Dr. Juris Meier presented results from a study evaluating the mechanistic differences between the short- and long-term effects of Sanofi’s Lyxumia (lixisenatide). The open-label study randomized 28 patients with type 2 diabetes treated with metformin to receive once-daily doses of either lixisenatide or insulin glargine (Sanofi’s Lantus) for four weeks, followed by combined treatment with both products for four weeks. At baseline, week 4, and week 8, participants underwent an intravenous glucose tolerance test and two mixed meal tolerance tests, one after breakfast (immediately after drug administration) and one after a late lunch (eight hours after breakfast). Results showed that lixisenatide increased first- and second-phase insulin secretion to a greater extent than insulin glargine and that the combination of the two had the greatest effect. Lixisenatide reduced postprandial glucose excursions after both meals but only delayed gastric emptying after breakfast; it also led to reduced insulin secretion after breakfast. Dr. Meier concluded that delayed gastric emptying is the main driver of lixisenatide’s immediate effects on postprandial glucose, and that this may induce an “insulin-sparing” effect that allows beta cells to “recharge” and secrete more insulin after a later meal, thereby reducing postprandial glucose even though very little lixisenatide remains in the system. Of course, as one attendee noted during Q&A, most people do not space their meals eight hours apart, so patients are likely still experiencing some direct effects of lixisenatide even at the second meal after dosing.
Questions and Answers:
Q: Why did you do a late lunch after eight hours instead of a more normal time frame like four or five hours?
A: We wanted to make sure people had achieved complete gastric emptying after the first meal.
Comment: I understand the scientific rationale, but clinically people eat breakfast at 7 or 8 AM and lunch at 12 or 1 PM, so they may still have some tail and see gastric emptying.
Q: You didn’t see an effect on gastric emptying at the late lunch. Was the explanation a different time-action profile regarding insulin secretion and gastric emptying or what?
A: We believe that eight hours after injection, there is probably no lixisenatide in the circulation, which is why there was no effect at all. All you see is probably secondary to what you induced after breakfast. I doubt after eight hours that there would be a direct effect. What you see later is probably indirect and mediated by the earlier insulin sparing.
Atsuhiko Kawabe, MD (Dokkyo Medical University School of Medicine, Tochigi, Japan)
Dr. Atsuhiko Kawabe presented data on a study that performed Holter-electrocardiography (ECG) and power spectrum analysis of heart rate variability before and after treatment of long-acting GLP-1 agonist liraglutide (titrated up to 0.9 mg) and short-acting GLP-1 agonist lixisenatide (up to 20 micrograms). The study randomized 40 people with type 2 diabetes to either the liraglutide or lixisenatide arm, observing and comparing the changes in the heart rate and frequency powers every hour in a 24-hour period. The findings showed that those in the liraglutide group experienced significantly greater increases in heart rate compared to those in the lixisenatide group. Specifically, the liraglutide group had a heart rate increase from 96,321 bpm to 117,376 bpm with significant increases observed every hour while the lixisenatide group experienced an increase from 99,618 bpm to 104,426 bpm with a significant increase at only three time-points throughout the 24 hours. From these results, Dr. Kawabe discussed that the drugs’ heart rate increases likely reflect the enhancement of sympathetic nerve activity, with each GLP-1 agonist’s enhancement of activity matching its half-life, ultimately suggesting that the half-life influences sympathetic nerve activity. In conclusion, Dr. Kawabe highlighted the Framingham study’s finding that heart rate elevation can increase both ischemic heart disease incidence and mortality, stressing the need for further investigation of GLP-1 agonists’ exocrine pancreatic action and these effects’ implications.
Oral Presentations: ADA Presidents Oral Session
Brain Reward-System Activation in Response to Anticipation and Consumption of Palatable Food is Altered by GLP-1 Receptor Activation in Humans (384-OR)
Liselotte van Bloemendaal, MD (VU University Medical Center, Amsterdam, Netherlands)
Dr. Liselotte van Bloemendaal presented data on GLP-1 agonists’ effects on brain reward-system activation, demonstrating that GLP-1 receptor activation may have important central mechanisms of action in reducing food cravings and preventing overeating. The randomized, placebo-controlled, crossover study (n=48) had healthy lean individuals, obese normoglycemic individuals, and obese individuals with type 2 diabetes undergo three fMRI sessions with the receipt of chocolate milk or a tasteless solution. For each fMRI session, the participants received either exenatide, exenatide with exendin 9-39 (a GLP-1 receptor blocker), or placebo. They found that BMI was negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of the receipt of chocolate milk in brain areas regulating reward, appetite, and motivation. Notably, exenatide vs. placebo increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk, which was paralleled by reductions in food intake (-23% in the lean arm; -24% in the obese arm; and -14% in the type 2 diabetes arm). On the other hand, the GLP-1 antagonist, exendin 9-39, largely blunted the effects on brain responses to chocolate milk and on food intake. Thus, Dr. van Bloemendaal concluded that GLP-1 receptor activation can decrease anticipatory food reward which may reduce food cravings, as well as increase consummatory food reward, which may prevent overeating. This strengthens evidence for the drug class’ effect on the central regulation of feeding. At times like this we can’t help but wonder: is there anything GLP-1 agonists can’t do?
Questions and Answers
Q: Did you also measure subjective feelings of satiety and appetite?
A: We also asked subjects to rate their feelings of hunger, satiety and prospective food consumption. But we found no significant differences between the different test days in these ratings
Q: Have you statistically looked at the correlation of CNS response and subsequent food intake?
A: We didn’t look at that yet. In our previous study, in which we determined the effects of exenatide on brain responses to watching food pictures, we found that the exenatide-induced reductions in CNS responses correlated with exenatide-induced reductions in food intake.
HW Rodbard, BW Bode, SB Harris, L Rose, L Lehmann, H Jarlov, J Thurman
The DUAL IV trial randomized 435 people with type 2 diabetes to Novo Nordisk’s Xultophy (insulin degludec/liraglutide) or placebo. Topline results were first released in January 2014. After 26 weeks from a baseline A1c of 7.9%, the Xultophy arm achieved a mean 1.5% A1c reduction to 6.4% compared to a 0.5% reduction on placebo – this represents a substantial decrease from a somewhat low base. Nearly 80% of people on Xultophy achieved an A1c of <7% (the ADA goal) compared to only 30% of those on placebo. The Xultophy arm experienced statistically significantly higher rates of hypoglycemia (42% of Xultophy patients vs. 17% placebo), and the Xultophy arm also gained 1.0 kg (2.2 lbs) compared to a weight loss of 0.5 kg (1.1 lb) on placebo. The unfavorable weight result runs contrary to DUAL I and II results where Xultophy was associated with weight loss (0.5 kg in DUAL I for patients on 1-2 OADs, and 2.5 kg in DUAL II for patients previously on basal insulin). The higher rate of hypoglycemia is not unexpected with the addition of a GLP-1 agonist/basal insulin to SFU (in DUAL I and II, hypoglycemia rates on Xultophy were better compared to Tresiba [insulin degludec] or Victoza [liraglutide], and there was no placebo comparator). At the end of the trial the average dose of Xultophy was 28 dose steps (28 units insulin degludec/1.0 mg liraglutide) – this information had not been reported previously and demonstrates the power of relatively low doses. With regards to safety, the Xultophy arm seemed to experience a higher rate of elevated lipase (a potential marker of pancreatic damage; 9.7% of patients in the Xultophy were investigated for elevated lipase vs. 4.1% in the placebo arm, but statistical significance was not reported), which is consistent with the known effects of GLP-1. No other concerning safety issues were reported.
S Azar, A Echtay, WMW Bebakar, S Al Araj, A Berrah, M Omar, A Mutha, K Tornoe, M Kaltoft, N Shehadeh
Fasting during Ramadan in patients with type 2 diabetes is associated with increased risk of severe hyper- and hypoglycemia. In this 33-week open-label trial, patients with type 2 diabetes on stable baseline sulfonylurea and metformin were randomized to switch to once daily liraglutide 1.8 mg and background metformin (n=172) or continue pretrial sulfonylurea and metformin (n=171). In this study, from a baseline A1c of 8.3%, liraglutide led to a mean A1c reduction of 1.2% vs. a -0.7% change with SFUs, for a statistically significant treatment difference of 0.6% in favor of liraglutide. A similar decline in fructosamine from start to end was seen in both the liraglutide- and sulfonylurea-treated groups, despite patients treated with liraglutide having lower fructosamine and A1c levels (baseline 8.3% to 7.2% at start in the liraglutide group vs. 8.2% to 7.8% in the sulfonylurea group) at the beginning of Ramadan. There were also fewer confirmed hypoglycemic episodes in the liraglutide-treated group (8.6% vs. 17.8%) – not particularly surprising given the agents being compared. Overall, this study indicates an improved safety profile with liraglutide versus sulfonylurea during Ramadan as well as improved glycemic control. We applaud Novo Nordisk for considering the unique needs of the Ramadan-observant patient population enough to support a full-scale clinical trial. These results are also important in the context of exploding diabetes prevalence in the Middle East.
- This was a 33-week open-label trial that compared a switch to liraglutide versus continuing pretrial sulfonylurea in patients with type 2 diabetes who fasted for Ramadan. In the study, patients with type 2 diabetes on stable baseline sulfonylurea and metformin were randomized to switch to once daily liraglutide 1.8 mg and background metformin (n=172) or continue pretrial sulfonylurea and metformin (n=171). Patients underwent a three-week dose escalation period followed by a six to 19-week maintenance period prior to four-week fast for Ramadan. Duration of diabetes was similar in both groups (8.0 years in the liraglutide group vs. 7.2 in the sulfonylurea group).
- During Ramadan, a similar decline in fructosamine (a measure that reflects recent blood glucose changes over a one to two week period) from start to end was seen in both the liraglutide (mean 291.8 to 279.0 μmol/L; baseline 320.3 μmol/L) and sulfonylurea-treated (mean 301.6 to 285.2 μmol/L; baseline 316.0 μmol/L) groups (p=0.43). This was despite patients treated with liraglutide having lower fructosamine and A1c levels (baseline 8.3% to 7.2% at start in the liraglutide group vs. 8.2% to 7.8% in the sulfonylurea group) at the beginning of Ramadan.
M Brod, FC Perez Manghi, PA Garcia-Hernandez, P Norwood, H Jarlov, JH Kongso, I Lingvay
In an publish only sub-analysis from the DUAL V study, the full results of which were presented as an oral, researchers demonstrate that Novo Nordisk’s Xultophy (insulin degludec / liraglutide) improved patient-reported outcomes in type 2 diabetes patients inadequately controlled on insulin glargine plus metformin. Patient-reported impact of treatment on functioning and well being was assessed by Treatment Related Impact Measure for Diabetes (TRIM-D) and Short-Form 36 Health Survey (SF-36 v2). TRIM-D scores were summed from five subdomains – treatment burden, daily life, diabetes management, compliance, and psychological health-- and weighed together to give a total score. Change from baseline was higher with Xultophy verses insulin glargine for total score (p=0.003), treatment burden (p=0.017) and diabetes management (p<0.001) subdomains. The SF-36 validated multi-purpose questionnaire was grouped into eight domains that were further divided into a physical component summary (PCS) score and a mental component summary score (MCS). The improvements in PCS (p<0.001) and three of the physical domain scores – physical functioning (p=.045), bodily pain (p=.012), and general health (p=.008) -- were significantly greater with Xultophy compared to insulin glargine. The mental component summary (MCS) score and the mental domain scores, however, were similar for both arms.
- DUAL V was a 26-week, open-label trial compared the efficacy and safety of Xultophy versus insulin glargine in subjects with uncontrolled type 2 diabetes on 20-50U of insulin glargine and metformin. See above for the full coverage of the primary DUAL V results.
Robert Henry, MD (VA San Diego Healthcare System, San Diego, California)
This poster presented the full results from the FREEDOM-1 HBL open-label study investigating Intarcia’s implantable exenatide mini-pump ITCA 650 in patients who fell above the baseline A1c cut point (10%) for the pivotal FREEDOM 1 study. Topline results from this trial were the first glimpse at phase 3 results we received from Intarcia, and even in the context of patients with high baseline A1c they were quite impressive. FREEDOM-1 HBL found a mean A1c reduction of 3.4% from a mean baseline of 10.8% after 48 weeks, with no comparator group in this open-label study. The ITCA 650 pump also sustained up to 3.0-4.0 kg (~7-9 lbs) greater weight loss, had satisfactory tolerability, and had low discontinuation rates at the target dose. While the pivotal FREEDOM-1 trial had results that were a bit more applicable for most patients, it is positive to see just how powerful ITCA 650 was in patients with the poorest control at baseline.
Symposium: New Developments with GLP-1 Receptor Agonists
Differentiating Current and Emerging GLP-1 RAs
Kathleen Dungan, MD (Ohio State University, Columbus, OH)
Dr. Kathleen Dungan reviewed the advantages (substantial A1c reductions, weight loss, low risk of hypoglycemia) and disadvantages (GI side effects, cost) of GLP-1 agonists and summarized the results of head-to-head studies of the various options. Her main big-picture conclusion was that longer-acting agents (like AZ’s Bydureon [exenatide once weekly], Novo Nordisk’s Victoza [liraglutide], Lilly’s Trulicity [dulaglutide], and GSK’s Tanzeum [albiglutide]) generally produce greater A1c reductions due to a greater effect on fasting glucose, while shorter-acting agents like AZ’s Byetta (exenatide twice daily) and Sanofi’s Lyxumia (lixisenatide) hold the advantage for immediate postprandial glucose reductions due to a greater effect on gastric emptying. Dr. Dungan otherwise declined to suggest advantages of specific agents over others, stating that clinicians have to evaluate the various criteria and make case-by-case decisions for individual patients. She did note that reconstitution and ease of administration could definitely be key differentiating factors for many patients – this would give the edge to ready-to-use products like Trulicity, Victoza, and Lyxumia. However, she also acknowledged that cost and insurance coverage often prove to be the deciding factors in practice – “it’s not really our choice or our patient’s choice.”
GLP-1 Receptor Agonists in Combination with Basal Insulin
John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)
Dr. John Buse, a leader on this frontier for several years, reviewed the bounty of evidence supporting the combination of GLP-1 agonists and basal insulin. He reviewed data for AZ’s Byetta (twice daily exenatide) added onto Sanofi’s Lantus (insulin glargine), Novo Nordisk’s Xultophy (insulin degludec/liraglutide), Sanofi’s LixiLan (lixisenatide/insulin glargine), and GSK’s Tanzeum (albiglutide) added onto insulin glargine. In all, when GLP-1 agonist/basal insulin combination therapy is compared to its component parts, it provides greater A1c-lowering efficacy, far less weight gain than basal insulin, minimal nausea, and no increased risk of hypoglycemia. Most GLP-1/basal combinations confer pretty stunning ~1-1.5% A1c reductions (often nearly normalizing glucose levels) with remarkably low rates of hypoglycemia. Furthermore, a recent meta-analysis demonstrated that GLP-1/basal therapy even outperforms basal-bolus therapy with regard to A1c lowering efficacy and reduced weight gain and hypoglycemia. Dr. Buse also discussed some unresolved issues under investigation – first, does adding insulin to GLP-1 agonist therapy work just as well as adding a GLP-1 agonist to basal insulin? The evidence supporting this comes from a study demonstrating that the addition of Novo Nordisk’s Levemir (insulin detemir) in patients with inadequate control on Victoza conferred an additional 0.5% A1c reduction (DeVries et al, Diabetes Care 2012). Secondly, could one use a long-acting “basal” GLP-1 therapy with prandial insulin? The AWARD-4 trial found that the combination of Lilly’s Trulicity (dulaglutide) and Humalog (insulin lispro) appeared to work just as well as Humalog and Lantus, and also conferred less weight gain and hypoglycemia.
- As a reminder, the rationale for combining these drug classes comes from their complementary efficacy and side effect profiles – basal insulin provides fasting glucose coverage, and GLP-1 agonists provide postprandial coverage. In addition, combining the two allows for uses of submaximal doses of each individual agent, thus minimizing dose-related side effects: nausea in GLP-1 agonists and weight gain and hypoglycemia in basal insulin.
GLP-1: To Use or Not to Use? Safety is the Question
Jane Reusch, MD (University of Colorado, Denver, CO)
Dr. Jane Reusch reviewed the current status of safety concerns associated with incretin-based therapies. She opened by acknowledging the very high potential for this class to be the game-changer that everyone hopes it will be. However, she remarked that due to the extremely high prevalence of diabetes, even rare side effects will ultimately affect large numbers of people, so it is important to tease out even uncommon safety issues. At the same time, she strongly cautioned against being too risk averse because the risks of any treatment must also be weighed against the very real risk of poor glycemic control (“diabetes is common and deadly”). We appreciated her very firm grounding in reality on this front. Dr. Reusch focused on the issues of cardiovascular outcomes and pancreatitis. In short, she stated that the data to date supports a neutral cardiovascular risk profile with reason to “keep our eyes open” for patients who might be predisposed to developing heart failure on DPP-4 inhibitors, and she believes future studies still have the potential to show some CV benefit of GLP-1 agonists (she named Novo Nordisk’s LIVE study of liraglutide in heart failure patients as an example). With regards to pancreatitis, she believes that there appears to be a real, but exceedingly small, signal in clinical trials. She opted not to comment on pancreatic or thyroid cancer due to the lack of rigorous data on these fronts. Ultimately, she reminded the audience that these small risks must be weighed against the benefits of improved glycemic control, weight loss, decreased hypoglycemia, and patients’ perception of self-efficacy with a treatment that works.
- With regard to cardiovascular outcomes, Dr. Reusch reported that the data so far support a neutral CV profile, though more data will become available over the next four years. She noted that the ELIXA CVOT for Sanofi’s Lyxumia (lixisenatide) would be presented the following day and will show neutrality – however, she reminded the audience that FDA-commissioned CVOTs are designed to rule out CV risk rather than demonstrate CV benefit. She also mentioned the now well-known findings from DPP-4 inhibitor CVOTs that showed overall neutral CV safety, but a slight signal for congestive heart failure (CHF). She stated that at this point there is no reason to be concerned about increased CV risk on incretin therapies, but that “we should keep our eyes open” for potential patients who might suffer from heart failure.
- Notably, Novo Nordisk is evaluating a potential protective effect of its GLP-1 agonist Victoza (liraglutide) on cardiac function in patients with heart failure (protocol described in Jorsal et al., BMJ 2014; ClinicalTrials.gov identifier NCT01472640). During a March investor update, Novo Nordisk management also offered optimistic commentary on the potential for the LEADER trial (Victoza’s CVOT) to demonstrate cardioprotection, as there is greater exposure with a long-acting GLP-1 agonist like Victoza compared to a shorter-acting agent like Lyxumia or a DPP-4 inhibitor.
- With regard to pancreatitis, Dr. Reusch believes there is probably a real, but exceedingly small, clinical signal. The FDA and EMA’s independent evaluations of postmarketing reports and clinical study databases found no reason for concern based on clinical data (Egan et al., NEJM 2014). However, while toxicology studies revealed no toxic pancreatic effects of high doses of incretins in healthy rodent models, there was an exacerbation of background pancreatic injury in diabetic mouse models (Egan et al., NEJM 2014). In addition, a recent publication examining pooled results from Victoza’s clinical trial program hinted at an increased pancreatitis risk (1.6 cases/1,000 patient-years of exposure on liraglutide vs. 0.7 cases/1,000 patient-years of exposure on active comparators) (Jensen, Diabetes Care 2015). However, another recent publication of a nation-wide case-control Danish database study suggested no increased odds ratio of incretin-use in patients with pancreatitis. Given all of this, Dr. Reusch concluded that the signal is probably there, but exceptionally small.
GLP-1 Receptor Agonists as Adjunctive Treatment in Type 1 Diabetes
Paresh Dandona, MD, PhD (University at Buffalo, Buffalo, NY)
Dr. Paresh Dandona discussed the many benefits of GLP-1 agonists in type 1 diabetes (sizable A1c reductions, more time in range, lower insulin doses, weight loss, lower carbohydrate intake) demonstrated in a study presented last year at AACE. Toward the end of the talk, he turned to his group’s intriguing retrospective analysis (130-LB) investigating triple therapy with insulin, Novo Nordisk’s Victoza (liraglutide), and AZ’s Farxiga (dapagliflozin) in type 1 diabetes, ambitiously speculating that such a combination could eventually allow at least 50% of patients with type 1 diabetes to achieve an A1c <6% (whoa). Results demonstrated significant reductions in A1c (0.7% from a baseline of 8%), mean plasma glucose (28 mg/dl), body weight (2 kg) and an 11% increase in time in range (70-160 mg/dl) with the addition of dapagliflozin to the other components. Notably, when either the GLP-1 agonist or the SGLT-2 inhibitor was stopped, “chaos reemerged” in terms of glycemic variability. Dr. Dandona also noted that one case of euglycemic DKA occurred during the study, which he attributed to an excessive reduction in the insulin dose – this is one of the first cases of euglycemic ketoacidosis we have heard reported from a clinical trial. We would love to see future prospective trials of this combination in type 1 diabetes and are curious how often it is currently used off-label in clinical practice – possibly very effective, but not cheap!
- There is always reason to be excited about drug combinations in diabetes, but a healthy dose of caution and patience are important in this case. Given the safety questions that are emerging with type 2 diabetes drugs used in type 1 (like euglycemic ketoacidosis), we imagine that triple combinations are still a ways down the road in terms of reaching the broader market. Additionally, results we saw elsewhere in the meeting on GLP-1 agonists in type 1, such as the LIRA-1 trial. did not come out glowingly positive. Still, there is plenty of reason to keep moving forward given that the unmet need for non-insulin therapies for type 1 diabetes to reduce glycemic variability is huge.
GLP-1 Receptor Agonists for the Treatment of Obesity
Sun Kim, MD (Stanford University, Stanford, CA)
Dr. Sun Kim reviewed the role of GLP-1 agonists in weight management as well as the drug class’ weight-dependent and weight-independent effects. She began by illustrating the weight loss effects of GLP-1 agonists in people both with and without type 2 diabetes, highlighting that added lifestyle intervention leads to greater weight loss and that people with diabetes experience less weight loss compared to individuals without diabetes. Dr. Kim explained that while the mechanisms of GLP-1 agonists are not completely known, the class is hypothesized to lead to greater weight loss due to mechanisms that act both centrally and peripherally – specifically by suppressing appetite (see our coverage of an oral on GLP-1 agonists’ central action in this report [384-OR]). Dr. Kim cited data from her lab’s study, which randomized people with prediabetes to either Novo Nordisk’s Victoza (liraglutide 1.8 mg) or placebo for fourteen weeks. The results showed that those on Victoza lost twice as much weight compared to placebo (-8% vs. -4% from baseline BMI of 32 kg/m2). The Victoza arm also experienced improvements in insulin resistance, with higher insulin concentrations and lower rises in glucose concentrations. When looking at the association between weight loss and these changes, Dr. Kim noted that degree of weight loss did not have any bearing on effect on certain endpoints, including heart rate and insulin concentration. From these findings, Dr. Kim highlighted the importance of understanding what effects of weight loss drugs are associated with weight loss and which ones are direct effects of the drug, especially in people without diabetes. For more on these separate effects of liraglutide, please see our coverage of new SCALE data on Saxenda’s (liraglutide 3.0 mg) non-weight-dependent impacts.
Q: We know from our clinical experience and seeing patients on these drugs that not everybody is a good responder. Some patients are poor responders to one drug. My question is if you change to a different GLP-1 receptor agonist, will that patient who is a poor responder to one then respond to a second?
Dr. John Buse (University of North Carolina, Chapel Hill, NC): The only study I know that answered this affirmatively was a comparison of exenatide BID to liraglutide. The point we were able to work out was that among the patients with high titer antibodies to exenatide, there was a subset that did not have particularly good responses to exenatide. When switched to liraglutide, they did have good responses. There may be a small subset (a few percent of patients) that don’t respond very well to exenatide due to antibodies, but will respond to liraglutide when the antibodies don’t cross react. That’s the only situation I’m aware of where you can switch from one to the other and change effectiveness.
Q: We have lots of diabetic patients using high doses of insulin, and when you combine it with a GLP-1 agonist, the dose of insulin decreases profoundly, and they lose weight. But after eight months or a year or so, you see patients start to need more insulin, as if there’s a sort of drug failure or no efficacy from the GLP-1 agonist. If we’re using the maximum dose, should we keep increasing the dose or say no and go back to insulin? These studies were for four months or six months in studies, so what happens long term?
Dr. Buse: We do have some studies out to a year. I don’t know of a specific analysis to tease out a subset that loses control later, but the eyeball view doesn’t suggest a particular loss of control. The only thing I can think of in your case is if patients were on a really high dose of insulin and added a GLP-1 agonist and had lots of weight loss related to calorie restriction, maybe when people stop losing weight, they start to require more insulin. That’s the only thing I can think of. I haven’t seen it in clinical practice or clinical trials.
Q: Would you increase the dose of the GLP-1 agonist to more than 1.8 mg?
Dr. Buse: We always used the maximum dose in the studies. In the prefixed combination, you titrate up as needed, which has its rationale as well. It depends on the exact formulation.
Dr. Matthew Riddle: What does the clinical experience from trials say about secondary failure?
Dr. Kathleen Dungan (Ohio State University, Columbus, OH): In general, for all these therapies, the durability of the agents is a very important outcome. This is the kind of data we need. And this is already underway with the GRADE trial. Probably, all agents have some failure rates over time. The best way to figure this out is to actually compare head-to-head in the long term to see when failure occurs.
Q: I have two questions. First, do you recommend the use of off label medications in the general clinical setting? And if it is to be used for individual patients do you recommend IRB approval for each patient? Secondly, do you consider hypoglycemia unawareness as an absolute contraindication for GLP-1 analogs?
Dr. Paresh Dandona (University of Buffalo, Buffalo, NY): As far as off label use is concerned, in general, there seems to be a consensus that once a drug is licensed, it is the prerogative of the physician to make the decision clinically as to how and when to use it. The other issue related to hypoglycemia is that certainly if you substitute GLP-1 RAs, any of them, in place of insulin, you will diminish incidence of hypoglycemia, and that might be justification of use for this class of drug with maximal oral therapy when you start injectable therapy. So clearly there is an advantage there. I teach my fellows that the beta cell is much more clever than all of us put together. The beta cell generates the right amount of insulin at the right time. That’s what the GLP-1 RA is doing for you.
Dr. Buse: Just to add that if you are doing off label things, particularly things that are way off label, like something that the package insert says not to do, it would be a good idea to have a conversation with the patient and document it clearly in the medical record that you did so. If you’re doing one patient at a time, there is no reason to go to the IRB, but if you’re doing it with the intent of collecting data and presenting it then you should definitely go to the IRB. On the second issue I agree with Dr. Dandona that in patients having issues with hypoglycemia, some of these off label uses of type 2 diabetes drugs suggests less hypoglycemia, but I think it can be a bit scary as you transition patients. So caution during the transition period would be wise.
Q: Does adding a GLP-1 agonist have an effect for highly insulin resistant patients?
Dr. Sun Kim (Stanford University, Stanford, CA): A majority of the prediabetes patients we studied had high insulin resistance and they had a benefit in terms of weight loss. So there’s a benefit there because when you lose weight you improve insulin resistance. Your question is two-fold: in non-diabetic people we’re enhancing insulin secretion, and it levels out after weight loss. In the type 2 diabetes population, weight loss and decrease in appetite will help towards becoming insulin sensitive, so it’s worthwhile to try.
Q: Is there evidence for adding it to MDI?
Dr. Buse: There is a paper I’m aware of by Dr. Lane from Asheville with people on very high doses of insulin who added a GLP-1 agonist. As I remember, it wasn’t very well controlled but there was a suggestion of benefit. There’s not a lot of data in that population. There is on TZDs, but there’s a real risk around fluid retention and weight gain. Very recently Raskin published a paper using bromocriptine QR on high dose insulin. It wasn’t controlled but there was a dramatic response.
Dr. Dandona: Unfortunately some patients don’t absorb all of the insulin. There were some studies published in 2004 led by CDEs where people were put on pumps and with a continuous infusion reduced their insulin dosages by 50-70% while improving A1c. It’s not an issue of tissue level resistance but bioavailability. Along the same lines, the beta cell is clever and delivers insulin at the right time to the right place. When you’re using a GLP-1 agonist it increases endogenous insulin, and that small amount makes more of a difference than hundreds of units.
Dr. Riddle: In the case of varying insulin resistance in a person using a lot of insulin, one question that comes up is adherence to injections and high doses, as that can contribute to difficulties in control. And there’s this general problem of behavioral aspect for any drug class. Dr. Reusch, can you comment on how we should be thinking about counseling of patients and how to optimize weight control and minimize hypoglycemia?
Dr. Jane Reusch (University of Colorado, Denver, CO): Related to high doses of insulin, I would concur with Dr. Riddle that you need to make sure that the patient is taking all of his or her insulin before making any adjustments. We also need to explain to patients requiring greater than 200 or 400 units of insulin that there might be other options in terms of injectability. They might be able to take U300 or U500, which may or may not improve absorption. You should never forget that they also need to eat less and move more. What I do is that I take a specific diet history to understand when they are eating and to try to find low-hanging fruit to use to get rid of specific carbohydrate calories. And when do they move? Can I increase that? Especially around mealtime, there is some new data from a Japanese poster here showing that if you hop up a couple flights of stairs with each meal, you can get a lower A1c.
Dr. Buse: Someone just texted me about late breaking poster #8: high dose insulin patients adding liraglutide vs. placebo in a blinded fashion ended up with a 1.1% A1c difference after 6 months. [Audience laughter].
Q: I was very impressed by the combination of GLP-1 receptor agonists and basal insulin and struck, particularly, by the lack of increase in hypoglycemia despite the incredibly aggressive achieved A1c goals. We’re all aware that GLP-1 receptor agonists have a glucose-dependent mechanism of action. But is that sufficient to explain why we have such a low risk of hypoglycemia?
Dr. Buse: I think everybody was surprised. We thought there would not be any more hypoglycemia with the combination, but that there was actually less hypoglycemia with a lower A1c is stunning. We think it might be a beneficial effect of GLP-1 on alpha cell function in addition to the presumed benefit on beta cell function. I think it remains unexplained. The observation has been seen over and over and over again.
Dr. Dandona: There is a beautiful study published about four years ago that looked at liraglutide in type 1 diabetes. In that study, following a meal, they put patients on a bicycle and gave them exercise. So they deliberately lowered blood sugar. What they discovered was that in spite of glucagon suppression at basal levels, once exercise and hypo came along, [patients on liraglutide] had a surge of glucagon. So there is evidence that there is conservation of glucagon that is released at the appropriate time.
Q: When you’re dealing with doses of 200-400 units and high resistance, you can’t forget that if they’re more diligent with eating and activity it makes a big difference. Are researchers looking at what type of weight is lost with these medications, like lean tissue vs. non-lean?
Dr. Kim: Some studies have said there’s more fat loss in particular. It’s not the preferentially lean tissue loss that you’re worried about. There’s nothing particular about weight loss with drugs vs. other means in terms of the degree of fat vs. lean tissue.
Q: It would be interesting to know down the road what percentage was lean vs. non-lean tissue. Maybe there could be a study looking at medication in combination with exercise, which might magnify the benefit.
Dr. Kim: I tried to make point in my presentation that with any weight loss drugs, if you don’t combine them with lifestyle interventions, the benefit is much less.
Dr. Reusch: In preclinical studies in rodents, we were able to demonstrate that the combined effects of exercise and a DPP-4 inhibitor or GLP-1 agonist have an additive effect on improvements in exercise function, but not as consistent of an effect on glucose.
Q: You shared information about SGLT-2 inhibitors in type 1 diabetes. As I was listening carefully, you talked about gentle adjustments of insulin. Can you expand on that please?
Dr. Dandona: If you get a great insulin deficit, relatively speaking, you could move into a situation of ketoacidosis, which has been talked about a lot. We’ve seen that in our patients. There’s a critical level that we’ve determined from our experience – this is the start of the story – you should not get to an insulin dose of less than half a unit per kilogram of body weight. As part of this initial enthusiasm, it’s important to settle to safe ways of doing things.
Corporate Symposium: Complementary Treatments to Enhance Insulin Efficacy: Theory and Strategies (Supported by Joslin and Sanofi)
Basal Insulin and Complementary Treatments: Summary of Pathophysiology and Pharmacology
Anne Peters, MD (University of Southern California, Los Angeles, CA)
The brilliant Dr. Anne Peters provided an overview of clinical considerations for initiating basal insulin therapy and selecting an add-on once basal insulin alone is inadequate. Dr. Peters set up the framework for the rest of the symposium with the following points: (i) in UKPDS, half of recently diagnosed people with type 2 diabetes required insulin after 6 years; (ii) hypoglycemia is the limiting factor for optimizing basal insulin therapy; and (iii) in the real world, people do not tend to get to treatment targets on basal insulin alone, likely because PCPs are hesitant to up-titrate insulin dose. Dr. Peters then reviewed the guidance on intensifying basal insulin therapy in the newly updated 2015 ADA/EASD position statement, which very much favors the combination of basal insulin and GLP-1 agonists.
Basal Insulin and Complementary Treatments: Basal Insulin Plus GLP-1 Agonists
John Buse, MD, PhD (UNC, Chapel Hill, NC)
The super-hero smart and highly renowned Dr. Buse reviewed the data in support of combining GLP-1 agonists with basal insulin therapy. He opened with a review of the rationale behind GLP-1/basal insulin combination therapy, noting strong glycemic control with additional benefits to hypoglycemia and weight loss observed in trials as compared to either of the components alone. Moving to the newer combinations, Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s LixiLan (insulin glargine/lixisenatide), he was encouraged by the convenience offered by combined single-injection devices. Despite strong evidence for the combinations, he noted it is still unclear where they should fit in the treatment toolbox – he hoped for future trials investigating this moving forward. He concluded with praise for the class: “I do believe this combination is here to stay and that they are also in need in the marketplace.”
- Dr. Buse opened with a review of the rationale behind GLP-1/basal insulin combination therapy. He noted the complementary glycemic effects, with increased portal insulin delivery (via GLP-1 agonism) and decreased glucagon secretion for postprandial control via GLP-1 and efficacy in reducing fasting plasma glucose via basal insulin. Looking to the GWCO study that combined insulin glargine and exenatide BID versus glargine and placebo, he highlighted the stronger decline in A1c with the combination (8.3% to 6.6% vs. 8.5% to 7.5%) with weight loss of 1.8 kg (4.0 lbs) versus weight gain of 1.0 kg (2.2 lbs). He noted additionally no increase in hypoglycemia (25% vs. 29%) though with increased nausea, diarrhea, vomiting, headache, and constipation.
- Dr. Buse moved to discuss the newer combinations of GLP-1/basal insulin, Xultophy and LixiLan. On Xultophy, he reviewed the DUAL trials (Dr. Buse himself presented the stellar DUAL I results at ADA 2013). He highlighted the stronger A1c declines and improved side effect profile of Xultophy versus either component alone. Looking to DUAL II, in particular, he stressed that in a blinded study, patients experienced similar rates of nausea, suggesting rates may similar when patients are unaware if the medication administered is nausea-provoking or not. Similarly, with LixiLan, he highlighted the improved A1c declines and weight loss seen with the combination versus insulin glargine alone. Finally, noting that comparisons of GLP-1/basal insulin may more appropriately be compared to a basal bolus regimen, he highlighted the results of a larger meta-analysis of three trials comparing the combination to basal bolus therapy that indicated an overall 0.1% greater decline in A1c as well as benefit to weight loss and hypoglycemia rates.
- Dr. Buse concluded by addressing some remaining unresolved issues in the use of GLP-1/basal insulin combinations. While the combination provides improved efficacy versus either of its component parts, he notes it is still unclear where it fits in the treatment algorithm as an enhanced insulin or enhanced GLP-1. It also remains unclear whether the combination should be used early or reserved for those failing either therapy. He hopes for trials looking at both approaches moving forward. In response to an audience question, he suggested that using GLP-1 agonist/basal insulin combination in type 1 diabetes is currently a “remarkably bad idea” given the need to get basal insulin titration exactly right, the lack of data on GLP-1 agonists’ efficacy in type 1 diabetes, and the cost.
Joslin Needs Assessment Data: Exploring Some “Disconnects”
Richard Beaser, MD (Joslin Diabetes Center, Boston, MA)
Dr. Richard Beaser presented some insights on discrepancies between patients’, PCPs’, and specialists’ perspectives on GLP-1 agonist treatment. One big disconnect was that more than 70% of PCPs surveyed believed patients would be deterred by the painfulness of injections, whereas fewer than 15% of patients expressed the same concern – we do continue to hear that better devices and smaller needles are making injections less and less of an obstacle to overcome. PCPs identified A1c reduction and cost of treatment as the two primary considerations when deciding whether to prescribe GLP-1 agonists, whereas patients were most interested in the composite profile of glucose control with weight loss and reduced hypoglycemia risk. We found it surprising that cost seemed to show up more on PCPs’ radars. In contrast to PCPs, specialists were more likely to weigh patients’ other comorbid conditions and age. In focus groups, PCPs identified the need for better methods of learning about new medications – PCPs are currently inundated with new information every day and struggling with how to validate various sources and synthesize all of that new information into courses of action. With more manufacturers entering the GLP-1 agonist market and looking to help that market grow, we expect to see an increase in CME and other educational events on GLP-1 agonists directed at primary care.
Mark Peyrot, MD (Loyola University, Baltimore, MD)
Dr. Peyrot provided practical recommendations for providers for overcoming barriers to care in the treatment visit. In the treatment visit, he notes, patients and providers often have different perspectives – patients hope for immediate efficacy with limited side effects and a “less is more approach” to care, while specialists may instead look for convenience in prescription and more aggressive regimens. Overall, his recommendations focused on an “Ask, Don’t Tell” approach to joint decision-making, in which the provider works with the patient to assess barriers to care, review treatment options and alternatives, and support treatment decisions. He suggested that paying attention to patient perceptions and beliefs, rather than taking a didactic approach, could smooth the prescription process and produce better outcomes.
Selected Q&A/Panel Discussion
The panel began with a case discussion about a 50-year old man with type 2 diabetes referred by his PCP for inadequate glycemic control on metformin and pioglitazone. The patient has a fear of needles but is also fearful of the severe diabetes complications he witnessed in his family. As was the case during the presentations this session, there was an emphasis on how to engage PCPs. Selected Q&A are included here.
Q: What would you recommend and why?
Dr. John Buse (University of North Carolina, Chapel Hill, NC): I agree with a GLP-1 RA as the drug of choice in this case […]. My approach is to offer therapies I think are reasonably likely to get them to target. Then I will write the options down on a piece of paper for the patient and a couple of phrases of what I see as the advantages and disadvantages and ask them to reflect on what I just reviewed […]. I think in the long haul it improves adherence, and they understand why the other options weren’t chosen, compared to saying, “I think this is the best thing for you.” Some patients ultimately do want you to say that, and of course you can tell them what you think.
Dr. Anne Peters (University of Southern California, Los Angeles, CA): When we’re talking about an injectable, I show them an injectable because the needle is so tiny and so much easier than they think it will be. In the office, the physics of taking off the cap, makes them feel like it is an option. Theoretically they may get scared but when they see it, it becomes more of a real option. I suspect with enough time the patient should get the signal.
Dr. Richard Beaser (Joslin Diabetes Center, Boston, MA): One tactic I use if the patient favors an approach that isn’t my first choice, I might let them do it for a while as long as it is not harmful. This proves to them that it is not as effective a treatment as the one I preferred, so then I can move them onto the treatment I prefer subsequently.
Q: Which GLP-1 would you choose? What properties are you looking for?
Dr. Buse: Right now we don’t have great data on the head-to-head comparison of the exenatide BID basal insulin combination versus long acting GLP-1. There’s certainly a lot more convenience today to the long acting GLP-1. The exenatide approach has benefits to postprandial glucoses so that could be good for a person who eats larger meals. Until I see more data, I’d focus on convenience though data coming with more variations of combinations.
Q: How do you address the PCP that has a lot of concerns as well?
Dr. Buse: I usually don’t call PCPs because they’re busy enough but I would just write in the note the titration scheme. For either a GLP-1 agonist or combination products likely to be available in the future should be very simple. These are very easy drugs to use compared to insulin.
Dr. Beaser: I would also encourage the PCP to look at postprandial glucose levels when a patient is on a GLP-1 agonist. If the patient is only measuring pre-meal values, then he may not see the effect of the GLP-1 and become discouraged.
Dr. Peters: In my neck of the woods, we email a lot. I have the patient summarize, in an email, what they think are the conclusions of what we discussed. And they email me and their PCP, and they have the three of us have a brief dialogue. I like that both because the patient is the one writing it, and we all can answer each others’ questions. PCPs don’t want to feel like you know everything and they know nothing. So there are ways to engage PCPs in doing this. Additionally, when I put a CGM on these patients and show the difference before and after, it’s amazing to see such an improvement in control. So use whatever tools you can use to engage your team.
Q: I’m wondering about the potential of IDegLira in type 1?
Dr. Buse: I think it’s a remarkably bad idea. Basal insulin is something you want to get right in type 1 diabetes, and GLP-1s are completely unproven in type 1 and extremely expensive. They’re not FDA approved. I certainly wouldn’t use the combination. If I were going to use a GLP-1, I would free style it. I’m not a huge fan of the approach.
Q: Can you comment on the combination of GLP-1 agonists and SGLT-2 inhibitors?
Dr. Peters: From my own clinical use I’ve used them in combination, and I think they work well. In some of my patients I’ve been able to get them off basal insulin on that combination with metformin. You could use a once-weekly GLP-1 RA and then that’s just two pills per day. However, it’s incredibly expensive, and we don’t have data supporting using it. On the other hand it does work. It’s a nice combination in terms of simplicity and effectiveness.
Q: If you have diabetes for 20 years can you still use GLP-1?
Dr. Buse: Even if you have a longer duration of disease you still respond very well. There is a loss of beta cell function in type 2 diabetes, and one of the major functions here is to restore beta cell function.
Corporate Symposium: Clinical Issues in Type 2 Diabetes: Discussions and Debates Around GLP-1 Receptor Agonists (Supported by AZ)
Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA), Daniel Einhorn, MD (Scripps Health, La Jolla, CA), and Jaime Davidson, MD (University of Texas Southwestern Medical Center, Dallas, TX)
This AZ-sponsored breakfast symposium featured wide-ranging commentary on the advantages of GLP-1 agonists. The symposium was organized by topic area, with several short presentations and discussion on each topic rather than a series of longer individual talks, and our coverage is divided accordingly.
Potential as First Injectable Therapy
Speakers offered a very positive take on the use of GLP-1 agonists as the first injectable therapy for type 2 diabetes. Dr. Daniel Einhorn described the class as an underutilized option that is much more attractive than insulin as an initial injectable therapy, particularly given the recent advances in delivery devices and the availability of once-weekly products. He did not comment on the relative advantages of specific agents within the class, but from our perspective, Lilly’s Trulicity (dulaglutide) is the GLP-1 agonist that most fully embodies these selling points. In Lilly’s 1Q15 update, management shared that early uptake of Trulicity has been very strong, and we agree with the company’s prediction that the product will likely serve as a catalyst for growth of the GLP-1 agonist class as a whole. Improvements in other once weekly agents (i.e. AZ’s new Bydureon pen) should help as well. With regard to side effects, Dr. Jaime Davidson suggested that the amount of nausea and vomiting produced by GLP-1 agonists is often overstated and that much of the nausea patients experience is actually a feeling of satiety that they are unused to.
- Dr. Davidson also discussed other potential risks associated with GLP-1 agonists, including acute pancreatitis, thyroid cancer, and renal impairment. He reported that post-marketing surveillance of GLP-1 agonists has not revealed an increase in acute pancreatitis risk but suggested proceeding with caution nevertheless. He suggested that clinicians consider other treatment options if patients have a history of pancreatitis and educate patients about the signs of acute pancreatitis so the therapy can be discontinued if an issue arises. Dr. Davidson does not recommend GLP-1 agonists for patients with a history of thyroid cancers based on the increased risk of medullary thyroid carcinoma seen in rodents. He also does not recommend GLP-1 agonists for patients with renal impairment.
Speakers also expressed great enthusiasm regarding the use of GLP-1 agonists in combination with other agents. Dr. Davidson reviewed clinical data on GLP-1 agonist/basal insulin combinations, which we continue to see as one of the most exciting new type 2 diabetes drug classes on the horizon. During Q&A, speakers debated the most appropriate role for such combinations compared to GLP-1 agonists alone. Dr. Davidson suggested that GLP-1 agonist monotherapy would be most appropriate for patients with a lower baseline A1c, while Dr. Einhorn argued that a combination approach is preferable at any stage of the disease, all other factors (such as price) being equal. Dr. Einhorn also spoke more broadly about the benefits of combination therapy during his prepared remarks. He strongly advocated for initial triple therapy with metformin, a GLP-1 agonist, and pioglitazone, which has shown better results in terms of time to treatment failure and glucose variability than adding the therapies sequentially. Dr. Einhorn also pointed to GLP-1 agonists and SGLT-2 inhibitors as a logical combination with greater than additive weight loss effects in clinical trials. We expect to hear much more about this approach in the coming years: trials of exenatide/dapagliflozin and liraglutide/canagliflozin combination therapy are ongoing and expected to complete within the next two years.
Dr. Einhorn and Dr. Davidson discussed motivational interviewing and bariatric surgery as best practices in treating overweight and obese individuals with type 2 diabetes. Dr. Einhorn underscored the importance of motivational interviewing when discussing lifestyle changes to promote weight loss with patients in order to establish a trusting relationship with them. He emphasized that patients do not have to reach a perfect target to get a better outcome – we have heard many times that the disconnect between patients’ and providers’ weight loss expectations can be one of the most challenging aspects of treating obesity for clinicians. At the other end of the spectrum for obesity therapies, Dr. Davidson reviewed results from the STAMPEDE study showing significantly greater A1c reductions with bariatric surgery added to intensive medical therapy vs. intensive medical therapy alone. The type of bariatric surgery – gastric bypass or sleeve gastrectomy – did not have an effect on the A1c results, though gastric bypass had a slight edge in terms of the percentage of patients achieving diabetes remission. It is not entirely clear whether it was some factor unique to bariatric surgery or simply the magnitude of weight loss that was responsible for these results; we agree with Dr. Timothy Garvey’s (University of Alabama, Birmingham, AL) suggestion at Obesity Week last year that a trial evaluating the effects of surgery vs. equal weight loss achieved with obesity medications would be very intriguing.
The symposium concluded with intriguing presentations by Dr. Einhorn and Dr. Davidson on the many potential expanded indications for GLP-1 agonists, including NAFLD/NASH, neurodegenerative diseases, polycystic ovary syndrome, and type 1 diabetes. Novo Nordisk’s Victoza (liraglutide) is already being investigated in several of these indications: two phase 3 trials (ADJUNCT ONE and ADJUNCT TWO) in type 1 diabetes are scheduled to report within the next few months, although data from the LIRA-1 trial presented on ADA Day #5, while demonstrating some benefit, were not as positive as we had been hoping. We also heard about intriguing academic studies in NASH and Alzheimer’s disease have been completed or are underway. According to Dr. Davidson, off-label use of GLP-1 agonists in type 1 diabetes is already fairly common, and he said he personally has been very satisfied with the results. In our view, this is part of a larger trend away from the view of type 1 and type 2 diabetes as entirely distinct diseases, and we expect the use of type 2 diabetes drugs (particularly GLP-1 agonists and SGLT-2 inhibitors) in type 1 diabetes to become increasingly common in the coming years.
Q: Is there any data regarding initial combination therapy with a non-insulin agent vs. initial combination therapy with insulin?
Dr. Daniel Einhorn (Scripps Health, La Jolla, CA): In the triple therapy study, one group had insulin and the other did not.
Dr. Lawrence Blonde (Ochsner Medical Center, New Orleans, LA): It was an option to add insulin but did everyone get it?
Dr. Einhorn: Insulin, sulfonylurea, and metformin were the options. It would be interesting to find what percentage ended up on insulin and how early they got it. Another question is whether the injectable part is such an issue. We all feel much less of that now.
Q: Do you agree that GLP-1 agonists are more effective early in the course of diabetes while insulin is effective in the entire natural history of diabetes?
Dr. Jaime Davidson (University of Texas Southwestern Medical Center, Dallas, TX): There is plenty of data showing that GLP-1 agonists are effective no matter when we use them. I prefer early because they provide better weight loss and better control over everything, not just glucose. That’s the advantage of GLP-1 agonists.
Dr. Blonde: There was a study that showed that A1c reduction was a little bit greater in people earlier in the course of diabetes. But even in that trial people who had diabetes for 10 years or longer showed reductions.
Dr. Einhorn: Earlier is better for everyone.
Q: Is there any human data suggesting that GLP-1 agonists improve beta cell function or mass?
Dr. Einhorn: There is clinical data suggesting that beta cells behave better. Whether they’re bigger or there are more of them, they seem to behave better longer.
Dr. Davidson: If they actually improved islet function in humans, then we wouldn’t see the slow rise in A1c. It’s the best drug on durability but there’s still that slow rebound. And when you stop the drug, you saw what happened. If you discontinue, in four weeks you see an increase in glucose. This is treatment, not prevention.
Q: Does the significant weight loss depend on a high nausea rate? People have thought that people lose weight because they get nauseated.
Dr. Blonde: Even in patients without nausea or vomiting, there is still a significant difference in weight loss. Nausea and vomiting is not the primary driver of weight loss. GI side effects are not the primary reason for the weight loss.
Q: Do you have any data or recommendations on the relationship between timing of meals and time of dosing?
Dr. Einhorn: Exenatide twice daily should be taken within an hour of the two main meals of the day so that’s six hours apart. Once you do it once a week, the nice thing is if they forget to take it in the morning, they can take it in the afternoon and maintain the good control. If you can do it anytime or once a week, that’s a completely different life. If you miss a day, you can take it the next day.
Dr. Blonde: If you’re starting a patient on a medication that has to be taken the next day that’s injectable, they have to give it to themselves the next day. With a once-weekly agent, you can explain how it works and the clinician can say I’ll give it today, you go watch the videos and read about how to use it, and come back in a week for a short visit and see if you can do it then. It makes the intensity of training at the first visit much less if people don’t have diabetes educators who can do it. They don’t even half to come back one week to the day. There’s some flexibility that can make it easier to start.
Q: Is it more effective to add a prandial GLP-1 agonist or a once weekly GLP-1 agonist to basal insulin?
Dr. Einhorn: There haven’t been any head to head studies. The advantage of the once-weekly agent is it’s more likely to be taken consistently, and I’m guessing in real life the impact of missed doses might exceed the relative impact on prandial glucose. I believe very strongly that making it easy should be the guiding principle, because easy means it will be adhered to. People are living with this for many years, and once a week vs. twice a day can make a difference.
Dr. Davidson: Some people do need to use a prandial agent. If they can’t get adequate postprandial control, that’s another option that’s been effective.
Dr. Blonde: Soon we will have fixed-ratio combinations of GLP-1 agonists and basal insulin. Where would you put them in the sequence and treatment algorithm?
Dr. Davidson: We will see posters here of that combination. It’s very effective. To me it depends on where A1c is at the beginning. When AACE gets new data, we will fit them in the algorithm somewhere between 8% and greater, but never below. Most clinical trials with basal insulin have people with an A1c above 8%. The people who designed them are very intelligent. If you start with an A1c of 7.5%, you will increase the risk of hypoglycemia significantly.
Dr. Blonde: The studies did show that though there was less hypoglycemia than with insulin, there was more than with a GLP-1 agonist alone.
Dr. Einhorn: In general, I would consider lower doses of the combination early on. There’s an advantage to harnessing different targets from the very beginning. I share your caution about hypoglycemia, but for me it’s a matter of dose. All things equal, if I can get two peptides I will get two. If it were more expensive, that would sway the decision.
Dr. Blonde: Is there some benefit to early insulin that would be a reason to accept some hypoglycemia and weight effects? If not, maybe we should reserve it for later. Those studies will be coming. We don’t have the answer right now.
Steven Edelman, MD (TCOYD, Del Mar, CA) & Troy Ross (Mid-America Coalition on Health Care, Overland Park, KS)
This was the first Intarcia-supported product theater we’ve seen out on the conference circuit so far, though as with Sanofi’s first product theater for the new inhaled insulin Afrezza there was no specific mention of Intarcia’s product. Instead, co-hosts Dr. Steven Edelman and Mr. Troy Ross made some general points about adherence, namely focusing on therapies that promote weight loss, reduce hypoglycemia, and have other benefits that are highly meaningful for patients. Though the content was valuable from a provider perspective and well delivered, we are more eager to see product-specific messaging once ITCA-650 draws closer to market.
A Case Study in Treating Adult Patients with Type 2 Diabetes (Sponsored by Lilly)
Stanley Schwartz, MD (University of Pennsylvania, Philadelphia, PA)
Dr. Schwartz led the product theater on Lilly’s once weekly GLP-1 agonist Trulicity (dulaglutide). Following an opening review of ADA treatment guidelines, he introduced Trulicity, emphasizing the once weekly dosing and noting that no reconstitution or shaking was necessary for administration. Moving to efficacy results, Dr. Schwartz underlined the strong glycemic control observed in the AWARD trials, suggesting Trulicity could be a good option before starting insulin due to the low incidence of hypoglycemia without weight gain. He concluded with practical tips from his clinical practice for educating patients in order to reduce nausea and vomiting rates.
- Following an opening review of ADA treatment guidelines, Dr. Schwartz introduced Trulicity, emphasizing ease of use with the auto-injector pen – the easiest-to-use device for any currently available GLP-1 agonist. With the pen, administration requires no reconstitution or shaking and the injection is delivered through a 29-gauge needle that patients never have to see. He felt that in his practice demonstrating this in office often helped patients get over preconceptions over pain and difficulty with injectables. He also promoted a sample pack offered by Lilly, which includes educational information and a savings card for patients to reduce costs.
- Moving to efficacy results, Dr. Schwartz underlined the strong glycemic control observed in the AWARD trials. Looking to AWARD-5, he noted 0.9-1.1% declines with Trulicity (baseline 8.1-8.2%) versus 0.4% with sitagliptin (baseline 8.0%). He also highlighted similar efficacy to liraglutide in AWARD-6 and insulin glargine in AWARD-2, suggesting Trulicity could be a good option before starting insulin due to the low incidence of hypoglycemia without weight gain.
- With regard to nausea and vomiting, Dr. Schwartz emphasized that in his practice he felt proper education could reduce event rates. He said it was important to teach patients that they will lose their appetite and not to eat in between meals out of habit. When eating, he instructs patients to stop eating at the first sign of fullness – continuing to eat when full, he suggested, prompts nausea. Anecdotally he felt these recommendations brought rates of nausea far below what was seen in trials.
The Effect of a Once-Weekly Therapy on A1C and Weight Over 3 Years (Sponsored by AstraZeneca)
Steven Edelman, MD (University of California San Diego, La Jolla, CA) & Kirsten Ward, CDE (Health Coach Boston, Boston, MA)
The renowned Dr. Steven Edelman and fantastic Ms. Kirsten Ward led a product theater on AZ’s GLP-1 agonist Bydureon (exenatide once weekly), highlighting the efficacy and safety profile of the drug. Following a review of the mechanism of action of GLP-1 class, Dr. Edelman moved on to highlight takeaways from the DURATION phase 3 trials, particularly emphasizing the strong A1c declines and maintained weight loss. He also noted the reduced nausea and increased potency as compared with Byetta, underlining the differences between the drugs. Ms. Ward concluded the session with a demonstration of the Bydureon pen, placing heavy focus on the SteadyStart post-prescription support system as a way to ease the patient’s transition to the drug – we see patient support program models like this as becoming increasingly important differentiators for new and existing drugs. Overall, it seemed the presentation aimed to reinforce the simplicity of prescription and administration – there was little mention of the single-use tray, which now accounts for only half of all monthly prescriptions.
- Following a review of the mechanism of action of the GLP-1 class, Dr. Edelman moved on to highlight takeaways from the DURATION phase 3 trials with Bydureon. In addition to strong A1c declines, he emphasized the weight loss observed in the trials, particularly noting the 5.5 lbs weight loss seen in DURATION-3 that was maintained until the end of the trial. Compared with Byetta, he reinforced the increased potency of Bydureon as well as reduced incidence of nausea.
- Looking to six-year safety data, Dr. Edelman underlined the lack of major hypoglycemia cases as well as the decreasing nausea with time. In the DURATION-1 extended trial, he noted that nausea declined from the initial controlled 30-week period at 0.85 events/year to 0.08 events/year by the end of six-year follow-up. Nevertheless, he cautioned that GI side effects serve as the primary adverse events directly related to GLP-1 administration. He also noted increased injection site reactions versus Byetta and insulin glargine given the components of the long-acting suspension.
- Ms. Ward went on to demonstrate the use of the Bydureon pen, promoting the SteadyStart program as a way to offer clinical educator support directly to patients. As described at last year’s product theater, the program includes full-time and on-demand educators and specialists to help educate patients on proper administration of Bydureon. The program includes a series of follow-up calls at 7, 30, 60, and 90 days post-prescription to ensure smooth transition to the pen. Patients have the option of enrolling in non-branded education sessions on healthy lifestyle change as well as opting in for dosing reminder emails. The concluding patient video included a series of testimonials in praise of the program and ease of use with the pen.
-- by Melissa An, Adam Brown, Eric Chang, Jessica Dong, Samiul Haque, Varun Iyengar, Emily Regier, Lisa Rotenstein, Mallika Tamboli, Manu Venkat, Alasdair Wilkins, Michelle Xie, and Kelly Close