November 12-16, 2016; New Orleans, LA; Full Report – 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, 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 we heard (i) very impressive phase 2 data for a PCSK9 RNA interference therapy – with a sustained LDL-cholesterol lowering effect out to three to six months!; and (ii) intravascular ultrasound data demonstrating dramatic reductions in atheroma volume with treatment with Amgen’s PCSK9 inhibitor Repatha (evolocumab). We’re so hopeful for the potential of both of these therapies in addressing the residual cardiovascular risk faced by too many patients with diabetes. 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. Our full report contains detailed discussion of all this and more. We are already dreaming ahead to next year’s AHA – hosted in Anaheim, CA.

Detailed Discussion and Commentary

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 priority 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 the FDA’s eHealth policy. 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.  
• “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, PhD (Midwest 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 discussed the demonstrated benefit of statins to reduce CV, but with some increase in the risk for the development of type 2 diabetes, ultimately presenting possible silver linings to the diabetes risk. Dr. Sattar argued that while the statin-diabetes link is “credible,” the 10-15% increase in diabetes risk is far outweighed by the robust clinical benefits to statin therapy –reduced CV events and 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 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 recommended to measure A1c prior to prescribing a statin, and that’s improving pick up of undiagnosed type 2 diabetes. That can only be a good thing.”

Insights from New Therapeutic Trials for Lipids

Inhibition of PCSK9 Synthesis via RNA Interference: 90 Day Data from ORION-1, a Multi-Center Phase 2 Randomized Controlled Trial

Kausik Ray, MD (Imperial College London, UK); Borge Nordestgaard, MD (Herlev-Gentofte Hospital, Denmark)

Dr. Kausik Ray (Imperial College London, UK) presented interim data from the ORION-1 phase 2 trial of inclisiran, an agent that inhibits the PCSK9 protein through RNA interference. Adults in-need of additional LDL-lowering, despite being on maximally-tolerated statin therapy (n=501), were randomized to one dose (at 200 mg, 300 mg, or 500 mg) of inclisiran, two doses (at 100 mg, 200 mg, or 300 mg) of inclisiran, or placebo. At 90 days from the time of first injection, participants receiving 500 mg inclisiran (n=64) experienced a ~50% drop in LDL levels from a mean baseline of 135 mg/dl, while participants on placebo (n=124) maintained relatively flat LDL levels near a baseline of 125 mg/dl (p<0.0001). Participants on 100 mg, 200 mg, or 300 mg of the agent also saw a significant, clinically meaningful, dose-dependent decline in LDL (p<0.0001 vs. placebo for all comparisons), with higher doses corresponding to more dramatic LDL reduction. Dr. Ray presented data on PCSK9 levels in parallel to LDL levels, showing a similar dose-dependent reduction in the amount of circulating PCSK9 protein (p<0.0001 vs. placebo for all comparisons). There was a more substantial drop in total cholesterol in the inclisiran-treated groups vs. the placebo arm. While total cholesterol declined by an average 1% for individuals given placebo, people on 100 mg (n=61), 200 mg (n=122), 300 mg (n=122), and 500 mg inclisiran experienced a mean 22%, 26%, 28%, and 30% decline in total cholesterol, respectively. Notably, Dr. Ray underscored that a second inclisiran injection led to a more sustained response of low LDL ­– otherwise, patients started to see a rise in LDL levels between 90 and 180 days following their initial dose. Optimal scheduling of doses is particularly pertinent to a discussion of inclisiran, since the most prominent advantage of RNA interference over existing PCSK9 inhibitor drugs is its potential to reduce injection burden with a longer-lasting therapeutic benefit, and to be cost-saving, as current PCSK9 inhibitors that require more frequent injection (once or twice a month) are prohibitively expensive for many. Dr. Ray and Dr. Borge Nordestgaard (Herlev-Gentofte Hospital, Denmark), who delivered discussant remarks following the presentation, emphasized the efficiency of the RNA interference technique – with injections just two or three times a year, people could see 50%-60% reduction in LDL.

• Treatment-emergent adverse events were balanced between the treatment and placebo arms of the study, occurring in 54% of both groups. Serious adverse events occurred in 6% and 4% of each group, respectively, while severe adverse events occurred in 3% and 4%, respectively. There was one death – an individual treated with a single injection of 500 mg inclisiran, who had a 20-year history of coronary artery disease, according to Dr. Ray. Injection site reactions were “impressively” low, appearing in 3% of inclisiran-treated patients and in no placebo-treated patients. Dr. Ray added that only 2% of participants experienced an injection site reaction lasting >four hours. He characterized inclisiran as well-tolerated overall. Dr. Nordestgaard corroborated this statement, suggesting that the efficacy of this approach to lipid-lowering far outweighs the mild signal for injection site reactions.
• Dr. Ray underscored that interim ORION-1 results support the start of a phase 3 study of inclisiran. An important objective of the present trial was to select optimal doses of the RNA interference agent. Drawing on the dose-response efficacy data as well as the sustained lipid improvement observed upon second injection over 180 days, Dr. Ray hinted that two injections of 300 mg inclisiran at once every six months might be an ideal dosing schedule. We’re very intrigued the potential for long-term efficacy with a single administration – this sort of “set it and forget it” approach to managing chronic disease reminds us of Intarcia’s implantable GLP-1 agonist ITCA 650 (exenatide mini-pump, changed every six months or a year) and we expect both candidates could potentially succeed very well with payers given the built-in patient adherence.
• Dr. Ray also pointed to the link between LDL-lowering and reduced risk for CV events, though he emphasized that outcomes data has yet to be collected for inclisiran therapy. We’re certainly intrigued by this promising drug candidate and by the benefits of an RNA interference approach to PCSK9 inhibition, but we recognize that inclisiran is still in development and that reliable outcomes data may be many years down the road. To this end, we appreciated Dr. Nordestgaard’s outlining of some of the lingering questions that will need to be sorted out in longer-term studies:
  
  • Will the marked reduction in LDL be sustainable, lasting beyond 180 days?
  • What is the CV benefit associated with inclisiran?
  • Is there a mortality benefit associated with inclisiran?
  • Will larger-scale studies reveal more severe injection site reactions?
  • Is there a problematic reduction in platelets associated with inclisiran treatment?
  • Are there neurocognitive symptoms?
  • What are the off-target effects?
  • We’ll also add: How will inclisiran be applicable to a diabetes patient population, especially those at high risk for CV events and in-need of more aggressive lipid-lowering after maximally-tolerated statin therapy in order to address their residual risk?

Effect of Evolocumab on Progression of Coronary Atherosclerosis in Statin-Treated Patients: A Placebo-Controlled Intravascular Ultrasound Trial

Steven Nissen, MD (Cleveland Clinic, OH); Raul Santos, MD (University of Sāo Paulo, Brazil)

Dr. Steven Nissen (Cleveland Clinic, OH) discussed results collected via intravascular ultrasound in the GLAGOV trial of Amgen’s PCSK9 inhibitor Repatha (evolocumab). Immediately following the presentation, the GLAGOV paper was simultaneously published in JAMA online. Patients randomized to statin plus evolocumab (n=423) experienced a mean 95% reduction in percent atheroma volume (the amount of abnormal fatty material in the artery), while patients randomized to statin monotherapy (n=423) experienced a mean 5% increase in this primary endpoint (p<0.0001). Researchers looked at change in total atheroma volume as a secondary endpoint: evolocumab led to a 6% reduction vs. <1% reduction with statins alone (p<0.0001). Plaque regression (signaling a lessening of atherosclerosis) was observed in 64% of individuals in the treatment group vs. 47% of the comparator, statin monotherapy group. Fewer patients in the evolocumab group experienced plaque progression as well: plaque progression was seen in 36% of the evolocumab group vs. 53% of the statin-only group (p<0.0001 for both comparisons). During the discussant, Dr. Raul Santos (University of Sāo Paulo, Brazil) pointed out that as per the GLAGOV data, statins also promote plaque regression, which is not to be overlooked despite the significantly greater efficacy of evolocumab. There are other factors (namely, cost) that limit access to PCSK9 inhibitors, so we were happy to see ultrasound-confirmed plaque regression, and a lessening of atherosclerotic disease severity, with statins as well. Dr. Santos remarked that a longer-term study should examine the cost-effectiveness of evolocumab as a lipid-lowering agent (boy would we love to see this study, for Repatha and/or other PCSK9 inhibitors!). One graph in Dr. Nissen’s presentation displayed a linear relationship between the amount of LDL-lowering and the amount of plaque regression achieved in the trial, lending more evidence to the notion that LDL reduction is an important step in treating atherosclerosis and avoiding downstream adverse events, including cardiovascular (CV) outcomes. On that note, Dr. Santos reminded the audience that FOURIER results are coming soon (early 2017, according to Amgen’s recent 3Q16 financial update) and will provide more definitive data on CV outcomes associated with Repatha. For now, he suggested that the PCSK9 inhibitor shows major promise for cardioprotection, based on substantial LDL-lowering and plaque regression.

• Dr. Nissen emphasized that evolocumab resulted in significantly greater plaque regression even in participants with baseline LDL <70 mg/dl, below the LDL level for which treatment is recommended by most major global guidelines. The implication is that the PCSK9 inhibitor does not require high risk to deliver high reward – it demonstrates a beneficial atherosclerotic effect even in individuals with lower baseline LDL. A post-hoc analysis zooming in on individuals with LDL <70 mg/dl at baseline showed a 58% mean reduction in LDL on evolocumab/statin treatment vs. a 16% rise in LDL on statin monotherapy. Moreover, these Repatha-treated participants achieved an LDL as low as 15 mg/dl at 80 weeks, which Dr. Nissen described as “much lower than what’s commonly achieved in people with coronary disease.”
• Safety findings showed no significant increase in risk for MI, stroke, hospitalization for unstable angina, coronary revascularization, injection site reactions, neurocognitive effects, myalgia, or new-onset diabetes with evolocumab vs. statins. A first major CV event occurred in 15% of statin-treated participants and only 12% of Repatha-treated participants after 80 weeks of data collection, which as Dr. Santos pointed out, bodes well for the cardioprotection signal to be determined in FOURIER. Dr. Santos also highlighted the lower drop-out rate in GLAGOV compared to prior intravascular ultrasound studies – 12.5% and 25%, respectively.

ionis-angptl3-lRx, an Antisense Inhibitor to Angiopoietinlike Protein 3, Reduces Plasma ANGPTL3 and Lipids in Healthy Volunteers with Elevated Triglycerides

Sotirios Tsimikas, MD (UC San Diego, CA); Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX)

San Diego’s Dr. Sotirios Tsimikas presented a phase 1/2 clinical trial of Ionis’ angiopoietin-like protein 3 inhibitor IONIS-ANGPTL3-LRx for the treatment of dyslipidemia. Healthy adult volunteers with BMI <35 kg/m² and elevated triglycerides were divided into single and multiple ascending dose cohorts. On day 37 of the study, participants in the 60 mg, multiple ascending dose arm (n=6) experienced mean LDL reductions of 35% from a baseline of 128 mg/dl compared to an ~18% increase in LDL among placebo-treated participants (n=8) from a baseline of 132 mg/dl (p<0.001). Participants in the 10 mg (n=6), 20 mg (n=5), and 40 mg (n=6) multiple ascending dose arms also experienced statistically significant LDL-lowering vs. placebo in a dose-dependent manner, with a higher dose corresponding to a greater magnitude of LDL reduction. Notably, participants randomized to 60 mg IONIS-ANGPTL3-LRx saw an 83% drop in plasma levels of the ANGPTL3 protein, which indicates that the drug candidate is working mechanistically as intended to treat dyslipidemia. The phase 1/2 study also examined safety, and Dr. Tsimikas underscored that no significant safety signals were associated with the active agent. In discussant remarks, Dr. Christie Ballantyne (Baylor College of Medicine, Houston, TX) suggested that longer-term data is necessary to rule out all possible safety concerns. Dr. Ballantyne emphasized that we’re at an “exciting point” for advanced dyslipidemia therapies, but that we’re still “at the beginning of a long journey” – these results, albeit promising, are early-stage, and we’re eager for a larger, longer trial to show the efficacy of IONIS-ANGPTL3-LRx. Of course, we’re also curious to see what IONIS-ANGPTL3-LRx’s efficacy is like on top of PCSK9 inhibitors – if PCSK9 inhibitors become accepted as standard-of-care following outcomes results, the bar will be set that much higher for Ionis.  At the time of the AHA oral presentation, Ionis also announced these results though a company press release.

Clinical Trials: Advanced Topics in the Classical Arena

Industry Perspective on the Future of Large Cardiovascular Trials

Daniel Bloomfield, MD (VP of Cardiovascular Global Clinical Development, Merck, Rahway, NJ)

Merck’s VP of Cardiovascular Global Clinical Development, Dr. Daniel Bloomfield, offered his perspective on the impact of large cardiovascular outcomes trials (CVOTs) on innovation in cardiovascular pharmacotherapies. While his presentation was focused on the development of cardiovascular medications, virtually all his observations and insights seemed applicable to new diabetes drugs as well – and those developed since 2008. Dr. Bloomfield described both the big picture challenges increasing the uncertainty of cardiovascular drug development and the specific challenges related to the design of large-scale CVOTs that compound the existing clinical development environment pressures. Overall, he emphasized that, for many pharmaceutical companies, the high cost of CVOTs coupled with the uncertainty surrounding the future success of the candidate is “diminishing the appetite for investment” in this area. In particular, he pointed out that, in addition to the uncertainty surrounding efficacy, safety, and regulatory outcomes, the payer uncertainty is increasingly huge – even if the drug makes it to market, will payers reimburse it and will it be able to achieve market success? Furthermore, he pointed out that companies like Merck have vast portfolios ranging over several disease areas (including HIV, arthritis, cancer, etc.) and must carefully determine how to allocate their resources. As he put it, no company has the resources to conduct more than one or two of CVOTs at a time right now. Strikingly, Dr. Bloomfield shared data indicating that 45% – nearly half – of cardiovascular development programs are discontinued due to commercial reasons, rather than safety concerns or a failure to meet a primary endpoint in a trial. For diseases for which there are multiple therapies but the residual need remains immense (such as cardiovascular disease – or diabetes), the decisions of which candidates to pursue in the clinical development pipeline depends on whether the company believes there is room for the candidate to differentiate itself from the rest of the market. This differentiation is difficult and costly to demonstrate – the candidate must demonstrate additional benefit on top of standard of care or a greater benefit than the standard of care (via a head-to-head trial). In contrast, trials of drugs for indications that lack any effective therapies only need demonstrate benefit relative to placebo.

• Many of Dr. Bloomfield’s points regarding the commercial and resource-allocation challenges facing the pharmaceutical industry echo ongoing pressures in the diabetes field as well. We are already beginning to see some of the trends Dr. Bloomfield highlighted and view his presentation as a potential forecast of where the diabetes field could be in the next few years. Indeed, the 2008 FDA CVOT guidance has made these extremely large and costly trials a standard requirement for all diabetes and obesity drugs – a demand for resources and investment that is already extremely challenging for most of the diabetes companies to meet currently and may become even more difficult for diabetes companies as the pricing pressures in the diabetes market intensify in the US and globally. Furthermore, the demonstration of cardioprotection in the EMPA-REG OUTCOME, LEADER, and SUSTAIN 6 trials for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) and Novo Nordisk’s GLP-1 agonists Victoza (liraglutide) and semaglutide were much welcome surprises, but have also raised the bar for new diabetes drugs even higher. If empagliflozin, liraglutide, or semaglutide become standard of care therapies for diabetes (only a matter of time, according to some, especially for empagliflozin), then new diabetes drugs will likely be expected to demonstrate a cardiovascular or renal benefit on top of these therapies as well, especially if payers are expected to reimburse new branded therapies over generic empagliflozin or biosimilar liraglutide in the future.
  
  • Many business executives have acknowledged that it’s not enough for a diabetes drug to “merely” lower A1c anymore – drugs are also expected to weight loss (or at least weight neutrality) and soon, drugs may be expected to offer cardiovascular or renal benefits (both of which require long and expensive hard outcomes trials to demonstrate). Indeed, we’ve seen a high rate of attrition among early- to mid-stage diabetes pipeline candidates – the terminations of development for Novo Nordisk’s phase 2 oral insulin and Lilly/Transition Therapeutics’ phase 2 GLP-1/glucagon dual agonist, despite positive phase 2 results for both candidates, were particularly disappointing. Novo Nordisk has even recently revised its R&D priorities to focus more on “diabetes-adjacent” areas of high unmet need and truly innovation diabetes candidates with disruptive potential. This was good to see since there are many unmet needs within complications in particular.
  • Given these growing challenges, we’re concerned that other disease areas will be increasingly attractive for some. Dr. Bloomfield acknowledged to some extent in his presentation that HIV, arthritis, and cancer are attractive indications to which to divert resources. Indeed, BMS’ high-profile and extremely disappointing exit from diabetes is widely attributed by many to the FDA’s CVOT policy and growing competitive challenges in diabetes – the same for Genentech, to name another example. We hope that payers can begin to recognize that too many patients with diabetes are still doing poorly, even those with access to new medications, and that, increasingly, it appears that combinations of diabetes medications may be necessary to manage the condition. With the growing realization of personalized medicine, now is certainly the time to invest more, in the right systems around patients, as well as in unrelated areas like behavior change.
• Dr. Bloomfield further outlined several specific challenges related to the design of large CVOTs. Overall, he emphasized that it’s getting harder, not easier, to conduct these trials and that the cost and complexity of traditional randomized clinical trials will be unable to keep up with regulatory and payer demands. Patient and site participation is falling, trials are increasingly complex and costly to operate, contracting for trials is lengthy and complicated, there’s an enormous range of potential endpoints, and there’s little consensus among various regulatory agencies surrounding development requirements. Furthermore, Dr. Bloomfield that the standard of care may change between the start and end of a long CVOT – if a new drug that was not included in the original trial becomes standard of care during the course of the trial, how does that impact how patients, providers, and payers view the results?
• Dr. Bloomfield highlighted “pragmatic clinical trials” as a potential way forward. He suggested that trial enrollment can be conducted through EHR systems, with simple inclusion/exclusion criteria and streamlined informed consent procedures. Trial procedures could also be simplified in Dr. Bloomfield’s view, with trial requirements performed as part of routine care visits and limited site monitoring and documentation. He suggested that the endpoints of the trial can be mined from the EHR systems, administrative claims, and participant-reported outcomes. These suggestions certainly represent a paradigm shift that would lower the administrative costs of conducting clinical trials and could perhaps provide a better sense of how therapies fare in “real-world” clinical practice – we expect this would be of enormous interest to payers. That said, we imagine that some regulatory agencies and clinical trial purists would express concerns about the quality of data collected from EHR systems (from what we understand, EHR adoption is still a challenge for many physicians). We hope that regulatory agencies can work closely with pharmaceutical companies – with input from patients, providers, and payers – to develop a more “pragmatic” clinical trial system that meets regulatory requirements.

Novel Pharmacologic Therapies for Diabetes: A Focus on Cardiometabolic Effects

Pharmacological Co-Management of Diabetes and Obesity: An Overview

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

Dr. Donna Ryan (Pennington Biomedical Research Center, Baton Rouge, LA) made the case for an earlier, “forward-thinking” approach to the co-management of diabetes and obesity. Given the positive cardiovascular outcomes trial (CVOT) data that has been published (or that is upcoming), healthcare providers should be considering CV prevention from the very beginning of diabetes and obesity care, she argued. This means starting patients on empagliflozin (Lilly/BI’s SGLT-2 inhibitor Jardiance, which showed CV benefit in EMPA-REG OUTCOME) or liraglutide (Novo Nordisk’s GLP-1 agonist Victoza, which showed CV benefit in the LEADER trial) right away if they’re in-need of both diabetes and weight management. Dr. Ryan also explained the elevation of bariatric surgery in treatment algorithms – recent guidelines recommend surgery for patients with BMI >35 kg/m² and poor glycemic control, and urge providers to consider surgery for patients with BMI as low as 30 kg/m² who have poorly-controlled diabetes. Dr. Ryan described the move to a “weight-centric” emphasis in diabetes as a good thing: “Good weight management is good diabetes management.” Turning to the data, she presented a secondary analysis of the Look AHEAD trial showing that weight loss of ≥10% in the first year of intensive lifestyle intervention did indeed result in a CV morbidity and mortality benefit in people with type 2 diabetes – the new paper was just published in Lancet Diabetes and Endocrinology. Despite no significant CV benefit found in the original Look AHEAD trial, Dr. Ryan suggested that weight loss in itself is cardioprotective, although a greater magnitude of change may be necessary to illustrate the CV effects of weight loss per se. We hope that further consensus can be built around the magnitude of recommended weight loss. So much discussion of weight management is centered around the notion that 5% weight loss is sufficient for health benefits, namely adipose tissue and liver insulin sensitivity (Dr. Ryan shared this insight at AADE 2016). And yet, ≥10% weight loss seems necessary for improved CV outcomes, which is arguably one of the most important goals in diabetes/obesity care – this circles back to Dr. Ryan’s point about the need for more “forward-thinking” CV prevention, and raises the crucial question of how to determine ideal weight loss goals for individual patients.

GLP-1 Agonism for Chronic Weight Management and Diabetes Prevention

Xavier Pi-Sunyer, MD (Columbia University, New York, NY)

Columbia University’s Dr. Xavier Pi-Sunyer continued the conversation on diabetes drugs and weight loss, pointing to obesity as an “early, effective therapeutic target” for the prevention of type 2 diabetes and its complications. He argued that more healthcare providers should be capitalizing on the weight loss benefits of GLP-1 agonists, particularly Novo Nordisk’s liraglutide. The agent is available in a 3.0 mg formulation as Saxenda, indicated for the treatment of obesity, and Dr. Pi-Sunyer reviewed major findings from the SCALE program showing the drug’s efficacy in promoting weight loss and delaying the onset of type 2 diabetes among people with prediabetes. But he also emphasized that Victoza (liraglutide 1.2 mg and 1.8 mg) confers a clinically meaningful weight loss benefit in addition to its CV benefit – indeed, the LEADER trial showed a 13% risk reduction for three-point MACE with Victoza treatment as well as 2.3 kg greater weight loss with Victoza vs. placebo at three years. Type 2 diabetes is becoming inseparable from obesity, and healthcare providers are being called upon to treat both chronic conditions simultaneously. Dr. Pi-Sunyer explained that short-term weight loss doesn’t correlate well with long-term maintenance of healthy weight, and pharmacotherapies such as liraglutide should be used to fill this treatment gap. The obesity pharmacotherapy field has been incredibly challenging, with Saxenda essentially driving the market by value (due in part to its very high list price). We imagine there is greater acceptance of Saxenda among some providers compared to other obesity pharmacotherapies due to their familiarity with the liraglutide molecule from their experiences with Victoza for diabetes. Furthermore, we expect Victoza’s positive cardiovascular data will further tip the scales in Saxenda’s favor within the obesity field – the other obesity therapy manufacturers are currently facing difficulties in funding the required CVOTs for their own drugs and it remains to be seen how that will play out.

SGLT-2 Inhibitors and Weight Loss: Not Just For Diabetes?

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

Dr. Sanjay Kaul summarized and offered his take on the variety of potential explanations for the mechanism of benefit observed in the EMPA-REG OUTCOME trial, which demonstrated a cardioprotective benefit for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin). Dr. Kaul introduced skepticism for most of the major potential explanations and definitively declared that “We can be sure it’s not an anti-atherothrombotic effect” and “It’s clearly not a glycemic control effect.” It’s generally accepted that the Kaplan-Meier curves in the trial diverged too rapidly for the benefit to be attributable to atherothrombotic improvements and that the A1c difference between the empagliflozin and placebo groups was too small to drive cardioprotection. Similarly, the cardioprotective benefit manifested too quickly for the benefit to be attributable to the modest weight loss associated with empagliflozin, according to Dr. Kaul. Dr. Kaul also pointed out that empagliflozin did not demonstrate a benefit on non-fatal stroke (in fact, the point estimate for stroke went in the wrong direction in the trial), suggesting that’s the modest blood pressure reduction produced by empagliflozin treatment isn’t a likely mechanism either (he also noted that the blood pressure difference is too small to have a clinically meaningful impact). Dr. Kaul found the volume depletion, possible anti-arrhythmic, and metabolic effect theories to be more plausible. On the other hand, he deemed Dr. Ele Ferrannini’s “thrifty substrate” hypothesis “very elegant, but highly unlikely.” Summing up the totality of the available evidence, however, Dr. Kaul posited that the cardiovascular benefits of empagliflozin are likely not unique to patients with diabetes and that the drug may be able to exert a cardioprotective influence in people without diabetes. To that end, he highlighted Lilly/BI’s plans to initiate two trials of empagliflozin in patients with heart failure with and without diabetes. We greatly appreciated Dr. Kaul’s nuanced overview of the evidence and speculation to date – and we can’t wait to learn more from future trials!

Management of Type 2 Diabetes in 2015 and Beyond: What’s on the Horizon?

Francisco Pasquel, MD (Emory University, Atlanta, GA)

Dr. Francisco Pasquel summarized the ongoing diabetes cardiovascular outcomes trial (CVOT) landscape and posited several questions that remain to be answered over the coming years. Dr. Pasquel pointed out that there’s a number of key questions that are important to clinical practice and decision-making, some of which are currently being investigated in ongoing trials. These include: (i) mechanistic studies to explore cardiovascular and renal effects (especially for SGLT-2 inhibitors); (ii) primary prevention of cardiovascular events as opposed to secondary prevention (though the DECLARE trial for AZ’s SGLT-2 inhibitor Farxiga [dapagliflozin] has enrolled a broader patient population); (iii) exploration of cardiovascular outcomes with an active comparator group rather than placebo (the CAROLINA trial for Lilly/BI’s DPP-4 inhibitor Tradjenta [linagliptin] will include glimepiride as an active comparator); (iv) the comparative efficacy of second-line agents for type 2 diabetes (the GRADE study purports to examine this, but was initiated before SGLT-2 inhibitors were available and thus does not include that class); (v) long-term exposure data; and (vi) cost. Despite the questions, however, Dr. Pasquel was optimistic that the results demonstrating cardioprotection for SGLT-2 inhibitors and GLP-1 agonists will change clinical practice – indeed, he pointed out that the ESC heart failure guidelines have already been updated to include a role for empagliflozin. Dr. Pasquel’s presentation was deeply thought-provoking – what’s the next frontier in diabetes clinical trials?

Panel Discussion

Q: Based on the CVOT data we’ve seen, there’s a relatively modest glycemic difference between treatment and placebo groups. So, are these really drugs for diabetes, or should they be thought of as drugs for cardiovascular disease?

Dr. Kaul: SGLT-2 inhibitors have predominant cardio-renal effects, and perhaps the glycemic effect is a collateral benefit. The major CVOTs in diabetes were designed not to demonstrate the A1c-lowering efficacy of these drugs, but to rule out CV safety concerns. By trial design, the contrast in A1c between groups is intentionally very small. So, we really can’t answer the question about whether glycemic control leads to CV benefits, at least not from these studies. This is why regulatory agencies are struggling – if you design a trial for safety and then produce an efficacy outcome, can you provide a label for CV risk reduction when the goal was to rule out CV harm? It’s unprecedented in this domain, and it’s why the FDA is still deliberating over this.

Dr. Ryan: What I took away from every speaker today is that these drugs have multiple therapeutic effects. We need to know more about these multiplicative effects. We should stop thinking about diabetes in a purely, glucose-centric fashion.

Q: Can the CV benefits shown in LEADER, for a 1.8 mg formulation of liraglutide, be applied to an obese population? Should there be a separate CVOT for Saxenda?

Dr. Pi-Sunyer: Liraglutide is a drug that’s been shown to be effective at 1.8 mg. It was tested for weight loss at 3.0 mg and for sleep apnea, but not for CV outcomes. Generally speaking, the safety data available for 3.0 mg is highly-similar to safety data available for 1.8 mg, so I think it’s likely that the higher dose would also have the same CV effects. But of course, we don’t have this data.

Dr. Ryan: I want to remind everyone that the FDA did not require a CVOT for Saxenda. This is a requirement for all new medications with an indication for chronic weight management, but Saxenda was exempt because the drug exposure for 1.8 mg and 3.0 mg of the active agent was similar across the two populations.

Dr. Kaul: One more comment – when you have active control safety studies such as linagliptin vs. glimepiride, those results are only interpretable if the safety of the active control has been established. This is why the FDA required a linagliptin vs placebo trial, and that’s CARMELINA. Otherwise, the comparator was sulfonylureas, and we have no idea about the CV safety of that compound.

Dr. Pi-Sunyer: Yes, it should have been a three-arm trial.

Dr. Kaul: Right. If it was a superiority trial, there are no issues with that because it’s designed to show efficacy. But for a safety trial, when you’re trying to rule out risk, you need an active control with established safety.

Q: If standards of care change, how will that impact ongoing trials and their interpretation?

Dr. Pi-Sunyer: I think it’ll be up to physicians how they want to interpret it.

Dr. Scirica: It’s a question that comes up often with clinical trials, especially when there’s long-term follow-up. Investigators would have to be fully-briefed if there’s a new standard of care. Standards of care can also be different country to country. So you’re right, that this would have an impact, but I don’t think it’ll have a major impact on ongoing trials. In designing new trials, yes definitely, a new standard of care would be factored in.

Primary Prevention of CVD: When to Start and What to Emphasize

Creating a Culture of Health – Changing the Food and Physical Environment to Promote Healthy Living

Lawrence Appel, MD (Johns Hopkins University, Baltimore, MD)

Dr. Lawrence Appel (Johns Hopkins, Baltimore, MD) reviewed some of the most compelling published data to show that food environment can have a direct impact on health behavior, although his overarching message was a strong call-to-action despite gaps in the literature: “We can’t wait for perfect evidence. We have to rely on what we have to start enacting policies and changing the food environment.” The Howard County Unsweetened Initiative, an all-hands-on-deck effort to reduce soda consumption as a means to counter childhood obesity and diabetes in the Howard County, new Baltimore area, successfully cut soda sales by 20% in Howard County stores vs. comparator stores in Southeast Pennsylvania. Dr. Appel underscored that these reduced sales of sugar-sweetened beverages lasted for at least three years, with lower soda sales stable from 2012-2015. (This paper by the Rudd Center for Food Policy and Obesity is currently under review.) Importantly, the Howard County initiative involved school districts, social media, 30-second commercial spots, direct mail, street teams, and participation from businesses, faith-based groups, and other community organizations – Dr. Appel argued that with a truly holistic approach to changing the food environment, we can do more to stop the obesity and diabetes epidemics. And make no mistake, these are massive epidemics, Dr. Appel emphasized. “Individual therapy is great for patients who show up in their 50s or 60s, but it’s not the solution to the obesity pandemic. We have to turn to prevention. We have to look at local food environments.” We couldn’t agree more with this sentiment. We continue to believe that much greater investment in prevention and in changing related policies and the built environment to facilitate healthier lifestyles is necessary to truly move the needle in the diabetes and obesity epidemics. We especially applaud efforts like the Partnership for a Healthier America that leverages private-public partnerships in order to change public attitudes around nutrition and physical activity – in an effort to “make the healthy choice the easy choice.” We also appreciate efforts like Novo Nordisk’s Cities Changing Diabetes initiative that aims to rigorously study social determinants of diabetes risk in urban populations globally. These efforts, along with the Howard County Unsweetened Initiative, further underscore the necessity and value of multi-stakeholder partnerships to tackle this issue. We only hope other regions can learn from their example!  

• Turning to taxes, Dr. Appel summarized data on the efficacy of the Berkeley and Mexico soda taxes in decreasing consumption of sugar-sweetened beverages. In Berkeley, soda consumption declined by 21% vs. 4% in comparator cities (p=0.046), and water consumption increased by 63% vs. 19% in comparator cities (p<0.01) four months after the excise tax on sugar-sweetened beverages was implemented. In Mexico, purchases of sugar-sweetened beverages dropped by 12% between January 2012 and December 2014. Moreover, Dr. Appel shared that the tax had its most pronounced effect on reducing soda consumption in groups of lower socioeconomic status – as a type 2 diabetes/obesity prevention effort, it’s targeting the most vulnerable populations for onset of these chronic conditions. This echoed cost-effectiveness data in support of the soda tax presented at the recent National Academy of Medicine meeting on the 30-year rise in obesity and type 2 diabetes globally. Ultimately, we’re glad that empirical evidence is revealing the real-world benefits of a tax on sugar-sweetened beverages. Our very own hometown of San Francisco just passed a soda tax last week – as did Boulder, Chicago, Oakland, and Philadelphia – and we’re so hopeful to see these policies spread ever more broadly in the US and globally.

Posters

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.

Effect of Alirocumab in Patients with Diabetic Dyslipidemia and Chronic Kidney Disease

J Dwyer, H Colhoun, FJ Tinahones, M Bujas-Bobanovic, J Mandel, MJ Louie, R Samuel, KK Ray, PP Toth, M Banach

A pooled analysis of phase 3 ODYSSEY studies (n=1,437) of Sanofi/Regeneron’s Praluent (alirocumab) demonstrated the agent’s lipid-lowering efficacy regardless of chronic kidney disease (CKD). ODYSSEY participants were categorized into one of two subgroups – moderate chronic kidney disease (CKD) or mild/no CKD. There were no statistically significant interactions between (i) CKD status and LDL reductions, (ii) CKD status and non-HDL reductions, or (iii) CKD status and reductions in Lp(a), meaning that the PCSK9 inhibitor was just as effective a lipid-lowering therapy in people with moderate CKD and people without. For example, after 24 weeks, individuals with moderate CKD given 150 mg of alirocumab experienced a mean 65% drop from baseline LDL vs. a 4% drop in LDL for their placebo-treated counterparts, and individuals with mild/no CKD on the same dose of alirocumab experienced a mean 58% drop from baseline LDL vs. a 0.1% drop in LDL for their placebo-treated counterparts (p=0.555 for interaction). These nonsignificant interactions extended to all doses of alirocumab and to non-HDL and Lp(a) measurements as well. Moreover, alirocumab treatment did not affect eGFR in either subgroup, which is a reassuring sign of the drug’s renal safety. Treatment-emergent adverse events occurred in 85% of alirocumab patients with moderate CKD, in 77% of alirocumab patients with mild/no CKD, in 82% of placebo patients with moderate CKD, and in 76% of placebo patients with mild/no CKD – incidence of adverse events did not differ significantly between subgroups. Listed as one of the conclusions of this poster is that upcoming results from the ODYSSEY Outcomes study will further investigate the impacts of Praluent on renal function. This outcomes trial is expected to complete in February 2018, and we’re greatly looking forward to the results.

• As is nephrology expert Dr. Jamie Dwyer (Vanderbilt University, Nashville, TN), who told us in a separate interview that more data will be necessary to determine if Praluent offers a renal benefit. ODYSSEY Outcomes will provide this larger-scale data, and while it’s too soon to speculate on what the results will show, Dr. Dwyer expressed a positive outlook on how the CVOT will connect the dots over our understanding of alirocumab’s renal effects.
• “Chronic kidney disease is common in patients with type 2 diabetes who are at high-risk for CV disease.” Dr. Dwyer explained why collecting outcomes data on Praluent (among other PCSK9 inhibitors) is so key, given the persistent unmet need in treating dyslipidemia, diabetes, and CV disease simultaneously.
•  

Impact of Alirocumab on Apolipoprotein B, Non-High-Density Lipoprotein Cholesterol, and Triglycerids in Patients with and without Moderate Chronic Kidney Disease

PP Toth, M Banach, A Koren, M Louie, A Letierce, J Mandel, J Kastelein

This poster displayed results from a pooled analysis of eight trials from the ODYSSEY program (n=4,629), which probed for alirocumab’s (Sanofi/Regeneron’s PCSK9 inhibitor Praluent) lipid-lowering efficacy in people with and without chronic kidney disease (CKD). Notably, a 150 mg dose of alirocumab given in combination with statins was significantly more effective in reducing Apo B levels in participants with moderate CKD vs. without, leading to 55% and 52% decline, respectively. Participants given 150 mg of placebo on top of background statin therapy experienced an average 9% decline in Apo B if they had moderate CKD and a 0% decline if they did not (p=0.003 for interaction). Alirocumab started at 75 mg and then escalated to 150 mg was significantly more effective in lowering non-HDL cholesterol among ODYSSEY participants with moderate CKD vs. without (p=0.028 for interaction). There were no significant interactions based on CKD status for fasting triglycerides, and treatment-emergent adverse events occurred at similar rates in all subgroups: (i) 82% of participants with moderate CKD on alirocumab; (ii) 78% of participants without moderate CKD on alirocumab; (iii) 83% of participants with moderate CKD on placebo; and (iv) 78% of participants without moderate CKD on placebo. These results indicate Praluent’s promise in lowering Apo B and non-HDL cholesterol levels specifically in individuals with comorbid CKD and dyslipidemia. This hints at the possibility of alirocumab, and perhaps PCKS9 inhibitors more broadly, conferring an even greater cardiovascular benefit among higher risk patients with CKD (which in and of itself is a cardiovascular risk factor). We’re certainly hopeful for the potential of PCSK9 inhibitors to address residual cardiovascular risk among patients with diabetes, CKD, or other co-morbidities and we’re glad to see that the data thus far continues to provide cause for optimism. Like much of the cardiovascular and diabetes fields, we await outcomes data with bated breath…  

PBI-4050 Reduces Cardiovascular Biomarkers in Type II Diabetic Patients with Metabolic Syndrome

P Laurin, B Grouix, A Laverdure, B Zacharie, L Gagnon

In a poster, ProMetic BioSciences presented full results for their phase 2, open-label, single-arm study of PBI-4050. PBI-4050 is an oral drug candidate with anti-fibrotic activity; its specific mechanism of action is undisclosed. The company previously shared topline results for the candidate less than a month ago – this poster contained no new data. In the trial, once-daily treatment with 800 mg PBI-4050 produced a significant mean A1c reduction of 0.8% in adults with type 2 diabetes at 12 weeks (n=20, p=0.003, baseline A1c=8.3%). Among patients with baseline A1c>7.5%, the mean A1c reduction at 12 weeks was 1% (p=0.003) Among the 10 participants that were followed for 24 weeks, the A1c reduction was sustained through the follow-up period. The candidate also produced favorable effects on a range of biomarkers associated with cardiac injury (vaspin, FGF21) and with acute kidney injury (IL-18, calbindin, cystatin C, KIM-1, TFF3). See our previous coverage for more details on these outcomes. Notably, the poster’s conclusions section offered a glimpse of how the money may eventually position the candidate. ProMetic emphasized that the A1c efficacy compares favorably to DPP-4 inhibitors and SGLT-2 inhibitors and that the candidate demonstrated similar pharmacokinetics in both individuals with and without chronic kidney disease, suggesting that no dose adjustment would be necessary for these patients. Furthermore, the company pointed out the waist circumference reduction associated with the candidate (p=0.01) and the range of improvements on the pro-inflammatory biomarkers, suggesting that PBI-4050 has the potential to positively impact risk of diabetes complications. In particular, ProMetic suggested that PBI-4050 may be able to alter the course of disease progression/fibrosis in the heart, kidney, pancreas, and liver. As the bar for new diabetes drug rises ever higher, it’s increasingly important for new drugs to demonstrate benefits beyond glucose-lowering – we’re certainly intrigued by this particular candidate and are curious if it has potential for diabetic nephropathy or NASH indications as well.

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