Hola from Barcelona! We’re here for the European Society of Cardiology’s (ESC) annual meeting – us and >31,000 other attendees! This year’s agenda features 77 poster sessions and 125 oral presentation sessions, with a larger number than ever before emphasizing diabetes as a CV risk factor and exploring the cardioprotective properties of advanced diabetes drugs. In this highlights report, we detail sessions from days #1-2 of the conference that we found particularly notable, which includes Dr. Faiez Zannad’s take on the statistical rigor underlying EMPA-REG OUTCOME (for Lilly/BI’s SGLT-2 inhibitor Jardiance), Dr. Michael Nauck’s poster discussion of granular MI data from LEADER (for Novo Nordisk’s GLP-1 agonist Victoza), and Dr. Jacob Udell’s thoughts on the amputation signal from CANVAS (for J&J’s SGLT-2 inhibitor Invokana). As expected, lots of CVOT talk.
We also enclose coverage of six exhibit hall booths: Amgen, AstraZeneca, Lilly/BI, Novartis, Novo Nordisk, and Sanofi/Regeneron. Note, this is a tremendous turnout of diabetes companies at a cardiology conference (!), which points to increasing recognition among HCPs, industry players, and thought leaders of the all-important diabetes/CV disease overlap. Novo Nordisk was absent from last year’s ESC exhibit hall floor, and from the exhibit hall at ACC 2017 this past March – a fitting turn of events that the company occupied a bright booth at ESC 2017, given the very recent EMA and FDA approvals of a new CV indication for Victoza (liraglutide).
Read on for six major highlights from ESC 2017 days #1-2, and click here to access our full conference preview (there’s so much more learning in store, as this meeting goes until Wednesday, August 26 at Barcelona’s Fira Gran Via).
Top Six Highlights
1. 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 spoke to exciting next steps for the SGLT-2 inhibitor Jardiance franchise, describing dedicated studies of the agent in heart failure and chronic kidney disease.
2. 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.
3. 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. All in all, we were quite disappointed in Dr. Schmidt’s speculations, as downplaying the cardioprotection associated with products like Jardiance (empagliflozin) and Victoza (liraglutide) inhibits patient access to medicine that could extend their CV disease-free life. Several audience members echoed our reaction.
4. 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).
5. Toronto’s Dr. Jacob Udell expressed a reassuring view on Invokana’s (canagliflozin) amputation signal, and issued a call-to-action for cardiologists to take ownership in prescribing diabetes drugs with demonstrated CV efficacy (including Invokana, Jardiance, and Victoza).
6. We were kept pretty busy on the exhibit hall floor, with more than ever before to cover at the intersection of diabetes and cardiology. We visited booths hosted by Amgen, AstraZeneca (where we learned fantastic detail on the ongoing clinical program around SGLT-2 inhibitor Farxiga), Lilly/BI (which featured strong messaging around Jardiance’s indication for the reduction of CV death), Novartis, Novo Nordisk (where reps highlighted Victoza as the only GLP-1 agonist indicated for CV prevention), and Sanofi/Regeneron (this coverage also includes our exclusive interview with Dr. Jay Edelberg, VP Head of CV Development and Head Global CV Medical Affairs at Sanofi).
Top Six Highlights
1. Dr. Zannad on Five-Point Rigor for EMPA-REG OUTCOME and Next Steps for Jardiance
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.
2. Liraglutide Associated with Lower Severity of MI in New LEADER Analysis
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.
3. Absolute vs. Relative Risk Reduction in EMPA-REG OUTCOME and LEADER: Where’s the Real Benefit?
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.”
4. EMPA-REG OUTCOME as the First Big Prize from the FDA’s 2008 CVOT Guidance
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.
5. Dr. Udell on SGLT-2 Inhibitors and Amputations
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.
6. Strong Showing of Diabetes Companies on the Exhibit Hall Floor
We were kept pretty busy on the exhibit hall floor, with more than ever before to cover at the intersection of diabetes and cardiology. We visited booths hosted by Amgen, AstraZeneca (where we learned fantastic detail on the ongoing clinical program around SGLT-2 inhibitor Farxiga), Lilly/BI (which featured strong messaging around Jardiance’s indication for the reduction of CV death), Novartis, Novo Nordisk (where reps highlighted Victoza as the only GLP-1 agonist indicated for CV prevention), and Sanofi/Regeneron (this coverage also includes our exclusive interview with Dr. Jay Edelberg, VP Head of CV Development and Head Global CV Medical Affairs). Read on in our detailed discussion and commentary directly below.
Detailed Discussion and Commentary
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.
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’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 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 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’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 Head of CV Development and Head Global CV Medical Affairs, 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