October 5-8, 2016; Boston, MA; Days #1-2 Highlights – Draft

Executive Highlights

Hello from beautiful Boston, Mass.! Our drug team is at the 11th annual Cardiometabolic Health Congress, taking place at the awesome Prudential Center in the heart of the city. Days #1-2 have been full of incredible insights from none other than Dr. Anne Peters on one of our favorite topics (earlier therapy intensification and outcomes beyond A1c), Drs. Bernie Zinman and Jay Skyler on the power of CVOT data, and Dr. Christie Ballantyne on the promise (but also substantial cost hurdle) of PCSK9 inhibitors. This intimate meeting has already given us so much to think about related to diabetes and to healthcare more broadly.

See below for our top six highlights from days #1-2. Look back on our CMHC 2016 preview for what’s coming up (day #3 will have a MAJOR diabetes presence!).

Top Six Highlights

1. The great Dr. Anne Peters strongly advocated for early, aggressive therapy intensification as well consideration of outcomes beyond A1c during a Novo Nordisk-sponsored corporate symposium.

2. 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.

3. Several speakers praised the role of cardiovascular outcome trials (CVOTs) in bringing new information to light.

4. 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.

5. 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.

6. Excitement over the PCSK9 inhibitor class permeated the discussion at two lunch symposia, one sponsored by Sanofi/Regeneron and the other sponsored by Amgen.

Top Six Highlights

1. 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.

2. 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.” See below for more from Dr. Miranda, including his take on TZDs, SGLT-2 inhibitor cardioprotective class effect, and Q&A.

3. 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!

4. 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.

5. 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).

6. Excitement over the PCSK9 inhibitor class permeated the discussion at two lunch symposia. 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.

• 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.  

Detailed Discussion and Commentary

Corporate Symposium (Sponsored by Janssen)

Invokana: Examining Options to Go Further in the Treatment of Type 2 Diabetes

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.

--by Abigail Dove, Helen Gao, Payal Marathe, and Kelly Close