Cardiometabolic Health Congress

October 22-25, 2014: Boston, MA – Days #3-4 Highlights – Draft

Executive Highlights

The final two days of the ninth annual Cardiometabolic Health Congress featured balanced discussion on pharmacotherapy for both diabetes and obesity, with additional presentations on the bionic pancreas – delivered by local Dr. Ed Damiano (Boston University, Boston, MA) – as well as the gut microbiome and insulin’s impact on neurodegenerative diseases. GLP-1 agonists received a great deal of discussion and enthusiasm from several presenters, particularly Dr. John Buse (University of North Carolina, Chapel Hill, NC). At the closing of the meeting, meeting co-chair Dr. Robert Eckel mentioned that although the congress will again be held in Boston in October 2015, there is interest in taking the show on the road in some way – we expect to learn more between now and next year’s meeting. Read on below for our top diabetes and obesity-related highlights, followed by more in-depth coverage of some of our favorite presentations.

1. Dr. Ed Damiano presented encouraging new data from the ongoing multi-center study of the bionic pancreas (an additional n of 3), which looked quite strong.

2. On combination therapy for type 2 diabetes, Dr. John Buse suggested that MDI will give way to combination therapy with basal insulin and either GLP-1 agonists or SGLT-2 inhibitors.

3. Dr. Buse voiced doubts about early triple therapy and the TZD class, in the latter case due to what he views as legitimate concerns about bone fracture safety.

4. Throughout the final two days, we heard significant enthusiasm about GLP-1 agonists, especially Lilly’s recently approved once-weekly Trulicity (dulaglutide).

5. Dr. Samuel Dagogo-Jack explored the results of a patient preference analysis indicating that on average, strong A1c-lowering efficacy is the highest priority for patients when evaluating treatment options.

6. Capping off a Lilly-sponsored morning symposium on GLP-1 agonists, the panel and audience were not overly enthusiastic that CVOTs for GLP-1 agonists will demonstrate cardioprotection, due to their design. We continue to believe that were the trials designed for superiority, they might show cardioprotection and we wonder to what extent the CVOTs will show to be a good use of resources.

7. Dr. Caroline Apovian (Boston University, Boston, MA) provided some very enthusiastic commentary about Takeda/Orexigen’s newly launched obesity therapy Contrave (naltrexone/bupropion).

8. Drs. Apovian and Lee Kaplan (Harvard Medical School, Boston, MA) suggested that obesity pharmacotherapy should stay on the table even for patients that are unwilling to implement meaningful lifestyle change.

9. Dr. C. Ronald Kahn (Joslin Diabetes Center, Boston, MA) raised the intriguing possibility that insulin may play a key role in the pathology of Alzheimer’s Disease, and that the neurodegenerative disease could be characterized as “type 3 diabetes.” There continues to be great interest in this arena though no meaningful long-term data reported.

10. Multiple symposia on PCSK9 inhibition raised attendees’ level of excitement for this novel class of LDL lowering drugs.

Top Ten Highlights

1. Dr. Ed Damiano (Boston University, MA) presented new encouraging data from the ongoing multi-center study of the bionic pancreas. The additional data from three more participants looked quite strong (see our Keystone 2014 coverage of the first two participants): the estimated mean A1c of the five participants on the bionic pancreas was ~6.4% (~137 mg/dl), and they spent just 0.5% of their time <60 mg/dl and 17% of their time >180 mg/dl – 82% time-in-range in a pretty real-world study is great in our book, especially at the low end.

  • As a reminder, the multi-center study represents the fourth outpatient study of the bionic pancreas, adding to Beacon Hill and the 2013 summer camp study and the 2014 summer camp study. The latter was recently completed and tested the device in six boys and 13 girls between six and 11 years old. The topline results were favorable and very similar to the prior outpatient studies: participants in the bionic pancreas group had a lower estimated mean A1c of ~6.4% (with all participants under the ADA goal of 7%) and spent significantly less time below 60 mg/dl (1.2%) and above 180 mg/dl (17%) compared to the control condition. We hope to see the data published sometime in 2015.
  • There are several bionic pancreas studies being considered for 2015: a bionic pancreas set point study; an alcohol tolerance clamp study; and an additional pediatric study. Dr. Damiano mentioned that his team is applying for funding for those studies.
  • In line with prior presentations, Dr. Damiano highlighted the bionic pancreas algorithm’s ability to handle a wide variety of insulin doses and patient types. The system gave on average 11 units of insulin per day to one six-year-old female participant who weighed only 47 lbs (21 kg) vs. nearly 15 times as much insulin on average (158 units per day) to a 300-lb (130 kg) subject in a previous study. As a reminder, the algorithm is adaptive and learns over time from it’s own insulin dosing; it can also automatically titrate insulin up or down based on transient insulin resistance, insulin sensitivity, etc.
  • Similar to the 2013 summer camp study, the 2014 summer camp study showed that despite the improvement in glycemic control, there was no significant difference in the average daily insulin dose between the control and bionic pancreas groups (control: 0.68 units/kg/day vs. bionic pancreas: 0.66 units/kg/day). This has been a consistent result in trials of automated insulin delivery, whereby the algorithms can improve glycemic control by more optimally distributing the same amount of insulin.

2. In a well-attended afternoon talk titled “Diabetes Management 2014,” Dr. Buse suggested that insulin/GLP-1 agonist and insulin/SGLT-2 inhibitor co-therapy will be the combinations of the future, while MDI is a less valuable option. As a lead investigator in the DUAL program for Novo Nordisk’s Xultophy (IDegLira, insulin degludec/liraglutide), it was not surprising that Dr. Buse dedicated a solid block of his comprehensive afternoon overview of type 2 diabetes pharmacotherapy to share his enthusiasm for the fixed-ratio combination. He emblazoned a slide with the takeaway message that Xultophy was able to bring patients from an A1c of ~8.4% down to 6.4%, with 32% less hypoglycemia than Tresiba (insulin degludec) alone and 50% less nausea than Victoza (liraglutide) alone – we saw some impressed nods in the audience. Insulin/SGLT-2 inhibitor co-therapy has received less airtime at conferences, but mechanistically the combination makes a lot of sense, as SGLT-2 inhibitors have an insulin-independent mechanism that does not rely on residual endogenous insulin secretory capacity.

3. Dr. Buse also voiced some opinions that, as he mentioned, run counter to views espoused by other thought leaders – particularly Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX). Although he is enthusiastic about certain drug combinations for type 2 diabetes, he argued that he would never begin treatment with three agents at once (Dr. DeFronzo’s triple therapy) due to the risk of adverse effects. “If there’s an adverse reaction,” he noted, “you wouldn’t know which drug it’s from and you’ve ruined three drugs forever.” Although he recognizes the very real benefits of TZDs (one of Dr. DeFronzo’s favorite drug classes), in his view the increased risk of bone fractures (an excess of one in 30 elderly women) is a dealbreaker, as bone problems can be miserable from a quality-of-life perspective.

4. Throughout the day, there was a great deal of discussion on GLP-1 agonists in particular. Lilly’s dulaglutide, even though it is not on the market just yet (a US launch is imminent, as we learned during Lilly’s recent 3Q14 update), still received a sizeable amount of airtime and enthusiasm. Dr. Buse focused on the positive comparison for Trulicity vs. basal insulin from AWARD-4, which showed that Trulicity led to better A1c lowering, better weight effects, and less hypoglycemia than Sanofi’s Lantus (insulin glargine) – he used this finding to support his assertion that GLP-1 agonists are arguably the single most effective glucose-lowering drugs.

  • Dr. Richard Pratley (Sanford Burnham Medical Research Institute, Orlando, FL) highlighted Trulicity’s superiority (in terms of A1c) vs. AZ’s twice-daily Byetta (exenatide) and comparable A1c reductions vs. Novo Nordisk’s once-daily Victoza (liraglutide). He spoke favorably about the Trulicity auto-injector and its hidden needle, although he did also suggest that the reconstitution processes for AZ’s Bydureon (exenatide once weekly) and GSK’s Tanzeum/Eperzan (albiglutide) are not too burdensome. He characterized the relatively low (<1 kg) weight loss seen in Tanzeum’s phase 3 clinical trials as a meaningful difference vs. other GLP-1 agonists. On the bright side (although Dr. Pratley did not mention this), Tanzeum also appears to be differentiated vs. the field by a relatively low rate of nausea.
  • Both Drs. Buse and Pratley agreed that GLP-1 agonists are likely (though not definitely) associated with a very modest excess risk of pancreatitis. Dr. Buse suggested that the risk with DPP-4 inhibitors is likely to be effectively nil. Although these two thought leaders appeared more or less fine with the possibility of a slight excess in pancreatitis given GLP-1 agonists’ many other benefits, it remains to be seen how clinicians at large would perceive a very slight degree of excess risk if it as ultimately proven to be a real signal; the likely lack of a connection to pancreatic cancer may provide some reassurance.

5. Dr. Samuel Dagogo-Jack (University of Tennessee Health Science Center, Memphis, TN) discussed results from a recently published analysis of patients’ preferences regarding their diabetes care. As background, Dr. Dagogo-Jack is the ADA President-Elect, but he was not speaking as an ADA representative in this role. This meta-analysis found that on average, patients rated strong A1c-lowering efficacy (patient willingness to pay per month [WTP] = $205 per 1% A1c improvement in some studies) as more important than other factors such as the avoidance of hypoglycemia (WTP = $45-$94). Of course, those goals are not mutually exclusive with many of the newer therapeutic options. The results also suggested that GI side effects, which providers often do not consider to be very serious, are a fairly important consideration for patients (WTP = $124-$220). Despite nausea concerns, Dr. Dagogo-Jack believes that GLP-1 agonists can effectively address many of the common barriers cited by patients and that the high rates of nausea at the beginning of treatment can often be mitigated by gradual titration. He also commented that the need for injections is not a dealbreaker for many patients, particularly with products that offer once weekly dosing and more user-friendly administration devices.

6. To cap off a Lilly morning symposium on GLP-1 agonists, the panel touched upon the intriguing prospect of cardioprotection with GLP-1 agonists. Dr. Dagogo-Jack, Dr. Pratley, and Dr. Buse generally agreed that the trials are unlikely to show cardiovascular harm but cautioned that they are also unlikely to show benefit, as they were designed as safety studies and typically enroll a high-risk population with longstanding diabetes. As. Dr. Dagogo-Jack frankly put it, glucose-lowering agents are unlikely to act as a Roto-Rooter that can plunge out ten to twenty years of vascular damage from poor glycemic control. The response rate to an audience poll on whether GLP-1 agonists could be cardioprotective was lukewarm (the session began at 6 AM), but of those that did respond, an equal number voiced belief in cardioprotection while the remainder suggested that neutrality was more likely the truth – there were no votes for increased risk.

7. Dr. Caroline Apovian (Boston University, Boston, MA) expressed significant enthusiasm about the potential of the obesity market’s newest drug, Orexigen/Takeda’s Contrave (naltrexone/bupropion). She praised the complementary mechanisms of Contrave’s two components, which (unlike many other obesity medications) target both the homeostatic and reward pathways involved in weight regulation. Reviewing data from Contrave’s phase 3 clinical trial program, she pointed out that while the drug’s average weight loss was relatively modest at ~5%, a significant portion (20%) of the participants lost ≥15% of their initial body weight, approaching the results seen with gastric banding. She also highlighted the results of the COR-BMOD trial as an illustration of the substantial benefits of using pharmacotherapy in combination with intensive behavior modification (including diet and exercise) – the trial’s active treatment arm (which received both Contrave and intensive behavioral modification) achieved greater average weight loss (8.1%) than the active groups in Contrave’s other clinical trials (COR-I, COR-II, and COR-Diabetes). For more background, see our reports on Contrave’s FDA approval in September and about its recent US launch.  

8. Obesity pharmacotherapy performs best when paired with diet and exercise, but what happens when patients simply aren’t willing (or able) to adopt optimal lifestyle changes? Should providers still prescribe these patients weight loss drugs? These questions were put to the test in a panel session on obesity, which closed out the conference. Understandably, nobody on the panel appeared highly enthusiastic about using obesity drugs in the absence of lifestyle intervention, as the drugs’ efficacy is maximized when used in conjunction with lifestyle-based therapy. However, as panelist Dr. Apovian eloquently put it, doctors are ultimately there to help their patients. Even in the absence of comprehensive diet and physical activity programs, obesity drugs can help many patients achieve significant weight loss.

  • Dr. Lee Kaplan (Massachusetts General Hospital, Boston, MA) expressed similar sentiments. He made the point that while lifestyle intervention can also be an effective treatment for diabetes, hypertension, and dyslipidemia, we do not forego drug therapies for these diseases if the patients do not succeed at implementing lifestyle changes. Given the strong recommendations for lifestyle-based treatment to accompany drug therapy, this is often a difficult issue for providers to deal with – because of the side effects associated with any drug, whether a not a patient is willing to adhere to recommended lifestyle changes could influence the benefit/risk assessment for a drug, but we agreed with Dr Kaplan and Dr. Apovian’s message of empathy.     

9. In one of the conference’s more intriguingly titled presentations, Dr. C. Ronald Kahn (Joslin Diabetes Center, Boston, MA) supported the idea that Alzheimer’s disease may be “type 3 diabetes.” This concept has received a great deal of press attention in recent years, and Dr. Kahn believes there is convincing preliminary evidence of at least some link between the two disease processes. He explained that the classic idea that insulin cannot cross the blood-brain barrier and exert effects on the central nervous system has proven to be incorrect, citing evidence from several epidemiological studies suggesting a correlation between diabetes and an increased risk of Alzheimer’s disease. Presenting data from mouse models, he also demonstrated that selectively knocking out insulin receptors in the brain leads to cognitive dysfunction and biomarkers of Alzheimer’s disease. Dr. Kahn stressed that the evidence of a link between diabetes and Alzheimer’s is far from definitive at this point, but he believes it is a promising area for continued research.

10. The conference has featured a number of corporate symposia focused on PCSK9 inhibitors and other treatments to lower LDL levels. A Sanofi-supported lunch symposium on day #2 discussed evolving strategies for LDL-lowering based on relevant genetic insights and clinical evidence; the company also supported a dinner symposium on the treatment of familial hypercholesterolemia (an area of particularly high unmet need, as this group of patients does not respond well to statins). During an Amgen-supported breakfast symposium, Dr. Marc Sabatine (Harvard Medical School, Boston, MA) presented impressive efficacy results from clinical trials of the company’s PCSK9 inhibitor evolocumab (AMG 145; BLA submitted to FDA in September), showing robust LDL-C reductions at 12 weeks (above 50% in many cases); he particularly highlighted the drug’s efficacy in heterozygous familial hypercholesterolemia and other statin-intolerant patient populations. Regarding other PCSK9 inhibitors in development, Dr. Sabatine noted that the phase 2 data on Sanofi’s alirocumab (against which Amgen has recently filed a patent infringement lawsuit) and Pfizer’s bococizumab have also shown similar robust LDL-C reductions. We have been very impressed by this drug class so far, as PCSK9 inhibitors will also greatly benefit many patients with type 2 diabetes who also have dyslipidemia.

Detailed Discussion and Commentary

Corporate Symposium: Innovations in GLP-1 Receptor Agonist Therapy – Individualized Treatment Strategies to Overcome Barriers and Reduce Cardiometabolic Risk in Type 2 Diabetes Mellitus (Sponsored by Lilly)

Clinical Practice Guidelines for Managing Patients with Type 2 Diabetes: Where do Incretins Fit Into the Treatment Paradigm?

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

Dr. John Buse shared his thoughts on the ideal treatment paradigm for type 2 diabetes, particularly highlighting the impressive efficacy of GLP-1 agonists. In a rebuttal of sorts to strong advocates of early triple therapy, he argued that he would never begin treatment with three agents at once due to the risk of adverse effects (“if there’s an adverse reaction, you won’t know which drug it’s from and you’ve ruined three drugs forever”). He also critiqued the typical approach of escalating basal insulin therapy by adding prandial insulin; in his view, combining basal insulin with either a GLP-1 agonist or an SGLT-2 inhibitor alone would likely be more efficacious. Aside from the merits of specific therapies, Dr. Buse characterized adherence as the biggest issue in diabetes care in 2014 – he cited studies demonstrating that over one third of patients never fill their prescriptions and almost half of those who do eventually stop taking their medications within one year. To resolve these issues, he emphasized the importance of effective communication with patients to ensure that they are invested in their own particular treatment regimens and to also make sure that patients are receiving solid support outside of the exam room, from diabetes educators and peer support groups.

  • For Dr. Buse, GLP-1 agonists offer more impressive efficacy than most other options included in the AACE/ACE algorithm for type 2 diabetes. However, in his eyes, other drugs come out on top in terms of tolerability (DPP-4 inhibitors) and cost (metformin and sulfonylureas). He noted that the evidence for metformin as the first-line therapy is relatively sparse but said that this paradigm is unlikely to change anytime soon due to the drug’s low cost and well-understood safety profile. He also challenged the common perception of insulin as the most efficacious drug for type 2 diabetes, as head-to-head studies have shown similar efficacy with GLP-1 agonists.
  • Dr. Buse believes that the ongoing GRADE study will provide more clarity on the best approach to second-line therapy. This study is a head-to-head comparison of the sulfonylurea Amaryl (glimepiride), Merck’s DPP-4 inhibitor Januvia (sitagliptin), Novo Nordisk’s GLP-1 agonist Victoza (liraglutide), and Sanofi’s basal insulin Lantus (insulin glargine) as an add-on to metformin. We heard enthusiasm for GRADE at multiple points during the conference, in part because the trial is aggressively recruiting at the moment. It is unfortunate in our view that SGLT-2s are not included (those putting together the study didn’t believe there was enough experience with them).

The Role of GLP-1 Receptor Agonists in Overcoming Common Patient Treatment Barriers

Samuel Dagogo-Jack, MD (University of Tennessee Health Science Center, Memphis, TN)

Providing the preface that consumer research is a relatively early-stage science in the healthcare and pharmaceutical industries, Dr. Samuel Dagogo-Jack discussed a recently published analysis  of patients’ preferences regarding their diabetes care. The study found that on average, patients considered strong A1c-lowering a higher priority (in terms of what they would be willing to pay for) than avoidance of minor hypoglycemia – of course, these goals are not mutually exclusive with many of the newer therapeutic options. The results also suggested that GI side effects, which clinicians often do not consider to be very serious, are a very important consideration for patients. Despite this concern, Dr. Dagogo-Jack believes that GLP-1 agonists (as well as other therapies) can effectively address many of the common barriers cited by patients in the analysis; according to him, these drugs offer strong efficacy along with weight loss and minimal risk of hypoglycemia, and the high rates of nausea at the beginning of treatment can often be mitigated by gradual titration. Dr. Dagogo-Jack also commented that the need for injections is not a deal-breaker for many patients, particularly with products that offer once weekly dosing and more user-friendly administration devices.

Questions and Answers

Q: How likely are GLP-1 agonists to be cardioprotective? If they are, are ongoing trials likely to be able to demonstrate that?

Dr. Samuel Dagogo-Jack (University of Tennessee Health Science Center, Memphis, TN): We have probably a dozen outcomes trials going on due to the FDA mandate. We have GLP-1 receptors in cardiac tissue and animal data of infarct size limitation during GLP-1 infusion, as well as other experimental data suggesting benefit. There’s little data suggesting harm. We are anxiously awaiting the results of LEADER and the trial for lixisenatide. A definitive answer will await hard data. Is the current design of the ongoing studies adequate to show results? My opinion is that in order to get enough events in a reasonable amount of time and to limit the cost of the trials, centers doing these studies have been encouraged to enroll people with high risk. In someone who’s had atherosclerosis for ten or 20 years, no product will be a Roto-Rooter and suddenly clear out the gunk and give them pristine arteries. That makes me circumspect about a positive result. If the results come out neutral, I’ll be happy. It’s a high bar to expect significant reductions in risk.

Dr. Richard Pratley (Florida Hospital Diabetes Institute, Orlando, FL): I don’t expect a signal of increased risk and I agree that we’re unlikely to see a significant difference in atherosclerosis. It will be interesting if there’s an effect on survival post-MI or something else; I could anticipate that. It’s difficult to predict

Audience poll: How many people think these trials will show cardioprotection? Neutrality? Increased risk?

[A handful of people raised their hands for cardioprotection and neutrality; none for increased risk].

Dr. John Buse (University of North Carolina, Durham, NC): We worry that studying people so advanced in the disease makes it hard to demonstrate benefit, and these were mandated as safety studies to make sure there’s no harm. In a meta-analysis across trials, it will be possible to carve out patients without pre-existing cardiovascular disease. The good thing about having so many trials is that meta-analyses allow for subgroup analyses. The only trial designed to show superiority is the EXSCEL trial with exenatide once weekly.

Q: Are GLP-1 receptors expressed in human endothelial cells?

Dr. Pratley: Yes, there is evidence that both native GLP-1 and GLP-1 analogs improve endothelial function. This might be the reason for the improvements seen in blood pressure.

Q: Would you recommend a combination of a GLP-1 agonist and an SGLT-2 inhibitor together? If so, which would you add first?

Dr. Dagogo-Jack: SGLT-2s are approved across the board after lifestyle and metformin. We’ll have to see the data. They do work by complementary mechanisms. Data from Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX) showed that SGLT-2 inhibitors suppress insulin and stimulate glucagon; that may explain why the efficacy is modest – reductions of 0.7% to 0.8% - and levels off. If a drug can shave off the glucagon response and further suppress glucagon, you can expect synergy and additivity. But it’s not widely done in clinical practice. I don’t have any patients on that combination.

Dr. Buse: It’s expensive. I have colleagues who use it a lot and say it’s great, but endocrinologists always say any combination they use is great. There has not been an adequately conducted trial on this yet. There are some in the pipeline.

Q: When do you recommend that patients dose Victoza? Does time of day make a difference on side effects or efficacy?

Dr. Pratley: I tend to dose around the patients – I don’t think it makes a huge difference in terms of efficacy.

Symposium: New Frontiers in Obesity Management – Advances in Neurobiological Treatment Strategies (Supported by Takeda and Orexigen)

Weight-Centric Approaches to Cardiometabolic Disease Management

Lee Kaplan, MD, PhD (Harvard Medical School, Boston, MA)

Dr. Lee Kaplan emphasized the heterogeneous nature of obesity, urging providers to focus more on individual responses to specific therapies and less on average results from clinical trials. He closed his talk by saying that while curing obesity is the ultimate goal of treatment, “if we do nothing more than stop abandoning patients with obesity, we’ll improve patient satisfaction and we’ll improve our own satisfaction.”

Food For Thought: Neurobiological Concepts to Appetite Regulation and Weight Loss - Beyond Individual Control

Joshua Thaler, MD, PhD (University of Washington, Seattle, WA)

From a neurobiological perspective, Dr. Joshua Thaler discussed how a high fat diet is associated with rapid onset of hypothalamic inflammation and leptin resistance. In rodent models, he showed that hypothalamic inflammation is necessary and sufficient for diet-induced obesity and demonstrated that high consumption of fat also led to critical neuron loss as well as the onset of gliosis, the glial response to central nervous system injury. Notably, Dr. Thaler’s research demonstrated that this was occurring in humans as well, as MRI scans found a positive correlation between BMI and gliosis. This basic science discussion augmented our understanding of how obesity is promoted by neurobiological processes beyond any sense of willpower, as high fat consumption can lead to neuronal stress, reactive gliosis, and structural changes to the hypothalamus that can alter energy homeostasis.

 

-- by Melissa An, Emily Regier, Manu Venkat, and Kelly Close

Editor's Note: A previous version of this report incorrectly indicated that Dr. Dagogo-Jack specifically endorsed GLP-1 agonists over other therapies during his presentation. He has clarified that he supports a range of therapies depending on patients' needs, and that combination therapy with several agents is often the most effective approach.