August 26-30, 2017; Barcelona, Spain; Full Report – Draft

ESC 2017 (European Society of Cardiology) took place in late August at the Fira Gran Via in Barcelona, Spain. We were among >31,000 attendees at this year’s meeting, and were amazed at the very substantial presence of diabetes on the agenda – we had more content to cover than ever before for a cardiology conference! This is fitting, of course, given the four positive diabetes CVOTs published in the past two years: EMPA-REG OUTCOME for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), LEADER for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide), SUSTAIN 6 for Novo Nordisk’s GLP-1 agonist candidate semaglutide, and CANVAS for J&J’s SGLT-2 inhibitor Invokana (canagliflozin). What’s more is that two of these products – Victoza and Jardiance – now boast CV indications, officially inviting cardiologists into diabetes care. Thought leaders at ESC spoke to the CV benefits of GLP-1 agonists and SGLT-2 inhibitors, emphasizing the opportunity for personalized medicine here: The GLP-1 agent may offer greater weight loss, while the SGLT-2 would likely be more effective in heart failure prevention. One of these drugs is injectable, the other comes in oral tablets, and patients can express preferences. We were impressed by the terrific attendance at these educational sessions about diabetes therapies with cardioprotective properties, a sign that cardiologists are interested and invested in being part of the diabetes care team. There was no shortage of new data at this meeting, either. Dr. Neil Poulter’s presentation of a new LEADER post-hoc analysis was the headliner (liraglutide showed consistent MACE benefits regardless of prior history of stroke/MI), but we also saw exciting new analyses from EMPA-REG OUTCOME, SUSTAIN 6, and CVD-REAL (AZ’s real-world study of all SGLT-2 inhibitors vs. other glucose-lowering drugs).

This full report contains our coverage of notable sessions from ESC 2017. Before you get to our detailed discussion and commentary, read our themes section for some high-level takeaways from the congress. We miss Barcelona dearly, but we’re already looking forward to next year’s ESC meeting (which will hopefully – likely – feature even MORE on diabetes)…see you in Munich, Germany!

Themes

CVOTs: The Gifts That Keep on Giving

• ESC 2017 showcased new post-hoc analyses of three diabetes CVOTs: Novo Nordisk’s LEADER and SUSTAIN 6, plus Lilly/BI’s EMPA-REG OUTCOME. Several speakers defended the FDA’s 2008 CVOT guidance because it has led (albeit, inadvertently, or at least unexpectedly) to this evidence for cardioprotection and to other clinically-valuable insights about the microvascular, macrovascular, and safety effects of these drugs. Indeed, we’ve been impressed by the high number of subsequent posters, presentations, and publications coming out of these CVOTs beyond the initial full results. Each adds to the study’s internal consistency, which expert clinical trialist Dr. Faiez Zannad highlighted as an important criterion for statistical rigor. Each builds evidence for a very real cardioprotective benefit to these drugs, or it yields new knowledge about how these medicines impact microvascular complications (especially renal outcomes, which were positive for empagliflozin, liraglutide, semaglutide, and canagliflozin). Dr. Darren McGuire (UT Southwestern, Dallas, TX) emphasized the “surprise” CV benefits seen first in EMPA-REG OUTCOME for SGLT-2 inhibitor Jardiance (empagliflozin), then a few months later in LEADER for GLP-1 agonist Victoza (liraglutide). Before 2008, the field operated under ICH guidelines (International Conference on Harmonization), which allowed diabetes therapies to be approved with as few as 250 patient-years of drug exposure, compared to the ~15,000 patient-years we get now. Dr. McGuire argued that the new regulatory requirements were critical in offering more complete pictures on an agent’s efficacy and safety. He mentioned the amputation signal found in CANVAS for J&J’s SGLT-2 inhibitor Invokana (canagliflozin), also underscoring the incredibly valuable CV efficacy finding from this CVOT, which supports the notion of an SGLT-2 cardioprotective class effect. These large outcomes trials in type 2 diabetes have also sparked interest in new indications for SGLT-2 inhibitors, including heart failure and chronic kidney disease (CKD), and we think the positive renal data from LEADER and SUSTAIN 6 was also an exceptionally pleasant “surprise.” We admit that for some time, we were negative about the required timing of the FDA’s 2008 CVOT guidance due to potential delays in product approvals, but the abundance of learning that has come from these datasets in the past few years has blown us away and the changes in cardioprotection alone has been nothing short of transformative.

Considerations for Cardiologists Prescribing Diabetes Drugs

• Now that there are not one, but two diabetes drug classes with known CV benefit, cardiologists are wondering how to choose between an SGLT-2 inhibitor and a GLP-1 agonist. We heard clinical advice from Drs. Neil Poulter (Imperial College London, UK), John Deanfield (University College London, UK), Naveed Sattar (University of Oxford, UK), and David Fitchett (University of Toronto, Canada), who all agreed that this presents a tremendous opportunity for precision medicine. Patients can express preference for oral or injectable dosing – while oral tablets seem to offer more daily convenience for most, some people may feel more committed to their treatment regimen with an injectable therapy, and Novo Nordisk’s once-weekly semaglutide (which showed CV benefit in SUSTAIN 6), if approved, will offer a lower injection burden. Drs. Poulter and Deanfield acknowledged that cardiologists tend to feel more comfortable with an oral rather than injectable product, especially when prescribing a therapy that’s out of their wheelhouse, but also asserted that this is going to have to change in the very near future. They touted the profound weight loss benefit associated with GLP-1 agonists, and explained how an agent from this class might be ideal for a patient with type 2 diabetes at risk for atherosclerotic CV events (stroke, MI). On the other hand, Drs. Sattar and Fitchett described how patients at high risk for heart failure might see better outcomes with an SGLT-2 inhibitor over a GLP-1 agonist. SGLT-2 inhibitors (AZ’s Farxiga and Lilly/BI’s Jardiance) are being investigated for heart failure indications, but based on the heart failure findings from LEADER, this is unlikely to happen for GLP-1 agonists, according to Dr. Sattar. We agree that the CV benefits associated with SGLT-2 and GLP-1 agents afford an exciting opportunity for personalized care plans, and we’re eager to see this take root in real-world clinical practice, with cardiologists integrated into the optimal diabetes care team. We’re also intrigued by the potential combination CV effects of a SGLT-2 inhibitor/GLP-1 agonist in combination – this is definitely a CVOT we’d like to see, if any industry player finds incentive to run it. Notably, both Lilly and AZ have an SGLT-2 inhibitor and a GLP-1 agonist as part of their diabetes portfolios, and AZ has already investigated Farxiga/Bydureon co-administration for glycemic and weight loss effects in DURATION-8.
• ESC 2017 featured a number of these conversation-style sessions in “the hub” at the Barcelona convention center, where attendees could ask questions and experts would provide the answers. The hub was quite crowded during these educational sessions related to diabetes, and we’ve never been more pleased to have to stand in the back or sit on the floor. Cardiologists are showing clear interest in learning the latest on diabetes/ cardioprotective therapy. Dr. Sattar called attention to the great attendance at these educational sessions, remarking that cardiologists are turning up to these conversations because they already prescribe these drugs (maybe they already conceive of them as cardiology drugs with a glucose-lowering effect) and/or because they want to learn more about this emerging area at the intersection of diabetology and cardiology. We do think part of the benefit is that they are far easier to prescribe for cardiologists than insulin …

Time to Swap Out Sulfonylureas?

• Sulfonylureas were the elephant in the room at ESC. With so much positive CV data to discuss on SGLT-2 inhibitors and GLP-1 agonists, the question remained: Should SUs, with their possibility for CV harm, still be prescribed? During Q&A at the end of a Lilly/BI-sponsored session, Toronto’s Dr. Jacob Udell advocated that it’s time to stop prescribing these agents, though he recognized that some endocrinologists will disagree based on what their patients can afford. Sulfonylureas are generic, and therefore low-cost. The cost consideration is inescapable in diabetes management: As we heard from educators at AADE 2017, cost is a leading factor in treatment decisions (if not the leading factor), and advanced therapies like GLP-1 and SGLT-2 are still inaccessible for many patients. To this end, Dr. Udell explained that head-to-head trials will be key. Optimistically, he suggested that “that’s where the field is moving toward.” Dr. Faiez Zannad echoed this sentiment, suggesting that upcoming head-to-head studies will provide compelling evidence against sulfonylureas in favor of other agents. Lilly/BI’s CAROLINA CVOT, for example, will compare DPP-4 inhibitor Tradjenta (linagliptin) vs. glimepiride (a sulfonylurea). The trial is expected to complete in March 2019, and we’ll be very keen to see the data. Dr. Darren McGuire took a firm stance on the issue, proclaiming that he would stop using sulfonylureas in any patient if he was concerned about CV safety, regardless of low cost. We appreciate these opinions from thought leaders, as we’ve felt for some time now that sulfonylureas should be de-prioritized in algorithms, if not knocked out of play entirely. We understand that cost can’t be overlooked, but we’re hopeful that other generics like TZD pioglitazone may gain favor in place of sulfonylureas, and we look forward to the days of generic DPP-4 inhibitors, known for their strong safety/tolerability profile. We hope payers are watching as head-to-head data accumulates, supporting the long-term cost-savings with other therapies that don’t spur hypoglycemia-related hospitalizations, weight gain, beta cell burnout, or possible CV harm. Above all, we’re glad to hear this recurring discussion at scientific meetings spanning endocrinology and cardiology, which will hopefully lead to more patients switching off SU therapy onto a safer, more effective alternative.

Prediabetes and Other Indications

• During many sessions, the conversation turned to new indications for anti-hyperglycemic agents, including heart failure, chronic kidney disease (CKD), and prediabetes. Two SGLT-2 inhibitors on the market, Lilly/BI’s Jardiance (empagliflozin) and AZ’s Farxiga (dapagliflozin), are being studied in patients with chronic heart failure and separately, in people with CKD. Dr. Faiez Zannad is a co-principal investigator on the EMPEROR HF trials for empagliflozin in heart failure, and he pointed out that both EMPEROR HF-Preserved and EMPEROR HF-Reduced will enroll participants with prediabetes. For one, this speaks to the immense overlap between hyperglycemia and CV disease. It also presents an opportunity to evaluate the SGLT-2 agent’s effects on diabetes progression in those at high-risk for new onset type 2, as well as to gauge how weight loss and CV benefits compare in a prediabetes population vs. a type 2 diabetes population. Suffice it to say, our curiosity is piqued for SGLT-2 inhibitors as diabetes prevention agents, and for the prospect of intervening even earlier to prevent adverse CV and renal outcomes stemming from hyperglycemia. On the renal front, Dr. David Fitchett hinted that diabetes patients with eGFR <60 ml/min/1.73m² may actually stand to benefit the most from treatment with an SGLT-2 inhibitor, in terms of CV and renal outcomes alike – the truth will lie in outcomes data, and we look very forward to that.

Diabetes Makes a Big Splash on the Exhibit Hall Floor

• We were kept pretty busy in the exhibit hall, and very notably, Novo Nordisk debuted its first-ever ESC booth this year, following the EMA- and FDA-approvals of new CV indications for GLP-1 agonist Victoza (liraglutide). The booth pitched Victoza as the only GLP-1 agonist approved for CV risk reduction, and featured clear educational messaging around the Victoza pen, liraglutide’s various physiological impacts (across multiple facets of the ominous octet), and the link between type 2 diabetes and CV disease more generally. Lilly/BI occupied a lot of square footage in the exhibit hall, promoting SGLT-2 inhibitor Jardiance (empagliflozin) as the first and only diabetes drug indicated for the reduction of CV death. An eye-catching yellow arrow moved up and down toward the floor, describing the 38% relative risk reduction for CV death seen with empagliflozin vs. placebo in EMPA-REG OUTCOME. We also visited AstraZeneca’s booth, where reps spoke about SGLT-2 inhibitor Farxiga’s (dapagliflozin) potential at the intersection of diabetes, CV disease, and renal disease. AZ has large trials ongoing investigating Farxiga’s CV outcomes in type 2 diabetes (DECLARE), effects on heart failure (Dapa-HF), and impact in chronic kidney disease (Dapa-CKD) – we’re pleased to note confidence from the company in its SGLT-2 inhibitor product even before these studies read out, and we’re excited about this continued clinical investment (which also includes CVD-REAL and a series of mechanism studies around dapagliflozin). See our coverage below of Sanofi/Regeneron’s, Novartis’, and Amgen’s exhibits as well. The sheer presence of diabetes companies on the floor signals a true paradigm shift in diabetes management – these manufacturers have found a whole new audience in the cardiology community – and this is a trend we’re extremely happy to see. We’d love for every patient to receive diabetes care with CV risk mitigation in mind.

Detailed Discussion and Commentary

Advances in Science: Cardiovascular Disease Prevention with Anti-Hyperglycemic and Cholesterol-Lowering Therapy in Type 2 Diabetes

Risk of Major Cardiovascular Events in Patients with Type 2 Diabetes with and without Prior Cardiovascular Events: Results from the LEADER Trial

Neil Poulter, MD (Imperial College London, UK)

Dr. Neil Poulter presented new data from the LEADER trial, emphasizing that history of stroke/MI at baseline had no mediating effect in the significant association between GLP-1 agonist liraglutide (Novo Nordisk’s Victoza) and CV risk reduction. Simultaneous to the start of this session, Novo Nordisk issued a press release announcing these exciting post-hoc findings. Across the entire CVOT (n=9,340), liraglutide reduced risk for the primary outcome of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) by 13% compared to placebo (p=0.01 for superiority). Among 3,692 patients with a prior history of stroke/MI, the hazard ratio for three-point MACE was 0.84 in favor of the GLP-1 agonist (95% CI: 0.72-0.97), which meets threshold for statistical significance since the upper bound of the 95% confidence interval falls below 1.00. Among the 5,648 patients without prior stroke/MI, this hazard ratio for primary endpoint was 0.89 (95% CI: 0.76-1.05), with a trend in the right direction (numerically fewer MACE events on liraglutide vs. placebo), though this was not statistically significant. Importantly, the p-value for treatment interaction here was a non-significant 0.56, meaning history of stroke/MI did not significantly influence the overall results. Several presentations at ADA 2017 ruled out alternative explanations for Victoza’s CV benefit, reporting non-significant p-values for interaction on severe hypoglycemia, concomitant medication use, and recurrent CV events – none of these variables could explain the robust cardioprotection seen in LEADER, and now we can add history of stroke/MI to this list as well. We see a few key implications of the results Dr. Poulter described: First, as post-hoc analyses eliminate alternative explanations, evidence builds in support of CV benefit inherent to the liraglutide molecule, which could be important in convincing real-world HCPs to prescribe Victoza. Second, these findings add to our knowledge of what works and what doesn’t in CV risk mitigation, which bolsters our ability to approach diabetes management with cardioprotection in mind (this paradigm shift is already underway, but additional insights on CV risk reduction are always welcome). Third, diabetes CVOTs published to-date already enroll a relatively small slice of what is overall a highly heterogeneous type 2 diabetes population. The FDA recently approved a new CV indication for Victoza, but limited its applicability to people with type 2 diabetes and established CV disease (not to undercut how incredibly excited we were about this regulatory decision). It is reassuring to learn that liraglutide’s CV effects extended consistently across the risk spectrum of participants enrolled in LEADER at least – whether or not cardioprotection extends to lower-risk individuals will have to be determined through future research.

• Dr. Poulter also broke down LEADER results for individual components of three-point and expanded MACE according to baseline history of stroke/MI. These are summarized in the table below.

Questions and Answers

Q: What is the place of compounds like empagliflozin and liraglutide that have shown CV benefit? Should they be moved to first-line therapy within treatment guidelines?

Dr. Poulter: In all fairness, this has been a huge sea change. There was uncertainty before with GLP-1 agonists, since lixisenatide came out with a neutral result (Sanofi’s ELIXA trial). I also admit that these trials were conducted in the context of patients with established CV disease, or at least very high CV risk, and medicine was given on top of standard of care. Based on these trials alone, I don’t believe we have sufficient evidence to support the use of these agents as first-line. On the other hand, the evidence for metformin as first-line treatment is also not great. Some guidelines are moving these drugs toward second-line.

Q: Have you stratified the results for patients with and without prior heart failure?

Dr. Poulter: We did. There was no statistical interaction, but the benefits of liraglutide were attenuated, though still in the right direction. Within LEADER, liraglutide reduced heart failure by 13% – again, this was not a statistically significant result, but it was in the right direction. This was reassuring following heart failure-related concerns for some of the DPP-4 inhibitors.

Q: Was the number of patients with heart failure at baseline relatively small?

Dr. Poulter: It was ~18%.

Q: Do you foresee GLP-1 agents being explored for heart failure in future trials?

Dr. Poulter: If you compare the benefits to heart failure we saw in EMPA-REG OUTCOME vs. LEADER, it really does look like the benefits of empagliflozin were driven by heart failure and CV death. There was blood pressure diuresis, there was rapid divergence of curves – all of this looks more beneficial from the heart failure point of view. The message from LEADER was that liraglutide looked safe from the heart failure point of view.

SUSTAIN 6: A Post-Hoc Analysis of the Effect of Semaglutide on Cardiovascular Outcomes Over Time in Subjects with Type 2 Diabetes

Esteban Jodar, MD (University Hospital, Madrid, Spain)

Dr. Esteban Jodar shared new insights on SUSTAIN 6, the pre-market CVOT for Novo Nordisk’s once-weekly GLP-1 agonist semaglutide. His slides featured extended Cox regression models to show that semaglutide’s CV benefits are sustained (no pun intended) throughout two years. Described another way, two-year graphs of three-point MACE (non-fatal MI, non-fatal stroke, and CV death), non-fatal MI, and non-fatal stroke all showed a consistent negative slope, designating relative risk reduction for the adverse CV outcomes with semaglutide vs. placebo at all points in time. As a reminder, the hazard ratio for these endpoints after two years was 0.74 for the primary outcome of three-point MACE (corresponding to a 26% relative risk reduction, p=0.02 for superiority), 0.74 for non-fatal MI (p=0.12), and 0.61 for non-fatal stroke (corresponding to a 39% relative risk reduction, p=0.04). Dr. Jodar explained how this constant benefit over time aligns with the hypothesis that semaglutide slows the progression of atherosclerosis, and thereby exhibits its cardioprotective properties – one possible explanation for the agent’s CV mechanism. The extended Cox regression line was near flat for CV death, and indeed, the hazard ratio for this component endpoint in SUSTAIN 6 was 0.98 (95% CI: 0.65-1.48). Dr. Jodar underscored that this was a short trial, designed to demonstrate non-inferiority for semaglutide vs. placebo. He pointed out that with longer-term follow-up, a relative risk reduction for CV death may have appeared. Moreover, that semaglutide demonstrated an advantage over placebo for atherosclerotic MACE events at every point in time suggests a durability of effect, according to Dr. Jodar. This supports Novo Nordisk’s plans for a longer, larger post-market CVOT. Semaglutide is currently under review with the FDA and EMA, and we eagerly await decisions expected in 4Q17.

Questions and Answers

Q: Can we say there is a class effect for the group of drugs known as GLP-1 analogs?

Dr. Jodar: For now, I don’t think we can say there is a class effect. We have four major CVOTs presented – two neutral, two positive. This is all very important and interesting. Probably, we are going to have a lot more data in the future. But for me, it’s pretty clear that we can’t argue for a class effect any longer.

Q: Can you say something about the A1c difference in the two SUSTAIN 6 treatment arms?

Dr. Jodar: All investigators were told to use local guidelines to manage their patients. With semaglutide, however, we are dealing with a very powerful drug, one that’s able to reduce blood glucose remarkably – the levels we’ve seen are incredible for something that’s not insulin. So yes, there were some differences in A1c between the groups, perhaps a big greater than other CVOTs, but that’s the reason.

Late-Breaking Science: Heart Failure

Does the Risk for Heart Failure Modulate the Effectiveness of Empagliflozin on Heart Failure Hospitalization or CV Death in Patients with Type 2 Diabetes without Heart Failure? Insights from EMPA-REG OUTCOME

Javed Butler, MD (Emory University, Atlanta, GA)

Dr. Javed Butler presented a late-breaking post-hoc analysis of EMPA-REG OUTCOME, reporting consistent benefits to SGLT-2 inhibitor Jardiance (empagliflozin) across all categories of baseline heart failure risk. The 6,314 participants in Lilly/BI’s large CVOT without a prior history of heart failure were stratified into (i) low-to-average, (ii) high, or (iii) very high risk groups for five-year likelihood of heart failure according to the Health ABC HF Risk Score (a well-validated assessment according to Dr. Butler). People in the lowest-risk category (~67%) experienced a 29% relative risk reduction with empagliflozin vs. placebo for the composite endpoint of heart failure hospitalization or CV death (HR=0.71, 95% CI: 0.52-0.96). Among those at low-to-average risk, the incidence of heart failure was 1.68/100 patient-years in the placebo group vs. 1.20/100 patient-years in the treatment group. As expected, this absolute risk increased for those categorized as high-risk for heart failure (~24%), with events occurring at an incident rate of 4.03/100 patient-years in the placebo arm vs. 2.07/100 patient-years in the empagliflozin arm. Still, empagliflozin conferred a significant CV benefit, in the form of 48% relative risk reduction for the heart failure/CV death composite (HR=0.52, 95% CI: 0.36-0.75). Moving up the scale to the very high-risk category (~5%), Dr. Butler reported heightened incidence of heart failure at 7.0/100 patient-years among placebo-treated participants vs. 3.8/100 patient-years among empagliflozin-treated participants. In this third category, Jardiance was associated with a 45% relative risk reduction for the heart failure/CV death composite (HR=0.55, 95% CI: 0.30-1.00). Due to fewer events in each subgroup compared to the overall EMPA-REG OUTCOME trial, it’s more challenging for any of these subgroup hazard ratios to meet criteria for statistical significance (hence the wide confidence intervals). That said, it’s quite notable that there was no significant interaction between baseline heart failure risk and Jardiance’s major CV benefits (p=0.428), because this underscores the drug’s potential cardioprotective value to a broader range of type 2 diabetes patients – in the real world, not all have established CV disease or a history of CV events, but these lower-risk people still stand to benefit from an agent effective in primary CV prevention. We’re impressed by the continued insights that have been gleaned from subsequent analyses of EMPA-REG OUTCOME, and this was no exception. Dr. Butler announced that these post-hoc findings are to be published soon in the European Heart Journal.

Heart Failure and Death in New Users of SGLT-2 Inhibitors vs. Other Glucose-Lowering Drugs – Consistent Risk Reduction Across Patient Groups in Four Countries and >270,000 Patients: The CVD-REAL Study

Anna Norhammar, MD (Karolinska Institute, Stockholm, Sweden)

Dr. Anna Norhammar presented late-breaking data from AZ’s CVD-REAL study, showing consistent benefits to SGLT-2 inhibitors vs. other glucose-lowering drugs on heart failure and all-cause death regardless of age, gender, CKD status, and concomitant medications. She concluded that this analysis adds to the robustness of initial CVD-REAL results, while also implying a potential benefit to this therapy class in a broader type 2 diabetes population. SGLT-2 inhibitors (whether AZ’s dapagliflozin – the most-prescribed SGLT-2 agent in Europe, J&J’s canagliflozin – most-prescribed in the US, or Lilly/BI’s empagliflozin) showed superiority over other glucose-lowering agents in reducing risk for heart failure regardless of age, with a hazard ratio point estimate of 0.58 (95% CI: 0.49-0.70) for those ≥65 years-old vs. 0.64 (95% CI: 0.44-0.93) for those <65 years-old (p=0.657 for interaction). This benefit was sustained for women (HR=0.54, 95% CI: 0.42-0.70) and men (HR=0.64, 95% CI: 0.54-0.76, p=0.275 for interaction), as well as for those with chronic kidney disease (CKD) at baseline (HR=0.46, 95% CI: 0.23-0.90) and those without (HR=0.63, 95% CI: 0.55-0.72, p=0.368 for interaction). Similarly, risk reduction for all-cause mortality was greater with SGLT-2 inhibitors vs. other diabetes drugs in both age groups (p=0.598), gender groups (p=0.971), and CKD status groups (p=0.097). SGLT-2 therapies were associated with superior risk reduction for a composite endpoint of heart failure or death in all subgroups: the p-value for interaction was a non-significant 0.76 for age, 0.452 for gender, and 0.76 for baseline CKD. As a reminder, relative risk reduction with SGLT-2 vs. other therapies in the overall CVD-REAL population was 39% for heart failure hospitalization (p<0.001), 51% for all-cause mortality (p<0.001), and 46% for the composite (p<0.001). Further detail on the consistency of effects seen with SGLT-2 inhibitors vs. other glucose-lowering drugs regardless of concomitant medications can be found below, but the key takeaway from this analysis is already apparent – the SGLT-2 class as a whole has demonstrated important benefits to heart failure and all-cause mortality in this real-world dataset, which includes people from a wide age range, from both genders, and with a variety of disease experiences in terms of comorbidities and other medications used. This latter point is particularly interesting, in our view, since randomized controlled trials of SGLT-2 inhibitors thus far have primarily evaluated CV effects in type 2 diabetes patients at high CV risk, which is only one slice of a heterogeneous type 2 population in real world. Dr. Norhammar called attention to the high number of primary prevention participants enrolled in DECLARE (AZ’s CVOT for dapagliflozin) compared to EMPA-REG OUTCOME (for Lilly/BI’s empagliflozin) or CANVAS (for J&J’s canagliflozin), suggesting that this upcoming RCT expected to complete in 2H18 will elucidate the impact of SGLT-2 inhibitors on lower CV risk patients. We look forward to this read out, since evidence from an RCT is much more likely to affect product labels and treatment guidelines (as opposed to an observational study like CVD-REAL, though we appreciate this tremendous effort/investment from AZ and the hint toward a cardioprotective class effect). We’d love to see SGLT-2 inhibitors indicated for CV protection in a broader type 2 diabetes population – the Jardiance (empagliflozin) label points to risk reduction for CV death among people with diabetes and established CV disease.

• When adjusted for concomitant use of ACE/ARB agents, loop diuretics, beta blockers, aldosterone antagonists, and statins (from the CV area) and of insulin and sulfonylureas (from the diabetes area), CVD-REAL still showed a beneficial effect of SGLT-2 inhibitors on heart failure, all-cause death, and a composite of heart failure/all-cause death. On the composite endpoint, the p-value for interaction was a non-significant 0.606 for ACE/ARB agents, 0.076 for loop diuretics, 0.325 for beta blockers, 0.999 for aldosterone antagonists, 0.979 for statins, 0.369 for insulin, and o.791 for sulfonylureas. More specifically, the hazard ratio point estimate was 0.52 (95% CI: 0.44-0.63) among people on insulin vs. 0.58 (95% CI: 0.48-0.72) among people not taking insulin. For CVD-REAL participants taking sulfonylureas, the hazard ratio point estimate on this composite outcome was 0.55 (95% CI: 0.44-0.70) vs. 0.57 (95% CI: 0.50-0.66) for those not taking sulfonylureas. These findings underscore the consistency of SGLT-2 inhibitors in lowering risk for heart failure and death, despite background medications in any given patient’s treatment regimen. More often than not, real-world patients are on multiple therapies or are likely to switch therapies – after all, people don’t live in the controlled environment of an RCT – so we were pleased to see this focused analysis of CVD-REAL that took concomitant medications into consideration.
• The positive results on SGLT-2 inhibitors in people with baseline CKD are intriguing in the context of recently-initiated outcomes trials from AZ and Lilly/BI of dapagliflozin and empagliflozin, respectively, in this patient population. The Dapa-CKD study for Farxiga was launched this past February, and is expected to complete in November 2020. Lilly/BI have yet to share timing for the Jardiance-in-CKD trial, but this clinical project was announced in June during ADA 2017. Data suggestive of renal protection has been a pleasant surprise finding from SGLT-2 inhibitor CVOTs so far, since all three commercial products in this class are actually contraindicated for people with renal disease. There’s certainly much more to unravel in this therapeutic area, and we’ll be keeping an eye out for updates on Dapa-CKD and on Lilly/BI’s planned trial.

Moderated Posters: Diabetes Mellitus: From “Omics to Complications”

Detailed Description of Myocardial Infarctions and the Various Subtypes in the LEADER Trial

Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Hanz, Germany)

In a moderated poster presentation, Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Hanz, Germany) shared more granular data on MI from Novo Nordisk’s LEADER trial. While the initial full results reported a non-significant difference in time to first non-fatal MI with GLP-1 agonist Victoza (liraglutide) vs. placebo (HR=0.88, 95% CI: 0.75-1.03, p=0.11), the data on total MIs – counting first and recurrent events – does in fact significantly favor liraglutide. There were 359 total MIs in the Victoza arm vs. 421 in the placebo arm of LEADER (p=0.02). Moreover, there were numerically fewer fatal MIs in the liraglutide group vs. placebo (17 and 28 events, respectively, p=0.28). Among patients with at least one symptomatic MI during the course of the trial, those treated with liraglutide were less likely to experience troponin levels >5x the upper reference limit (URL), which signals greater severity of infarct: ~61% of symptomatic MIs in the liraglutide group met troponin levels >5x URL (139 out of 229) vs. ~67% of symptomatic MIs in the placebo group (189 out of 282). Dr. Nauck thus concluded that Victoza may be associated with lower severity of infarct, even if it hasn’t met statistical criteria for risk reduction for non-fatal MI. If liraglutide confers a better prognosis following a heart attack, we absolutely agree with Dr. Nauck that this is indeed a notable benefit with real-world clinical utility. In addition, the imbalance in total MIs favoring the GLP-1 agonist is reassuring, and adds to the robustness of evidence pointing to liraglutide’s CV efficacy. This presentation of a LEADER post-hoc analysis was well-timed, coming just two days after the FDA approval of a new Victoza indication for the reduction of major adverse CV events, including MI, stroke, and CV death. The drug’s CV benefits can now be more publically promoted, and we’re excited for real-world patients to reap the benefits of a cardioprotective therapy that reduces CV death, reduces risk for three-point MACE overall (non-fatal MI, non-fatal stroke, CV death), and perhaps reduces the severity of MI when a heart attack does occur.

Rapid-Fire Abstracts: Impact of Obesity on Cardiovascular Prognosis – New Data

The Association Between Obesity, Diabetes Control, and Cardiovascular Outcomes: Insights from the TECOS Trial

Neha Pagidipati, PhD (Duke University, Durham, NC)

Duke University’s Dr. Neha Pagidipati used data from Merck’s TECOS trial of DPP-4 inhibitor Januvia (sitagliptin) to probe for a correlation between BMI and CV outcomes in a diabetes patient population. She found that no class of overweight/obesity significantly affected CV risk, but that BMI <20 kg/m² (indicating underweight) conferred heightened risk for adverse CV events. The hazard ratio for four-point MACE (non-fatal MI, non-fatal stroke, CV death, or hospitalization for unstable angina) was 1.87 (95% CI: 1.23-2.84) for TECOS participants who were underweight vs. those who were of a healthy weight, after adjusting for age, sex, race, history of CV disease, and other variables. The 95% confidence interval for four-point MACE hazard ratio crossed the line of unity for all other BMI subgroups: Among those with overweight (BMI 25-29.9 kg/m²) vs. healthy weight, the adjusted hazard ratio for four-point MACE was 0.96 (95% CI: 0.82-1.12). Among those with class I obesity (BMI 30-34.9 kg/m²) this value was 0.89 (95% CI: 0.76-1.05), among those with class II obesity (BMI 35-39.9 kg/m²) it was 0.97 (95% CI: 0.80-1.19), and finally, among those with class III obesity (BMI ≥40 kg/m²) it was 0.99 (95% CI: 0.76-1.28). Dr. Pagidipati speculated that having type 2 diabetes and being underweight perhaps indicates some other underlying disease, which is one possible explanation for the significant association with adverse CV outcomes. An important theme that arose during Q&A is how this analysis contributes to the controversy surrounding the obesity paradox, or the notion that obesity is sometimes associated with lower CV risk – Dr. Pagidipati pointed out that this paradox is especially murky in the context of diabetes. She summarized, “here, we don’t find evidence for the paradox, but we also don’t find that it’s necessarily worse to have overweight/obesity.” These findings were not meant to make any statement on weight recommendations in clinical practice, Dr. Pagidipati underscored, but rather, they serve as a launching pad for more dedicated inquiries into the relationship between obesity, diabetes, and CV disease. We agree that there’s a disappointing lack of research in this area, and we were glad to see the topic raised.

Symposium: Cardiovascular Risk in Type 2 Diabetes

Recent Outcomes Trials: How Will They Influence Clinical Decision-Making?

Neil Poulter, MD (Imperial College London, UK); John Deanfield, MD (University College London, UK)

Drs. Neil Poulter and John Deanfield, both hailing from London, led an interactive discussion of diabetes CVOTs and what cardiologists need to know. The conversation steered toward how to choose between an SGLT-2 inhibitor (Lilly/BI’s Jardiance or J&J’s Invokana) and a GLP-1 agonist (Novo Nordisk’s Victoza) when both have shown cardioprotection in people with type 2 diabetes and high CV risk. The speakers acknowledged that cardiologists tend to be more comfortable prescribing oral agents rather than injectable ones, especially when it comes to medicines originating in other disease areas (Dr. Poulter suggested that subcutaneous injection reminds the average HCP of hypoglycemia, even if GLP-1 agonists aren’t associated with this risk). That said, they rejected this hesitation, encouraging cardiologists in the audience to eagerly embrace Victoza in their prescribing habits now that liraglutide has demonstrated a 13% risk reduction for three-point MACE and a 22% risk reduction for CV death in the LEADER trial. Moreover, the FDA and EMA have each added CV indications to the Victoza label. It will still take time and concerted education to get Victoza incorporated into regular cardiology practice, according to Dr. Poulter, but he asserted that providers in this field now have a responsibility to engage with all glucose-lowering, cardioprotective therapies. He explained that Victoza could be particularly beneficial for type 2 diabetes patients with high CV risk and overweight/obesity, as liraglutide and other GLP-1 agents are associated with greater weight loss vs. empagliflozin, canagliflozin, and SGLT-2 agents on the whole. On the other hand, Dr. Poulter pointed out that SGLT-2 inhibitors may be the preferred cardioprotective choice for diabetes patients with incipient heart failure, since this class appears to confer beneficial CV effects through non-atherosclerotic mechanisms. Dr. Deanfield echoed these clinical opinions, and added that cardiologists are going to have to get on board with more injectable therapies now that PCSK9 inhibitors are also making waves in CV medicine. He speculated that HCPs will start co-administering an SGLT-2 inhibitor alongside a GLP-1 agonist “quicker than you think,” even though no RCT has yet investigated additive CV efficacy. AZ’s DURATION-8 study of SGLT-2 inhibitor Farxiga (dapagliflozin)/GLP-1 agonist Bydureon (exenatide once-weekly) has shown superior A1c decline and weight loss with dual therapy vs. either monotherapy, and Dr. Deanfield pointed to a substantial real-world dataset to support safety of this combo regimen, since many diabetes doctors are prescribing both to the same patient. But no CVOT has evaluated SGLT-2/GLP-1 combination therapy (it’s very unlikely that AZ would sponsor such a study, since Bydureon reported neutral topline CVOT data – we’ll see the full EXSCEL results soon, at EASD – but we wonder if Lilly might eventually consider this with Jardiance and Trulicity).

• Indeed, cardiologists are suddenly tasked with choice in diabetes therapy, but Drs. Poulter and Deanfield emphasized that these are very exciting decisions to be making. A couple years ago we didn’t have any diabetes drugs with CV benefit, and we now have three on the market. Dr. Poulter spoke to the “art of medicine,” and to the opportunity for personalized treatment regimens. We love the idea that diabetes patients can express preference for an oral or injectable, for a medicine more effective on blood pressure or body weight, and either way can pick up a prescription at the pharmacy that’s going to help prevent CV complications – we see this as an enormous win for the diabetes field, for the cardiology field, and for the patient community.

Symposium: Modern Management of Diabetes in Cardiology

Impact of SGLT-2 Inhibition on Cardiovascular Outcomes and Heart Failure

Naveed Sattar, MD (University of Oxford, UK); David Fitchett, MD (University of Toronto, Canada)

Drs. David Fitchett and Naveed Sattar shared practical advice for the cardiologist looking to prescribe an SGLT-2 inhibitor, answering key questions about renal safety, amputation risk, and the choice between GLP-1 and SGLT-2. This was an absolutely packed, standing-room-only session, an observation Dr. Sattar made to point out that SGLT-2 inhibitors are already of keen interest within cardiology settings (as they should be). Dr. Fitchett explained that the contraindication/recommended dose reduction for all SGLT-2 inhibitor products as eGFR falls <60 ml/min/1.73m² is not for safety concerns, but rather for a presumed attenuation of efficacy. This class of glucose-lowering agents works through the kidneys, and thus renal impairment seems incompatible with SGLT-2 therapy. That said, both EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin) and CANVAS for J&J’s Invokana (canagliflozin) showed impressive risk reduction for a composite renal endpoint, suggestive of renal-protective properties. In turn, Lilly/BI have announced plans to conduct an outcomes trial of Jardiance in people with chronic kidney disease (CKD), and AZ has initiated a similar study of its SGLT-2 inhibitor Farxiga (dapagliflozin) called Dapa-CKD. Dr. Fitchett hinted that diabetes patients with eGFR <60 ml/min/1.73m² may actually stand to benefit the most from treatment with an SGLT-2 inhibitor, in terms of CV and renal outcomes alike – the truth will lie in outcomes data, and we look very forward to that.

• In response to an audience question regarding canagliflozin and a signal for lower limb amputations, Dr. Sattar mentioned that the background amputation rate – even for a diabetes patient population – is relatively low, though he acknowledged that this is a very visceral, undesirable complication (“amputations aren’t a major issue generally, unless you have one”). Dr. Fitchett emphasized that EMPA-REG OUTCOME showed no imbalance in amputations. He outlined two possibilities for this divergence in safety data between Invokana and Jardiance: (i) difference in molecule or (ii) difference in study population. He did not mention differences in trial design, and explained that despite amputations being collected retrospectively in EMPA-REG OUTCOME, he doesn’t believe any events were missed. This has been a complicated story to unravel, and our thoughts continue to evolve. The best-case scenario, in our view, will be a post-hoc analysis of CANVAS that elucidates driving factors for the amputation signal, variables that can be controlled in real-world clinical practice, or that at the very least can inform patient selection. We’ll have to wait-and-see. We do hope the CANVAS safety data prompts better patient education around foot care.
• Other cardiologists in the audience wondered what factors they should consider in selecting a cardioprotective diabetes drug, especially in choosing between an SGLT-2 inhibitor and a GLP-1 agonist. Dr. Sattar chimed in about the value of oral dosing (for the SGLT-2 class) as compared to injectable dosing (for the GLP-1 class, at least for now), the former offering greater convenience and often being preferable to patients for that reason. He mentioned that the ongoing EMPEROR HF studies of empagliflozin in heart failure will collect quality of life outcomes (music to our ears!). Dr. Sattar emphasized the remarkable risk reduction for heart failure hospitalization found in EMPA-REG OUTCOME as well as CANVAS. While GLP-1 agonist Victoza (liraglutide) demonstrated non-inferiority on this endpoint in LEADER, Dr. Sattar implied that there’s very little chance GLP-1 agents will be investigated in dedicated heart failure studies (“it’s not going to happen”). Notably, this topic also came up during a similarly-structured, interactive session with Drs. Neil Poulter and John Deanfield (see above), who highlighted Victoza’s superior weight loss efficacy vs. SGLT-2 inhibitors. This clinical feature, they argued, makes the GLP-1 agonist a better choice for type 2 diabetes patients with high CV risk and overweight/obesity. From our point of view, it’s incredible that HCPs are faced with this choice in the first place, as this means we now have two diabetes therapy classes with demonstrated CV efficacy. We’re pleased that this will allow for more individualized treatment plans. And, we so appreciated that both sets of experts issued a resounding call-to-action for cardiologists to embrace the changing paradigm of treatment and to start prescribing these diabetes drugs, whether SGLT-2 inhibitors or GLP-1 agonists.

Symposium: Treatment of Type 2 Diabetes – Important New Aspects for the Cardiologist

Liraglutide and Empagliflozin: An Evaluation of Benefits

Thomas Schmidt, MD (Danish Diabetes Academy, Holbaek, Denmark)

In a rather controversial talk, Dr. Thomas Schmidt argued that the absolute risk reduction for CV events in EMPA-REG OUTCOME and LEADER was not all that impressive. He suggested that reporting relative risk reduction is a way to amplify the benefit. The EMPA-REG OUTCOME trial found a highly-significant 38% relative risk reduction for CV death with Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) vs. placebo, but according to Dr. Schmidt, only 2.2% of participants in this study avoided CV death with empagliflozin who otherwise would have experienced it. The relative risk reduction for all-cause death was 32% with empagliflozin (also highly statistically significant), but Dr. Schmidt announced that only 2.6% of trial participants avoided death with the active treatment. EMPA-REG OUTCOME also explored hospitalization for heart failure as a secondary endpoint, and found a highly-significant 35% relative risk reduction with Jardiance. Dr. Schmidt’s rebuttal to this was that only 1.4% of participants avoided a heart failure hospitalization on empagliflozin therapy who would otherwise have experienced this adverse outcome. Turning to LEADER, relative risk reduction for CV death was 22% with Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) vs. placebo, and Dr. Schmidt stipulated that only 1.3% of people enrolled really avoided a CV death with the treatment. Liraglutide was also associated with a 15% relative risk reduction for all-cause death, and Dr. Schmidt stipulated that only 1.4% of participants really avoided a death on treatment. These findings from LEADER were also highly statistically significant, and we want to emphasize that both diabetes drugs – Jardiance and Victoza – are now indicated for CV risk reduction based on FDA-approved product labels. And yet, Dr. Schmidt expressed major reservations about their true cardioprotective value. We were quite disappointed in these speculations, and many audience members echoed our reaction. Dr. Nikolaus Marx, who was chairing the session, pointed out that each CVOT investigated therapy on top of standard of care. Patients in the placebo arms of EMPA-REG OUTCOME and LEADER were still treated to target glucose, cholesterol, blood pressure, etc. The fact that each agent demonstrated statistically significant relative risk reductions vs. a well-controlled placebo group is incredibly compelling, and speaks to cardioprotective benefits that are very likely inherent to these molecules. Dr. Lars Ryden, another session chair, emphasized that both CVOTs technically have back-up from another in-class study (CANVAS for J&J’s SGLT-2 inhibitor Invokana to parallel EMPA-REG OUTCOME and SUSTAIN 6 for Novo Nordisk’s GLP-1 agonist semaglutide to parallel LEADER). This replication of evidence is understandably important to a clinical trialist, but with accumulation of positive outcomes data, it’s becoming less and less likely that any one of these studies is a chance finding or a fluke. One audience member put it very eloquently: “You can criticize any journal publication, but in the real world, we have to work with the evidence we have. And we now have evidence that makes empagliflozin and liraglutide seem like super drugs, to be honest, in treating our patients with type 2 diabetes and background CV disease.” We loved this sentiment, and we worry that conservative opinions like Dr. Schmidt’s will decelerate an already slow process of getting positive outcomes data on drug labels, getting it to influence clinical practice guidelines, and getting payers to listen and respond by enhancing reimbursement for advanced, highly-effective therapies. We believe it’s a near-crime to have information about the life-saving properties of medicines, collected via FDA-mandated, resource-heavy clinical trials, that is then hidden from or deprioritized to real-world patients/providers. Dr. Schmidt underscored that these newer drugs are expensive – we won’t argue with that, but we do take issue with cost as a reason to refute science. And, we can’t help but quote Dr. John Buse when it comes to the payer piece: “It is immoral that as a society we mandate a certain set of trials be done from a regulatory perspective, and then not require that insurance companies cover these drugs if they’re shown to reduce mortality. We’re not talking about reducing toenail fungus. We’re talking about reducing mortality.”

Corporate Symposium: Further Insights into Treatment Options for Patients with Type 2 Diabetes and Cardiovascular Disease (Sponsored by MSD)

Clarifying the Role for DPP-4 Inhibitors in the Treatment of Patients with Type 2 Diabetes at Risk of Heart Failure

Darren McGuire, MD (UT Southwestern, Dallas, TX)

Dr. Darren McGuire criticized treatment guidelines that have assigned heart failure risk to all DPP-4 inhibitor products as a class effect. In a similar vein, he questioned the FDA’s recent decision to add heart failure warnings to the Januvia (Merck’s sitagliptin) and Tradjenta (Lilly/BI’s linagliptin) labels, calling it a “curious action.” The TECOS trial for Januvia found a resoundingly neutral hazard ratio of 1.00 (95% CI: 0.80-1.20) for heart failure hospitalizations, with no imbalance between the sitagliptin and placebo arms. Two CVOTs for Tradjenta are ongoing: The CARMELINA study comparing linagliptin vs. placebo is expected to complete in December 2017, while the CAROLINA study comparing linagliptin vs. glimepiride (a sulfonylurea) is expected to complete in March 2019. Takeda’s EXAMINE trial for Nesina (alogliptin) reported a numerical imbalance in hospitalizations for heart failure, but this finding did not reach statistical significance (HR=1.22 in favor of placebo, p=0.22). Thus, the worry over heart failure/DPP-4 agents stems mainly from the SAVOR-TIMI study of AZ’s Onglyza (saxagliptin), which found an unexpected 27% increase in risk for this safety endpoint (p=0.007). That said, Dr. McGuire also reviewed a sub-analysis of EXAMINE, dividing participants by whether or not they had a baseline history of heart failure: The hazard ratio for heart failure hospitalization in the trial was 1.00 for people with a prior event (p=0.99) vs. 1.76 for people without a prior event (p=0.026). The p-value for this interaction was just above 0.06, not quite statistically significant, though it did approach that 0.05 threshold. Dr. McGuire argued that regulatory decisions, like clinical practice decisions, should be evidence-based – to this end, he underscored the robust safety data on Merck’s Januvia, published in peer-reviewed literature. We echo his surprise at the FDA’s label updates for Januvia and Tradjenta. While we certainly don’t want to undercut the importance of drug safety, and while we appreciate all FDA does on this front (with limited resources at that), we’d also hate to see providers discouraged from using Januvia or Tradjenta in patients for whom they are safe and for whom they could be incredibly beneficial. DPP-4 inhibitors have shown CV safety on three-point MACE, have demonstrated glucose-lowering efficacy, and boast a long history of safety/tolerability in the field. Thought leaders, including Dr. Robert Ratner, have touted the advantages of this therapy class for the elderly, for patients with renal impairment, and for any diabetes patient earlier in the course of disease progression. Dr. McGuire concluded his talk with a list of key questions that need to be addressed – hopefully these answers can put the DPP-4/heart failure issue to bed, so that safe/effective therapies are maximally accessible.

• Are these drug effects, or class effects?
• Are they patient-specific effects? Can we identify patients at-risk to inform patient selection?
• What’s the mechanism for saxagliptin/increase in heart failure?

Why Control Glycemia?

Lawrence Leiter, MD (University of Toronto, Canada)

Dr. Lawrence Leiter made a two-pronged pitch for why cardiologists should care about glycemia: (i) better glycemic control has resulted in less CV disease, and (ii) as cardioprotective therapies help people live longer with diabetes, more microvascular complications of hyperglycemia can build up over the longer term. The link between A1c and microvascular complications is uncontroversial – Dr. Leiter briefly summarized findings from the DCCT/EDIC to underline this fact. He acknowledged more confusing evidence from individual studies of how glycemic control impacts macrovascular disease, but presented a meta-analysis of four landmark trials – UKPDS, ACCORD, ADVANCE, and VADT – that did show a modest but significant 9% risk reduction for major CV events with improved glycemic control. The same meta-analysis calculated a 15% risk reduction for MI specifically, which Dr. Leiter described as clinically-meaningful. He alluded to a more recent study, just published in Diabetes, Obesity, and Metabolism in June 2017, that analyzes diabetes CVOTs completed to-date, and finds a greater magnitude of CV risk reduction with greater  estimated differential glycemic exposure (% A1c x years) between treatment groups. This is an interesting conclusion, since diabetes CVOTs are designed with glycemic equipoise in mind, so that CV effects can be linked to the specific molecule rather than to general glucose-lowering. Dr. Leiter’s main takeaway from this discussion, however, was not to undermine the exciting positive data we have on liraglutide, semaglutide, empagliflozin, and canagliflozin, but instead to emphasize that cardiologists shouldn’t ignore glycemia itself, even with the advent of cardioprotective diabetes drugs. He shared one graph of diabetes complication rates between 1990 and 2010: While MI and stroke were on the decline during these two decades, the incidence of end-stage renal disease was flat for the diabetes patient population overall, and actually rose among older people with diabetes. “This is not surprising,” Dr. Leiter articulated, “because if people aren’t dying of CV disease, they’re living long enough to encounter other complications of diabetes.” We appreciated this approach to convince cardiologists to attend to glycemia in their patients, especially since a majority of sessions at this meeting (and at many recent conferences, for that matter) have focused primarily on getting cardiologists to prescribe diabetes drugs once they have yielded positive CVOT data.

Corporate Symposium: Improving Cardiovascular Outcomes in Patients with Type 2 Diabetes: Where Does the Evidence Lead Us? (Sponsored by Lilly/BI)

Cardiovascular Risk Reduction with Empagliflozin: Exploring the Evidence from EMPA-REG OUTCOME

Faiez Zannad, MD (University Hospital of Nancy, France)

Dr. Faiez Zannad shared a clinical trialist’s perspective on EMPA-REG OUTCOME, endorsing the study’s rigor based on five criteria: (i) statistical significance, (ii) clinical significance, (iii) internal validity, (iv) external validity, and (v) mechanistic plausibility. He discussed each of these in turn. The first is captured in p-values. Dr. Zannad established Lilly/BI’s CVOT for SGLT-2 inhibitor Jardiance (empagliflozin) as a large, well-powered study (spanning 42 countries, enrolling ~7,000 participants, observing patients for a median 3.1 years), and he reviewed the statistically significant 14% relative risk reduction for three-point MACE (p=0.038 for superiority), 38% relative risk reduction for CV death (p<0.0001), 32% relative risk reduction for all-cause mortality (p<0.001), and 35% relative risk reduction for heart failure hospitalization (p=0.002). He tackled no. 2 swiftly, as no healthcare professional should argue against the clinical significance of saving lives or preventing hospitalizations for major cardiac events (in fact, we’re surprised how often thought leaders have had to say how non-trivial this is in pushing for greater appreciation of Jardiance’s CV benefits among regulators and guideline-writing committees). Dr. Zannad defined internal validity for a diabetes CVOT as consistency across components of the primary three-point MACE outcome, across primary and secondary endpoints, and across various subgroups. Notably, the primary benefit seen in EMPA-REG OUTCOME was driven by CV death, as there was no significant difference in non-fatal MI (HR=0.87, p=0.22) or non-fatal stroke (HR=1.24, p=0.16) – stroke even trended in the wrong direction, favoring placebo over empagliflozin, though this finding did not reach statistical significance and Dr. Zannad pointed out the very low number of total stroke events occurring across the trial. On the other hand, heart failure hospitalization was a secondary endpoint in the trial, and the data for this outcome was highly-consistent with the overall MACE benefit. Dr. Zannad also summarized several post-hoc analyses of EMPA-REG OUTCOME that have shown consistency across subgroups: For example, Jardiance reduced CV death regardless of baseline CV disease (data adjusted for coronary artery disease, history of MI, history of coronary artery bypass graft, peripheral artery disease, history of stroke, history of heart failure, and history of atrial fibriliation) in a poster presented at AHA 2016. J&J’s CANVAS trial for SGLT-2 inhibitor Invokana (canagliflozin) provides external validity, criteria no. 4. CANVAS reported a 14% risk reduction for three-point MACE with canagliflozin vs. placebo (p=0.0158 for superiority), similar to the results from EMPA-REG OUTCOME, and also showed a similarly impressive 33% risk reduction for heart failure hospitalization. No individual components of three-point MACE reached statistical significance in CANVAS, which raises questions about possible differences between the empagliflozin and canagliflozin molecules, but we’re reassured to hear a dominant view from thought leaders that these two CVOTs together do suggest a cardioprotective class effect. Lastly, on mechanism for empagliflozin’s CV effects, Dr. Zannad acknowledged that we’re still unsure, though it’s much more likely to be related to volume/sodium depletion, to renal-endocrine effects, or to reduced myocardial pre-load and after-load vs. anything to do with glucose control. As researchers continue to investigate these various mechanistic hypotheses, he urged HCPs not to wait for an explanation – rather, he advocated that the evidence from EMPA-REG OUTCOME was compelling enough to support increased use of this agent right away in patients with type 2 diabetes and CV disease.

• Elaborating on internal consistency, Dr. Zannad presented one slide showing that Jardiance reduced risk for heart failure hospitalization even in patients with eGFR <60 ml/min/1.73m². The hazard ratio was 0.59 in favor of empagliflozin for this subgroup (95% CI: 0.39-0.88). The suggestion here is that Lilly/BI’s SGLT-2 inhibitor may work even in people with a comorbidity of renal disease, which is intriguing given that all SGLT-2 agents are currently contraindicated for patients with severe renal impairment. The microvascular findings from EMPA-REG OUTCOME and subsequent post-hoc analyses motivated Lilly/BI to launch a dedicated study of empagliflozin in chronic kidney disease (CKD), alongside an investigation in people with heart failure (with and without type 2 diabetes). We can’t wait to learn more about Jardiance’s cardio- and renal protective effects, though we’ll have to be patient for now. Lilly/BI have not yet shared timing information for the CKD outcomes study, while the EMPEROR HF-Preserved and EMPEROR HF-Reduced trials (referring to ejection fraction) are expected to complete in June 2020.
• Dr. Zannad is a co-principal investigator for the EMPEROR HF clinical trials, which he called “very exciting and important” for several reasons, not the least of which is the inclusion of many participants with prediabetes. He suggested that researchers will be able to do an exploratory analysis on Jardiance in this sub-population, which will start to shed light on the potential for this effective therapy class (for glucose-lowering as well as weight loss) in prediabetes. Our curiosity is piqued for SGLT-2 inhibitors are diabetes prevention agents, and for the prospect of intervening even earlier to prevent adverse CV and renal outcomes stemming from hyperglycemia. J&J management has mentioned plans for a prediabetes CVOT of Invokana, though we haven’t heard any updates on this since the company’s 3Q16 earnings call.

Managing Cardiovascular Outcomes in Patients with Type 2 Diabetes – Where Have We Come from and Where Are We Going?

Darren McGuire, MD (UT Southwestern, Dallas, TX)

Dr. Darren McGuire provided an insightful defense of the FDA’s 2008 CVOT guidance for new diabetes drugs – a fitting way to open a Lilly/BI-sponsored symposium on SGLT-2 inhibitor Jardiance (empagliflozin), since EMPA-REG OUTCOME was the first CVOT to break ground with positive results (indicative of a cardioprotective benefit, rather than merely CV safety as seen with DPP-4 inhibitors, or at worst, CV harm). Prior to these new regulatory requirements in 2008, the field operated under ICH guidelines (International Conference on Harmonization). Under these previous rules, diabetes therapies could be approved to market with as few as 250 patient-years of drug exposure, which Dr. McGuire presented as insufficient to eliminate important safety concerns. Since 2008, manufacturers have been tasked with collecting nearly ~15,000 patient-years of drug exposure – this offers a much more thorough picture on safety, to be sure, but Dr. McGuire also emphasized the opportunity afforded to find “surprise” CV benefits, as in EMPA-REG OUTCOME, CANVAS for J&J’s SGLT-2 inhibitor Invokana (canagliflozin), and LEADER for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Indeed, this once-controversial FDA guidance has delivered many advantages to the diabetes field. We admit that for some time, we were negative about the required timing and any related delays in new product approvals, but the abundance of learning that has come from these outcomes studies since 2008 has blown us away. Knowledge of an agent’s cardioprotective value is of course the big prize from these recent studies, but we also note the contributions of microvascular outcomes data and safety results. Dr. McGuire briefly mentioned the amputation signal seen in CANVAS, with canagliflozin nearly doubling a patient’s risk for a lower-extremity amputation. He also pointed out that Invokana did not show statistically significant risk reduction for any individual component of three-point MACE (non-fatal MI, non-fatal stroke, or CV death), whereas Jardiance’s CV benefit was driven by a 38% risk reduction in CV death specifically. On both of these points, however, Dr. McGuire posed questions instead of making statements, underscoring that there’s still a lot we need to understand when it comes to different molecules in the SGLT-2 class. What we do know is that two of these products – empagliflozin and liraglutide – can now be prescribed for CV risk mitigation in patients with diabetes as supported by FDA-approved product label indications, and Dr. McGuire encouraged cardiologists in the audience to become familiar with the evidence from CVOTs and with the professional guidelines that now endorse these drugs for people with diabetes/high CV risk.

Using Empagliflozin in Your Patients with Type 2 Diabetes: Considerations for Daily Patient Care

Jacob Udell, MD (University of Toronto, Canada)

Toronto’s Dr. Jacob Udell expressed a reassuring view on Invokana’s (canagliflozin) amputation signal. He reviewed the safety data from CANVAS (J&J’s CVOT for its SGLT-2 inhibitor), focusing on the nearly two-fold increase in lower limb amputations seen with canagliflozin vs. placebo. He went on to explain that the FDA added a black box warning for this risk to Invokana in May 2017, while the EMA has taken a more conservative approach and has added amputation warnings to all SGLT-2 inhibitor product labels. Dr. Udell reminded everyone that there was no such signal in EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin). Zooming in on CANVAS, he underscored that the absolute risk for lower limb amputations was still very low, and that the number needed to harm (NNH) was 345 – quite high. This doesn’t mean the safety concerns should be minimized, but Dr. Udell rather presented amputations as something to be cautious about in prescribing Invokana. He advised looking out for amputation risk factors such as especially high CV risk, peripheral vascular disease, or prior history of amputation. This is a line of thinking we’ve heard from many diabetes thought leaders, including Dr. Kittie Wyne at AADE 2017 (she was particularly keen on the idea that baseline peripheral vascular disease may have heightened amputation risk in the CANVAS study population). We await further analyses of the CANVAS dataset for more answers. We’re also eager to see real-world data on all SGLT-2 inhibitors to more rapidly expand knowledge on this safety issue (we’d love for Lilly/BI, AZ, and J&J to all collaborate in generating this information as SGLT-2 manufacturers, given the massive value it could have and the responsibility to deliver high-quality medicine to patients). And, we hope this amputation finding sparks greater education around proper foot care in diabetes, which is all-too-often overlooked.

• Dr. Udell concluded with an inspiring call-to-action, encouraging cardiologists to take ownership in prescribing diabetes drugs with known CV benefit, including GLP-1 agonist Victoza (Novo Nordisk’s liraglutide) and SGLT-2 inhibitors Jardiance and Invokana. His talk was anchored by this message of a shift in best practice management of comorbid diabetes/CV disease – this novel paradigm is here, whether HCPs are ready or not, and Dr. Udell spoke to the incredible opportunity to individualize therapy now that there are two therapeutic classes within diabetes demonstrating CV efficacy. This fits with an overarching theme we’re noticing at ESC 2017, and an important one at that: the education of cardiologists on diabetes CVOTs and their widespread implications.

Corporate Symposium: PCSK9 Inhibitors: The Evidence-Based Story (Sponsored by Amgen)

PCSK9 Inhibitors: The Evidence-Based Story

Brian Ference, MD (Wayne State University School of Medicine, Detroit, MI); Stephen Nicholls, MD (South Australian Health & Medical Research Institute, Adelaide, Australia); Chris Packard, MD (University of Glasgow, Scotland); Kausik Ray, MD (Imperial College London, UK)

In an Amgen-sponsored lunch symposium, lipid experts Drs. Brian Ference, Stephen Nicholls, Kausik Ray, and Chris Packard attributed positive FOURIER results to the high margin of LDL reduction achieved by PCSK9 inhibitor Repatha (evolocumab). As such, they predicted similar findings to come from Sanofi/Regeneron’s ODYSSEY OUTCOMES study of Praluent (alirocumab), expected to read out in early 2018. Participants in FOURIER were followed for one-two years (median follow-up 26 months), and LDL dropped by a mean 59% on Repatha (from an average 92 mg/dl to 30 mg/dl). The relative risk reduction for the primary composite endpoint (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization) was 15% overall (HR=0.85, p<0.0001). Dr. Ference reported a hazard ratio of 0.83 (95% CI: 0.77-0.90) when the data is adjusted for duration of evolocumab treatment, which corresponds to 17% relative risk reduction. ODYSSEY OUTCOMES for alirocumab is a longer trial, following patients for two-three years instead of one-two, and Dr. Ference thus forecasted a slightly lower hazard ratio of 0.80 (95% CI: 0.77-0.83) for the same primary endpoint. He postulated that if statins trials were run for much longer, to the point where LDL dropped to a similar extent as in PCSK9 trials, we would see on par risk reduction for adverse CV outcomes. In fact, he set the stage for this symposium by establishing the link between LDL-lowering and proportional CV risk reduction – this holds true across a diverse array of clinical trials, meaning the mechanism of LDL-lowering doesn’t matter as much as the extent and efficiency of cholesterol reduction. This strong correlation indicates that any agent able to aggressively lower LDL, including Sanofi/Regeneron’s PCSK9 inhibitor Praluent, would be expected to also show a meaningful decline in CV events – hence, the suggestion that we’ll have a second positive PCSK9 CVOT before too long. This optimism for ODYSSEY OUTCOMES (at an Amgen-sponsored session, no less) was exciting to hear. Dr. Packard expressed a positive outlook for the field of lipid management. He described an unmet medical need – at the population level, people are failing to reach LDL goals with statins alone – that can now be filled by PCSK9 inhibitors. We have good reason to believe in lowering LDL to prevent CV disease, and we now have a way to achieve the necessary LDL-lowering for almost all patients (>95% of participants in clinical studies of a PCSK9 inhibitor have reached or surpassed target LDL) – Dr. Packard called this a “fortunate situation.” We’re then left with the unfortunate situation of very poor reimbursement for these medicines. According to a National Lipid Association (NLA) survey, prior authorizations for a PCSK9 inhibitor are denied 96% of the time (this is scary high). ODYSSEY OUTCOMES could be a light at the end of the tunnel, as having two positive PCSK9 inhibitor trials showing a decrease in CV events could sway payers in the right direction (preventing heart attacks and hospitalizations holds tremendous cost-saving potential).

• Dr. Nicholl’s remarks were focused on how PCSK9 inhibitors affect plaques, promoting a regression of atherosclerosis. This is a clear mechanism for CV risk reduction associated with PCSK9 agents. Given the hypotheses circulating in the diabetes field that GLP-1 agonists (namely, Novo Nordisk’s liraglutide and semaglutide) may also be cardioprotective due to atherosclerotic effects, we’re curious about the combined CV benefits that might be achieved through PCSK9/GLP-1 co-administration. On the other hand, SGLT-2 inhibitors (namely, Lilly/BI’s empagliflozin and J&J’s canagliflozin) appear to offer CV benefits through a non-atherosclerotic mechanism, since the overall risk reduction with these agents seems to be driven more so by heart failure and CV death vs. stroke and MI. PCSK9/SGLT-2 co-administration might then cover more bases in improving CV outcomes for people with diabetes, and possibly comorbid dyslipidemia (but even without the comorbidity, thought leaders at this meeting have emphasized the power of lipid-lowering in best practice diabetes care). This is all speculation for now, but we’d love to learn more about these therapeutic possibilities. As attendees were finishing their sandwiches, Dr. Ray concluded this lunch symposium with a list of lingering questions for the PCSK9 inhibitor class, one of which was “how can these agents be applied in specific populations?” – like diabetes.

Exhibit Hall

Amgen

Amgen occupied a large, central (and often very crowded, i.e. popular) booth in the ESC exhibit hall. Visitors could interact with a map of Europe mounted on one wall to find specific information on their country: the overall incidence of CV events, the total cost of CV morbidity, the rate of CV death, the rate of people achieving target LDL levels, and finally, how to access PCSK9 inhibitor Repatha (evolocumab). Given that reimbursement is the predominant issue slowing real-world uptake of PCSK9 inhibitors (both Repatha and Sanofi/Regeneron’s Praluent), we appreciated this clear display on how different countries approach coverage (we checked on Portugal, for example, where Repatha has to be requested by a physician). That said, we also hope to see Amgen (along with Sanofi/Regeneron) do more to negotiate better payer coverage and to reduce out-of-pocket costs for patients who truly stand to benefit from a more efficient lipid-lowering therapy compared to statins. Positive data from the FOURIER trial, in which Repatha demonstrated significant risk reduction for adverse CV outcomes, will hopefully start to sway payers in the right direction. A movie on loop in Amgen’s booth reviewed evidence on Repatha’s profound lipid-lowering efficacy, and correlated lipid-lowering with CV risk reduction. Conference attendees could also put on goggles and headphones to watch an immersive video on the evolocumab molecule and its mechanism of action. Messaging throughout the exhibit presented Repatha as a way to “climb down the LDL ladder” – diet/exercise was listed at the top, followed by statins, followed by this PCSK9 inhibitor.

AstraZeneca

One section of AZ’s bustling booth was dedicated to SGLT-2 inhibitor Farxiga (dapagliflozin), and more specifically, to ongoing trials investigating the agent’s mechanism and its impact on CV and renal outcomes – eight studies fall under this umbrella of the DapaCare clinical program. Visitors could explore details on each trial (design, expected enrollment, timing, endpoints, etc.) through an interactive touchscreen monitor. We learned about three mechanistic studies (sub-categorized as DapaMech): (i) DEFINE-HF compares dapagliflozin vs. placebo in people with comorbid diabetes/heart failure, will evaluate heart failure-related biomarkers, and is expected to complete September 2018; (ii) PRESERVED-HF compares dapagliflozin vs. placebo on heart failure-related biomarkers in people with diabetes or prediabetes (alongside heart failure), and is expected to complete March 2019; and (iii) DAPASALT, just launched in July and expected to complete March 2018, will investigate 24-hour sodium excretion following dapagliflozin treatment, with the aim of elucidating the agent’s action on the kidneys. Other studies encompassed by DapaCare include the DECLARE CVOT (expected to complete 2H18), as well as the Dapa-HF and Dapa-CKD outcomes trials investigating Farxiga in heart failure and chronic kidney disease, respectively (and expected to complete December 2019 and November 2020, respectively). Moreover, the DELIGHT trial will assess the impact of dapagliflozin monotherapy and of dapagliflozin/saxagliptin (AZ’s SGLT-2/DPP-4 combo product Qtern) on A1c and albuminuria in patients with comorbid diabetes/CKD – this is expected to complete May 2018. CVD-REAL is AZ’s ongoing real-world study comparing all SGLT-2 inhibitors (Farxiga, J&J’s Invokana, and Lilly/BI’s Jardiance) vs. other glucose-lowering drugs on outcomes such as heart failure hospitalization and all-cause death. It’s terrific to see AZ’s ongoing commitment to its SGLT-2 inhibitor franchise, not only through marketing efforts but through clinical investments as well. Company reps underscored Farxiga’s potential at the intersection of diabetes, CV disease, and renal disease.

Lilly/BI

Lilly/BI’s booth would catch your eye from all the way across the exhibit hall with its large yellow arrow moving up-and-down, pointing toward the floor and describing a 38% relative risk reduction for CV death with empagliflozin (SGLT-2 inhibitor Jardiance) vs. placebo. EMPA-REG OUTCOME results and Jardiance’s new indication for reduced risk of CV death were a major focus of the exhibit. Messaging was once again centered around the theme of battle: Slogans such as “Are you ready to take on the #1 killer in type 2 diabetes?” were displayed on banners, above shadow images of a soldier (representing Jardiance) attacking a ferocious dragon (representing CV death). A big screen on one side of the booth flashed multiple choice quiz questions (i.e. What percent of diabetes patients are aware that their condition may lead to premature CV disease or death?), and booth visitors could slash a videogame sword in the air to designate their answer (the correct one here was only 17%!). We’ve been pleased to see this education around Jardiance’s CV benefits at recent cardiology meetings (see also our coverage of the ACC 2017 exhibit hall). Indeed, as we learned from Harvard’s Dr. Christopher Cannon, one exciting implication of the expanded indication is that it officially invites cardiologists to prescribe this SGLT-2 inhibitor. At ESC 2016, one cardiologist even remarked that doctors in his field may “want to look at empagliflozin as a cardiovascular drug with a glucose-lowering effect.” This was music to our ears, as we’d love to see even more collaboration between endos and cardiologists to deliver optimal diabetes care – now more than ever, this includes efforts to reduce CV risk. We’re glad to see Lilly/BI play a role in generating awareness of the diabetes/CV disease overlap. To this end, the companies recently announced support for an ACC program that aims to improve diabetes care within cardiology clinics.

Novartis

Novartis hosted one of the largest booths in the ESC exhibit hall. If its size didn’t grab your attention, its bright yellow coloring definitely would. CV drug Entresto was the main focus of the exhibit, and conference attendees could follow an individual patient’s story via a guided audio tour as they walked through. We learned about a 70-year-old patient named George, whose heart failure was getting in the way of gardening and a good night’s sleep. As is common for patients with heart failure, George wasn’t recognizing these effects on his daily life as symptoms, and his HCP had to be inquisitive and sensitive. Several signs posted around the booth highlighted that Entresto should be prescribed as soon as a patient starts showing symptoms. One banner asked, “what would your patients do with more years in their life?” We loved this emphasis on patient experience and quality of life, an outcome that is too-often overlooked in treating diabetes and related diseases. Our interest in Entresto was piqued at ACC 2017, after learning the results of a PARADIGM-HF sub-analysis focused on 3,778 participants with diabetes – Entresto was associated with significant A1c decline and a decreased likelihood for new initiation of insulin therapy. There was no explicit mention of diabetes within Novartis’ exhibit hall booth, but we’ll continue to be on the lookout for applications of Entresto in this patient population.

Novo Nordisk

Novo Nordisk debuted its first-ever ESC exhibit hall booth this year, promoting the brand new CV indication for GLP-1 agonist Victoza (liraglutide) – this was EMA-approved last month and FDA-approved just last week. The company’s presence on the exhibit hall floor was in itself exciting, signaling a true paradigm shift in the treatment of diabetes and CV disease, where patients can now take medicine that not only lowers the biomarker of A1c, but that actually prevents heart attacks, strokes, and CV death. Booth visitors could view a demo of the Victoza pen up close, could have their A1c checked, and could take a quiz about the GLP-1 agonist on an interactive monitor. One poster read “in type 2 diabetes, change the course of treatment by reducing cardiovascular risk,” which is a key message in this era of diabetes CVOTs and increasing focus on cardioprotection. We imagine this is just the beginning for Novo Nordisk’s education efforts on Victoza’s CV benefit, now that LEADER data has supported an official label change (after all, the CV indication is very, very new). We can’t wait to see how the company shows up at ACC 2018 and other upcoming cardiology meetings.

Sanofi/Regeneron

Sanofi/Regeneron’s booth featured key data on PCSK9 inhibitor Praluent (alirocumab) – up to 80% of patients achieve cholesterol goals, patients experience as much as 60% reduction from baseline LDL, and 92% of people find Praluent self-injection to be very acceptable or acceptable. Company reps distributed special glasses so that visitors could watch a 3D film on the alirocumab molecule, how it binds, and the mechanism by which it brings down LDL levels. The trial design for ODYSSEY Outcomes was displayed in bright, bold text on one wall (>18,000 enrolled, double blind treatment with alirocumab or placebo for two-five years). In a separate conversation with us, Dr. Jay Edelberg, VP of PCSK9 Strategic Development & Launch Unit at Sanofi, expressed distinct optimism for what this CVOT will show. He confirmed that the final patient will be seen by end of year, and that the data is expected to read out in early 2018. We are eager to see these results, and we have our fingers crossed for CV efficacy similar to what Amgen’s Repatha (evolocumab) showed in FOURIER (especially since the CV risk reduction in FOURIER has been strongly correlated with aggressive lipid-lowering, which is achieved by alirocumab as well). Having not one, but two positive CVOTs for the PCSK9 class could start to move the needle on reimbursement, which Dr. Edelberg acknowledged as a significant hurdle to uptake right now. “ODYSSEY Outcomes will provide important information on the value of these agents,” he explained, and once these results are in tow, he hopes all players can work together to improve access, especially for patients facing exceptionally high CV risk who stand to benefit the most from a more efficient lipid-lowering drug. Indeed, we’d love to see Amgen and Sanofi/Regeneron collaborate toward this end.

Turning to implications of PCSK9 inhibitors on the diabetes field, Dr. Edelberg described the highest-risk patient (for CV events) he’s encountered in his personal, clinical experience as someone with pre-existing diabetes, a recent CV event, and uncontrolled lipids. In other words, diabetes and dyslipidemia are both independent CV risk factors. There is certainly room for improvement in lipid management within diabetes care, and we were happy to see positive data from the ODYSSEY DM program investigating Praluent in people with diabetes at ADA 2017. Dr. Edelberg shared that new data from ODYSSEY DM to complement the initial results of lipid-lowering efficacy in this patient population will be presented at EASD in Lisbon, Portugal in a matter of weeks. He added that ODYSSEY Outcomes includes a substantial number of participants with baseline diabetes, and we look forward to an eventual sub-analysis of this population.

-- by Payal Marathe and Kelly Close