Hello from beautiful Boston, Massachusetts! Our drug team was at the 11th annual Cardiometabolic Health Congress, taking place at the awesome Prudential Center in the heart of the city. As always, we appreciate this intimate meeting for teaching us about diabetes through the lens of its cardiovascular co-morbidities. We broke down this packed conference into five sessions: (i) Opening Session; (ii) Dyslipidemia, Atherosclerosis, and Cardiovascular Disease Risk Reduction; (iii) Hypertension, Cardio-Renal, and Heart Failure; (iv) Diabetes Management; and (v) Session IV: Obesity, Lifestyle Management, and Cardiovascular Disease.
Read on for our full report of the conference. We’re already looking forward to returning to Boston for CMHC 2017 – October 4-7, mark your calendars!
- Executive Highlights
- Detailed Discussion and Commentary
- Opening Session
- Corporate Symposium: Insights on Repatha (evolocumab): A Clinical Perspective (Sponsored by Amgen)
- Corporate Symposium: Invokana: Examining Options to Go Further in the Treatment of Type 2 Diabetes (Sponsored by Janssen)
- Session I: Dyslipidemia, Atherosclerosis, and Cardiovascular Disease Risk Reduction
- Late-Breaking Clinical Trials and FDA Update
- Lipid-Modifying Therapies 2016: Opportunities and Challenges
- Challenging Lipid Cases
- Corporate Symposium: Patient-focused LDL-C Management and Risk Reduction in Clinical Practice: The Utility of PCSK9 Inhibitors (Sponsored by Sanofi and Regeneron)
- Corporate Symposium: New Developments in Insulin Therapy: Expert Insights in Individualizing Treatment (Sponsored by Novo Nordisk)
- Session II: Hypertension, Cardio-Renal, and Heart Failure
- SGLT2s: Should They Be Second Line Therapy?
- Corporate Symposium: New Frontiers in the Prevenion and Management of Heart Failure (Sponsored by Arbor Pharmaceuticals and Metabolic Medical Institute)
- Session III: Diabetes Management
- Update on Cardiovascular Outcome Trials in Diabetes
- Insulin Therapy Options: What’s in Store for 2017?
- Non-Insulin Therapy Options: A Look Ahead for 2017
- Panel Discussion: Implications of Recent Trials on Management of Diabetes – Should the Algorithms be Changed?
- Jay Skyler, MD (University of Miami, FL); George Bakris, MD (University of Chicago, IL); Robert Eckel, MD (University of Colorado, Denver, CO); Irl Hirsch, MD (University of Washington, Seattle, WA); Robert Ratner, MD (ADA, Alexandria, VA); Christie Ballantyne (Baylor College of Medicine, Houston, TX)
- Corporate Symposium: Combining GLP-1RAs with Insulin to Improve Glucose Control (Sponsored by Sanofi)
- Session IV: Obesity, Lifestyle Management, and Cardiovascular Disease
- Opening Session
Detailed Discussion and Commentary
Corporate Symposium: Insights on Repatha (evolocumab): A Clinical Perspective (Sponsored by Amgen)
Yehunda Handelsman, MD (Metabolic Institute of America, Tarzana, CA)
In an Amgen-sponsored session, past AACE president Dr. Yehunda Handelsman (Metabolic Institute of America, Tarzana, CA) provided detailed commentary on Repatha (evolocumab). He emphasized Repatha’s patient-friendly dosing options (a pen injection once every two weeks, or a once-monthly injection mediated by the newly-approved patch pump-like Pushtronex on-body infuser device called Pushtronex) and reviewed efficacy data from select clinical trials. In the LAPLACE-2 trial (n=2067), the addition of Repatha to statin therapy led to mean LDL-C reductions of 63%-75% versus placebo, taking upwards of 85% of patients to an LDL-C of under 70 mg/dl over the 12-week study duration. Furthermore, in the DESCARTES trial (n=901) patients randomized to evolocumab saw a mean 57% reduction in LDL-C compared to placebo injection (-51.5% vs. +6.0% for evolocumab and placebo, respectively), and 82% of evolocumab patients achieved an LDL-C goal of <70 mg/dl at week 52 (compared to 6% of patients on placebo). Dr. Handelsman reminded the audience that the FOURIER cardiovascular outcomes trial for Repatha will be completed soon (expected 1Q17 according to Amgen’s latest statements), forecasting that positive results may make it easier for patients to get reimbursed for this currently costly drug. We certainly hope this is the case, given Repatha’s impressive efficacy and the growing number of patient who could benefit from LDL-lowering therapy. For more on Repatha, see our coverage of Amgen’s 2Q16 update.
Cres Miranda, MD (University of Nevada, Reno, NV)
University of Nevada’s Dr. Cres Miranda described the ideal treatment regimen for type 2 diabetes as “Invokana, metformin, and an incretin-based drug,” and expressed frustration over the disconnect between clinical trial findings and what is being implemented in clinical practice. This trio of agents, he explained, attacks multiple facets of the disease – Dr. Miranda especially emphasized beta cell preservation, weight loss, and avoidance of hypoglycemia as top priorities for a diabetes treatment regimen. Dr. Miranda described a beta-cell preservation role for the incretin-based drug, preferably a GLP-1 agonist – according to Dr. Miranda, protecting insulin-producing islets in the pancreas should be the first priority in diabetes care. Dr. Miranda also presented his ideal drug trio as a way to “unleash” weight loss potential: Janssen’s SGLT-2 inhibitor Invokana (canagliflozin) is associated with a mean 3.5-4% weight reduction, compounded by metformin’s satiety effect and the known weight loss benefit of GLP-1 agonists. Notably, he characterized Janssen’s Invokana (canagliflozin) as not only an SGLT-2 inhibitor, but also a partial SGLT-1 inhibitor. By this latter pathway, canagliflozin allows for reabsorption of glucose and galactose in the GI- and intestinal-tracts, stimulating GLP-1 production, which in turn increases postprandial glucose control and confers a mild satiety effect. This is perhaps why patients lose more weight on Invokana compared to AZ’s Farxiga (dapagliflozin) or Lilly/BI’s Jardiance (empagliflozin), suggested Dr. Miranda.
- Turning to hypoglycemia, Dr. Miranda argued that the results from the ACCORD trial are frequently misinterpreted to suggest that tighter glucose control reduces life expectancy for patients with diabetes, when the real signal according to Dr. Miranda is that we shouldn’t treat diabetes with drugs that cause hypoglycemia. He argued that continued use of only metformin, insulin, and sulfonylureas in diabetes management is suboptimal and outmoded. He presented a recent survey reporting that 52% of patients with type 2 diabetes in the US are on metformin, 30% are on insulin, and 27% are on sulfonylureas. “This is the way diabetes is treated in the US, and it’s also the way it was treated back in the 1970s.” Dr. Miranda expressed intense incredulity that we know about the high hypoglycemia risk associated with sulfonylureas, not to mention their negative CV effects, and yet healthcare providers continue to prescribe them. We absolutely agree, and we think it is so important that results from the forefront of clinical research find their way into the clinic. To this end, we appreciated Dr. Miranda’s strong advocacy for SGLT-2 inhibitors and GLP-1 agonists given their effects on pathophysiology of diabetes, A1c, and weight loss, among other important patient outcomes. Cost is of course a looming factor that limits access to newer drug classes, but Dr. Miranda also had a sharp response when the issue arose during Q&A that sulfonylureas are cheap: “If you want to give your patients something that doesn’t kill them, give them placebo. That’s free.”
- “If there’s one thing to take away from this session, it’s that you should never, never, never write a sulfonylurea.” Dr. Miranda explained that on top of increasing risk for hypoglycemia, sulfonylureas decrease glucagon excretion, hindering a safety element that might block hypoglycemia. He also drew attention to their negative cardiovascular (CV) effects, pointing out the irony that these agents are still prescribed at such high volume given the FDA’s push for CV safety of all diabetes drugs since 2008: “Why they still allow sulfonylureas if they think like this, I don’t know. You’re still allowed to write that poison.”
- Dr. Miranda shared his view that TZDs are the most under-prescribed diabetes drug, because they also act to preserve pancreatic beta cells. Pioglitazone is prescribed to 5.7% of type 2 diabetes patients in the US, which in his view reflects “remarkable underuse because of fallacies and myths that this is a dangerous drug.” Indeed, pioglitazone in particular has appeared to experience a renaissance of sorts among those in the diabetes field – the IRIS trial suggested a cardioprotective benefit for the agent among patients with a previous history of stroke and recent findings suggest that pioglitazone may be helpful for NASH. Dr. Ralph DeFronzo includes pioglitazone as a key cornerstone of his triple therapy cocktail (also with metformin and AZ’s Byetta [exenatide twice-daily]). Indeed, in a later Novo Nordisk-sponsored session, Dr. Bernie Zinman pointed out that TZDs are the only class known to have a beta cell-protective, insulin sensitizing effect and that there are real positives to the pioglitazone despite its “warts.” Similarly, Dr. Peters offered positive commentary on the emerging benefits of pioglitazone, though she acknowledged that she would never use the full 45 mg dose due to concerns about heart failure and edema. Further, Dr. Peters suggested that the potential combination of pioglitazone and empagliflozin (to counteract heart failure concerns) is certainly intriguing – we’ve heard similar commentary from EMPA-REG OUTCOME and IRIS trial leader Dr. Silvio Inzucchi.
- Dr. Miranda also spoke optimistically about the upcoming CANVAS results for Invokana, predicting a cardioprotective class effect for SGLT-2 inhibitors. During Q&A, he called EMPA-REG OUTCOME a “landmark trial with astounding results,” and highlighted that canagliflozin has similar physiological effects to empagliflozin (lower blood pressure, weight loss, glucose excretion, reduced uric acid levels, arterial stiffness, and oxidation of free fatty acids) as a reason to believe that Invokana will also show CV benefit, especially a reduction in CV death. We are certainly eager for the next SGLT-2 inhibitor CVOT results; as of J&J’s 2Q16 financial update, CANVAS is expected to report in mid-2017.
Questions and Answers
Q: What are your thoughts on EMPA-REG OUTCOME?
A: I’m glad you asked. EMPA-REG OUTCOME is a landmark trial with astounding results – 38% risk reduction in CV death, 35% risk reduction in congestive heart failure, 32% risk reduction for any death. As an aside, you should keep in mind that it was designed as a non-inferiority trial because the FDA in all its wisdom has said that every diabetes drug that gets to market must show CV safety vs. placebo; why they still allow sulfonylureas if they think like this, I don’t know, because you’re still allowed to write that poison. What is the mechanism for this wonderful result? I told you that with SGLT-2 inhibition, you lower blood pressure, weight, and sugar without causing hypoglycemia. You see decreases in uric acid levels and arterial stiffness. You’re oxidizing more free fatty acids because of all the glucose excretion, and getting rid of lipids is theoretically a way to decrease the frequency of CV events. I do think cardioprotection is a class effect – these drivers of the CV benefit seen in EMPA-REG OUTCOME apply to Farxiga and Invokana as well. Invokana happens to be more efficient at it. When J&J comes out with their clinical trial (CANVAS) in the next one or two years, I suspect the CV results will be similar.
Q: What are your recommendations for obesity?
A: Invokana, metformin, and a GLP-1 agonist all together. You’ll see your patients lose weight.
Q: What option do we have for uninsured patients? Sulfonylureas are cheap.
A: Right, the only reason you write them is because they’re cheap and on the formulary. In a survey of the top diabetologists around the world, a majority said their top priority is avoiding hypoglycemia. What was the very last thing, of least importance to them? The cost of medication. If you want to give your patients something that doesn’t kill them, give them placebo. That’s free.
Q: Can you discuss the safety of SGLT-2 inhibitors for people with type 1 diabetes?
A: The bottom line is that your patients have to be vigilant, monitor regularly, and never interrupt their insulin doses. As a clinician, you need to look at risk factors that might predispose someone to DKA. Be careful.
Session I: Dyslipidemia, Atherosclerosis, and Cardiovascular Disease Risk Reduction
Late-Breaking Clinical Trials and FDA Update
Bernard Zinman, MD (University of Toronto, Canada); Jay Skyler, MD (University of Miami, FL)
Several speakers praised the role of cardiovascular outcome trials (CVOTs) in bringing new information to light. Dr. Bernie Zinman passionately defended the 2008 FDA CVOT guidance, arguing that, from a clinical standpoint, the cardioprotective impact of Lilly/BI’s Jardiance (empagliflozin), Novo Nordisk’s Victoza (liraglutide), and others would never have been made clear without the guidance. He suggested that the results from EMPA-REG OUTCOME and LEADER impact his own clinical decisions and practice. Dr. Jay Skyler also presented compelling evidence of the excitement generated by the latest cardiovascular outcomes trials over the last year, reviewing the impressive results from EMPA-REG OUTCOME, LEADER, and SUSTAIN 6 in a rapid-fire presentation on late-breaking clinical trials in diabetes. He underscored that SUSTAIN 6 made semaglutide the third diabetes drugs to show cardioprotection, when up to last year no diabetes drug had ever done so. He characterized the findings from cardiovascular outcomes trials a “crucial observations.” Dr. Skyler did not provide much discussion or commentary on the impact of these trials on his own thinking or on clinical practice, but tantalizingly noted that he would dive into these insights (and delve into the SUSTAIN 6 results in particular) in his upcoming session on diabetes CVOTs Friday afternoon. The presentation will mark three weeks to the day since the presentation of full SUSTAIN 6 results at EASD 2016 and we’re certainly looking forward to what Dr. Skyler has to say, especially given his prior caution in interpreting the topline results of the trial given its small size and short duration. We expect a nuanced discussion of the impressive 26% risk reduction in the primary MACE outcome and the less-welcome increase in retinopathy now that the results have had three weeks to percolate – we also certainly hope there will be time for audience questions as well!
Lipid-Modifying Therapies 2016: Opportunities and Challenges
Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX)
Baylor’s Dr. Christie Ballantyne shared fascinating insight on why treatment guidelines don’t always translate to real-world patient care and suggested ways to beat these barriers. To illustrate the issue, Dr. Ballantyne presented 2015 data on 1 million veterans with cardiovascular disease in the VA healthcare system: only 21% of females and 24% of males are on high-dose statins. He also cited a recent publication in the Journal of the American College of Cardiology which reported that of 215,193 patients with diabetes in the American College of Cardiology registry, only 62% were prescribed a statin, despite a scientific consensus that statin therapy greatly reduces risk for cardiovascular morbidity and mortality. Dr. Ballantyne called these statistics “disappointing,” especially the VA data because the drugs are very low-cost within that particular healthcare system. As he summed it, “In 2016, there’s a disconnect between fantastic science and how well these things are being implemented.” To explain this disconnect, he listed several avoidable factors: (i) Lack of awareness of the current guidelines – Dr. Ballantyne shared that >10% of HCPs are not aware of >78% of guidelines for lipid-lowering; (ii) Lack of familiarity with guidelines; (iii) Lack of agreement, in that guidelines don’t always recommend the same things, causing confusion for busy HCPs in real-world settings; (iv) Lack of self-efficacy for patients and no counseling or psychosocial support to help them; (v) Provider inertia to sway from previous practice – this affects at least 20% of HCPs, according to Dr. Ballantyne; (vi) Inability to reconcile patient preferences, especially when individuals are reluctant to go on high-dose statin therapy; (vii) Practical costs, including drug prices and under-staffed clinics.
- While this list can appear overwhelming, Dr. Ballantyne proposed that many of these hurdles can in fact be overcome with dedicated effort. We found this to be a highly informative talk elucidating one of the many reasons that we can’t seem to bridge the gap between research and the real world – many of these issues also apply to diabetes management. We’d certainly like to see greater emphasis on patient and provider education to address the gaps in knowledge and familiarity of guidelines, as well as to address patient hesitations to try evidence-based treatment approaches. Psychosocial support is also key, and something still sorely lacking in lipid management as well as diabetes management (and certainly, other disease areas).
Challenging Lipid Cases
Robert Eckel, MD (University of Colorado, Denver, CO)
In a case-based discussion panel, University of Colorado’s renowned Dr. Robert Eckel called attention to the lack of satisfactory guidelines for the management of cardiovascular risk in type 1 diabetes. He pointed out that lipid therapy guidelines from the AHA, ACC, and ADA do not distinguish between type 1 and type 2 diabetes and lamented that cardiovascular risk is much less well-characterized for type 1 diabetes. He argued that international treatment guidelines should address the heterogeneity between the two forms of diabetes, rather than just extending type 2 recommendations to patients with type 1 diabetes. The AHA, ACC, and ADA guidelines currently recommend statins for all diabetes patients over the age of 40, largely on the basis of data collected in patients with type 2 diabetes. However the type 1-specific evidence base is much weaker and, in Dr. Eckel’s view, there are “no satisfactory guidelines” on when a statin should be started in patients with type 1 diabetes. At the end of the case discussion, which was framed around the question of whether to prescribe statins for a 50-year-old woman with type 1 diabetes and perfect cholesterol numbers, Dr. Eckel concluded that a patient like this should be placed on statins, though he wishes he could recommend this on “more substantial evidence.” The field’s attentiveness toward the cardiovascular complications of diabetes, as illustrated by our current era of CVOTs and enthusiasm over drugs with cardioprotective benefits beyond glycemic control, is certainly admirable, but Dr. Eckel brings up an excellent point that there may be nuances in cardiovascular risk between type 1 and type 2 diabetes.
- That said, a large proportion of the population would probably benefit from statin therapy – which also is now relatively inexpensive as a generic – even without considering diabetes status and we expect many older patients with type 1 diabetes would likely qualify for statin usage based on other parameters. Further, the prevalence of type 1 diabetes is much lower than that of type 2 diabetes (and the growing numbers of aging patients with type 1 diabetes is a relatively new phenomenon of the last few decades as our management of micro- and macrovascular complications improves), so we expect it’s fairly challenging to enroll sufficient numbers of patients with diabetes in large-scale lipid-lowering trials in a cost-effective manner. Perhaps it would be possible to harness big data or innovative trial designs to better elucidate cardiovascular risk modification in type 1 diabetes efficiently.
Henry Ginsberg, MD (Columbia University, New York, NY)
In a Sanofi/Regeneron-sponsored session, Dr. Henry Ginsberg (Columbia University, New York, NY) highlighted the PCSK9 inhibitor class’ uniquely rapid progress from lab bench to clinic – PCSK9 itself gained attention as a target just a little over a decade ago after a 2003 Nature paper exposed a correlation between hypercholesterolemia and PCSK9 mutations and two PCSK9 inhibitors are currently approved (Sanofi/Regeneron’s Praluent [alirocumab] and Amgen’s Repatha [evolocumab]) already with several others in development, including Pfizer’s phase 3 bococizumab. Despite the PCSK9 inhibitor class’ “profound” LDL-reducing potential, both alone and in combination with statins, cost is a major barrier. Dr. Christie Ballantyne (Baylor College of Medicine, Houston, TX) described this issue, sharing that getting this highly efficacious drug to patients has been more difficult than anticipated. Coverage has a denial rate of 80%-90%, and even after expensive appeals only about 27% of privately insured patients and 46% of Medicare beneficiaries are able to obtain approval for PCSK9 inhibitors. Although most of the discussion at this symposium centered on the use of PCSK9 inhibitors in patients with familial hypercholesterolaemia (FH), the indication of PCKS9 inhibitors for patients with ASCVD includes many patients with diabetes as well. While the class is not indicated for primary prevention (as we await cardiovascular outcomes data from the ongoing trials), we’re optimistic about the impact their potent LDL lowering might have on addressing the residual cardiovascular risk faced by many patients with diabetes – though of course the cost question will need to be addressed if PCKS9 inhibitors are to reach a broader primary prevention population.
Anne Peters, MD (USC, Los Angeles, CA)
Dr. Anne Peters strongly advocated for early, aggressive therapy intensification as well consideration of outcomes beyond A1c during a Novo Nordisk-sponsored corporate symposium. She pointed to UKPDS and DCCT/EDIC trial data to underscore the long-term macrovascular and mortality benefits associated with early, intensive glucose control and emphasized that it doesn’t really matter which drug option is used as a second-line therapy after metformin, as long as it is initiated early and the patient’s A1c is not allowed to creep up to 8% or 9% before initiation. Looking to observational data from the Kaiser health system, she noted that patients are more likely to be able to get to goal following insulin initiation if the starting A1c is 8.2% vs. 9.2%. While the symposium as a whole was focused on the use of new insulin options, Dr. Peters emphasized that the ADA/EASD guidelines position several drug classes on equal footing as second-line therapy options after metformin and the decision of which to use depends on the patients’ individual characteristics and circumstances (for instance, she is often forced to use sulfonylureas or insulin after metformin in her underinsured patients, who do not have adequate access to other, newer therapeutic options). Dr. Peters especially highlighted several factors that she takes into consideration beyond an agent’s glycemic-lowering efficacy, such as the recent findings of a cardioprotective benefit for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), Novo Nordisk’s GLP-1 agonists Victoza (liraglutide) and once-weekly semaglutide, and the TZD pioglitazone. She also pointed out that pioglitazone recently demonstrated promising benefits in patients with type 2 diabetes and NASH – an area of high unmet need in which very few therapeutic options currently exist. She also further underscored the importance of glycemic variability and time-in-range and their impact on patients’ quality of life (as measured through patient-reported outcome measures).
- That said, Dr. Peters acknowledged that there are not many validated measures translating clinical parameters into patient-reported outcomes in wide clinical use and shared her personal approach in which she tracks patients’ average weekly blood glucose and standard deviation, setting an average goal of 140 mg/dl with a standard deviation no larger than 50 mg/dl. Looking to insulin, Dr. Peters specifically praised the flat profile of action of Novo Nordisk’s next-generation basal insulin Tresiba (insulin degludec) in Q&A, pointing out its ability to reduce overnight glycemic variability. She went so far to suggest that Tresiba may be better than insulin pumps for overnight variability, as infusion sets have the potential to clog or malfunction in other ways. As always, we greatly appreciated Dr. Peters’ patient-centered discussion and her emphasis on non-A1c outcomes that are often just as important to patients, if not more important – see our coverage of the recent FDA meeting on this topic for more.
- In contrast to recent commentary from others, Dr. Peters remains a strong proponent of widespread metformin usage as a first-line therapy in type 2 diabetes – or, indeed, even earlier in prediabetes. She noted that in her experience as a member of the ADA/EASD guidelines-writing committee, there were only two points that the committee could completely agree on in terms of the treatment algorithm over the two years of discussion: (i) lifestyle therapy is foundational and should continue throughout the course of treatment and (ii) metformin, with its many benefits, should absolutely remain the go-to first-line therapy. Dr. Peters offered high praise for the agent (“I could devote a whole symposium to metformin”) and shared that she starts metformin early and keeps patients on it, regardless of what other therapies she might add or subtract throughout the course of the condition. Furthermore, during Q&A, she highlighted metformin’s impressive impact on preventing progression to type 2 diabetes from prediabetes and shared that she and several others are petitioning the FDA to include prediabetes as an official indication for metformin on its label. We’re so glad to hear that leaders in the diabetes field are pushing for this very important step and we’re hopeful that an expanded indication can help reduce some of the provider and patient reluctance to medically treat prediabetes.
Session II: Hypertension, Cardio-Renal, and Heart Failure
SGLT2s: Should They Be Second Line Therapy?
George Bakris, MD (University of Chicago, Chicago, IL); Jay Skyler, MD (University of Miami, Miami, FL)
Dr. George Bakris argued that both GLP-1 agonists and SGLT-2 inhibitors should be preferred second-line diabetes treatment options. He pointed to LEADER and EMPA-REG OUTCOME, which demonstrated substantial and impressive reductions in cardiovascular risk for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) and Lilly/BI’s Jardiance (empagliflozin), respectively. He also looked favorably upon both agents’ demonstrated benefit on blood pressure lowering. Furthermore, Dr. Bakris strongly emphasized the continued efficacy of liraglutide and empagliflozin in patients with reduced renal function and highlighted the impressive positive renal data for both agents. Notably, he expressed some surprise at how the two trials have been received: while he thought SGLT-2 inhibitors would be huge following the EMPA-REG OUTCOME results, it appears that endocrinologists are actually much more comfortable with the LEADER results, presumably due to the greater uncertainty around the mechanism of benefit in EMPA-REG OUTCOME. Indeed, we’ve heard that new prescriptions of the SGLT-2 inhibitor class are actually plateauing a year after the release of the EMPA-REG OUTCOME results. Interestingly, there was noticeably more buzz surrounding empagliflozin than liraglutide among the cardiologists at ESC 2016, likely reflecting the acute hunger for better options to treat heart failure in the cardiology field. While Dr. Bakris positioned both GLP-1 agonists and SGLT-2 inhibitors as preferred second-line options, he acknowledged that there were safety and tolerability considerations for both that patients and prescribers should be aware of, such as acute gallbladder disease and GI side effects for GLP-1 agonists and DKA risk and genital mycotic infections for SGLT-2 inhibitors. In fact, Dr. Bakris stated he avoids SGLT-2 inhibitors entirely in uncircumcised men (though he shared that he had one patient who was willing to undergo a circumcision in his 50s in order to stay on SGLT-2 inhibitors because he so appreciated their efficacy profile).
- Dr. Jay Skyler agreed that GLP-1 agonists and SGLT-2 inhibitors should be preferred second-line options and suggested that the decision of which to initiate could be informed by measurements of high-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) to determine heart failure risk. He pointed to a recent paper published in JAMA Cardiology demonstrated that high levels of hsTnT and NT-proBNP were both associated with a nearly four-fold increased risk of hospitalization for heart failure in the SAVOR-TIMI cardiovascular outcomes trial for AZ’s Onglyza (saxagliptin). Dr. Skyler envisioned a future in which patients would be screened for these biomarkers and SGLT-2 inhibitors would be favored in patients with higher levels of either of these. This is the first time we’ve heard a leader in the diabetes field advocate for BNP and other biomarker measurements to help distinguish between patients who might be best suited for one diabetes therapy (SGLT-2 inhibitors) over another (GLP-1 agonists) and we hope that similar practices could help pave the way for truly personalized medicine in diabetes (where the concept lags behind the oncology field). Heart failure status and BNP measurements have been the center of increasing attention and focus since the release of full EMPA-REG OUTCOME results with their surprising heart failure finding at EASD 2015. Many have questioned the potential prevalence of undiagnosed heart failure in the trial, leading some such as Dr. Eberhard Standl to suggest that future CVOTs include BNP measurements at baseline as standard. We’re intrigued by the potential findings that could be derived from such results and the test itself is rather simple to administer and merely requires a blood sample, but it’s unclear how many of the numerous ongoing CVOTs had the foresight to collect blood samples and BNP measurements at baseline.
Keith Ferdinand, MD (Tulane University, New Orleans, LA)
The esteemed Dr. Keith Ferdinand (Tulane University, New Orleans, LA) discussed the interpretation of CVOT results in the context of African-American heart failure risk, underscoring the need for greater diversity in clinical trial enrollment. Among cardiovascular risk factors, heart failure is an issue of particular concern for African Americans, occurring at a higher prevalence, earlier age, and with greater association of hospitalization and mortality than in European American counterparts. Dr. Ferdinand went on to explain that different diabetes drugs have heterogeneous cardiovascular effects; for instance, the EMPA-REG OUTCOME trial showed particularly a robust 35% risk reduction for heart failure with the SGLT-2 inhibitor empagliflozin (HR=0.65; 95% CI=0.50-0.85; p=0.002), whereas the LEADER trial did not show a statistically significant benefit for heart failure with the GLP-1 agonist liraglutide (HR=0.87; 95% CI: 0.73-1.05; p=0.14). Dr. Ferdinand noted that, given the increased heart failure risk in African Americans, it would be of great interest to see a sub-analysis of these data assessing the impact of race. Unfortunately, none have been performed, which Dr. Ferdinand attributed to the small number of African Americans enrolled in these trials to begin with. Dr. Ferdinand concluded by surmising the need for diversity in clinical trials: “I just hope that the idea that we need to do studies quick and dirty doesn’t persist in medicine. Even though it is more expensive and more difficult, we need to do the studies right and enroll 20%-25% people of color.”
Session III: Diabetes Management
Update on Cardiovascular Outcome Trials in Diabetes
Jay Skyler, MD (University of Miami, FL)
Just three weeks after the reveal of the SUSTAIN 6 cardiovascular outcome results for Novo Nordisk’s once-weekly GLP-1 agonist semaglutide at EASD 2016, Dr. Jay Skyler offered a comparison of its trial design and outcomes to the larger EMPA-REG OUTCOME and LEADER trials. In particular, Dr. Skyler pointed out the small size (n=3,297) and short treatment duration (median two years) of the trial. He acknowledged that he initially scratched his head at the trial design, before realizing that, as a pre-approval trial, SUSTAIN 6’s goal was to demonstrate a hazard ratio lower than the FDA’s 1.8 threshold for approval, rather than the 1.3 post-marketing threshold that the other CVOTs thus far have been designed to meet. He emphasized that the positive results – demonstrating a 26% reduction in three-point MACE (cardiovascular death, non-fatal MI, and non-fatal stroke) were a huge surprise to everyone and that statisticians would have argued that it’s impossible to show cardiovascular superiority with only 254 events. As Dr. Skyler put it, “It really makes you sit back and take notice – what’s going on here?” Furthermore, Dr. Skyler highlighted the early separation of Kaplan-Meier curves (within 16-24 weeks) and the heterogeneity in the components of the primary MACE outcome. He noted that the positive primary outcome was almost entirely driven by the highly significant 39% reduction in non-fatal stroke, whereas non-fatal MI was reduced but non-significant due to a small number of events and cardiovascular death was essentially the same between the semaglutide and placebo groups (a departure from the impressive reductions in cardiovascular death observed in EMPA-REG OUTCOME and LEADER). Given this heterogeneity in the components of three-point MACE, Dr. Skyler suggested that the field may need to carefully evaluate the individual components of the composite as we analyze the results.
- In a side-by-side comparison of the three positive CVOTs, Dr. Skyler especially highlighted the substantial A1c difference between the semaglutide and placebo arms in SUSTAIN 6: a 0.7% and a 1% difference in the 0.5 mg and 1.0 mg semaglutide arms, respectively, compared to placebo. For comparison, the A1c difference with liraglutide compared to placebo in LEADER was 0.4% and in EMPA-REG OUTCOME it was 0.24% and 0.36% with the two doses of empagliflozin. Dr. Skyler speculated that perhaps the A1c reduction efficacy of semaglutide played a role in its positive results expressed anticipation and expectation for patient-level post-hoc analyses to better understand the impact of A1c on outcomes in the trial. In terms of the cardiovascular results of the trials, Dr. Skyler emphasized that the absolute risk reductions across all three trials were small (ranging from 1.6% to 2.3%) and that there was significant heterogeneity in the impact of all three agents on the components of the primary three-point MACE composite. As a result, Dr. Skyler implied that these agents may have specific and distinct roles in clinical practice.
- We were very glad to hear Dr. Skyler’s early take on the SUSTAIN 6 results. We appreciated Dr. Skyler’s detailed comparison of the design and outcomes of the CVOT landscape and his pointing out of the nuances between the SUSTAIN 6 results and the LEADER and EMPA-REG OUTCOME results. While he didn’t offer much commentary on the potential mechanism behind any of these cardioprotective effects, the clear comparison gave us much to chew on. We expect we’ll hear more discussion of these unexpected but impressive results in the coming months – and we’re particularly eager to hear diabetes experts dig into the microvascular (renal and retinopathy) results from SUSTAIN 6 further.
Insulin Therapy Options: What’s in Store for 2017?
Irl Hirsch, MD (University of Washington, Seattle, WA)
Dr. Irl Hirsch (University of Washington, Seattle, WA) continued to rally against the worrisome increases in the cost of insulin. Although Dr. Hirsch acknowledged the excitement for better basal insulins with the potential to further reduce nocturnal hypoglycemia and for faster prandial insulins with the promise for use in insulin pumps and closed loop systems, he underscored that the future of insulin therapy is daunted by the tremendously increasing price of insulin. Dr. Hirsch pointed out that US insulin prices have tripled from 2002 to 2013 and forecasted that outrage over insulin pricing is on the brink of producing a phenomenon similar to the ongoing outcry over Mylan’s EpiPen. As underscored by a series of heartbreaking quotes from Dr. Hirsch’s own patients, many people struggle to afford their insulin, and patients with high deductibles and young people newly off of their parents’ insurance plans are hit particularly hard. Lack of transparency in the prescription drug industry on pricing and rebates between pharmaceutical companies, insurers, and the pharmacy benefits manager (PBM) middlemen makes it difficult to trace precisely how this troubling situation has transpired to such an alarming scale, but Dr. Hirsch noted that this is not entirely the responsibility of insulin companies, citing PBMs as the “pituitary gland growing this whole mess.”
- How can we solve this? Dr. Hirsch made the following suggestions: (i) government involvement to ensure better insulin access, particularly for those with type 1 diabetes; (ii) more active and visible actions from professional societies such as the ADA, EASD, and AACE; and (iii) better professional and patient education about how to best use human NPH and regular insulins (which patients are increasingly turning to given their lower cost). “Insulin can still be profitable for pharmaceutical companies and PBMs without causing so much suffering for our patients,” Dr. Hirsch concluded.
Non-Insulin Therapy Options: A Look Ahead for 2017
Robert Ratner, MD (ADA, Alexandria, VA)
ADA Chief Medical Officer Dr. Robert Ratner proposed the inclusion of cardiovascular risk as an additional consideration in treatment guidelines when weighing second-line therapy options, though he suggested that this won’t be incorporated into the 2017 standards of care because cardiovascular class effects have yet to be determined. As he described it, pre-existing cardiovascular (CV) disease would join A1c-lowering efficacy, hypoglycemia, weight effects, side effects, and cost as variables in the decision for a second diabetes drug after metformin. If the evidence we’ve gathered so far persists as more data becomes available, Dr. Ratner explained that:
- (i) sulfonylureas would be labeled with a designation for increased CV events to drive awareness of the existing a black box warning for the class – this would be fantastic to see from our view (along with weight gain and hypoglycemia);
- (ii) TZDs could achieve some CV benefit designation at low-doses based on the IRIS trial – though he noted that these agents still have a question mark looming over them because of increased frequency of heart failure;
- (iii) DPP-4 inhibitors would be marked as CV-neutral based on results from SAVOR-TIMI (for AZ’s Onglyza [saxagliptin]), EXAMINE (for Takeda’s Nesina [alogliptin]), and TECOS (for Merck’s Januvia [sitagliptin]);
- (iv) among GLP-1 agonists Novo Nordisk’s Victoza (liraglutide) and semaglutide would receive recognition for the distinct CV benefit demonstrated in LEADER and SUSTAIN 6, respectively, although the neutral CV effects found in ELIXA for lixisenatide (Sanofi’s Lyxumia) stand in the way of an endorsement of CV benefit for the whole class – we look forward to hearing more on this since we felt the difference in trial design had something to do with the results; and
- (v) insulin would be marked CV-neutral based on the ORIGIN trial.
Notably, Dr. Ratner suggested that the SGLT-2 inhibitor class, or “the new kids on the block,” must await additional CVOT results before a determination can be made about cardioprotective class effect (the only published study is EMPA-REG OUTCOME for Lilly/BI’s Jardiance [empagliflozin]). To this end, Dr. Ratner announced that CANVAS for J&J’s Invokana (canagliflozin) will present full results at ADA 2017 (and we cannot wait!). For now, the ADA will conservatively refrain from adding these CV considerations to its treatment algorithm due to the lack of consistent or repeat evidence on the CV benefits of GLP-1 agonists and SGLT-2 inhibitors, and we hope that the next guidelines-writing committee will choose to include these considerations sooner rather than later. CVOTs are such a tremendous investment of time and money – not to mention that CV events are the leading cause of mortality for people with type 2 diabetes – that we would hope positive CV data has an impact on treatment guidelines, and in turn, on real-world patient care. Notably, the AACE/ACE diabetes treatment guidelines already include potential cardiovascular effects for diabetes drugs and we appreciate the guidance provided by these designations as we wait for further CVOT data over the coming years. Dr. Ratner was cautiously optimistic that CV effects will become a concrete component of guidelines in years ahead (though not so soon as 2017). This is a change we’d love to see, especially as CVOTs gain more traction and more is unraveled regarding the mechanism of cardioprotection for various agents and regarding potential class effects.
- Of the current factors listed in the ADA treatment algorithm, Dr. Ratner emphasized that cost cannot be overlooked – we were so glad to hear this since so many patients are in so much worse shape since employers have begun so much more cost-shifting. During his talk as well as the ensuing panel discussion with other diabetes experts, Dr. Ratner argued that the cost element is what has maintained metformin as first-line therapy, and what has kept sulfonylureas in play on the diabetes drug market. Dr. Jay Skyler (University of Miami, FL) advocated for the elimination of sulfonylureas from the game altogether – “take them out of the algorithm!” – to which Dr. Ratner replied, “not yet.” He did agree that the negative CV effects of sulfonylureas make them less-than-ideal agents, especially with cardioprotective drugs now available for the treatment of type 2 diabetes, but again reiterated that cost is an important variable in choosing a second-line therapy for patients inadequately controlled on metformin alone. Dr. Ratner suggested that results from the GRADE study or from CAROLINA (a CVOT comparing Lilly/BI’s DPP-4 inhibitor Tradjenta [linagliptin] vs. glimepiride) could finally allow for the extraction of sulfonylureas. While cost is widely held up as the one redeeming quality for sulfonylureas in the face of its increasingly unfavorable clinical profile, we strongly believe that this argument does not fully account for the larger health economic costs of the increased hypoglycemia risk, to say nothing of the even further downstream costs that might be associated with the weight gain and related comorbidities. While we can see why the ADA might want to at least acknowledge the use of sulfonylureas in its algorithm, we’d appreciate a greater emphasis on the downsides of these agents to especially help primary care physicians make informed decisions, as they may be less familiar with the clinical profile of diabetes agents (and sulfonylureas, along with insulin and metformin, may have been the only diabetes drugs they learned about in medical school!) We do appreciate the suggested hierarchy of usage employed by the AACE/ACE algorithm, which places sulfonylureas at the bottom of its options for mono, dual, and triple therapy and labels the class with a yellow warning icon. We expect a similar shift in the ADA/EASD guidelines may be necessary at this point to noticeably shift patients and providers from sulfonylureas to safer, more effective diabetes medications given their long history and generic status – in our view, this is a shift that needs to happen in diabetes care, and needs to be agreed upon now.
Panel Discussion: Implications of Recent Trials on Management of Diabetes – Should the Algorithms be Changed?
A lively panel discussion featuring several top diabetes experts offered renewed interest in the use of TZDs and tempered expectations for the next-generation ultra-rapid-acting insulins on the horizon. Echoing the enthusiasm for TZDs expressed in the first half of the conference, Drs. Jay Skyler, Robert Eckel, and George Bakris shared that they use pioglitazone at low doses (15 mg or 30 mg) in their patients, albeit cautiously. Dr. Eckel went so far as to suggest that pioglitazone could be considered one of the top treatment choices for diabetes, if used conservatively. Furthermore, Dr. Robert Ratner pointed to the promising cardiovascular and diabetes prevention outcomes hinted at by the IRIS, ACT NOW, and PROactive trials. Notably, he suggested that the the PROactive trial was a victim of bad trial design and that if the investigators had employed a more conservative three-point MACE primary endpoint, they would have had a “blockbuster” trial. On faster-acting insulins, Dr. Irl Hirsch suggested that patients with diabetes, especially those with type 1 diabetes, are more excited about products like Novo Nordisk’s faster-acting insulin aspart than they are about MannKind’s inhaled insulin Afrezza, even though Afrezza has a faster pharmacokinetic profile. That said, Dr. Hirsch acknowledged that faster-acting insulin aspart will only be an incremental improvement over NovoLog (insulin aspart), rather than a huge improvement. Similarly, Dr. Eckel stated that he was underwhelmed by the postprandial benefit of faster aspart and suggested that something better is necessary for patients with dangerously high, DKA-levels of hyperglycemia. Dr. Ratner chimed in that a truly improved ultra-rapid-acting insulin would also be a huge boon for closed loop systems. In either case, it’s unclear at this point when exactly the US market will see its first next-generation rapid-acting insulin – Novo Nordisk’s faster-acting insulin aspart disappointingly received a Complete Response Letter from the FDA only hours after the panel discussion ended and the timeline for resubmission is yet unknown. An EU decision on faster-acting insulin aspart is still pending, expected by 1Q17. See below for a full transcript of the nearly hour-and-a-half long panel.
Dr. Skyler: Dr. Hirsch, you talked about profit margins for pharma companies vs. benefit managers. PBMs don’t carry inventory – they’re people sitting in a room forcing prices one way or another to put things on various tiers, but they don’t add value to the system at all. These guys are the ones who should be criticized the most. In the US, we’ve legalized bribery and extortion by the PBMs.
Dr. Hirsch: This has been an incredible learning experience for me. Last year at ADA in Boston, I was pointing my finger at the pharma industry. I didn’t understand what each party brings to the table, which is very little for PBMs. The biggest issue isn’t even transparency – it’s trying to talk to the PBMs and have them come to meetings. This is a really horrible situation, and one that we need to do away with.
Dr. Ratner: It’s a battle, that’s for sure. We invited Irl to come talk about insulin cost at ADA and at our post-grad course in San Francisco. Last year there was a public statement that insulin is life-saving and no individual should lack access to insulin. We’ve called for transparency in the pricing of insulin – how does the price go up from manufacturer to the patient’s pocket? It’s a very, very complex pathway. I’ve only see one public statement from an insulin producer: Eli Lilly reported to the Wall Street Journal how much they pay to PBMs, and it was a 52% rebate for Humalog. This means the average wholesale price is already reduced by 52%, but they’re paying a lot more. That’s the bribery and extortion that Dr. Skyler is talking about. We are making the effort to move the needle on this, but it’s very difficult, particularly so because insulin is a small piece of the bigger pie when you have Mylan and the EpiPen coming forward (Editor’s note: Epipen was about a $1.0 billion dollar product last year compared to an insulin field of $20 billion – plus).
Dr. Eckel: I have two sons with type 1 diabetes. Clark, my youngest, still lives in Denver and he’s participated in multiple clinical trials because he couldn’t afford insulin and his trials allowed him to get insulin when he couldn’t afford it.
Dr. Hirsch: At the University of Washington, we get an email every year from the Dean saying our goal is to teach evidence-based medicine. But I tell them, we don’t practice evidence-based medicine. We practice PBM-based medicine.
Dr. Skyler: Right, and it might be justifiable if they were adding value to the system somewhere. But everyone is losing while they walk away with huge profits for doing absolutely nothing.
Dr. Ratner: PBMs claim that they are controlling costs, but by that virtue they are also limiting choice, so we have a dilemma – do we allow them to bring down cost but you can only use one kind of insulin, or pump, or sensor, or do we want the choice and we’re going to have even more problems controlling cost? I don’t have a solution to this dilemma, but this is the situation, as I see it.
Q: Can you comment on the inhaled insulin? It seems to have been glossed over in other talks thus far. Is it a more rapid insulin?
Dr. Hirsch: Here’s the thing, we’ve done trials with both the older inhaled from Pfizer and newer one from Mannkind, and it’s had a very rocky start. As far as the insulin itself, patients who have used it – especially in clinical trials and the few after launch – they love it. They love it because it gets in quickly and they don’t see postprandial spikes. The patients who use it absolutely love it. The concern that some of us have is what happens over the course of weeks, years, and decades when one puts a growth factor in the lungs? It’s a theoretical concern, but it is a concern. That’s why there’s so much more excitement for faster aspart in type 1 diabetes. The other problem is that very few people are using Mannkind’s inhaled insulin because its marketing relationship with Sanofi has gone away. As a result, the use of Afrezza is very low, but it hasn’t completely gone away. Whether it’ll be used more frequently in year or two or it’ll go away completely, I can’t predict. Overall though, the kinetics of Afrezza are very impressive.
Dr. Skyler: Alveolar surface area is the size of a tennis court, and you’re tossing a few drops of liquid into that large tennis court. The chances of a drop hitting in the same spot repetitively enough to cause uncontrolled growth are essentially non-existent. So, you have this theoretical concern that’s led the FDA to say we need an eight-year, 8,000-patient study with patients who have a 15-year history of smoking but are not current smokers. This study would cost $6 million and doesn’t prove anything. It’s the insanity of the FDA requiring these things, and I think it’s a pity, because there’s much potential utility for inhaled insulin.
Dr. Eckel: I was underwhelmed by the postprandial benefit of faster aspart, though the A1c did look more promising. That said, one of the most critical things about type 1 diabetes or about type 2 diabetes on basal-bolus is rapidly correcting hyperglycemia. We need something better than aspart.
Dr. Hirsch: I agree that we need something better than what we have right now. Faster-acting aspart will be an incremental improvement – not a big improvement, but it’ll be something.
Dr. Skyler: I once had a patient who’d had 40 DKA episodes. She called me many years later and said she was doing much better, and she explained that she wasn’t taking insulin before because having to come into the hospital meant she wasn’t at home, where her mother was beating her. The message is that there are other reasons people aren’t taking their insulin, particularly adolescents.
Dr. Ratner: If I can go back to ultra-rapid-acting insulins, I think there’s going to be particular niche for these insulins: closed loop systems. One of the limiting factors in any closed loop is the long tail. Even if the pump gets turned off, it still takes too long to start bringing insulin down, even with the hybrid systems you have. This is part of the reason you’re working on dual chamber systems – if insulin works for too long, you better have glucagon on board when the glucose goes too low. If we have really good ultra-rapid insulins, I expect the primary niche will be closed loop systems.
Dr. Eckel: Based on cost issues, what do people think about using regular insulin?
Dr. Hirsch: In type 1 it’s not an option, I may have one person on it as things ebb and flow with that person’s finances. I use a lot of human insulin, regular and NPH, in type 2 diabetes. When you look at the data for regular insulin in type 2 diabetes, what one finds is that the hypoglycemia advantages over the years for type 1 diabetes don’t exist for type 2 diabetes. Because of that, I feel very comfortable using regular insulin in type 2 diabetes with one huge exception – in the hospital as it takes too long for use in the hospital.
Dr. Athena Philis-Tsimikas (Scripps Health, La Jolla, CA): Dr. Ratner, I loved your conclusions with regards to second-line therapy choice and the relationship with CVOTs completed. I think primary care physicians are not going to hear the message. Do you have any recommendations on what will be coming out to help guide them?
Dr. Ratner: In the 2017 standards of care, which are being finalized literally as we speak, there’s far greater discussion of the impact of CVOTs and we’ve even been able to include the LEADER trial. We’re trying to get the word out about these positive results. Keep in mind that our standards of care are meant to be a reference module that people can go to for very specific things. In the last year, we’ve abridged the ADA standards of care specifically for primary care providers. A primary care physician committee looked at the differences between what a primary care provider would do and what a specialist would do, and eliminated most of the material which would only be relevant once a patient has already been referred to an endocrinology specialist. The hope is that we’ll be able to integrate this with electronic medical records (EMR) in such a way that pop-ups occur to guide you, at least in terms of directions to think about. Unfortunately though, EMR-integration is still a long way off.
Dr. Bakris: For blood pressure, at least in the VA system, an abridged version like this already exists that offers a practical treatment approach.
Dr. Skyler: Dr. Ratner, you said that there’s still a black box around sulfonylureas. I think that’s well deserved, because in multiple studies when one looks at sulfonylureas vs. various comparators, they always have higher risk of cardiovascular disease. There may be differences amongst the sulfonylureas in the class, but I think it’s a real phenomenon. Considering the weight gain, increase hypoglycemia, and cost of treating hypoglycemia – the black box is well deserved. I don’t think sulfonylureas should be used, expected in those with genetic KATP channel defects. So take them out of the algorithm!
Dr. Rather: Well, we can’t, not yet. I’m hoping that one useful aspect of the GRADE study will allow that. I don’t think anyone would expect the FDA to approve another sulfonylurea, but it’s their long history and low-cost that continues to drive use. On the CV aspect: In developing a CVOT for linagliptin, BI said “let’s take advantage of this” and do an active comparator study rather than a placebo-controlled one. So CAROLINA takes individuals with type 2 diabetes at risk for CV events and randomizes them to either glimepiride or linagliptin. About nine months in, the FDA says it’s not a fair comparison, because all they’re doing is showing it’s better than sulfonylureas rather than showing an intrinsic CV benefit. So now, the company has to do another study that’s placebo-controlled (CARMELINA). I think CAROLINA has the potential of finally putting a stake in the heart of sulfonylureas.
Dr. Skyler: Isn’t just asking BI to do the second study de facto admission from the FDA that the sulfonylureas suck?
Dr. Ratner: All you have to do is go to one FDA EMDAC meeting – I go to an awful lot of them. It’s difficult to understand where they’re coming from. I’ll give them credit though – a little over a month ago, on August 29, the FDA Office of the Commissioner held an open workshop on outcomes beyond A1c – what is it that’s important to patients and clinicians with diabetes in the regulatory process. It was a full day workshop, industry was involved, as were patient groups, patient advocacy groups like The diaTribe Foundation and JDRF, and AACE, ADA. The number one outcome impacting patients’ daily lives according to a dQ&A diabetes market research study was time spent in the normal blood glucose range, and better general well-being was up at the top of their list of goals for future diabetes therapies, along with reduced complications risk. The idea was that we need to come up with definitions and tools that can measure across studies so these outcomes can actually make it into the label so patients and providers can see the differences between these drugs. (The study Dr. Ratner cites can be seen at diaTribe.org – write us if you would like to see the overview and study results.)
Dr. Skyler: We have a really great commissioner at the moment. I hope he is retained, he can do a lot of good.
Dr. Hirsch: I don’t want to play devil’s advocate, but another point about sulfonylureas: 47% of prescriptions in the US are for sulfonylureas – that’s huge. They’re not going to disappear with the snap of a finger. Having said that, there are other populations that use them a lot, including gestational diabetes and women with pre-gestational type 2 diabetes. Thanks to ADA funding, we’re doing another study using CGM in vulnerable populations to determine how much hypoglycemia actually occurs on sulfonylureas.
Dr. Bakris: That will be a supremely important trial. I’ll predict the results – it’s going to be horrifying. And I’ll tell you why – many of these vulnerable patients are actually depressed, they’re not eating well, and so hypoglycemia is a very real threat.
Dr. Hirsch: I think you’re right.
Dr. Skyler: You mentioned acarbose – those aren’t in the algorithm, but in some parts of Asia, it’s the most commonly prescribed diabetes drug.
Dr. Ratner: The original EASD/ADA group actually limited the agents they would consider based on utilization in Europe and North America. The utilization of alpha glucosidase inhibitors in the US is vanishingly small – it’s only marginally above Welchol (colesevelam) and bromocriptine. You’re right that in other countries that eat incredibly high carbohydrate rich meals, alpha glucosidase inhibitors have been used extensively. What I don’t know is the tolerance of those populations for GI side effects and flatulence compared to the US – clearly they must be more tolerant, because it’s not that they don’t get side effects. I think it’s combination of cost and dietary intake that driving it. That said, I hear even in India they’re disappearing and in China their usage is going down.
Dr. Skyler: One class of agents we haven’t talked much about is TZDs. Is there a real difference between pioglitazone and rosiglitazone, or is that just nonsense?
Dr. Eckel: When I was active at the AHA, we wrote scientific statements with Sanjay Kaul and others and we didn’t implicate rosiglitazone as causing cardiovascular events. I think pioglitazone is a very effective agent that should be near the top of the treatment algorithm and the bladder cancer concerns appear to be history. The bone fracture risk seems to be related to dosage. I think using only 15 mg or 30 mg of pioglitazone could put it closer to the top of the treatment choices.
Dr. Bakris: I use a fair amount of pioglitazone, but I rarely go to 30 mg. I use it at 15 mg, never alone (usually with metformin), and never with an SGLT-2 inhibitor.
Dr. Ratner: I think there are differences between rosiglitazone and pioglitazone beyond the once a day and twice a day dosing (which would be a big enough difference in and of itself). The lipid changes are also a little different.
Dr. Eckel: The HDL effect is greater for pioglitazone; rosiglitazone has a small negative effect on LDL cholesterol. That’s the case with SGLT-2 inhibitors too though, the LDL does go up a little there and it didn’t bother anyone at the FDA for approval and clearly didn’t have a negative impact on risk as demonstrated in EMPA-REG OUTCOME.
Dr. Ratner: The interesting thing about TZDs and pioglitazone in particular are some of the outcomes trials. The ACT NOW trial looked at pioglitazone as primary prevention for diabetes – you see quite profound, long-term effects even after you stop the drug. You’ve also got the IRIS study that showed that even in individuals without diabetes, you decrease recurrent stroke. In PROactive, if you cut out the peripheral vascular component, it’s clearly quite positive. I think that trial was a classic example of bad study design – if they had been more conservative and used three-point MACE, they would’ve had a blockbuster study.
Dr. Skyler: I use pioglitazone in the 15 mg a day dose for six to eight weeks for people with hepatomegaly, which I assume is liver fat. I’ve found that to be extremely helpful.
Dr. Eckel: It’s not an FDA indication, but we’ve all experienced some success using pioglitazone in NAFLD.
Dr. Skyler: Dr. Ratner, you justified metformin on the grounds that it’s effective, well-tolerated, and inexpensive. I’m not convinced the first two of those features always hold true – metformin only showed 0.4% A1c-lowering in UKPDS and most people can’t tolerate a full dose. PK/PD studies show that unless you take 2,000 mg/day, you’re not experiencing the effects of the drug. My bias is that metformin is way overplayed, and therefore the algorithm should suggest starting with a GLP-1 or SGLT-2. If I still need additional glucose control, I add insulin. Really, I don’t see a reason to use any of the other classes beyond these three given the data we have today. The ORIGIN CVOT shows that insulin is not harmful in a cardiovascular sense. DPP-4 inhibitors are safe, but show minimal A1c-lowering, no weight loss, and no CV benefit across three published trials. So why bother with those? I stick to GLP-1 agonists, SGLT-2 inhibitors, and insulin.
Dr. Ratner: It all depends on where patients live – it’s $40 a year for metformin vs. $400 a month or a quarter for the other drugs that you’re talking about.
Dr. Skyler: If it’s not working and it’s not well-tolerated, you’re wasting even $40.
Dr. Ratner: Let’s look at ADOPT. The sulfonylurea worked and then failed rapidly, so I’m willing to scrap it. Metformin was not as good as rosiglitazone, but it was pretty good. We’re learning more about the tolerability of metformin and genetic markers to identify those that are intolerant. The GI side effects clearly appear to be dose-responsive. There’s increasing evidence that metformin need not be absorbed to be effective – if you can affect the microbiome, if you can get rid of the GI and renal disease limitations as we learn more about how metformin works (and don’t ask me how after 60 years we still don’t know how this works, but we don’t). The combination of safety and efficacy for metformin, at $40 a year, makes it really kind of hard to argue with as a first-line agent in combination with lifestyle.
Dr. Skyler: In UKPDS, the biggest effect was lifestyle.
Dr. Ratner: So in the panel earlier today, the comment was made that lifestyle was far and away the best intervention to lower blood pressure and control cardiovascular risk. The efficacy of lifestyle intervention in clinical trials is best demonstrated by DPP and Look AHEAD. The effect in Look AHEAD? Nothing. But the effect in DPP? It reduces progression to diabetes. The durability of lifestyle is poor. I was part of DPP for 17 years. We were giving out free Nikes every year, giving out health club memberships. Even then we saw 50% weight regained at 3.5 years. At 10 years, metformin was just as effective as a weight loss agent as intensive lifestyle. There was no way in our algorithm that we could exclude lifestyle – we said that you begin with lifestyle, but with symptomatic diabetes, you immediately initiate metformin as well to get people moving. Tomorrow we’re going to talk about clinical inertia and this incremental movement is just incredibly slow. How often do you see an A1c of 8.5% and say, “We need to add something, I don’t care what” and the patients says “I have had a really bad couple of weeks, I promise I’ll come back and I’ll be better.”
Dr. Skyler: If you don’t give lifestyle a chance by itself, the patient will attribute all of the benefits to the drug you prescribe. You can’t sabotage your therapy by avoiding lifestyle but it’s something to consider.
Dr. Bakris: There is a big difference between looking at UKPDS versus the EMPA-REG OUTCOME trial and the LEADER trial. The quality of care the patients had in these recent studies is astronomical, so it is difficult to compare old studies to current ones. In my world, lifestyle is always the fundamental route, but we all know that no one is going to follow these recommendations exactly. It is much easier to get someone to reduce sodium than to reduce weight. It is an ongoing effort in many patients. We give it 3 months. If the patient can prove they’ve changed their behavior and made a meaningful difference in 3 months, then I’ll give them a break.
Dr. Skyler: The question is which comes first with GLP-1 agonists and SGLT-2 inhibitors? My hypothesis is based on the paper that appeared last week in JAMA Cardiology showing that if you have a high level of high-sensitivity troponin or N-terminal pro-BNP, you have a four-fold increased risk of heart failure over the next four years. Maybe we should routinely measure this at initiation of therapy and favor empagliflozin as opposed to a GLP-1 agonist in those who have that. Otherwise, I generally start with GLP-1 agonists first, because of their weight loss and greater A1c efficacy.
Dr. Bakris: I was there when the saxagliptin data were presented at the FDA. We went back and looked at pro-BNP and looked to see if we had measure that and whether it would make any difference if we had measured it a priori. The highest quartile group had very high BNP and they were the ones by and large getting in trouble. We looked into diuretic use and there was no difference in EXAMINE. With all due respect, rather than ordering a BNP test, I think a physical exam is in order. It’s not happening often enough and that’s a problem.
Dr. Ballantyne: To reframe, the core issue here is: what happened to the prevention of heart failure? Classifying people as high-risk or low-risk, to me that’s ridiculous because it’s non-quantitative. Measuring age and race alone predicts clinical variables and I guarantee these methods will beat your physical examination. With EMPA-REG OUTCOME, there were unfortunately no samples available to measure this. Hopefully in the SPRINT follow-ups we’ll have this measured and get that data a year from now.
Dr. Ratner: When the algorithm got started, there were limited biomarkers to draw on.
Dr. Ratner: When we started with the diabetes algorithm, the issue was class effect and adequate biomarkers that can be measured. Weight is easy, efficacy is based on A1c, cost is easy. As we get better measures, whether its cardiovascular risk, events, or plasma biomarkers, then we begin to get much more granular and personalized medicine could actually take place. As biomarkers evolve, I promise we’re trying to incorporate them, but we first need to validate the data and second need to have research that points out the value of the outcome. We are moving toward personalized medicine and getting the right drug for the right person at the right time. We’re saying, if you personalize the therapy, would you actually come up with better outcomes?
Dr. Hirsch: I agree with Dr. Ratner from the point of view that we’re just at the very beginning. My guess it that endocrinologists and primary care physicians are not looking at more specific biomarkers – they’re not even ordering these tests. That said, as these biomarkers become more sophisticated, we’ll teach them to physicians and they will be more available. We’ll be able to see how these biomarkers are influenced by different drugs, by renal disease, etc. Take A1c, for example – there’s a biomarker we’ve been using forever, and it turns out we’re still learning about it. This supposed gold standard in diabetes is so complicated, and at times problematic. A better biomarker is glucose with CGM results. The only reason to order A1c then is meaningful use, because I don’t really need it.
Dr. Eckel: If we return to the clinical trials on the benefits of diabetes treatments, we should look at the various outcomes in more detail. In particular, in SUSTAIN 6, the weight reduction and A1c reduction were much greater – I’m not sure the results adequately modeled the impact of the weight or A1c reduction.
Dr. Skyler: They’re doing that. They were rushing to get the analysis done for EASD and didn’t have enough time to delve into it. But you’re right, the greater A1c, greater weight loss, and blood pressure (which was impressive but not huge) probably contributed as well.
Dr. Ballantyne: Should clinical practice be changed? We might not be ready to change the algorithms, but the communication between endocrinologists, primary care physicians, and cardiologists needs to be improved. High sensitivity troponin tests are not approved in the US, but pro-BNP is, so perhaps we should regularly assess risk for future heart failure.
Dr. Bakris: I myself order BNPs in people I’m unsure of. I’ve almost always been right, so it helps with making decisions when I’m unsure.
Dr. Ballantyne: There needs to be more discussion about the patient’s level of risk. I think empagliflozin was also helping people with heart failure with preserved ejection fraction as well as reduced ejection fraction.
Dr. Skyler: Both SUSTAIN 6 and LEADER included people with risk and no previous cardiovascular disease. In subgroup analyses, those groups didn’t show benefit and the benefit was seen only in those with established cardiovascular disease. What we don’t know is if you need to have some evidence of disease for these drugs to work.
Dr. Bakris: If you jumped in and treated blood pressure and it was normal, you didn’t get a benefit. You were trying to fix something that didn’t have a problem with it in the first place. So you’re either trying to change outcome in someone who has already had an event, or you’re doing a prevention trial – for that, let’s put a few exponentials on that minimum number of events, because it’s going to take a lot more.
Dr. Hirsch: What we need is an ORIGIN-like trial for an SGLT-2 inhibitor and a GLP-1 agonist, ideally ones that have already been in a fascinating, published trial. If we have people with prediabetes and very early-stage type 2 diabetes, my guess is that we’d show benefit in both those populations, but we can’t say until we have the concrete evidence. If you gave these drugs to people who don’t yet have diabetes – this is just a guess – but I think you could prevent diabetes. Now, a separate issue becomes: who is the bartender for these different drugs? Do I handle insulin and none of the patient’s other doctors are supposed to touch it? What about the patient’s statin, beta-blocker, and other blood pressure medications? If a nephrologist and cardiologist take over, where does that leave me and the primary care physician? It becomes a mess, especially when all these doctors are part of different healthcare systems. I once had another type of doctor stop postprandial insulin in one of my type 1 diabetes patients and replace it with metformin.
Dr. Skyler: You’re absolutely right. We have all these different healthcare systems and none of them talk to each other.
Dr. Ratner: We’re a bunch of blind men feeding different parts of the elephant. We need more coordinated care.
Dr. Skyler: I think what you’re saying is that Christie gets the ivory of the elephant, and we get the tail.
Robert Ratner, MD (ADA, Alexandria, VA); Robert Eckel, MD (University of Colorado, Denver, CO); Julio Rosenstock, MD (University of Texas Southwestern, Houston, TX)
A lively (despite the 6:30am start time!) breakfast symposium highlighted the value of a combination therapy approach to diabetes care. We heard from an all-star panel, featuring Drs. Robert Ratner (ADA, Arlington, VA), Robert Eckel (University of Colorado, Denver, CO), and Julio Rosenstock (University of Texas Southwestern, Houston, TX).
- ADA Chief Medical Officer Dr. Robert Ratner made a convincing case for earlier insulin therapy initiation. The rationale for this comes from insulin’s effectiveness as a diabetes therapy; Dr. Ratner highlighted the ability of insulin therapy to (i) swiftly reverse acute hyperglycemia; (ii) preserve beta cell function; and (iii) directly address insulin resistance. Perhaps more importantly, “you can give insulin to a patient who feels ill and immediately make them feel well.” He further argued that aggressive and early treatment of type 2 diabetes with insulin can therefore induce a so-called “honeymoon phase” where beta cell function still exists, making diabetes much easier to treat. The biggest barrier to early initiation of insulin therapy is the concept that insulin therapy is a ‘last resort,’ indicative of treatment failure. Dr. Ratner underscored that physicians must counsel their patients that “insulin isn’t a punishment – it’s effective.”
- Dr. Robert Eckel (University of Colorado, Denver, CO) discussed the importance of combination therapy, highlighting the synergistic effects of insulin and GLP-1 agonists in particular. Citing Dr. Ralph DeFronzo’s famed “ominous octet” of pathophysiological deficits in type 2 diabetes, Dr. Eckel emphasized that multiple therapeutic mechanisms are needed to target these multiple metabolic defects. Building on Dr. Ratner’s previous discussion on the need to initiate insulin therapy earlier, Dr. Eckel framed insulin and GLP-1 agonists as an ideal example of combination therapy. Their mechanisms are complementary (insulin promotes glucose uptake and decreases endogenous glucose production, whereas GLP-1 agonists increase glucose-mediated insulin secretion, may preserve beta cell mass, and decrease appetite), likely producing additive benefits for glycemic control. (This was demonstrated in the phase 3 LixiLan-O trial, which found statistically superior A1c reductions with the GLP-1 agonist/insulin co-formulation LixiLan [lixisenatide/insulin glargine] vs. either lixisenatide or insulin glargine alone.) Furthermore, Dr. Eckel pointed out that this combination therapy regimen reduces the negative side effects of either monotherapy: the GLP-1 agonists’ weight loss effects cancel insulin’s tendency for weight gain, and the GI side effects commonly associated with GLP-1 agonists are reduced in the presence of insulin.
- Dr. Julio Rosenstock (Dallas Diabetes Research Center at Medical City and University of Texas Southwestern, Dallas, TX) concluded the session with an update on the new basal insulin and GLP-1 agonist co-formulations. Dr. Rosenstock explained the rationale for the complementary effects of basal insulin and GLP-1 receptor agonists to further improve glycemic control and mitigate their respective side effects. He provided an extensive and very well balanced review of the multiple studies with different basal insulins and insulin regimens in combination with GLP-1 receptor agonists conducted over the years that demonstrated consistent A1c reductions and weight loss culminating with the fixed-ratio formulation of both agents in the same solution. Sanofi’s GLP-1 agonist/insulin glargine fixed-ratio combination iGlarLixi (lixisenatide/insulin glargine; also known as LixiLan) will likely be first-to-market in the US – a decision on its approval is expected from the FDA in November 2016, after a three month delay this past August. Novo Nordisk’s counterpart IDegLira (liraglutide/insulin degludec) expects an approval decision from the FDA in December 2016, also after a three month delay in the regulatory review process. (The drug is currently approved in the EU under the trade name Xultophy.) Dr. Rosenstock forecasted that, once available, these titratable fixed-ratio formulations may become the preferred option to initiate and/or advance therapy in type 2 diabetes, given the robustness of this dual drug approach in reducing A1c levels with weight loss and without increasing hypoglycemia in the convenience of a single injection.
Session IV: Obesity, Lifestyle Management, and Cardiovascular Disease
A Dialogue Between the Experts: The Newest Evidence on Metabolic Surgery
Lee Kaplan, MD (Harvard University, Boston, MA); Francesco Rubino, MD (King’s College, London, UK)
We heard compelling discussion on the utility of bariatric surgery as a treatment for obesity and type 2 diabetes alike. The esteemed Dr. Lee Kaplan (Harvard University, Boston, MA) described the mechanisms underlying the effectiveness of bariatric surgery, making the fascinating point that bariatric surgery is physiologically the opposite of dieting: as opposed to caloric restriction, RYGB has the effect of (i) raising energy expenditure; (ii) decreasing appetite; and (iii) reducing the stress response – thereby lowering an individual’s set point weight rather than counteracting it. Furthermore, bariatric surgeries such as RYGB and sleeve gastrectomy induce system-wide physiological changes in cholesterol (lowering LDL, raising HDL), gut hormones (increasing GLP-1 and PYY, decreasing ghrelin and leptin), and glucose homeostasis (increasing beta cell function and insulin sensitivity) that promote lasting reductions in not only weight but A1c and, a point of utmost importance at CMHC, cardiovascular risk.
- Bariatric surgery extraordinaire Dr. Francesco Rubino (King’s College, London, UK) further emphasized bariatric surgery’s benefits for type 2 diabetes, remarking that it is “unacceptable that we know of a therapy that produces a dramatic benefit in diabetes and are not encouraging it.” He pointed to the recommendations established at the 2nd Annual Diabetes Surgery Summit (DSS-II) he organized in 2015, which recommend bariatric surgery as a treatment for diabetes in individuals with a BMI >40 kg/m2 regardless of glycemic control and BMI between 30-35 kg/m2 (27.5-35 kg/m2 in Asians) for individuals with poor glycemic control. If bariatric surgery is embraced, he boldly forecasts that it will be the most radical change in the past century of diabetes care. We’ve certainly been impressed by the metabolic outcomes of bariatric surgery, as demonstrated by the STAMPEDE trial, but we believe most providers are not quite ready except in extreme cases to embrace this procedure. Of course, the dream is to be able to replicate the effects of bariatric surgery via a pharmacotherapy (such as through a PYY and GLP-1 agonist combination, potentially) or through a less invasive procedure (such as Fractyl’s Revita duodenal mucosal resurfacing procedure) – we hope that further research into the mechanism of action behind the metabolic effects of bariatric surgery can help make this a reality.
Case Consults on Lifestyle and Obesity Management of CVD
Lee Kaplan, MD (Harvard University, Boston, MA)
Harvard’s Dr. Lee Kaplan argued that aggressive obesity therapy is vastly underutilized because of a persistent “cycle of misinformation” in obesity care. He explained that challenges such as the perception that obesity is not a disease or that weight loss is a matter of willpower have the consequences of (i) discouraging people with obesity from seeking care; (ii) limiting the availability of and reimbursement for proven pharmacological and surgical obesity therapies; (iii) fostering stigma against providers using these therapies; (iv) discouraging the development of novel obesity therapies. He urged for wider education for health care professionals and the public about obesity and its treatment options – a sentiment echoed by many leaders in the field and one we hope will continue to gain traction. The obesity pharmacotherapy field, in particular, continues to face significant challenges from a combination of inadequate reimbursement and physician reluctance to prescribe the agents – Novo Nordisk’s Saxenda (liraglutide 3.0 mg) remains a lone bright spot in the field driving obesity market growth, but this is partly driven by its high list price as it only holds 10% of the market in terms of total prescriptions (TRx). We assume it is mostly wealthy, self-funded patients purchasing it.
-- by Abigail Dove, Helen Gao, Payal Marathe, and Kelly Close