American Heart Association (AHA) Scientific Sessions 2016

November 12-16; New Orleans, LA; Days #1-3 Highlights – Draft

Executive Highlights

Hello from the Big Easy, where our team is on the ground bringing you all of the diabetes-related insights from the American Heart Association 2016 Scientific Sessions. Most notably, we saw another brand-new post-hoc analysis of EMPA-REG OUTCOME, demonstrating consistent benefit on cardiovascular mortality regardless of type of baseline cardiovascular disease (including atherosclerotic forms of cardiovascular disease). Despite the continuing excitement for EMPA-REG OUTCOME (as evidenced by the preference for Jardiance (empa) as a therapy expressed even in debates about the use of GLP-1 agonists and DPP-4 inhibitors this past weekend), Dr. Sanjay Kaul expressed caution in the statistical interpretation of the results – this is not surprising to us as this is, of course, uncharted territory for EMDAC/FDA. Outside of diabetes, we were treated to dynamic presentations exploring the future of precision medicine from the FDA and Silicon Valley perspectives from FDA Commissioner Dr. Robert Califf and Verily CMO Dr. Jessica Mega. On the PCSK9 inhibitor front, anticipation for outcomes results continues to build, though the ongoing commercial and reimbursement woes for the class continue. Reimbursement woes and a lack of outcomes data were hot topics of discussion on the obesity front as well.

See below for our top highlights from the first three days of the meeting. We’ll be back tomorrow with more from the last 1.5 days of the meeting – check out our preview for a look at what’s to come!

Top Highlights

1. A poster presented data from a new post-hoc analysis of EMPA-REG OUTCOME, demonstrating the consistency of the cardiovascular (CV) mortality benefit for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) regardless of baseline CV disease, whether peripheral artery disease, history of MI or stroke, single- or multi-vessel coronary artery disease, etc. We’re especially reassured to see the robustness of the results in patients with a history of atherosclerotic cardiovascular disease.

2. Dr. Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) presented several caveats to results from the EMPA-REG OUTCOME trial, ultimately concluding that “mortality but not MACE data meets regulatory criteria based on substantial evidence for effectiveness.” He outlined three features of statistical rigor that regulatory bodies look for in evaluating efficacy ­– pre-specification, replication, and preservation of type 1 error. We greatly appreciated learning this pure statistics perspective, as it holds tremendous weight in important FDA decisions including the label update for Lilly/BI’s Jardiance (empagliflozin) based on the EMPA-REG OUTCOME data reflecting a cardiovascular mortality benefit (expected in early December).

3. FDA Commissioner Dr. Robert Califf and Verily CMO Dr. Jessica Mega offered enlightening FDA and Silicon Valley viewpoints on the future of precision medicine. Dr. Califf emphasized the FDA’s top priority of protecting the public health and discussed the need to balance that mission while also encouraging innovation. Dr. Jessica Mega offered a glimpse into the next frontiers of health data collection and organization and underscored the need to create engaging technology that harnesses people’s motivations – “Can we make healthcare delightful?” We’d settle happily for more accessible and easier but we certainly don’t discourage aiming high.

4. A series of debates shed light on how the cardiology field is digesting the results of the cardiovascular outcomes trials (CVOTs) for diabetes drugs that have reported thus far. Dr. Rajagopalan (University Hospitals, Case Western Reserve) presented encouraging results of GLP-1 analogues and debated the use of these agents with Dr. Schernthaner. SGLT-2 and DPP-4 inhibitors were reviewed with leading experts taking to the stage to advocate for or caution against widespread adoption of these drugs. Finally, Drs. Faiez Zannad and Michael Farkouh presented viewpoints on whether CVOT policy and study design should be revisited.

5. PCSK9 inhibitors were the talk of the town at AHA 2016. We attended phenomenal sessions reviewing their efficacy, ongoing CVOTs (FOURIER for Amgen’s Repatha [evolocumab] is wrapping-up according to Dr. James McKenney, and will likely report at ACC 2017), development woes (Dr. McKenney offered fascinating commentary on Pfizer’s discontinuation of phase 3 bococizumab), and unfortunate high-cost and poor reimbursement status.

6. In a session on cardiovascular outcomes data for obesity drugs – or lack thereof – obesity expert Dr. Donna Ryan (Pennington Biomedical Research Center, Baton Rouge, LA) defended the safety and potency of the liraglutide molecule as a weight loss agent (Novo Nordisk’s Saxenda). She emphasized that the FDA didn’t require a post-marketing CVOT for Saxenda because there is overlap in the biological exposure of Victoza (low-dose liraglutide) and Saxenda (high-dose liraglutide).

7. In the same session, Cleveland’s Dr. Goutham Rao previewed four pipeline candidates for obesity that may be on the market in the next five years: Tesofensine (which we’ve heard about forever), Empatic (same), pramlintide/metreleptin, and Cetilistat. To add to the conversation, Dr. Jamy Ard (Wake Forest University, NC) suggested that we will start to see greater acceptance and uptake of obesity drugs as providers move on from the “graveyard” of past failures. This was reassuring to hear, though we’ll need to see it to believe it, as the obesity drug market (excluding Saxenda) has faced extremely difficult market challenges in recent quarters. We would be surprised at this stage to see successes of most of the compounds above, though anything is possible (most have already faced major development challenges and as we’ve seen in the PCSK-9 market, a weak commercial field is a major challenge).

8. Dr. Peter Wilson offered a discussion separating the residual cardiovascular risk posed by diabetes from the other risk factors. In the same session, the highly respected Dr. Robert Eckel provided an evidence-based overview on the impact of lifestyle interventions on cardiovascular risk associated with diabetes.

Table of Contents 

Detailed Discussion and Commentary


Consistent Effect of Empagliflozin on Cardiovascular Death in Subgroups by Type of Cardiovascular Disease: Results from EMPA-REG OUTCOME

B Zinman, S Inzucchi, J Lachin, J George, M Mattheus, A del Parigi, H Woerle, D Fitchett

In this post-hoc analysis of the EMPA-REG OUTCOME trial for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), investigators demonstrated that the treatment benefit of empagliflozin on cardiovascular (CV) death remained consistent regardless of type of CV disease at baseline (as a reminder, EMPA-REG OUTCOME enrolled patients with type 2 diabetes and a history of CV disease). The analysis found non-significant interactions for all CV disease classifications, meaning the risk of CV mortality remained consistent and lower with empagliflozin than with placebo regardless of type of CV disease at baseline.  The p-values for interaction were: (i) p=0.647 for single vessel coronary artery disease; (ii) p=0.327 for multi-vessel coronary artery disease; (iii) p=0.667 for history of MI; (iv) p=0.398 for history of coronary artery bypass graft; (v) p=0.668 for peripheral artery disease; (vi) p=0.556 for history of stroke; (vii) p=0.56 for heart failure; and (viii) p=0.557 for history of atrial fibrillation. This analysis was also conducted for all-cause mortality, yielding non-significant p-values for interaction of (i) p=0.617, (ii) p=0.86, (iii) p=0.574, (iv) p=27, (v) p=0.565, (vi) p=0.774, (vii) p=0.457, and (viii) p=0.193, respectively. The authors thus conclude that specific type of background CV disease does not interfere with the cardioprotection conferred by empagliflozin therapy. This post-hoc adds to the robustness of clinical data supporting Jardiance’s positive impact on CV outcomes, especially because the reduced risk for CV death drove the overall CV benefit seen in the original study (first presented at EASD 2015). Furthermore, the results notably demonstrate that empagliflozin confers cardioprotection even in patients with a history of atherosclerotic cardiovascular disease, despite the widely-held consensus that the drug largely improves heart failure outcomes rather than significantly impacting atherosclerosis. Overall, the data further contributes to the wealth of reassuring post-hoc analysis data suggesting that empagliflozin benefited the broad variety of patients enrolled in the trial, rather than the benefit being driven by a particular subgroup. The fact that the benefits seem to happen in a much broader group of patients is positive not only for the broader group of patients but also for the prescribers (easier to remember). For more, see our coverage from ESC 2016, ACC 2016, and AHA 2015.

Groundbreaking Studies in the Practice of Cardiovascular Medicine

empagliflozin, Too Good to be True?

Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA)

Dr. Sanjay Kaul has approached the groundbreaking EMPA-REG OUTCOME data with a healthy dose of skepticism, and in front of a standing-room-only crowd the revered cardiologist outlined caveats to how we should interpret results from this and other cardiovascular outcomes trials (CVOTs). Dr. Kaul listed three key criteria that regulatory authorities consider when evaluating the robustness of clinical findings: (i) pre-specification; (ii) replication; and (iii) preservation of type 1 error. (i) Pre-specification refers to the design of the CVOT. Researchers conducting EMPA-REG OUTCOME pre-specified methods of analysis for standalone CV mortality, all-cause mortality, and hospitalization for heart failure, but did not pre-specify the statistical hierarchical testing strategy eventually applied in superiority analysis for each of the secondary outcomes (rather, the focus was on statistical hierarchy for the three-point MACE primary endpoint and the key secondary endpoint of four-point MACE). (ii) On the topic of replication, Dr. Kaul explained that the FDA used to require two separate clinical trials, both with p<0.05, before considering an agent’s efficacy, because this would ensure a replication probability of >90%. The FDA now allows approvability based on one highly-reliable, statistically-persuasive (p<0.001) study. Among the EMPA-REG OUTCOME results, only the risk reduction in CV death is statistically-persuasive by this definition, because the p<0.001 of this singular trial result ensures a replication probability >90%. In contrast, the benefit in three-point MACE (p=0.038) is not statistically-persuasive – Dr. Kaul pointed out that three extra events in the empagliflozin treatment arm would have overturned superiority on the three-point MACE metric, thereby exposing the “fragility” of the evidence. (iii) The last criterion stipulates that type 1 error should be preserved even after adjustment for multiple comparisons. In EMPA-REG OUTCOME, this once again held true for CV death but not for three-point MACE, leading to Dr. Kaul’s conclusion: “In my opinion, the mortality but not MACE data meets regulatory criteria based on substantial evidence for effectiveness.” Notably, Lilly/BI is seeking a Jardiance label update for reduction in CV death, not the 3-point MACE. He added that in an ideal world, to guarantee true statistical rigor, even the CV mortality data should be replicated in a separate study. (Easier said than done but presumably “big data” will be instructive.)

  • In our view, Dr. Kaul’s insight from the perspective of pure statistics was immensely valuable. This way of thinking feeds directly into the FDA’s decision on a label update for Lilly/BI’s Jardiance (empagliflozin) to include positive CV data (coming in early December), and we heard more than one mention of the pre-specification and replication issues at the Advisory Committee meeting to discuss this label change. That said, well-respected biostatistician Dr. Stuart Pocock publicly defended the cardiovascular results at the Advisory Committee meeting. Indeed, Dr. Kaul’s caveats appeared related to the robustness of the three-point MACE results, rather than the cardiovascular death outcomes. The heart failure, largely non-atherosclerotic benefit of empagliflozin came as a surprise to many and, prior to release of the results, few expected such divergence in the three components of the MACE outcome. In light of this, some have even called for a re-evaluation of the use of a composite MACE outcome. In any case, the impact of empagliflozin on cardiovascular death is highly significant and very clinically meaningful and we find it important for this information to be displayed clearly on the drug label so that the impressive findings from EMPA-REG OUTCOME are able to reach busy patients and HCPs.
  • Following Dr. Kaul’s presentation, Dr. Naveed Sattar remarked that upcoming results from the CANVAS CVOT for J&J’s Invokana (canagliflozin) could offer “replication.” Scheduled to report at ADA 2017, CANVAS will be the second CVOT after EMPA-REG OUTCOME for an SGLT-2 inhibitor. If the results are as positive as J&J management has suggested (“very similar data to what was reported with EMPA-REG OUTCOME”) this trial would go toward demonstrating a cardioprotective class effect for SGLT-2 inhibitors, which would be such tremendous news.

Precision Medicine 2016

Precision Therapeutics for Cardiovascular Disease: The FDA Perspective

Robert Califf, MD (FDA, Silver Springs, MD)

FDA Commissioner Dr. Robert Califf offered an enthusiastic, yet measured, take on the FDA’s role in the future of precision medicine. He emphasized that precision therapeutics is not a new idea within the FDA by any means and that there is a tremendous opportunity to improve health – but also underscored the opportunity for harm as well. The FDA’s chief mission, according to Dr. Califf, is to protect the public health by ensuring the safety, efficacy, and security of the array of products regulated by the agency (which, he pointed out, goes far beyond medical therapies and devices to also include food and cosmetics – overall, $0.20-$0.25 of every GDP dollar is regulated by the FDA). But he stressed that it is also A secondary a priority is to advance public health by speeding innovations. Thus, the FDA is faced with determining how best to protect public health without stifling innovation and to explain technological and therapeutic advances to the public in a manner that allows patients and providers make informed decisions about their use. To this end, Dr. Califf advocated for a paradigm shift to a national system of health data collection in order to better facilitate the FDA’s achievement of its goals. Aspects of this new system would include (i) leveraging real-world evidence to support regulatory decisions throughout a product’s life cycle; (ii) active surveillance to better protect patients; (iii) data collection embedded within the healthcare system in routine clinical care; and (iv) a shared system that informs all stakeholders, including patients, clinicians, providers, payers, the FDA, and device firms.

  • Dr. Califf also highlighted the importance of “patient-focused” drug and device development. He underscored the importance of understanding patient preferences and needs so that the FDA is better able to steer therapies in the right direction and noted that the medical device field has been making particular strides in this direction. We’re also hopeful for advances on this front in the diabetes drug field – the recent FDA workshop on outcomes beyond A1c was a particularly promising dialogue on how the FDA may begin to place greater weight on outcomes that truly matter to patients and on what those outcomes really are.
  • In a separate presentation later in the morning, Dr. Califf talked about the importance of big data as part of suggested that the FDA’s eHealth policy. is forced to make tough regulatory choices due to capacity constraints. As he put it, most mobile apps are not medical devices. He shared that while some mobile apps may fit this definition of a device, the FDA focuses its regulatory oversight on only a small subset of mobile applications that may impact the performance or functionality of currently regulated medical devices and may pose a risk to patients if they don’t work as intended.  Through this policy, the FDA seeks to protect the public health while promoting innovation.  the FDA has the authority to regulate a huge variety of apps, including patient self-management tools, but that it would “exhaust everyone at the FDA to deal with it. As a result, the FDA has adopted a policy of largely leaving the field alone unless something goes wrong, at which point the agency does hold the authority to regulate. These statements further enforce the need to invest in expanding workforce capacity and resources at the FDA, especially given the rapid expansion in healthcare technologies and therapies.
  • “When I was offered the job by the President, he spent 10 minutes telling me that precision medicine isn’t only critical to our health, but it’s probably the basis of the American economy for the next several decades.” We were glad to hear this further confirmation of President Obama’s commitment to advancing the health of the nation and can only hope that this recognition of the importance of health and health innovation to the US as a whole continues through the next administration.

Precision Medicine: A Silicon Valley Perspective

Jessica Mega, MD (Chief Medical Officer, Verily, Mountain View, CA)

In a very engaging presentation, Verily’s (formerly Google Life Sciences) Chief Medical Officer Dr. Jessica Mega advocated for three key catalysts for the convergence of technology and healthcare toward the vision of precision medicine: (i) innovation in how health information is collected; (ii) improved organization of massive amounts of health data; and (iii) activation of health information to engage patients and providers. Formerly a prominent cardiologist from Harvard, Dr. Mega translated Verily’s ambitious goals for the future of healthcare to the individual patient level. In particular, she highlighted the 415 million patients globally with diabetes and the alarming forecasts that the population of people with diabetes will rise to 642 million by 2040. On the individual level, she described her own grandfather’s complex diabetes care routines with daily fingersticks and stacks and stacks of handwritten BGM values, surmising that diabetes, like many diseases, is one in which “disease states are both variable and often manually collected” and patients spend their entire lives managing diabetes, but only 20 or 30 minutes at a time with their primary care physician. As a result, Dr. Mega characterized technology as an opportunity to make episodic data collection and decision-making more continuous and actionable. We so appreciated Dr. Mega’s digestible and dynamic discussion on the role of technology in health – and we’re so glad that she and Verily are focused on this area!

  • Dr. Mega highlighted the potential of turning everyday devices into instruments of data collection. She pointed out that our phones are able to track and collect a variety of health data currently, from an ever-growing multitude of fitness, activity, and health apps. Going further, Dr. Mega briefly highlighted the company’s efforts to produce a tiny Dexcom-partnered CGM sensor – spotlighting the recently-unveiled next generation sensor that is seven times smaller than current sensors, about the size of an M&M – and to produce a glucose-sensing contact lens with Novartis. She suggested that both of these innovations are only now possible due to the advances toward increasingly small electronics and tools that facilitate ubiquitous connection of devices to the cloud with no need for complicated set up.
  • Artificial neural networks and machine learning will be critical to useful organization of collected health data, according to Dr. Mega. Rather than programming technology with a static set of explicit rules, modern artificial neural networks attempt to learn from input and examples that build on each other until the network is capable of complicated functions. An example of this sort of learning is the sorting of photos by facial recognition on iPhones. In the diabetes and health arena, Dr. Mega suggested that similar machine learning systems could be employed to analyze large amounts of eye imaging data, making it easier to screen for diabetic retinopathy on a scale large enough to keep up with growing diabetes rates globally.
  • “Can we make healthcare delightful?” Dr. Mega emphasized the role of design thinking in truly motivating patients and providers in meaningful ways. Traditional clinical data capture tools (such as the food diary and blood glucose log) can often feel like work, but perhaps gamification of data collection or reframing goals around different motivations can be more effective. For instance, a bike enthusiast with diabetes may be more motivated by potentially being able to ride more quickly than by a blood glucose value. Dr. Mega underscored that, despite all of technological advances on the horizon, we won’t shift the needle unless we understand what truly motivates people. To that end, she highlighted the role of A/B testing to collect information on what sort of motivation actually improves outcomes.

Cardiovascular Outcome Trials (CVOT) in Type 2 Diabetes Mellitus: Controversies to Consensus

Glucagon Like Peptide-1 (GLP-1): Cardiovascular Effects are Compelling vs. There are Troubling Signals and a Cautionary Approach is Appropriate

Sanjay Rajagopalan, MD (University Hospitals, Case Western, Cleveland, OH) and Gerit Schernthaner, MD (Medical University of Vienna, Austria)

Drs. Sanjay Rajagopalan and Gerit Schernthaner debated the implications of the recent cardiovascular outcomes trials (CVOTs) for GLP-1 agonists. Dr. Rajagopalan advocated for broader use of the class based on the compelling results from the LEADER and SUSTAIN 6 trials for Novo Nordisk’s Victoza (liraglutide) and once-weekly semaglutide, while Dr. Schernthaner cautioned that several questions surrounding GLP-1 agonists remain unanswered. In particular the CV mortality and total mortality signals from LEADER were compelling albeit at a different time scale than EMPA-REG OUTCOME. Dr. Schernthaner emphasized the heterogeneity in the results of the three GLP-1 agonist CVOTs to report full results thus far: (i) the LEADER trial demonstrated a significant reduction in cardiovascular and all-cause mortality but not a statistically significant reduction in non-fatal stroke or non-fatal MI; (ii) the SUSTAIN 6 trial demonstrated a statistically significant reduction in non-fatal stroke and a trend toward reduction in non-fatal MI, but no reduction in cardiovascular or all-cause mortality; and (iii) the ELIXA trial for Sanofi’s Adlyxin/Lyxumia (lixisenatide) was resounding neutral overall (but was however performed in an ACS population). By way of potential explanation, he pointed out that the severe hypoglycemia rate was much higher in the placebo arm of the LEADER trial than in the liraglutide trial, which may be driving mortality benefit rather than a cardioprotective effect of liraglutide itself (SUSTAIN 6 did not find a similar disparity in severe hypoglycemia rates, Dr. Schernthaner noted). Indeed, Dr. Rajagopalan flipped this point around to suggest that a reduction in severe hypoglycemia – a benefit of GLP-1 agonist therapy – may be part of the mechanism by which liraglutide exerts its cardioprotective benefit. Overall, however, Dr. Schernthaner concluded that the heterogeneity in the results among the different trials is difficult to reconcile.  

  • Turning to adverse events, Dr. Schernthaner raised the point that the increased risk of retinopathy found with semaglutide treatment in SUSTAIN 6 is worrisome. Additionally, Dr. Schernthaner expressed concerns about the potential risks of bile duct and gallbladder disease or pancreatic cancer and melanoma associated with GLP-1 agonist. By way of rebuttal, Dr. Rajagopalan acknowledged that GLP-1 agonists may be associated with some increased risks (though he largely dismissed the hullabaloo over GLP-1 agonists and cancer – indeed, even the infamous Dr. Peter Butler has acknowledged that the data to date is vastly reassuring), but emphasized that, given the considerable cardiovascular benefit, the overall risk-benefit ratio still falls in favor of their use.
  • Ultimately, Dr. Schernthaner favored the use of Lilly/BI’s Jardiance (empagliflozin) over GLP-1 agonists, characterizing the EMPA-REG OUTCOME CVOT results for empagliflozin as much more compelling from a cardiovascular standpoint. He pointed out that EMPA-REG OUTCOME demonstrated a larger relative risk reduction for cardiovascular and all-cause mortality than either LEADER or SUSTAIN 6, and furthermore demonstrated substantial benefit in reducing hospitalization for heart failure and doubling of serum creatinine. On the other hand, Dr. Rajagopalan emphasized that empagliflozin and GLP-1 agonists should be viewed as potentially complementary therapies, rather than a choice of either-or. We’ve been encountering significant discussion at scientific meetings on how SGLT-2 inhibitors and GLP-1 agonists should be positioned relative to each other and other glucose-lowering drugs – we continue to be intrigued by the idea of a combination of SGLT-2 inhibitors and GLP-1 agonists (further supported by the DURATION-8 results presented at EASD 2016) and continue to believe that the choice of therapy might come down to individual evaluation of patient risk factors/biomarkers and preferences. 

DPP-4 Inhibition: Overall Safety and Glycemia Lowering Should Indicate CV Benefit Over Long Term vs. Worrisome Heart Failure Signal and Very Modest Effect on Glucose Do not Indicate Enduring CV Benefits

Jacob Udell, MD (Women’s College Research Institute, Toronto, CA) and Benjamin Scirica, MD (Brigham and Women’s Hospital, Boston, MA)

Drs. Jacob Udell and Benjamin Scirica took to the podium to discuss the role of DPP-4 inhibitors in the modern treatment algorithm, given their lack of cardioprotective benefit and possible signal for increased risk of hospitalization of heart failure. Dr. Udell emphasized that the three DPP-4 inhibitor cardiovascular outcomes trials (CVOTs) thus far – TECOS for Merck’s Januvia (sitagliptin), SAVOR-TIMI for AZ’s Onglyza (saxagliptin), and EXAMINE for Takeda’s Nesina (alogliptin) – have demonstrated a reassuring neutral cardiovascular impact for the class overall. That said, Dr. Scirica retorted that, in a world where cardioprotective glucose-lowering drugs exist, the selling point of being “as good as placebo” just doesn’t quite cut it anymore. Furthermore, Dr. Scirica expressed concerns about the increase in hospitalizations for heart failure observed in the SAVOR-TIMI and EXAMINE trials and especially pointed out that we still don’t know the mechanism behind this increased risk, which makes it difficult to manage or mitigate. Dr. Udell also acknowledged the worrisome increased heart failure risk, but suggested that the concerns could be managed by following the FDA’s 2016 label update to proceed with caution with saxagliptin and alogliptin, particularly in patients with existing heart failure or chronic kidney disease, and to monitor for heart failure after initiation.

  • Overall, however, Dr. Scirica argued that, in the context of alternative glucose-lowering therapies that have demonstrated cardioprotection, DPP-4 inhibitors should be relegated to fourth or fifth-line therapy. While Dr. Udell similarly expressed his belief that SGLT-2 inhibitors will ultimately become first-line therapy for type 2 diabetes, he advocated for a role for DPP-4 inhibitors for additional glucose-lowering if patients are not able to get to goal on the diabetes drugs that have demonstrated cardioprotection. We expect DPP-4 inhibitor/SGLT-2 inhibitor fixed-dose combinations may gain popularity due to this sentiment, especially companies invest in positioning and promoting the combinations well. That said, DPP-4 inhibitors do not product further A1c reductions on top of GLP-1 agonist use and we’ve heard some leaders in the diabetes field express strong preference for the use of GLP-1 agonists over DPP-4 inhibitors given the greater A1c efficacy and potential for cardioprotection. On the other hand, Dr. Udell expressed skepticism that patients by and large would be willing to tolerate GLP-1 agonists due to their administration by injection and suggested that they were largely be a niche product unless they are combined with other medications, such a poly-shot with a PCSK9 inhibitor. That’s certainly an intriguing possibility, especially if GLP-1 agonists are able to demonstrate cardiovascular benefit in non-diabetes patients and a “poly-shot” can be applied to individuals with very high cardiovascular risk without diabetes. Of course, in the diabetes field, fixed-ratio single injection combinations of GLP-1 agonists and basal insulin are already available in Europe and are right around the corner in the US and could be considered a “poly-shot” themselves. Overall, cardiologist Dr. Udell’s preference for empagliflozin over GLP-1 agonists appears to reflect the growing difference among cardiologists and endocrinologists that we and others have noticed lately: in very broad strokes, cardiologists appear to be much more eager to embrace the EMPA-REG OUTCOME results while endocrinologists are extremely enthusiastic about the GLP-1 agonist results.

Sodium-Glucose Co-Transporter-2 Inhibitors: The Hemodynamic Effects of EMPA-REG are Compellin vs. EMPA-REG Cardio-Renal Results are Attributable to Changes in Fuel Metabolism

George Bakris, MD (University of Chicago, IL) and Sunder Mudaliar, MD (UC San Diego, CA)

Drs. George Bakris and Sunder Mudaliar succinctly summarized two of the dominant hypotheses regarding the mechanism of benefit demonstrated in the EMPA-REG OUTCOME trial for Lilly/BI’s Jardiance (empagliflozin). A nephrologist by training and trade, Dr. Bakris advanced the hemodynamic effect hypothesis while Dr. Mudaliar presented the case for the fuel energetics hypothesis (the “thrifty substrate” hypothesis first described by Drs. Mudaliar and Ele Ferrannini at ADA 2016). Dr. Bakris highlighted empagliflozin’s intra-renal effects (single nephron hyperfiltration prevention and albuminuria lowering) and systemic mechanisms (A1c, blood pressure, body weight, and extracellular fluid volume reduction), emphasizing that all of these can contribute to the heart failure benefits observed in the trial. On the other hand, Dr. Mudaliar likened the increased ketones associated with empagliflozin usage to a more efficient fuel for a car and suggested that increased cardiac efficiency and function may be responsible for the reduction in heart failure observed in the trial. In his rebuttal, Dr. Bakris ultimately suggested that the actual mechanism of benefit may be due to a combination of both hypotheses, with the hemodynamic effect “getting the ball rolling,” with the metabolic effects contributing as well.

Current Non-Inferiority Designs Have Worked Well and There is No Need to Change the Paradigm vs. Traditional Non-Inferiority Trials for CVOT of Historic Interst and Alternatve Designs are Important for the Future

Faiez Zannad, MD (Centre Hospitalier Universitaire, France); Michael Farkouh, MD (University of Toronto, Canada)

Drs. Faiez Zannad and Michael Farkouh presented the pros and cons, respectively, of the traditional, non-inferiority design for cardiovascular outcomes trials (CVOTs). Dr. Zannad focused on positive consequences of the FDA’s 2008 guidance stipulating a post-marketing CVOT: (i) The requirement pushed industry to consider, and to empirically estimate the CV risk associated with therapeutic agents; (ii) It incidentally led to the discovery of cardioprotective benefit for new diabetes agents such as empagliflozin (Lilly/BI’s Jardiance), liraglutide (Novo Nordisk’s Victoza), and semaglutide (Novo Nordisk’s once-weekly GLP-1 agonist, in phase 3 for type 2 diabetes); and (iii) It encouraged more industry investment in research and development instead of marketing. Dr. Farkouh then took the stage to highlight some of the negative consequences of non-inferiority study designs: Most notably, experts have trouble accepting superiority data as credible if a trial sets out to show non-inferiority. We heard this argument at the FDA Advisory Committee meeting considering a label update for Jardiance based on results from EMPA-REG OUTCOME – the FDA delayed a decision on the label revision by three months, to early December. That said, many large-scale trials employ a hierarchical statistical test for non-inferiority, followed by superiority, though truly surprising results with no clearly pre-specified methods of superiority analysis (such as the cardiovascular death and heart failure findings from EMPA-REG OUTCOME, as pointed out by Dr. Sanjay Kaul at another Sunday session) may cause some skepticism among regulators and providers. Despite these concerns, the cardiovascular death results from EMPA-REG OUTCOME are compelling for many, a view echoed by numerous respected thought leaders, including Drs. Neil Poulter, Juris Meier, and Bernard Zinman at EASD 2016. Overall, the 2008 FDA guidance has clearly set the stage for the impressive CVOT results we’ve seen thus far, but we continue to believe that the FDA CVOT guidance could be revised to maximize efficiency in light of the limited resources within diabetes. We would love to see incentives for companies to conduct superiority CVOTs for drugs that may show cardioprotection. We’d also like to see requirements for CVOTs for drugs that may have the potential for harm, but less stringent outcomes requirements for the many products that fall between these two ends of the spectrum. We imagine the high cost of conducting a CVOT serves as a major barrier to entry for smaller biotech companies that might otherwise be interested in investing more seriously in diabetes.

Corporate Symposium: Navigating the Complex Maze of LDL-Lowering Therapies (Sponsored by Sanofi & Regeneron)

Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA); Michael Davidson, MD (University of Chicago, IL); James McKenney, PharmD (Virginia Commonwealth University, Richmond, VA); Vivian Fonseca, MD (Tulane University, New Orleans, LA)

This outstanding expert panel reviewed the latest clinical evidence on lipid-lowering therapies, with Dr. Vivian Fonseca (Tulane University, New Orleans, LA) focusing on patients with diabetes as a particularly high-risk group in need of moderate-to-intensive lipid-lowering. He cited real-world data showing that <56% of patient-days for people with diabetes are covered with statin therapy of any intensity, despite consensus among guidelines that statins should be prescribed for lipid-lowering as a way to manage CV risk and other complications of diabetes. Only ~10% of patients with diabetes are put on high-intensity statin therapy, which Dr. Fonseca described as clear under-use. A key takeaway from his talk was that “LDL matters” in diabetes care, and he argued that reducing cholesterol is not emphasized to the extent that it should be in managing the chronic disease. To encourage better lipid treatment in diabetes, Dr. Fonseca suggested that we need to define optimal lipid goals for this patient population – this has yet to be determined empirically. Other speakers also shared valuable insights on lipid-lowering drugs – particularly PCSK9 inhibitors, their advantages and disadvantages – and provided exciting updates on these “new kids on the block”:

  • Dr. James McKenney (Virginia Commonwealth University, Richmond, VA) spoke to the timeline for FOURIER results: “I can tell you tonight that the FOURIER study is done, and that results will probably be presented at ACC 2017.” Indeed, Amgen management mentioned during the company’s recent 3Q16 update that CVOT results for Repatha (evolocumab) are expected in the first quarter of 2017. Amgen’s CVOT would be the first to report for a PCSK9 inhibitor, and you can bet we’re incredibly eager for the results. For context, the ODYSSEY Outcomes CVOT for Sanofi/Regeneron’s Praluent (alirocumab) is expected to complete in February 2018.
  • Dr. McKenney speculated that allergic reactions may have been behind Pfizer’s discontinuation of phase 3 PCSK9 inhibitor bococizumab. During the company’s 3Q16 earnings update, Pfizer management attributed the decision to an increased frequency of injection site reactions with bococizumab vs. placebo, higher levels of immunogenicity, and an attenuation of the lipid-lowering effect over 52 weeks in phase 3 investigations. Allergy could be the glue linking these three variables, according to Dr. McKenney. Like us, he remarked that he was quite surprised by the bococizumab discontinuation.
  • Insufficient payer coverage of PCSK9 inhibitors is a substantial challenge that permeates the drug class – to help surmount this hurdle, Dr. Michael Davidson (University of Chicago, IL) proposed a three-pronged approach to obtaining a prior authorization: (i) Document that your patient has tried maximum-intensity statin therapy, to no avail; (ii) Illustrate familial hypercholesterolemia (FH) or atherosclerotic cardiovascular disease by established clinical criteria; and (iii) Show that LDL cholesterol remains dangerously high in your patient (LDL between 70-100 mg/dl with a recent CV event, for example, or LDL > 130 mg/dl with FH). Encouraging HCPs to put in this extra effort is a tall but worthwhile task – ideally, we’d love to see payers recognize the value of PCSK9 inhibitors for patients not adequately controlled on statins alone, and we’d hope to see better reimbursement. Poor payer coverage was touched upon by Pfizer management as a reason for the bococizumab discontinuation as well, which goes to show the unwanted consequences of insufficient reimbursement on industry incentives to develop the next-generation of advanced therapies.

Update on CVD Prevention in Type 2 Diabetes

Epidemiology of Diabetes and CVD: Is Diabetes Really CVD Risk Equivalent?

Peter Wilson, MD (Emory University, Atlanta, GA)

Emory University’s Dr. Peter Wilson (Atlanta, GA) discussed the considerable challenge of separating the increased cardiovascular (CV) risk associated with diabetes from the risk posted by other, associated factors and biomarkers, including adiposity, glomerular filtration rate, triglyceride levels, and elevated glucose, to name a few. He presented different pieces of contradictory data that illustrates the challenge: One study found a 19% heightened risk for a subsequent CV event given a prior CV event and a very close 20% heightened risk given a diabetes diagnosis, but a separate meta-analysis demonstrated that diabetes doubles or triples risk for CV events, while prior MI increases this risk four-fold. The discrepancy lies in the details. Dr. Wilson explained that a patient with more controlled hyperglycemia doesn’t face the same CV risk as someone with less controlled hyperglycemia. Obesity likely compounds the risk for CV morbidity and mortality among people with diabetes, but he pointed out that not all risk calculators incorporate adiposity. As obesity rates rise, adiposity becomes an even more important physiological marker to consider, especially because it lies upstream to so many other cardiometabolic risk factors such as high triglycerides and blood pressure. The trifecta of obesity, diabetes, and a prior MI almost guarantees a CV event – Dr. Wilson shared that women with all three of these conditions face a 79% risk for a CV event, while men face a frightening 87% risk. Glomerular filtration rate in the kidneys and a patient’s medication adherence are additional aspects of chronic disease that directly impact CV risk, and Dr. Wilson argued that these characteristics along with obesity must be weighed heavily in the management of CV risk in patients with diabetes. Given his frequent participation on FDA Advisory Committees (see our coverage of the meeting to discuss a label update for Lilly/BI’s Jardiance [empagliflozin] and to discuss approval of Sanofi’s LixiLan [lixisenatide/insulin glargine]), Dr. Wilson’s view on a topic as prominent as CV outcomes is tremendously valuable. We’d be curious to see CV risk evaluations that more seriously consider specific risk factors, and we wonder if and how these calculators might be used to the benefit of empirical studies and CVOTs.

  • Though most of his talk focused on type 2 diabetes, Dr. Wilson underscored an important point about CV risk in type 1 as well: Cause of death in this patient population used to be split into three, with one-third of mortality attributed to DKA, one-third attributed to kidney disease, and one-third attributed to CV disease. Now, “people aren’t dying of DKA anymore, and CV disease is the leading cause of death for type 1 diabetes,” Dr. Wilson shared. This somber statement emphasized his argument on the need to more rigorously examine CV risk in individual patients based on the unique features of their diabetes, rather than referring to diabetes on the whole as “risk equivalent” to a prior CV event. The latter tendency ­­– still common in the diabetes field – oversimplifies CV risk management and is holding us back from more optimal diabetes care.

Do Lifestyle Changes Reduce CV Outcomes in Diabetes?

Robert Eckel, MD (University of Colorado, Denver, CO)

The straightforward answer to Dr. Robert Eckel’s assigned talk title is – very plainly – “yes” (in fact, he described his “real title” as “How Lifestyle Impacts CVD Risk in People with Diabetes”). Of course, Dr. Eckel took this much further, summarizing some of the evidence-base for the value of diet and exercise in CV risk management and diabetes care. A Mediterranean diet has demonstrated several clinically meaningful, statistically significant effects: (i) reducing systolic blood pressure by a mean 2.1 mmHg (p=0.043); (ii) reducing total cholesterol by a mean 5 mg/dl (p=0.05); and (iii) raising HDL cholesterol by a mean 3 mg/dl (p=0.017). The diet also lowers A1c by an average 0.3%, which might not “knock your socks off,” but still has a profound influence on complications, Dr. Eckel explained. The large-scale PREDIMED study (n=7,447) conducted across multiple centers in Spain found that the Mediterranean diet supplemented with extra virgin olive oil reduces risk for three-point MACE (acute MI, stroke, or CV death) by 30% (p=0.009); the Mediterranean diet supplemented with mixed nuts also reduces risk for three-point MACE by 30% (p=0.02). Importantly, a sub-group analysis by diabetes diagnosis confirmed that these beneficial dietary effects hold true for patients with type 2 diabetes (p=0.63 for interaction). Dr. Eckel also presented data on the DASH diet, which is correlated with a 3 kg excess weight loss vs. control diet (p=0.006) and a 5 cm excess reduction in waist circumference (p=0.002) – he particularly highlighted the change in waist circumference as a “major, meaningful impact.” Finally, turning to exercise, he described how physical activity and modest weight loss lead to a mean 0.5% A1c reduction, which is about equivalent to the therapeutic glucose-lowering effect of a DPP-4 inhibitor (we thought this was a pretty neat comparison!). Ultimately, Dr. Eckel established a heart healthy lifestyle as step #1 to effective management of CV risk in people with diabetes. We loved this overview of the empirical data supporting the health benefits of specific lifestyle interventions, namely changes to diet and exercise – in a world where we’re inundated with various fad diets, this evidence-based guidance on lifestyle interventions is much appreciated.

Cardiovascular Outcomes with the New Generation of Obesity Pharmacotherapy: The Good, the Bad, and the Ugly

Obesity Pharmacotherapy in the Context of the 2013 AHA/ACC/TOS Guidelines for Obesity Treatment

Donna Ryan, MD (Pennington Biomedical Research Center, Baton Rouge, LA)

We’re in the midst of a paradigm shift in our approaches to obesity management, according to Dr. Donna Ryan. While 2013 guidelines positioned obesity drugs as a rescue effort, or last resort for individuals who couldn’t lose weight with lifestyle modification, 2016 guidelines recognize the therapeutic value of pharmacotherapies for chronic weight management. Dr. Ryan described this paradigm shift as a positive change. Instead of treating large body size – which she equated to something as cosmetic and trivial as “dress size” or “belt size” – healthcare professionals are starting to treat obesity as a way to improve someone’s overall health. Addressing why obesity drugs are still prescribed at low volume, Dr. Ryan reminded the audience that most currently-available weight loss pharmacotherapies have only been on the market for two-three years (Contrave and Saxenda were both approved in 2014), which means the field is still accumulating experience and familiarity with these agents. “We’re in the dawn of helping patients sustain weight loss,” she claimed with most-welcome optimism, since the dominant perspective on the obesity drug market seems to be less-than-enthusiastic. During the ensuing panel discussion, Dr. Ryan suggested that acceptance and uptake of obesity drugs will take time and provider education – “I’m glad there’s not some land rush to prescribe these drugs, because there are techniques to using them that are really important. Doctors like to be part of the herd,” and she conveyed a sense that this herd is building slowly. We certainly hope this is true, although Novo Nordisk’s Saxenda (liraglutide 3.0 mg) seems to be the only obesity product faring well in terms of sales growth (most major obesity products experienced sales decline in the first half of 2016). We hope the other obesity pharmacotherapies may be able to remain financially sustainable as comfort with their use slowly builds but this is hard to call at this stage.

  • Dr. Jamy Ard (Wake Forest University, Winston-Salem, NC) corroborated Dr. Ryan’s argument in his talk during this session as well, explaining low prescription volume for obesity drugs as a product of past failures. The field is still recovering from the “graveyard” of obesity pharmacotherapies that demonstrated adverse side-effects post-approval. On the bright side, Dr. Ard continued, healthcare providers and regulators are coming around to the notion of obesity as a chronic disease as opposed to a cosmetic issue. This shift in perspective to obesity as a biological disease confers two important benefits, in his view – increasing prescriptions of new, effective agents for chronic weight management and encouraging better reimbursement of these drugs from payers. We were glad to hear Dr. Ard speak on this last point, since the often-prohibitive cost of drugs cannot be ignored in this discussion of obesity pharmacotherapy: use and underuse.

Current FDA-Approved Obesity Pharmacotherapy and Cardiovascular Outcomes: What Do We Know?

Tiffany Powell-Wiley, MD (NIH, Bethesda, MD)

NIH’s Dr. Tiffany Powell-Wiley underscored the lack of clinical outcomes data on the  CV effects of currently-available obesity drugs and pointed to the lack of clinical outcomes data for this drug market. While studies have investigated a range of biomarkers for CV health (i.e. systolic blood pressure, heart rate) stemming from obesity drug use, no reliable trial has yet shown the benefit or detriment of an obesity drug to the real-world occurrence of MI, stroke, or CV death. Orexigen’s LIGHT trial for Contrave (naltrexone/bupropion extended-release) was terminated early due to interim data disclosures; Vivus is currently negotiating with the FDA to conduct a retrospective cohort study probing for CV effects in place of a traditional prospective CVOT for Qsymia (phentermine/topiramate extended-release). Liraglutide is the only agent that has shown meaningful cardioprotection in the LEADER trial, but Dr. Wiley-Powell underscored that this CVOT was examining treatment with lower-dose liraglutide (Novo Nordisk’s Victoza) rather than 3.0 mg liraglutide (Novo Nordisk’s Saxenda, indicated for obesity). To be sure, we understand that conducting a CVOT is no simple feat – these trials require tremendous time, investment, and company resources, which many obesity companies are not able to devote to a large CVOT at this time given the sluggish sales of most obesity drugs currently. That said, we appreciated Dr. Wiley-Powell’s call for better data on this front, since obesity is such a key risk factor for CV morbidity and mortality.

  • During Q&A, Dr. Donna Ryan emphasized that the FDA did not require a post-marketing CVOT for Saxenda due to overlap in the exposure of 1.8 mg liraglutide (Victoza) and 3.0 mg liraglutide (Saxenda). “Exposure of the active agent in Victoza is higher in women because of sex differences in how the drug is distributed in the body, so it didn’t seem necessary to do a separate CVOT with 3.0 mg liraglutide. It’s important to get your head around that – 3.0 mg liraglutide is not a scary thing. We have the data we need on exposure to be confident in its benefits.”

Cardiovascular Considerations of Obesity Pharmacotherpay on the Horizon

Goutham Rao, MD (Case Western University, Cleveland, OH)

Dr. Goutham Rao described the next generation of obesity pharmacotherapies, specifically focusing on four drugs that may become available in the next five years:

  • Tesofensine: This phase 2b candidate in Saniona’s pipeline was first-developed as an Alzheimer’s treatment, though it actually shows greater efficacy as an appetite suppressor via inhibition of norepinephrine, serotonin, and dopamine reuptake. According to Dr. Rao’s presentation slides, the agent is associated with up to 10% weight loss at high doses and reduces waist circumference by >9 cm, which he described as quite meaningful for important health outcomes. On the other hand, increases in systolic blood pressure and heart rate over the course of phase 2 trials raise some safety concerns – in fact, these two variables have been cause for discontinuation of obesity pipeline candidates in the past.
  • Empatic (bupropion/zonisamide): This upcoming obesity therapy from Orexigen, which Dr. Rao predicted will reach the market within two-three years, is also in phase 2b. Dr. Rao called attention to the advantages of a fixed-dose combination, namely that it allows for a lower dose of each individual agent to minimize side-effects. He also mentioned that no cardiometabolic outcomes data has been worked out yet.
  • Pramlintide/metreleptin: This combination was being developed by Amylin/Takeda until August 2011. Dr. Rao expressed a positive outlook on the future of the drug candidate, sharing his belief that someone else will eventually pick up on the license and carry the combination through clinical investigations. A 12-month phase 2 trial showed significantly greater weight loss with pramlintide/metreleptin treatment vs. either agent alone, as well as significant and substantial LDL-lowering with the treatment. Dr. Rao also endorsed the candidate’s effective mechanism of action – the amylin analog and the leptin analog together regulate hunger cues and promote healthy energy homeostasis over the long term.
  • Cetilistat: Highly similar to Orlistat, which has been commercially-available for ~20 years, this agent has been studied in phase 2 in Japan. Dr. Rao presented that the therapeutic candidate leads to ~3% weight loss and modest A1c improvements, though no CV effects have been reported. Importantly, only ~13% of participants discontinued Cetilistat due to treatment-related side-effects. According to Dr. Rao, this rate for Orlistat is 30%-40%. As a provider who works with many adolescents, Dr. Rao highlighted the significance of socially-undesirable side-effects like bloating, gas, and leaking stool, suggesting that Cetilistat could be a more attractive weight loss option for real-world patients if it makes it to market.

Panel Discussion

Donna Ryan, MD (Pennington Biomedical Research Center, Baton Rouge, LA); Jamy Ard, MD (Wake Forest University, Winston-Salem, NC); Tiffany Powell-Wiley, MD (NIH, Bethesda, MD); Goutham Rao, MD (Case Western University, Cleveland, OH)

Q: Many of you have suggested that we need a CVOT for phentermine – who might fund such a study? The NIH?

Dr. Ard: I do think this is a trial we need. The Veteran’s Association (VA) has guidelines for weight loss, and they could generate a significant amount of data.

Q: What’s the youngest age for which you consider these medications?

Dr. Rao: You can use Orlistat in patients as young as 12. When Meridia was available, I used it in children as young as 14 or so. For adolescents and younger, however, the rule I use is never to prescribe a weight loss pharmacotherapy for more than six months, and always in conjunction with lifestyle modification. These agents should be prescribed as a boost for children or adolescents who are just about to give up, but then they should be tapered off. By no means should they be used as monotherapy in your youngest patients.

Comment: Thank you, Dr. Ryan, for highlighting the need for lifestyle intervention on top of medication. A lot of providers don’t help structure that lifestyle component to therapy – this is usually only done in clinical trials, not in the real world.

Q: The LEADER trial was done with 1.8 mg liraglutide, so we don’t know the effect of 3.0 mg liraglutide. Despite being safe, there’s been some recent talk of increase in systolic heart failure and concerns over increasing heart rate. How do you deal with this when there are so many comorbidities?

Dr. Ard: In case-by-case situations, you first “do no harm.” That means you think about pharmacotherapy as an adjunct for someone who’s feeling stuck and having difficulty achieving significant weight loss based on reported effort. You start with options that have safety data behind them. For some patients, 1.8 mg liraglutide may be enough – we’ve seen that there’s some weight loss effect with this dose.

Dr. Ryan: Remember, the FDA did not require a CVOT for liraglutide at 3.0 mg. This is because of the exposure. Exposure of the active agent in Victoza is higher in women because of sex differences in how the drug is distributed in the body, so it didn’t seem necessary to do a separate CVOT with 3.0 mg liraglutide. It’s important to get your head around that – 3.0 mg liraglutide is not a scary thing. We have the data we need on exposure to be confident in its benefits. Additionally, your target is dependent on health indication – if you’re working on diabetes prevention, you want to see 10% weight loss, whereas if you’re treating fatty liver disease, you want more than 10% weight loss. Once that’s determined, you give your patients the tools they need to reach weight goals – it might be medication that helps them do that. There’s an emerging group of physicians with the skills needed for effective obesity care. I don’t think these drugs are ready for primetime, for people to write them like they’d write a statin in primary care. Providers need to be educated on chronic weight management.

Q: I’ve used Qsymia in a couple of my patients, and I’ve noticed a limiting factor in psychological problems. Have you seen that, and do you screen for that?

Dr. Ard: Qsymia is very clearly a drug where adverse events go up when you titrate the dose up. There’s a clear dose response curve when it comes to side-effects. This is where that patient-centered discussion comes in, and you share decision-making with your patient to determine the right dose based on benefits vs. side-effects for that individual person. My general rule of thumb is to prescribe the lowest effective dose of the drug. You can also mitigate side-effects by encouraging your patients to stay well-hydrated, or by tweaking schedule. Sometimes an every-other-day schedule can be just as effective for maintenance of weight loss as an every-day schedule, so once you’ve gotten to a point where you and your patient are satisfied with weight loss, you can ease up on dose.

Dr. Ryan: Patients should be counseled on settling of their weight – it’s crucial to set these expectations straight. It’s normal to see weight loss plateau after a certain time point, and patients need to understand that their weight has settled at a point of harmony with their environment, which includes their medication. A big mistake is pushing dose up to get more weight loss – I notice this tendency particularly with phentermine. There’s no increased dose response after ~30 mg, so don’t push the drug more if the patient has reached a settled weight.

Dr. Rao: I’ll also point out that Qsymia is better in terms of side-effects than phentermine monotherapy. But I absolutely agree that dose is important. After a certain dose, you don’t get more weight loss, but you do see these odd side-effects such as trouble concentrating.

Q: Can any of you comment on the under-prescription of these agents for weight loss and weight management?

Dr. Ryan: Doctors like to be part of the herd. I’m glad there’s not some land rush to prescribe these drugs because there are techniques to using them that are really important.

Dr. Ard: I agree. As more people get comfortable with these products, and as we move past the graveyard of failures that are still on people’s minds, we’ll see a higher volume of prescriptions. Cost is another issue, because most of these medications aren’t covered by insurance.

Dr. Rao: Looking at data around Belviq in particular, you see that fear is a leading factor that inhibits providers from prescribing the drug – more specifically, fear stemming from the phen/fen controversy of the past.

Q: Is there a role for these drugs in prevention of weight regain following bariatric surgery?

Dr. Ard: Yes. There’s even a role for them pre-surgery, to make the bariatric surgeon’s job easier. Then, five or 10 years out, these medications can be very helpful in controlling eating behaviors and preventing weight regain. Individuals who undergo bariatric surgery experience the same counter-regulatory response to weight loss that people feel when they try restrictive dieting, although it may be delayed by a few years rather than in the immediate aftermath of a bariatric procedure.

Cholesterol Controversies

Debate: Statin-Induced Diabetes

Kevin C. Maki, MD PhD (MB Clinical Research & ConsultingMidwest Biomedical Research/Center for Metabolic & Cardiovascular Health, Glen Ellyn, IL); Naveed Sattar, MD (University of Glasgow, UK)

In a lively discussion of statin-induced diabetes, Drs. Kevin Maki and Naveed Sattar weighed discussed the demonstrated therapeutic benefit of statins to reduce CV, but with some increase in the risk for the development ofvs. the ~10-30% increased onset of type 2 diabetes, ultimately presenting possible silver linings to the diabetes risk. Dr. Sattar argued that while the statin-diabetes link is “credible,” it’s the 10-15% increase in diabetes risk is overpowered far outweighed by the robust clinical benefits to statin therapy – lipid-lowering, reduced CV risk factors,events and reduced mortality. Dr. Maki suggested that rates of statin-induced diabetes may be underestimated in randomized controlled trials, since observational studies have reported risk increases in the neighborhood of ~50%, although he emphasized that this should not be viewed as a reason to avoid statin therapy in patients with sufficient CV risk.  As counterpoint, Dr. Sattar emphasized the “huge publication bias” that plagues observational research – people only report and journals commonly prioritize observational findings when they’re unusual or extreme. Moreover, he suggested that, in some ways, healthcare providers can even capitalize on the slight type 2 diabetes risk when prescribing statins, namely by motivating their patients to simultaneously engage in lifestyle modifications – healthy diet, regular exercise,activity, weight control – to mitigate the threat of new-onset diabetes.  Another piece of good news stemming from the statin-diabetes link:? “In the UK, we’re now required recommended to measure A1c prior to prescribing a statin, and that’s moving improving up diagnosis of pick up of undiagnosed type 2 diabetes. That can only be a ’s bloody good thing.”


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