November 10-12, 2018; Chicago, IL; Day #1 Highlights – Draft

Hello from Chicago, where our team attended American Heart Association 2018. Below, we’ve divided our 14 highlights from the conference into the following categories: (i) New CVOT Results and Commentary; (ii) CVOT Subgroup Analyses and Post-Hocs; (iii) Heart Failure and Coronary Syndrome; and (iv) Awareness and Prevention of CV Disease. Key coverage includes full, positive results from the DECLARE (AZ’s SGLT-2 inhibitor dapagliflozin) and REDUCE-IT (Amarin’s icosapent ethyl) CVOTs, a CARMELINA post-hoc analysis ensuring heart failure safety with linagliptin, full real-world data from EMPRISE, and impressive in human data on cardioprotective mechanisms from EMPA-HEART. Read on for all this and more.

New CVOT Results and Commentary

1. Full DECLARE Results: 27% Risk Reduction on Hospitalization for Heart Failure with Farxiga Drives Superiority on Co-Primary Composite, Balanced Across Primary and Secondary Prevention; No Superiority on MACE or Components; Impressive Renal Effects and Safety Profile

• Dr. Stephen Wiviott presented full results from the DECLARE CVOT to a standing-room-only crowd: AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) reduced risk for the co-primary endpoint of hospitalization for heart failure/CV death by 17% vs. placebo (HR=0.83, 95% CI: 0.73-0.95, p=0.005 for superiority), making it the first SGLT-2 to show significant benefit on heart failure. Dapagliflozin was non-inferior to placebo on three-point MACE (the other co-primary endpoint), though results trended in favor of the SGLT-2 inhibitor (HR=0.93, 95% CI: 0.84-1.03, p<0.001 for non-inferiority, p=0.17 for superiority). DECLARE is unlike any other SGLT-2 CVOT to date and carries significant implications for the class and for patients. Most pertinently, DECLARE solidifies the heart failure benefit of dapagliflozin specifically and SGLT-2 inhibitors broadly – if there was any question before – by including HHF in a primary endpoint (heart failure was only assessed as a secondary endpoint in Lilly/BI’s EMPA-REG and J&J’s CANVAS). In an interview with our team, AZ management underscored heart failure as the most prevalent and important CV endpoint for patients with type 2 diabetes. Indeed, patients with type 2 are at a 2.5-times greater risk of developing heart failure compared to a background population, and heart failure is just as costly to the healthcare system as cancer, according to AZ CEO Mr. Pascal Soriot.
• DECLARE’s large (~60%) primary prevention cohort also makes the CVOT unique, and piques our curiosity about the potential for a CV indication that applies to the entire type 2 diabetes population rather than only to those patients with established CVD. Importantly, HHF/CV death was significantly reduced in both primary (HR=0.83, 95% CI: 0.71-0.98) and secondary prevention participants (HR=0.84, 95% CI=0.67-1.04). This consistency across primary and secondary prevention cohorts should support a new indication for reducing risk of heart failure (and possibly CV death) in a much broader population than ever before. To this end, AZ management reiterated to us that they plan to submit the data to regulatory agencies as soon as possible, likely in 1H19. Our biggest question, perhaps, is whether FDA will grant a dual HHF/CV death indication because this was the primary endpoint, or an indication for HHF only, the outcome which drove superiority. An indication solely for heart failure would parallel Jardiance’s indication solely for CV death, which drove overall MACE results in EMPA-REG. For context, AZ management explained that the decision to pair CV death with HHF in the study design was based (very rationally in our opinion) on the compelling results from the EMPA-REG trial indicating Jardiance’s reduction of CV death. AZ hypothesized that heart failure may be the driver of CV death improvements (as opposed to atherosclerotic events like stroke or MI), making HHF and CV death a natural primary endpoint pairing.
• On a similar note, AZ emphasized to us that because the results of the trial are much more generalizable, it should give PCPs and HCPs greater confidence in prescribing Farxiga: They won’t have to spend as much time thinking about how to determine which patients may benefit from Farxiga, given the broad population studied. AZ management acknowledged the immense educational opportunity ahead of them with prescribers, both with respect to raising awareness of heart failure as the most prevalent CV complication of diabetes, as well as the general benefit of Farxiga for a wide variety of patients. Looking forward, the Dapa-HF (n=4,500 with established heart failure with reduced ejection fraction; results expected 2020) and DELIVER (n=4,700 with established heart failure with preserved ejection fraction; results expected 2020+) trials have the potential to extend Farxiga’s now-known benefit on heart failure to even more patients, namely those with established heart failure and without type 2 diabetes.
• Simultaneous to Dr. Wiviott’s presentation, results from DECLARE were published in NEJM: “Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.” Key findings are summarized as follows: 

• Hospitalization for Heart Failure & CV death: On the co-primary composite endpoint of CV death and hospitalization for heart failure (HHF), dapagliflozin demonstrated a significant 17% reduction compared to placebo (HR=0.83, 95% CI: 0.73-0.95, p=0.005 for superiority, event rate: 4.9% vs. 5.8%).
• Three-Point MACE: On DECLARE’s second co-primary endpoint, dapagliflozin was non-inferior to placebo on three-point MACE, though results trended in favor of the SGLT-2 inhibitor (HR=0.93, 95% CI: 0.84-1.03, p<0.001 for non-inferiority, p=0.17 for superiority, event rate: 8.8% vs. 9.4%). We wonder if, over more time, the effect may have reached significance.
  • Moreover, dapagliflozin was not superior to placebo on any component of three-point MACE. It came closest on MI, with a hazard ratio of 0.89 (95% CI: 0.77-1.01). Both CV death (HR=0.98, 95% CI: 0.82-1.17) and ischemic stroke (HR=1.01, 95% CI: 0.84-1.21) showed resoundingly neutral results. See the table below for how these compare to results from other completed SGLT-2 CVOTs.
• HHF: Farxiga gave a 27% reduction on HHF (HR=0.73, 95% CI: 0.61-0.88), making HHF the dominant driver of the primary endpoint result. We find this result unsurprising, given consistent risk reduction on HHF in both EMPA-REG OUTCOME and CANVAS, as well as in real-world data studies.
• CV death: The hazard ratio for CV death was 0.98 (95% CI: 0.82-1.17), slightly favoring Farxiga over placebo. In a conversation with our team, Dr. Naeem Khan (VP of CVMD, AZ) suggested that this result in likely a function of population; indeed, data from other SGLT-2 CVOTs (below) support this notion.
• All-cause death: Interestingly, a trend in favor of dapagliflozin on all-cause mortality (HR=0.93, 95% CI: 0.82-1.04) was driven by non-CV death (HR=0.88, 95% CI: 0.73-1.06). In an interview with our team, AZ management explained this is likely an artifact of the collective benefit of dapagliflozin on many factors (renal endpoints, hypoglycemia, severe adverse events, etc.) rather than a specific benefit on any one non-CV outcome.

• As a reminder, DECLARE is the longest (median 4.2 years follow-up) and largest (n=17,160) SGLT-2 CVOT to date. The primary prevention cohort (multiple CV risk factors but no established CV disease at baseline) alone (n=10,189) is bigger than the total enrolled populations of both EMPA-REG OUTCOME (n=7,020, <1% primary prevention) and CANVAS (n=10,142, 34% primary prevention). We hope that annual follow-up on these patients, even at a basic level, will be possible. A few other points for consideration include:

• Benefit on HHF/CV death was virtually identical in the primary and secondary prevention cohorts – a huge win for AZ. The hazard ratios for the composite were nearly the same in the primary (HR=0.83, 95% CI: 0.71-0.98) and secondary (HR=0.84, 95% CI=0.67-1.04) prevention groups (the latter narrowly crossed unity, though of course these analyses were not powered for superiority). The fact that benefit on HHF/CV death persists regardless of baseline risk is of paramount importance for prescribing practice and for AZ’s ability to garner a primary prevention indication. For three-point MACE, data was neutral in the primary prevention cohort (HR=1.01, 95%: 0.86-1.20) but trended in favor of dapagliflozin in the secondary prevention cohort (HR=0.90, 95% CI: 0.79-1.02). This raises the question of whether dapagliflozin’s benefit on atherosclerosis might rest primarily in patients with type 2 diabetes and established CV disease. To be sure, a post-hoc analysis of CANVAS presented at last year’s AHA found significant three-point MACE benefit to Invokana (canagliflozin) among secondary prevention participants but not among primary prevention participants; meanwhile, Invokana reduced HHF risk in both cohorts. It seems likely that SGLT-2s as a class offer MACE benefit only in those with comorbid diabetes/CV disease, but perhaps their benefit on heart failure extends across the spectrum of baseline CV risk – Dr. Itamar Raz has predicted as such, and DECLARE certainly supports this notion. AZ management emphasized this finding to us in an interview, noting that no trial has found atherosclerotic benefit with an SGLT-2 inhibitor in a primary prevention population (though none have tried).
• On a composite renal endpoint comprising 40% decrease in eGFR to <60 ml/min/m², end-stage renal disease (ESRD), or renal death, dapagliflozin demonstrated an extremely impressive 47% relative risk reduction (HR=0.53, 95% CI: 0.43-0.66). This furthers our understanding of nephro-protection as a class effect of SGLT-2 inhibitors, following positive CREDENCE news, and it bodes well for Dapa-CKD (dapagliflozin in chronic kidney disease patients, with or without type 2 diabetes). However, when the endpoint also included CV death (as was pre-specified), the benefit was lower, at a 24% relative risk reduction (HR=0.76, 95% CI: 0.67-0.87). Moreover, given hierarchical testing, our understanding is that this finding is technically exploratory.
  • With respect to DECLARE’s design, it should be noted that only patients with an eGFR >60 ml/min/m² were enrolled in the trial (CANVAS and EMPA-REG both enrolled patients down to eGFR of 30 ml/min/m²), as FDA does not currently recommend dapagliflozin for use in patients with an eGFR below this threshold. As reflected in the table below, the average baseline eGFR in DECLARE (85 ml/min/m²) was 8-11 units higher than that of CANVAS and EMPA-REG OUTCOME. For context, Dr. David Fitchett explained at ESC 2017 that this original contraindication/recommended dose reduction for all SGLT-2 inhibitor products as eGFR falls below 60 ml/min/m² is not for safety concerns, but rather for a presumed attenuation of metabolic efficacy. Notably, on systolic and diastolic blood pressure outcomes, SGLT-2 inhibitors have been shown to offer greater reductions with decreasing renal function. Farxiga just received a positive CHMP opinion for an expanded indication down to an eGFR of 45 ml/min/m², based on results from the DERIVE trial, and FDA is currently reviewing a similar update in the US.
• Dapagliflozin’s safety profile was strong. Most notably, there was no significant difference in amputations with dapagliflozin vs. placebo (1.4% vs. 1.3%, respectively), nor was there any imbalance in bone fractures (5.3% vs. 5.1%). Significant benefit with dapagliflozin was found in treatment-emergent severe adverse events (34% vs. 36%, p<0.001), major hypoglycemia (0.7% vs. 1.0%, p=0.02), and bladder cancer (0.3% vs. 0.5%, p=0.02). On the other hand, safety signals with dapagliflozin were seen in treatment-emergent adverse events leading to drug discontinuation (8.1% vs. 6.9%, p=0.01), DKA (0.3% vs. 0.1%, p=0.02), and genital infections (0.9% vs. 0.1%, p<0.001). Farxiga’s advantage on major hypoglycemia is particularly important to note, in our view. We have always thought this was a significant benefit of the entire SGLT-2 class, and this point isn’t raised as often as it could be with doctors. The same is true for weight loss benefit (see below).
• Dapagliflozin showed a significant benefit on body weight compared to placebo (LS mean difference=1.8 kg, 95% CI: 1.7-2.0, p<0.001), stimulating weight loss from a baseline BMI of 32 kg/m² on average. As we see it, HCPs need to be made more aware of the weight loss benefit associated with SGLT-2 inhibitors, because this is an outcome that matters to patients and that affects health and quality of life.
• On metabolic outcomes, dapagliflozin demonstrated a significant reduction in A1c vs. placebo over 48 months (LS mean difference=0.42%, 95% CI: 0.40-0.45, p<0.001). This result is comparable to what was seen with empagliflozin in EMPA-REG OUTCOME (0.36% relative A1c reduction) and with canagliflozin in CANVAS (0.58% relative A1c reduction).

• Comparison of Relevant Results from CANVAS (for Invokana) vs. EMPA-REG OUTCOME (for Jardiance)
• This chart is for illustrative purposes only, as differences in enrolled population and trial design make it inherently impossible to draw comparisons between molecules. We continue to believe that a large outcomes trial examining SGLT-2 inhibitors and GLP-1 agonists in comparison to each other would be immensely valuable to patients, clinicians, and payers.

2. Drs. Javed Butler & Subodh Verma Promote Broad SGLT-2 Inhibitor Use for HF Reduction + Renal Function Irrespective of MACE Effect; Challenge Primary/Secondary Prevention Distinction in HF Paradigm; Call for Expansion of Diabetes Care Considerations

• In his discussant following the DECLARE presentation, Dr. Javed Butler asserted that SGLT-2 inhibitors should be used in type 2 diabetes patients to reduce heart failure risk, irrespective of their effect on the classic three-point MACE. Supporting this claim was compelling data from a recent Swedish cohort study: Controlling A1c, smoking, LDL, blood pressure, and albuminuria attenuated risk for MI (HR=0.84, 95% CI: 0.75-0.93) and, non-significantly, stroke (HR=0.95, 95% CI: 0.84-1.07) relative to matched controls without diabetes. However, the hazard ratio for heart failure hospitalizations remained elevated (HR=1.45, 95% CI: 1.34-1.57) even after managing these other risk factors, suggesting that type 2 diabetes confers heart failure risk independent of A1c, smoking, LDL, blood pressure, and albuminuria. Moreover, once patients with type 2 diabetes develop heart failure, their mortality risk skyrockets and fewer than 10% survive five years, compared to ~80% of those with type 2 diabetes without heart failure. With this in mind, Dr. Butler stated that any therapy indicated for improving heart failure outcomes (as dapagliflozin likely will be, based on DECLARE results) should be a welcome addition to the diabetes care armamentarium. We couldn’t agree more, and we hope that as medications prove their efficacy on heart failure, they will be better utilized in diabetes care alongside lifestyle modification.

• During a talk on heart failure and diabetes, Dr. Subodh Verma (University of Toronto, Canada) highlighted a recent comment piece he co-authored in The Lancet, which contextualized the use of SGLT-2 inhibitors in primary and secondary prevention populations. Entitled “Pump, pipes, and filter: Do SGLT-2 inhibitors cover it all?,” the editorial discusses a simultaneously published meta-analysis by Dr. Marc Sabatine et al. examining SGLT-2 CVOT data published to date, including the recently-presented DECLARE full results. In this comment, Dr. Verma emphasizes that these data demonstrate that cardio-renal benefits appear to vary across the diabetes continuum (see reproduced graphic below), juxtaposing those at risk vs. those with established CVD. From his perspective, risk reduction for MACE events with a drug seems to be limited to secondary prevention populations with established CVD, while the effect of SGLT-2 inhibitors in preventing heart failure hospitalizations and protecting renal function appears to apply to both secondary and primary prevention populations. On this note, Dr. Verma challenged the conceptual separation of primary and secondary prevention in relation to the risk of hospitalization for heart failure and renal disease. He pointed out that the meta-analysis of SGLT-2 CVOT data indicates a strong association between declining renal function and HHF, irrespective of atherosclerotic vascular disease. And so, while the distinction between primary and second prevention populations may be appropriate for atherosclerotic outcomes, Dr. Verma thinks that this framework is not useful when considering renal disease and hospitalization for heart failure. We’re curious to see what framework Dr. Verma would instead use to better differentiate between risk levels in these patients – or, does he not believe risk stratification is necessary at all and all type 2s should be treated with a therapy that lowers heart failure and renal risk? Overall, we’re thrilled to see Dr. Verma strongly support the broadened use of SGLT-2 inhibitors as first-line therapy after metformin regardless of whether the diabetes patient has established atherosclerotic vascular disease, chronic kidney disease, or heart failure.

• Dr. Butler called for an expansion of the diabetes care paradigm beyond control of A1c, CV risk factors, and MACE endpoints, to include risk of heart failure and CKD. As he put it, “regardless of what primary endpoint was chosen in these clinical trials based on the guidance from regulators, all CV outcomes are important to the patients and doctors, including CKD, HF, and MI and stroke – and, even worse, CV mortality.” Drawing on Dr. Verma’s recent Comment, Dr. Butler pointed out that the terms “primary” and “secondary” prevention come from the perspective of atherosclerotic CV disease, which is closely related to the traditional primary outcome of three-point MACE and comes from regulatory guidance – however, it doesn’t necessarily reflect what’s most important to patients or the healthcare system. To this point, Dr. Butler cited a 2010 article by the venerable Dr. Rich Bergenstal, which demonstrated that congestive heart failure (CHF) is the single-most prevalent complication in patients with diabetes relative to those without diabetes. Bringing all of this together, Dr. Butler concluded his argument with the assertion that any quality improvement effort that does not consider HF and CKD will likely fall short of the potential benefit patients can receive. We certainly agree that heart failure and CKD cannot be ignored in diabetes care, and we agree with Dr. Butler that diabetes management must account for all aspects and comorbidities of the disease, not just those recommended to be used as primary outcomes.

3. REDUCE-IT Proves It with Impressive Full Results: Highly Significant Benefits on Primary (25% RRR) and Secondary Endpoints, Driven by Secondary Prevention Group; Benefit in Large Diabetes Cohort (~58% of Participants)

After weeks of buildup following a splashy release of positive topline results, the full presentation of REDUCE-IT CVOT (n=8,175) results did not disappoint, demonstrating highly significant results for Vascepa (4 g/day icosapent ethyl) vs. placebo on both primary and key secondary endpoints. Following the presentation, full results were also published in NEJM: “Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.” Dr. Deepak Bhatt (Brigham and Women’s Hospital) took the stage to present these full results in front of a packed-beyond-capacity room. As a reminder, the study’s primary prevention cohort was comprised entirely people with type 2 diabetes over age 50 with ≥1 CV risk factor, so these results are highly relevant to people with diabetes, and somewhat lower CV risk at that; overall, ~58% of participants had type 2 diabetes. The secondary prevention cohort included those over age 45 with established CVD and comprised ~70% of the study population. Read on below for key takeaways on Vascepa’s impressive benefits on primary and secondary endpoints, effects on primary and secondary prevention cohorts, safety data, and a brewing controversy surrounding the use of mineral oil in REDUCE-IT’s placebo arm, which may have contributed to a higher rate of CV events:

• Primary Endpoint Results: Vascepa delivered a 25% relative risk reduction compared to placebo. On the prespecified composite primary endpoint of CV death, MI, coronary revascularization, and unstable angina, treatment with icosapent ethyl gave a highly significant 25% relative risk reduction vs. placebo (HR=0.75, 95% CI: 0.68-0.83, p<0.00001). Dr. Bhatt individually read out each of the “zeros” – there were actually seven – in this miniscule p-value (accompanied by hearty laughter from the audience), underscoring just how solidly Vascepa conveyed this risk reduction. The absolute risk reduction was 4.8%, with a number needed to treat of 21 (95% CI: 15-33) to prevent one primary endpoint event over the median follow-up of 4.9 years. The total number of adjudicated primary endpoint events was 1,606, with a rate of 17% in the icosapent ethyl group vs. 22% in placebo.
  • Key Secondary Endpoint Results: Vascepa gave a 26% relative risk reduction on three-point MACE compared to placebo. On this prespecified key secondary endpoint (CV death, MI, and stroke), treatment with icosapent ethyl led to a highly statistically significant 26% relative risk reduction (HR=0.74, 95% CI: 0.65-0.83, p=0.0000006). This corresponds to an absolute risk reduction of 3.6%, with a number needed to treat of 28 (95% CI: 20-47) to prevent once three-point MACE event over 4.9 years.

• Vascepa’s benefit was most strongly seen in secondary-prevention patients, although Vascepa still trended toward benefit in the primary prevention cohort. In REDUCE-IT’s secondary-prevention cohort (which represents ~70% of the study population), treatment gave a clear 27% relative risk reduction (HR=0.73, 95% CI: 0.65-0.81) on the primary composite endpoint. Meanwhile, a non-significant 12% relative risk reduction was seen in the primary prevention cohort, with the confidence interval crossing unity (HR=0.88, 95% CI: 0.70-1.10). To be sure, REDUCE-IT was not powered to demonstrate significant benefit in primary prevention alone, but given the somewhat narrow overlap between these two confidence intervals, our assessment it that there’s a clear trend toward greater benefit in higher-risk patients. Certainly, this doesn’t mean that a longer follow-up would not have shown benefit in primary prevention, but we can only speculate on that point. On this note, we’re curious to see how this data will play into discussions with regulatory agencies concerning Vascepa’s potential label expansion – will an indication still be pursued for a primary prevention population? This situation brings to mind the LEADER CVOT for GLP-1 agonist Victoza, which enrolled a similarly-sized primary prevention cohort and achieved significance on MACE strongly driven by the secondary prevention patients; FDA limited Victoza’s CV indication to those with established CV disease.
• Notably, consistent benefit was seen regardless of diabetes status; REDUCE-IT enrolled ~58% of its population with patients with diabetes, including the ~30% primary prevention cohort. Patients with diabetes at baseline experienced a 23% relative risk reduction (HR=0.77, 95% CI: 0.68-0.87), while patients without diabetes saw a 27% relative risk reduction (HR=0.73, 95% CI: 0.62-0.85). We find this data to be highly compelling in terms of Vascepa’s potential in reducing CV risk in patients with diabetes. Importantly, the primary prevention cohort was entirely composed of patients with diabetes “and at least one additional risk factor.” A total of 4,787 patients with diabetes were enrolled in the study, with 2,394 from the primary-prevention cohort and the remaining 2,393 having established CVD and included in the secondary prevention group. Given fairly different effects between the primary and secondary prevention cohorts, however, we assume that the majority of risk reduction in the diabetes population was seen in those patients with established CVD.
• Vascepa either demonstrated or trended toward benefit on all individual and composite ischemic endpoints in prespecified hierarchical testing. This includes separate analyses on CV death or non-fatal MI, fatal or non-fatal MI, fatal or non-fatal stroke, and other endpoints. See the figure below for the complete rundown. The benefit across the board on these prespecified endpoints is surely impressive, and stands in contrast to somewhat heterogeneous results from CVOTs we’ve seen with diabetes drugs (e.g., positive topline results are sometimes driven specifically by one individual components of three-point MACE).

• Adverse events signals for Vascepa treatment included significantly higher rates of atrial flutter, diarrhea, peripheral edema, and constipation. Most notable was the higher rate of hospitalization for atrial fibrilization or flutter (3.1% vs. 2.1% for treatment vs. placebo, p=0.004); still, absolute rates were still low for these events. More broadly, overall rates of serious adverse events between the two groups were well balanced: Both rates of serious adverse events (30.6% vs. 30.7%) and serious adverse events leading to withdrawal of study drug (2.2% vs. 2.2%) were essentially identical. As a whole, we view Vascepa treatment as having a relatively clean side effect profile, strengthening its position as a potential CV risk lowering agent (we note that many patients remain very resistance to statin therapy).
• Future studies will examine the mechanism of action for Vascepa’s CV benefit as well as its cost-effectiveness as a treatment option. Dr. Bhatt noted during his presentation that no comment can be made at this time on a potential mechanism of benefit for Vascepa. However, we do note that the simultaneous NEJM publication of the study posits that the timing of divergence for the Kaplan-Meier curves suggests a delayed onset of benefit –reflecting time needed for either triglyceride-related effects or other putative mechanisms to take hold. Antithrombotic, antiplatelet/anticoagulation, membrane-stabilizing, and coronary plaque stabilizing effects were also hypothesized. Dr. Bhatt remarked that detailed biomarker and genetic analyses are planned to investigate these mechanisms; no timetable was given for when results from these studies may be disclosed. Dr. Bhatt also mentioned that cost-effectiveness analyses are also planned – currently, Vascepa costs $3 per month for most patients using a co-pay card, and total cost of the medication for the system at large stands at ~$2,400/year. A low number needed to treat, in the 20s range, bodes very well for cost effectiveness.  
• Amarin and Vascepa’s commercial success will partly hinge on how willing and able HCPs are to prescribe this relatively novel therapy. On this front, the reception of REDUCE-IT at AHA was certainly encouraging, as ~80-90% of the audience indicated in a post-session poll that they would be willing to prescribe Vascepa in high CV risk patients with moderately elevated triglycerides. While this is certainly a start, those on the front-lines of patient care – primary care practices – will be critical in getting Vascepa to as many patients who may benefit as possible. It appears as if Amarin realizes this as well: On the company’s 3Q18 earnings call, management explained that, in their expansion of targeted physicians for Vascepa educational marketing, around 85% are GPs, compared to 7% cardiologists and 5% endocrinologists.
• Casting a shadow over these positive results is the emerging concern that mineral oil used in the placebo arm interfered with baseline statin therapy, causing an uptick in CV events. To better mimic the color and consistency of Vascepa, Amarin chose to use placebo capsules containing mineral oil. However, some cardiologists have suggested that the mineral oil may be one factor behind certain biomarkers in the placebo group trending the wrong way (specifically, LDL-C and C-reactive protein), possibly by interfering with statin absorption and artificially elevating rates of CV events in the placebo group. We’re still learning more on this front and, but our current understanding is that, although the use of mineral oil may have contributed to the impressive magnitude of the risk reduction seen in the Vascepa group, it’s unlikely that this was the driving factor behind the result. The decision to use mineral oil in the placebo arm was approved by FDA in discussions during the design of REDUCE-IT – we’ve heard more about the issue from Amarin and will be back with more soon.

4. Amarin Product Theater Offers Granularity on REDUCE-IT Results: A Dramatic 25% CV Benefit with Vascepa is Independent of Baseline Triglycerides (TG) and TG Lowering; Dr. Eliot Brinton Downplays Possible Confounding by Use of Mineral Oil Placebo

Following presentation of full results for REDUCE-IT on Saturday, an Amarin-sponsored Vascepa product theater discussed the science behind the drug, REDUCE-IT results, and implications for future use of Vascepa. We certainly sensed a buzz as conference attendees shuffled into this session, eager to learn more about a previously below-the-radar drug (pure prescription EPA) that’s caused a splash in the media. For our part, we remain very excited about Vascepa’s potential to improve outcomes for people with diabetes – who comprised 58% of REDUCE-IT’s enrolled population. We’ve picked out some of the most salient points from the presentation given by Dr. Eliot Brinton (Utah Lipid Center, Salt Lake City, UT and REDUCE-IT Steering Committee) below:

• Dr. Brinton emphasized the surprising findings that Vascepa’s CV benefit did not appear to be dependent on baseline TG or even on TG lowering. He noted that this was “an astounding result” of REDUCE-IT: comparable CV benefit was seen across the full range of baseline TG levels studied (even in the 10% of subjects with TG < 135 mg/dL). As a lipidologist, Dr. Brinton joked that he felt “threatened” by these surprising findings. Further, citing comparable CV benefit above and below an on-treatment TG of 150 mg/dL, equally unexpected, he also said there is no need to “think Vascepa fails if it doesn’t get your patient’s TG below 150.” We find these points quite intriguing, as they suggest Vascepa might benefit a very broad patient population; of course, any official indication would have to reflect the study population, with elevated TG levels, that was enrolled in REDUCE-IT.  

• Vascepa treatment had no effect on A1c; information is still being collected on diabetes agents added on during the trial, but no imbalance is expected. As a reminder, a major fraction (~58%) of the study population had diabetes at baseline, and the entire primary prevention cohort (~30%) in REDUCE-IT was comprised of patients with diabetes. Dr. Brinton remarked that he’s “sure that [some] diabetes agents were added [during] the trial” as patients tried to manage their A1c levels, but Amarin’s (very reasonable) belief is that there was no imbalance between these agents between the two groups, given that Vascepa did not impact A1c. Still, the impact on drop-in medication use must be assessed, particularly given that two classes of diabetes drugs are now known to be cardioprotective. Dr. Brinton mentioned that more details on diabetes-specific care in REDUCE-IT will be released at a later date – we’ll be sure to look out for this.
  

• In response to chatter that the use of a mineral oil as the placebo may have contributed to the apparent magnitude of CV benefit with Vascepa by increasing placebo group risk, Dr. Brinton pointed toward the JELIS trial to reinforce Vascepa’s CV benefit. In that earlier randomized clinical CV outcomes trial (also testing pure EPA) there was no placebo agent used at all, and yet a 19% CV event reduction was still seen, roughly comparable to that in REDUCE-IT. Dr. Brinton leveraged these data to suggest that concerns over the effect of a mineral oil in placebo pills have been overblown: “If mineral oil is the entire explanation for what happened in REDUCE-IT, then tell me what happened in JELIS?” That being said, our understanding is not that critics have alleged the effect was entirely due to placebo, but perhaps exaggerated relative to a slight increased risk due to mineral oil in the placebo group. More reassuring was that, in a conversation with our team, Amarin CMO Dr. Craig Granowitz explained that increases in LDL-C and CRP values in the placebo group were relatively small, and that these lab values were not collected in an extremely rigorous fashion – therefore, he doesn’t put much stock into the significance of these results. He emphasized that the net difference on LDL-C at trial end was 5 mg/dl (+7 mg/dl in placebo, +2 mg/dl in Vascepa), which has arguably low clinical relevance; on CRP, he drove home the points that inflammation is highly variable and EPA has anti-inflammatory properties, which likely dampened any increase in inflammation in the Vascepa group. Dr. Granowitz also mentioned that separate analyses were performed for placebo group participants whose LDL-C levels increased vs. those whose level did not, and no difference in outcomes was observed.

CVOT Subgroup Analyses and Post-hocs

5. CARMELINA’s Reassuring Trend on HHF with DPP-4 Tradjenta Holds Across Nearly All Subgroups, Save European Participants and Those on Insulin; First DPP-4 with Favorable Results

To a jam-packed room, UT Southwestern’s Dr. Darren McGuire expanded on heart failure results from CARMELINA, the CVOT for Lilly/BI’s DPP-4 Tradjenta (linagliptin), reinforcing the study’s reassuring result on hospitalization for heart failure (HHF) across subgroups. As a reminder, the HHF results in the full cohort trended solidly in favor of Tradjenta (HR=0.90, 95% CI: 0.74-1.08, p=0.2635 for superiority, 209 vs. 226 events), as presented at EASD 2018. The positive HHF trend held for all sensitivity analyses, HF-related outcomes (below), and almost all subgroups; subgroups included those based on age (above/below 65), region (North America, Latin America, Europe, Asia), insulin use (yes/ no), history of heart failure (yes/no), eGFR (above or below 60), UACR (less than 30, 30-300, >300). The only groups in which the HR hit 1.00 or above were (i) participants on insulin (HR=1.00, 95% CI: 0.61-1.24) and (ii) the European cohort (HR=1.13, 95% CI: 0.85-1.51); interaction p-values were significant for insulin vs. non-insulin (p=0.04) and geographic (p=0.04) subgroups, though interpretation of this results should take into account the testing of 33 pre-specified subgroups for interaction without correction for multiplicity. The insulin interaction in particular calls to mind a talk we heard at ESC 2018, in which Dr. Deborah Cosmi argued for further investigation of an observed link between insulin use and risk of heart failure in patients with type 2 diabetes, based on pooled and observational data – of course, a HR or 1.00 is still completely neutral. This being said, given the complex history of DPP-4 inhibitors and heart failure, these results certainly bode well for Tradjenta and the DPP-4 class. As a reminder, initial concerns about DPP-4s and HHF risk were sparked by the SAVOR-TIMI trial for AZ’s Onglyza (saxagliptin), which found a small but concerning signal for increased risk on this endpoint with saxagliptin (HR=1.27, 95% CI: 1.07-1.51, p=0.007). However, in the group that exhibited excess heart failure risk in SAVOR, there was no increased risk of all-cause mortality, occurrence of the primary endpoint (MACE), or occurrence of the secondary endpoint (MACE plus hospitalization for heart failure, unstable angina, or coronary revascularization).

• Dr. McGuire highlighted that linagliptin is now the 2nd DPP-4 with no signal for increased HHF risk, along with sitagliptin, with each of the 2 analyzed by pre-specified exploratory analyses. As stated above, SAVOR-TIMI found a concerning increased risk for HHF with Onglyza, while EXAMINE for Takeda’s Nesina (alogliptin) trended strongly in favor of placebo (HR=1.19, 95% CI: 0.89-1.59). TECOS for Merck’s Januvia (sitagliptin) was resoundingly neutral (HR=1.00, 95% CI: 0.83-1.20). When asked about this within-class heterogeneity on HHF, Dr. McGuire posited that saxagliptin’s relatively short half-life may have contributed to its concerning signal, based on emerging evidence that DPP4i exposure induces increases circulating DPP4. Indeed, saxagliptin’s half-life is 2.5 hours, compared to 12.4 for sitagliptin, ~12 hours for linagliptin, and 21.4 hours for alogliptin. Considering that all are taken once daily and that the DPP-4 enzyme degrades a number of substrates in the body in addition to GLP-1, Dr. McGuire explained that any number of factors could be at play.

6. Computational EMPA-REG OUTCOME Analysis Demonstrates Cost Effectiveness of Jardiance in Patients with Type 2 Diabetes and Heart Failure; ICER of ~$22,000 per QALY; ~1.2 Year Average Increase in Lifespan

An interesting computational analysis based on results from the EMPA-REG OUTCOME CVOT suggested that Lilly/BI’s Jardiance (empagliflozin) is a cost-effective treatment option for patients with type 2 diabetes and heart failure, from the perspective of commercial payers in the US – see the full poster here. The model projected outcomes for 10,000 patients over a 3-year mean trial duration (EMPA-REG OUTCOME enrolled 7,020 for a median 3.1 years) and utilized the hazard ratios and 95% confidence intervals for 11 endpoints (first HHF, subsequent HHF, CV death, non-fatal MI, non-fatal stroke, unstable angina, transient ischemic attack, revascularization, macroalbuminuria, renal injury, and renal failure) in the CVOT’s population of patients with heart failure at baseline (n=706). For each event that occurred, an associated quality of life reduction and average cost was applied, informed by the US Department of HHS, the IBM Micromedex RED BOOK, Medicare and Medicaid data, and other publicly available sources; the model included an estimation which accounted for overlapping QoL decrements as patients accumulated multiple clinical effects. Cost to the health plan assumed a 50% rebate for empagliflozin (we’re not sure how realistic this rebate is, and our understanding is that this data is not public), yielding a $401 monthly cost to payers per patient on empagliflozin. No other pharmacy costs were considered. In the base case analysis, clinical event costs were reduced by $5,957/patient, which partially off-set the cost of empagliflozin ($21,144/patient) and gave an incremental cost of $15,187/patient; longer survival of patients and reduced rate of clinical events translated to an incremental 0.67 Quality Adjusted Life Years (QALYs). Dividing the incremental cost by the incremental QALYs produced an incremental cost-effectiveness ratio (ICER) with empagliflozin plus standard of care vs. standard of care only of $22,644/QALY – which is well below the $100,000/QALY US cost-effectiveness threshold (this benchmark  is flexible and commonly ranges from $50,000/QALY to $150,000/QALY). The QALY threshold indicates the highest price the system is willing to pay for improvements in health – the lower the threshold, the more frugal. Investigators also performed sensitivity analyses examining the effects of varying discount rates (0-5%), drug costs (±20%), and other factors, which gave ICERs ranging from $12,465/QALY to $32,248/QALY, robustly supporting the conclusion that empagliflozin is cost-effective for patients with type 2 diabetes and heart failure across a variety of assumptions and at a threshold of $100,000/QALY.

• Modeled patients treated with empagliflozin survived 1.22 years longer compared to standard of care alone. This aligns with a recent actuarial analysis of EMPA-REG OUTCOME which found an ~1 to 4.5 year increase in life expectancy with empagliflozin vs. placebo. Our understanding is that the 1.22 year figure refers to patients with existing heart failure included in the model, and it’s not surprising that these patients would exist on the low end of the alternative actuarial spectrum.

• We would love to see this type of analysis at varying rebate levels and with different SGLT-2 inhibitors/GLP-1 agonists. Heart failure has been thrust even more strongly into the diabetes care spotlight following positive results from the DECLARE CVOT (for AZ’s SGLT-2 inhibitor dapagliflozin) at AHA 2018. Moreover, AZ’s CEO recently proclaimed that heart failure is “as costly to the healthcare system as cancer.” Perhaps more accurate models can be constructed based on results from the Dapa-HF (dapagliflozin in heart failure with reduced ejection fraction; n=4,500) and DELIVER (dapagliflozin in heart failure with preserved ejection fraction, n=4,700) trials for Farxiga, or the analogous EMPEROR-Reduced and EMPEROR-Preserved studies for Jardiance.

• As with all computational studies, assumptions and limitations abound. Foremost, EMPA-REG OUTCOME was not powered or designed to assess treatment benefit in its HF subgroup, and even baseline HF status isn’t great – data collection on this comorbidity was, to our understanding, a check box for the investigator to fill out. Moreover, the analysis assumed a constant treatment effect for each event type regardless of changes in event or treatment history, and that changes in risk for clinical events due to changes in treatment were implicitly captured in event rate trajectories.

7. Belviq Superior to Placebo on CAMELLIA’s Composite Renal Endpoint, Driven by Improvements in Albuminuria, CKD; Small but Significant Improvement in eGFR Over Three Years

On the heels of full metabolic results at EASD, Dr. Erin Bohula presented renal outcomes from the CAMELLIA CVOT for Arena/Eisai’s obesity therapy Belviq (lorcaserin) – see results presented at ESC 2018. As a reminder, Lorcaserin achieved superiority vs. placebo in the composite microvascular endpoint of persistent microalbuminuria, diabetic retinopathy, and diabetic neuropathy in patients with diabetes at baseline (HR=0.79, 95% CI: 0.69-0.92, p=0.001). This was driven by a significant (p=0.001) reduction in persistent microalbuminuria vs. placebo (HR=0.77, 95% CI 0.66-0.90, p=0.53). Only non-inferiority was established on diabetic retinopathy (HR=0.84, 95% CI: 0.50-1.43) and diabetic neuropathy (HR=0.94, 95% CI: 0.67-1.32), making us eager to see full renal outcomes – Belviq did not disappoint. On the prespecified renal composite outcome of new or worsening albuminuria, new or worsening CKD, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death, Belviq demonstrated a 13% relative risk reduction vs. placebo (HR=0.87, 95% CI: 0.79-0.96, p=0.006) with event rates of 4.2% and 4.9% per year, respectively. Superiority on the composite was driven by (i) persistent new or worsening albuminuria (HR=0.86, 95% CI: 0.76-0.97, p=0.017) and (ii) persistent new or worsening CKD (HR=0.81, 95% CI: 0.72-0.93, p=0.0018). Persistent doubling of creatinine trended toward Belviq (HR=0.75, 95% CI: 0.26-2.15, p=0.59) while ESRD trended towards placebo (HR=1.40, 95% CI: 0.72-2.71), both with very wide confidence intervals. Renal transplant/death rates were too low to establish a confidence interval. Lorcaserin also significantly improved eGFR vs. placebo with sustained mean treatment differences between 0.8 and 1.2 ml/min/m² at each 6, 12, 24, and 36 months (p<0.001 for all) – the clinical significant of this difference, however, seems quite mild. UACR was not different between the two groups, though both experienced an increase of ~25 mg/g at the end of the three-year trial. An abbreviated Kaplan-Meier curve for the endpoint, consisting of annual data points for the three-year trial, demonstrated that the two groups began to diverge before the one-year mark (HR=0.86, 95% CI: 0.74, 1.01, p=0.061). The overall composite endpoint trended in favor of Belviq across all subgroups of primary vs. secondary CV prevention and baseline eGFR, UACR, BMI, and glycemic (diabetes, prediabetes, normoglycemia) levels.

• We’re fairly surprised to see significant benefit with lorcaserin, given very mild effects on weight and A1c in CAMELLIA; Dr. Bohula said as much during her presentation. Over 3.3 years of follow-up, Belviq gave a mean treatment difference vs. placebo of ~four pounds and a 0.2%-0.3% drop in A1c. We’re not certain about the magnitude and clinical relevance of the improvements seen with Belviq, but it seems possible that lorcaserin is exerting an effect outside of A1c and weight lowering.

• We’ll be interested to see if these results at all convince Eisai to focus more strongly on Belviq, after deprioritizing it for an Alzheimer’s candidate in 2Q18. Our guess is no, and we acknowledge the desperate need for better obesity pharmacotherapy in the ever-challenging obesity landscape. As Dr. Naveed Sattar put it at EASD 2018, “We still need safe weight loss drugs…We have excellent cholesterol, blood pressure, and diabetes drugs. Things are really, really good there. Yet, obesity and associated complications are rising, in part due to the obesogenic environment…Obesity is now, as I see it, the biggest challenge to those of us in the metabolic profession.”

8. ODYSSEY Outcomes Economic Study Shows PCSK9 Praluent ~Three Times More Cost Effective in Those with Baseline LDL-C ≥100 mg/dl; Max Price of $6,319 Per Year at $100,000 Per QALY

In his second Saturday late-breaker, Dr. Deepak Bhatt presented results from the ODYSSEY Outcomes Economics Study of Sanofi/Regeneron’s PCSK9 inhibitor Praluent (alirocumab), demonstrating greater cost-effectiveness for the agent when used in those with baseline LDL-C >100 mg/dl. In the overall intention-to-treat population from Odyssey Outcomes, the maximum annual price of alirocumab to achieve cost-effectiveness at $100,000 per QALY (quality-adjusted life year) would be $6,319. However, that number climbed to $13,357 when considering those with baseline LDL-C ≥100 mg/dl and plummeted to $2,083 when considering those with baseline LDL-C <100 mg/dl – indicating that Praluent use is most cost effective in patients with higher baseline LDL-C. In other words, “The higher the baseline LDL-C, the higher the value of alirocumab…” These data led Dr. Bhatt to conclude that, considering the absolute clinical benefit and cost-effectiveness analyses, Praluent might offer good value in patients with recent ACS and baseline LDL-C of at least 100 mg/dl. This is the most robust cost-effectiveness analysis we’ve seen on PCSK9s to date, and it offers significant insight on which patients stand to benefit most efficiently from the class. Our sense has very much been that, despite strong thought leader enthusiasm for the LDL-lowering benefits of the two-member class, clinical enthusiasm and uptake have been hampered by cost barriers and utilization management procedures. Moreover, we’ve observed that the field simply isn’t sure which patients should receive PCSK9s, and physicians are wary of prescribing such costly agents to the “wrong” patients. To this end, we’re interested to see what more can be done to characterize patients who garnered the most benefit from Praluent in ODYSSEY Outcomes and also in FOURIER for Amgen’s Repatha.

• Cost effectiveness is a fairly subjective measure. The $100,000 willingness-to-pay threshold is, as discussant Dr. Andrew Moran explained, the midpoint of commonly-accepted thresholds ranging from $50,000-$150,000 per QALY. The number equates with a payer’s willingness to invest in new treatments for gains in patient health; on the flip side, the lower the number is, the better it controls healthcare costs. Dr. Moran noted that PCSK9s have been a fairly unique situation in this regard: Cost-effectiveness analyses rarely impact drug pricing, but we’ve seen both manufacturers slash prices partly in response to these emerging data.
  • Dr. Moran corroborated the findings presented by Dr. Bhatt: He cited (i) another recent analysis setting value-based pricing at $100,000/QALY from $4,000 to $9,000 annually and (ii) ICER’s recommended Praluent price, at the same QALY threshold, of $5,300 if baseline LDL-C >100 mg/dl and $2,300 if >70 mg/dl (annually). The second of these is particularly well aligned with this analysis, given both used ODYSSEY Outcomes data.

• PCSK9 inhibitors remain remarkably expensive and difficult to access. For reference, Amgen recently dropped the cost of PCSK9 inhibitor Repatha from $14,000 to $5,850 per year; Sanofi/Regeneron have agreed to lower Praluent’s list price in exchange for simplified access, but we’re not certain where the average list price currently stands. That said, we’re not exactly sure how list price relates to the QALY analysis, given complex rebating and discount schemes, though the point stands that PCSK9 inhibitors remain very, very expensive.
• As a reminder, ODYSSEY Outcomes (n=18,924) enrolled patients with recent ACS (1-12 months) on a high-intensity statin dose; after a median follow up of 2.8 years, Praluent conferred a 15% risk reduction vs. placebo on the primary composite CV endpoint (HR=0.85, 95% CI: 0.78-0.93) and a 15% reduction on all-cause death (HR=0.85, 95% CI: 0.73-0.98). However, the magnitude of benefit was greater in those who started with LDL-C ≥100 mg/dl: Those participants saw a 24% risk reduction on MACE (HR=0.76, 95% CI: 0.65-0.87) and a 29% reduction on all-cause death (HR=0.71, 95% CI: 0.56-0.90). (Dr. Moran noted that analyzing effects by LDL-C subgroup was not pre-specified.) For comparison, the HR on all-cause mortality was 0.95 for those with LDL <100 mg/dl; of course, the trial wasn’t powered to show benefit, but the difference is quite striking. Our understanding is that the greater magnitude of benefit in the ≥100 mg/dl subgroup drives the superior cost effectiveness.
• Dr. Bhatt identified four primary limitations of this analyses: First, modeling was done with the HR for all-cause mortality, which was nominally significant due to the study’s hierarchal testing plan. Second, US costs were applied to the study’s global population. Third, cost only includes event-based costs, not follow-up costs (though, he notes, this makes the results more conservative). Last, he noted that factors outside high LDL-C may identify additional patients in whom Praluent offers favorable cost effectiveness – LDL-C shouldn’t be the only factor considered. One key strength, he added, is that this analyses leverages very robust data from a long-term CV outcomes trial, allowing for fewer assumptions than other cost analyses.
• In terms of methods, a specific cost was applied to CV death and non-fatal events, based on Medicare reimbursement rates adjusted to 2018 dollars. Costs were adjusted to commercial rates for those <65 years old. For CV death that cost was $20,225, compared to $18,862 for non-fatal MI without revascularization, $12,617 for non-fatal ischemic stroke, and a staggering ~$40,000 for ischemia-driven coronary revascularization or unstable angina. Importantly, cost of concomitant medications and follow-up were not included, which actually makes these costs an underestimate. This analysis estimated long-term survival probability by extrapolating based on age-specific mortality rates in the ODYSSEY Outcomes placebo arm, and the observed HRs from the trial were applied to this curve.

Heart Failure and Coronary Syndrome

9. Lilly/BI’s Real-World EMPRISE Study Confirms Benefit on Hospitalization for Heart Failure with Jardiance, SGLT-2 Class in US Cohort; Balanced Across Both Primary and Secondary Prevention

Following the release of topline results ~one week ago, Lilly/BI presented a jam-packed poster on the EMPRISE study, examining the real-world impact of Jardiance on heart failure hospitalizations. Importantly, two definitions of hospitalization for heart failure were used: HHF-specific refers to a primary HF discharge diagnosis, while HHF-broad refers to a HF discharge diagnosis in any position. Among people with type 2 diabetes starting Jardiance (n=17,539) or a DPP-4 inhibitor (n=17,539), those receiving Jardiance saw a 53% relative risk reduction (HR=0.47, 95% CI: 0.26-0.85) for HHF-specific over a brief mean follow-up of 5.4 months. HHF-broad was reduced by 44% (HR=0.56, 95% CI: 0.43-0.73) with Jardiance vs. DPP-4s. The 44% risk reduction was reported by Lilly/BI is the recent press release on EMPRISE. Very notably, these results were consistent between patients with (n=4,217) and without (n=13,243) established CVD at baseline, inasmuch as the confidence intervals overlapped; the HHF-broad risk reduction was 47% (HR=0.53, 95% CI: 0.39-0.72) among those with a history of CVD, compared to 65% among those without prior CVD (HR=0.35, 95% CI: 0.20-0.61). We would expect risk reduction to be greater in secondary prevention patients vs. their primary prevention counterparts, though in this case, we attribute the discrepancy to short follow-up time and the fact that this was an observational study. There was very little difference based on 10 mg vs. 25 mg dose of Jardiance, which gave 47% vs. 54% risk reductions, respectively. The specific event rate (IR/1,000 person-years) was 5.4 in the DPP-4 group vs. 2.1 in the Jardiance group (broad rates were 19.9 vs. 10.5, respectively). See the full table of results below.

• Encouragingly, the broader SGLT-2 inhibitor class showed a similar 58% relative risk reduction for HHF-specific (HR=0.42, 95% CI: 0.35-0.50) and a 32% relative risk reduction for HHF-broad (HR=0.68, 95% CI: 0.63-0.74). This part of the EMPRISE analysis compared 112,017 SGLT-2 initiators to an equal number of DPP-4 initiators over a mean follow-up of 6.8 months. There was similar consistency between primary and secondary prevention cohorts at this level (see table below).

• For comparison, EMPA-REG OUTCOME identified a 35% relative risk reduction on hospitalization for heart failure (HR=0.65, 95% CI: 0.05-0.85), a 38% risk reduction on CV death (HR=0.62, 95% CI: 0.49-0.77), and a 32% risk reduction on all-cause death (HR=0.68, 95% CI: 0.57-0.82) with Jardiance in people with type 2 diabetes and established CVD. The event rate (IR/1,000 person-years) was 14.5 in the placebo group and 9.4 in the empagliflozin group, roughly double that seen in the real world, which is a reflection of EMPA-REG OUTCOME’s enriched population.
  • Heart failure benefit with SGLT-2s has also been found with J&J’s Invokana in CANVAS, which found a 33% risk reduction on HHF (HR=0.67, 95% CI: 0.52-0.87), and AZ’s Farxiga in DECLARE, which found a 27% risk reduction on HHF (HR=0.73, 95% CI: 0.61-0.88). Real-world evidence has strongly corroborated this effect, most notably through the AZ-sponsored CVD-REAL program. CVD-REAL (n=309,046), in the US and western Europe, found a 39% reduced risk for HHF with all SGLT-2s vs. other diabetes therapies (p<0.001), while CVD-REAL 2 (n=470,128), a more multi-national cohort, found a 36% reduced risk for HHF (p=0.001).
• It’s very encouraging to see Jardiance’s heart failure benefit corroborated in a real-world cohort, demonstrating that the HHF risk reduction translates to routine clinical practice. That said, when it comes to real-world evidence, the issue of confounding remains a significant point of discussion. To be sure, RWE has an important role to play, but in the case of EMPRISE, for example, there’s the inherent risk that people who received SGLT-2s/Jardiance were different from those who received DPP-4s in some way that cannot be controlled for. We remain very interested in learning more about how the EMPRISE design (comparing those on SGLT-2s vs. DPP-4s) compares to the CVD-REAL design (SGLT-2s vs. all other diabetes classes) and whether one design is more robust than the other. It is somewhat limiting that EMPRISE examines only US patients.
• Study design: EMPRISE utilized data from two commercial databases (Optum Clinformatics and Truven Health MarketScan) and Medicare fee-for-service data, only from the US. The study cohort was matched 1:1 via propensity scoring; over 140 baseline characteristics were controlled. This specific analysis is based on data from August 2014 to September 2016 but, as Lilly/BI have previously stated, EMPRISE will eventually include data through 2019. No SGLT-2 inhibitor or DPP-4 inhibitor use in the prior year was allowed. Future analyses will include a greater number of patients and examine clinical, safety, and economic outcomes. Lilly has stated a goal to examine >200,000 patients from the same databases.
• Baseline characteristics: The DPP-4/Jardiance and DPP-4/SGLT-2 cohorts were both very well matched across baseline characteristics, drug use, comorbidities, and healthcare utilization. Among those in the DPP-4/Jardiance analysis, mean age was 59 years old, 46% were female, and mean A1c was 8.5-8.6%; 8% were previously hospitalized (the time frame is unclear), while 25% had a history of CVD, 5% heart failure, 7% CKD, and 76% hypertension. Among the DPP-4/SGLT-2 cohort, mean age was 61 years old, 46-47% were female, and mean A1c was 8.6%; 8% were previously hospitalized, while 26-27% had a history of CVD, 6% heart failure, 7-8% CKD, and 76-77% hypertension.

10. EMPA-HEART Shows Significant Reduction in Left Ventricular Mass with Jardiance, Offering Evidence of SGLT-2 Mechanism for Heart Failure Benefit in Humans

Dr. Subodh Verma (University of Toronto, Canada) presented primary results from the EMPA-HEART CardioLink-6 Trial, demonstrating that Jardiance (empagliflozin) significantly reduced left ventricular mass (LVM) in patients (n=97) with type 2 diabetes and established coronary artery disease. The study just completed in September, and these results represent an important mechanistic finding that helps unshroud some of the uncertainty surrounding SGLT-2 inhibitors’ mechanism of action for cardiovascular benefit, and more specifically for their effects on heart failure. Dr. Verma explained that results from EMPA-HEART indicate that empagliflozin treatment may promote reverse remodeling of the heart, contributing to observed CV benefits. In the trial, 97 patients between the ages of 40 and 80 years old with a history of type 2 diabetes and established, well-treated CAD were randomized to either once-daily 10 mg empagliflozin treatment or placebo and tracked for six months. For the primary outcome of LVM, patients were assessed by cardiac MRI, which is considered the “gold standard” for this endpoint; further, LVM is thought to be a strong predictor of CV outcomes. On this primary endpoint, empagliflozin treatment was associated with a significant reduction in LVM from baseline, reducing LVM by 2.6 g/m² vs. 0.01 g/m² with placebo. The adjusted mean difference between groups was -3.35 g/m² (95% CI: -5.9, -0.81; p=0.01). This result remained statistically significant even after conducting sensitivity regression analyses over height and weight, reinforcing the robustness of the result.

• As the discussant for these results, Dr. Elliot Antman (Brigham and Women’s Hospital, Boston, MA) called EMPA-HEART a “very important mechanistic study” and posited that the reduction in systolic blood pressure along with the increase in hematocrit seen with empagliflozin treatment may be potential drivers of the LVM reduction. He also noted the robustness of the primary endpoint result and called for more similar studies to be conducted (e.g. with other SGLT-2 inhibitors) in order to evaluate physiologic effects of SGLT inhibition. Importantly, he particularly called for studies that would investigate direct myocardial effects from these agents – for example, animal model results have suggested an increase in cardiac energy production through glucose and fatty acid oxidation, and Dr. Verma himself has also hypothesized an improvement in myocardial energetics through reduction of intracellular sodium and calcium levels via inhibition of the sodium-hydrogen exchanger in myocytes, which drives a downstream sodium-calcium antiporter. Other model studies have supported a shift to ketone metabolism that lowers left ventricular remodeling. All in all, our understanding of the effects SGLT-2s have on human physiology continues to evolve and is far from complete, from EMPA-HEART represents an important step in examining these agents in humans specifically.

11. Diabetes Drugs and Heart Failure: Drs. Verma and McMurray Detail What We’ve Yet to Learn About Prevention and Treatment of HF

In a session on the metabolic aspects of heart failure, a true dynamic duo of Drs. Subodh Verma and John McMurray discussed the knowns and unknowns of diabetes drugs, with a particular eye toward heart failure. Dr. Verma was crystal clear in enumerating nine key unknowns and pointing to anticipated answers on four points:

• Will DECLARE change clinical practice guidelines for a broader use of SGLT-2 inhibitors for HHF and renal benefit in people without ASCVD?

• Are GLP-1 agonists efficacious in patients without diabetes but with ASCVD?

  • The SELECT CVOT for a high dose (2.4 mg) of Novo Nordisk’s Ozempic in obesity (with or without type 2 diabetes) will offer an answer. SELECT recently began recruiting 17,500 participants and should complete September 2023.

• Are GLP-1 agonists benefit in type 2 diabetes without ASCVD?

  • The REWIND CVOT for Lilly’s Trulicity will offer an answer. While last week’s topline release indicates the trial was positive overall, we’ll have to see subgroup analyses for primary vs. secondary prevention to have a definitive answer on this question.

• Do SGLT-2 inhibitors offer renal protection in type 2 diabetes?

  • The CREDENCE renal and CV outcomes trial for J&J’s Invokana will offer an answer. CREDENCE was stopped ~one year early this summer for meeting its primary endpoint ahead of schedule; results are anticipated “around Christmastime” this year.

• Do SGLT-2 inhibitors offer renal protection outside of diabetes?

  • Both Dapa-CKD and EMPA-KIDNEY will offer answers. Dapa-CKD for AZ’s Farxiga is still enrolling 4,000 participants with CKD and should complete November 2020, while EMPA-KIDNEY is just about to start enrolling 5,000 participants with CKD and should complete June 2020.

• How do we prioritize and individualize secondary prevention therapies based on ischemic risk vs. heart failure risk? (i.e., how do you pick and choose for a specific patient?)

• Will GLP-1 agonist and SGLT-2 inhibitor combination therapy offer the greatest CV risk benefit?

• Will metformin ever be displaced as first-line therapy in diabetes?

• Will SGLT-2 inhibitors be used in the treatment of HF with preserved and/or reduced ejection fraction?

Dr. McMurray delved deeply into the final question, first drawing the key distinction between prevention of heart failure (“where we are today”) and treatment of heart failure (“the next step”). Going forward, this distinction will only become more important: As he explained, we’ve learned much about the prevention of incident heart failure with SGLT-2 inhibitors, but we know very little about those who have HF at baseline. In EMPA-REG OUTCOME and CANVAS, no information was collected on ejection fraction or biomarkers at baseline; investigators simply checked a box. Very positively, however, in the three completed SGLT-2 inhibitor CVOTs, participants benefitted on the composite of CV death and HHF regardless of recorded baseline heart failure status, as per this very-recent meta-analysis from Dr. Marc Sabatine et al. While more data is expected to come out of DECLARE, little can be concluded about the specificity of these “tantalizing” signals. Forthcoming data will reveal (i) whether HHF risk reductions apply to only patients with diabetes or to everyone with heart failure, (ii) whether the reduction applies to HF with preserved ejection fraction and/or with reduced ejection fraction, and (iii) whether the reduction impacts existing HF, or only prevents new HF episodes. Dr. McMurray found it encouraging that, so far, it doesn’t seem that the mechanism of CV benefit with SGLT-2s is mediated by any glucose or “metabolic” effects, particularly because the benefit appears so quickly. That said, even if benefit is dependent on dysglycemia, the majority of at-risk patients with HF will fall under that umbrella. Sooner rather than later, though, we’ll have a more definite answer (or a few of them), from five dedicated trials of SGLT inhibitors in heart failure:

• Dapa-HF is investigating dapagliflozin in 4,744 participants with HFrEF and should complete December 2019. Dr. McMurray noted that the average eGFR in this study will be much lower than in DECLARE (85 ml/min/1.73 m²), which could be important.

• DELIVER is investigating dapagliflozin in 4,700 participants with HFpEF and should complete June 2021.

• EMPEROR-Reduced is investigating empagliflozin in 2,850 participants with HFrEF and should complete June 2020.

• EMPEROR-Preserved is also investigating empagliflozin in 4,126 participants with HFpEF and should also complete June 2020.

• SOLOIST-WHF is investigating sotagliflozin in 4,000 participants with worsening HF and type 2 diabetes and should complete January 2021.

12. CGM-Measured MAGE and Hyperglycemia Predict Recurrent Expanded MACE Events in Post-Acute Coronary Syndrome Patients; Cause vs. Correlation Remains Unclear

Researchers at Yokohama City University Medical Center found that mean amplitude of glycemic excursion (MAGE; measured and calculated via CGM) is a significant predictor of MACCE events (CV death, stroke, recurrent ACS, angina requiring revascularization, acute decompensated heart failure, stroke) in patients with prior acute coronary syndrome (ACS). The study (n=417), with a median 39-month follow-up, fitted patients with Medtronic’s iPro2 for at least 24 consecutive hours during a stable phase after ACS. For reference, MAGE is the mean difference between consecutive peaks and valleys if the difference was >1 standard deviation of the overall mean glucose level; it serves as a well-accepted marker of glycemic variability. It was found that 34% of the patient population (n=140) had type 2 diabetes, and average A1c was 5.9%. During follow-up, 66 patients experienced MACCE events: There were 5 CV deaths, 14 recurrences of ACS, 27 anginas requiring revascularization, 8 acute decompensated heart failure events, and 16 strokes. A univariate logistic regression of 25 demographic and metabolic factors revealed that high MAGE (>52 mg/dl) was the strongest predictor of a MACCE event (HR=2.35, 95% CI: 1.38-4.00, p=0.001). This was closely followed by high-sensitivity c-reactive protein >0.1355 mg/dL in stable phase post-ACS (HR=2.28, 95% CI: 1.33-3.92, p=0.002) and a glucose >180 mg/dl on admission (HR=2.24, 95% CI: 1.29-3.89, p=0.004). The Kaplan-Meier survival for patients grouped by MAGE (low vs. high, with 52 mg/dl as the threshold) separated at ~one year (below).

• The most important question, in our assessment, is whether glycemic variability has an associative or causative relationship with CV risk in post-ACS patients (a particularly high risk group from a cardiovascular perspective) – a relationship that Dr. Lawrence Leiter discussed in detail at Diabetes Canada 2018. Given that the association between hyperglycemia and macrovascular risk seems to be grounded more in a common causative pathophysiology (i.e. insulin resistance) than a directional relationship, we imagine high glycemic variability serves more to “mark” high risk patients than to drive that risk. On the other hand, the specific question of hypoglycemia’s relationship to subsequent CV events remains open, and there is certainly data to suggest that episodes of severe hypoglycemia promote a high-risk state. Still, the question is far from answered, and it’s hard to imagine a definitive resolution coming anytime soon given the inherent impossibility of conducting an RCT to test this hypothesis. Taken together, we do feel these results reinforce the importance of CGM for patients with diabetes; at this point, that data is hardly actionable from a cardiovascular risk perspective, but could certainly play a role in helping to minimize hypoglycemia in those at risk.

Awareness and Prevention of CV Disease

13. “Are We Ready to Bell the Cat?” – Dr. Mikhail Kosiborod Advocates for Cardiologists to Take a More Active Role in Type 2 Diabetes Management and Better Utilize GLP-1 Agonists + SGLT-2 Inhibitors

In two separate presentations, Dr. Mikhail Kosiborod lamented that diabetes drugs proven to lower CV risk are still woefully underutilized by cardiologists and called for his field to take a greater role in managing CVD in patients with diabetes. Referencing a recent editorial, which he co-authored in Circulation, Dr. Kosiborod compared cardiologists’ current relationship to managing ASCVD in people with diabetes to the old fable “Belling the Cat”: A concerned group of mice are debating the best way to minimize the threat from a cat that has tormented them; one proposes putting a bell around the cat to signal when the threat will arrive. This solution is met with support until a wise old mouse asks, “Who is to bell the cat?” Each of the mice offer reasons why they cannot be the one to do so, so the cat continues to hunt the mice. In the words of Dr. Kosiborod, “It is one thing to say that something should be done but quite a different matter to actually do it.” He explained that the current state of cardiologists treating patients with diabetes displays a similar dynamic: The benefit of certain glucose-lowering drugs in reducing CV risk is readily apparent, yet their actual use by cardiologists in patients with diabetes is still stunningly low. Both empagliflozin (Jardiance) and liraglutide (Victoza) have robustly demonstrated MACE reductions and received indications from FDA and EMA for reducing CV risk in patients with diabetes; nevertheless, an overwhelming number of patients who stand to benefit from these drugs are not receiving them. In his editorial, Dr. Kosiborod cited previous analyses that have shown (i) only 5% of patients who met the inclusion criteria for EMPA-REG OUTCOME were on an SGLT-2 inhibitor, and (ii) only 6% of those who met LEADER inclusion criteria were on a GLP-1. As early as the year 2000, thought leaders were calling for cardiologists to be more involved in diabetes – see this JACC editorial from Drs. James Gavin and Gottlieb Friesinger. Why then, he asks, are cardiologists still sitting on the sidelines, when now more than ever they have powerful tools at their disposal?

Dr. Kosiborod placed significant blame for this underuse on cardiologists being hesitant to prescribe what are, in name, primarily glucose-lowering therapies. He acknowledged several other oft-cited justifications for this phenomenon: Cardiologists may not see it as “their place” to get involved with glucose management and may feel ill-equipped to prescribe diabetes therapies or follow up on diabetes issues. Moreover, they may be hesitant to “step on the toes” of referring clinicians, be they endocrinologists or PCPs. Cardiologists may fear hypoglycemia and other side effects, or be unfamiliar with diabetes reimbursement and patient education specifics. In response, he argued for a decoupling of glycemic control and cardiovascular benefits: “Cardiologists should not shy away from the initiation of these agents simply because they also happen to lower blood glucose, just like we would not shy away from initiating high-intensity statins in [patients with diabetes] with established ASCVD.” Dr. Kosiborod has previously shared the view that it’s completely within a cardiologist’s scope of practice to prescribe a GLP-1 or SGLT-2 for CV risk lowering. Moreover, he sees a huge opportunity for cardiologists to be coordinators of care for patients with diabetes by improving outcomes in both volume- and value-based models of care delivery. He floated the idea of “Cardiometabolic Centers of Excellence” that could coordinate the care of patients with type 2 diabetes and established CVD within preventative cardiology practices – ideally involving close collaboration with endos and PCPs and with a focus on event reduction. We’re always impressed by Dr. Kosiborod’s relentless advocacy for greater involvement of cardiologists in lowering CV risk and improving outcomes for people with diabetes.

• Dr. Kosiborod challenged the notion that SGLT-2 inhibitors exert their effects on heart failure by acting as a diuretic. Session chair Dr. Naveed Sattar referenced Dr. David Nathan’s well-published comment that SGLT-2s are little more than a more expensive diuretic, questioning whether diabetologists might get closer to outcomes that matter with better use of diuretics. Dr. Kosiborod explained that while evidence does clearly suggest a volume-related effect with SGLT-2 inhibitors, thinking of these agents as diuretics alone is insufficient. While it can be helpful to conceptualize them as such, he says, it seems like there’s much more going on physiologically. Whether there are within-class differences in how well these emerging effects are exerted, we think, remains to be seen. Further, this comment reflects the opinion we’ve heard from a variety of thought leaders, notably Dr. Subodh Verma at ESC 2018. Additionally, during Dr. Kosiborod’s Sunday presentation, he highlighted the increasingly well-demonstrated benefits of SGLT-2s on CKD (specifically, for slowing the progression of kidney disease), adding another layer to the impressive and unique benefits of the class.

14. Drs. Will Cefalu and Eduardo Sanchez Kick Off ADA/AHA’s “Know Diabetes by Heart” Initiative; Why and How the Partnership Plans to Reduce MACE + HF Events in Diabetes; Abstracts Discuss Role of Stress, Mental Health, Eating Schedules in CVD/Type 2 Link

ADA’s Chief Scientific, Medical, and Mission Officer Dr. Will Cefalu and AHA’s Chief Medical Officer for Prevention Dr. Eduardo Sanchez officially launched AHA/ADA’s multi-year partnership, “Know Diabetes by Heart,” offering details on the what, why, and how of the initiative during two events on Saturday. The partnership’s dedicated website already has a plethora of resources and educational materials devoted to the critical link between diabetes and CV disease. The initiative is funded by Novo Nordisk, Lilly/BI, and Sanofi.

• What: Know Diabetes by Heart is an initiative to raise awareness about and ultimately reduce heart failure, CV death, heart attack, and stroke in patients with diabetes. The initiative targets patients, providers (first and foremost PCPs), and healthcare systems.
• Why: We thought Dr. Cefalu summed it up particularly well in saying: “because the problem [of diabetes and cardiovascular disease] is too large to tackle alone.” He emphasized the extreme cost of diabetes on the healthcare system: “One out of every two Americans has a glucose problem. We can’t afford that. It cost $327 billion to care for diabetes in 2017.” That said, he continued, diabetes care is at an incredibly exciting point, with >40 new products on the market since he trained as an endocrinologist 30 years ago. Unfortunately, CV risk among those with diabetes is still a tremendous problem, and the increasing number of people with diabetes makes the epidemic all the more difficult to fight. Indeed, in the initiative launch video, ADA CEO Ms. Tracey Brown explained that 228 people with diabetes die every day, primarily from CV disease and complications. Dr. Sanchez offered color on how AHA is approaching the initiative, articulating, “The AHA has a new mission statement: To be a relentless force for longer, healthier lives. I believe this gives us license to do all sorts of things we haven’t done before. In my mind, this says that we must be working with ADA.” He explained that, for people over age 60 with type 2, CVD attenuates life expectancy by about 12 years – but CV risk is modifiable and life expectancy can be extended if we do certain things better, which is what this partnership aims to promote. In his assessment, patients need to be made more aware of their personal risk and providers need to discuss it more proactively.
• How: Four large-scale aims are outlined below. In truth, details on the specifics of each of these goals were sparse during the launch (we heard quality improvement initiatives and streamlining navigation within healthcare systems as two ideas), though both Dr. Cefalu and Dr. Sanchez underscored the importance of accountability in sticking to these endeavors. Currently on the partnership’s website are discussion guides for patients to spark conversation with doctors, a sign-up link for ADA’s free Living with Type 2 Diabetes Program (printable guides, monthly newsletters, access to ADA’s Diabetes Forecast, and an online community with local events), and registration links for the partnership’s Ask the Expert Q&A series, which will answer patient questions asked by phone, online, or live.
  • (i) Raising awareness and understanding of the link between diabetes and cardiovascular disease;
  • (ii) positively empowering people to better manage their risk for cardiovascular disease, heart attacks, and strokes;
  • (iii) supporting health care providers in educating their patients living with type 2 diabetes on cardiovascular risk and increasing their patients’ engagement in prevention of cardiovascular deaths, heart attacks and strokes;
  • (iv) and following improved guidelines and treatment algorithms that take a patient-centered, individualized, and holistic approach to diabetes/CV disease care, such as the recently published ADA/EASD consensus statement.
• As part of the partnership’s holistic approach, we heard three fantastic “mini-presentations” demonstrating how the intimate connection between CVD and diabetes extends beyond CVOTs:
  • UCSF’s Dr. Jonathan Butler demonstrated how cumulative psychosocial stress is associated not only with CVD but also type 2 diabetes in women over the age of 60, using data from the Women’s Health study. The study demonstrated that increasing quartiles of cumulative stress (adjusted for race, ethnicity, socioeconomic status, and CV disease risk factors) were associated with increasing risk of incident diabetes, with the highest hazard ratio for a quartile reaching ~2.5. Indeed, noted in the press release for the partnership’s launch were recent focus groups conducted by the ADA and AHA in September, which reinforced that many people living with type 2 diabetes experience distress related to the day-to-day management of this chronic disease. They also reported feelings of hopelessness, which can decrease the likelihood of taking action to reduce the long-term complications of diabetes. We find the multi-dimensional impact of diabetes on physical, mental, and emotional well-being too often understated and are encouraged by the holistic approach being taken by the partnership.
  • Yale’s Dr. Murrium Sadaf delineated the relationship between mental illness and diabetes in victims of sudden, unexpected death. Over the course of two years, ~30% of sudden unexpected death victims (aged 18-64) had diabetes. Mental illness was shockingly more prevalent in those with diabetes (57%) than those without diabetes (35%), with prevalence of mental illness higher in those with “severe diabetes” (64%) compared to “mild diabetes” (53%).
  • Columbia’s Dr. Nour Makarem presented an intriguing study suggesting that, when it comes to eating, it matters not only how much one eats but also when they eat it affects – temporal eating pattern impact diabetes and CV risk factors. The study population consisted of 12,708 cancer- and diabetes-free patients from the Hispanic Community Health Study/Study of Latinos. It was found that those who consumed ≥30% of their energy (in calories) after 6 pm had higher fasting glucose (93.7 vs. 93.0 mg/dl; p=0.001), insulin (12.4 vs. 11.6 mU/L; p=0.003), HOMA-IR (2.9 vs. 2.7; p=0.001), systolic BP (118.7 vs. 117.5 mmHg; p=0.004), and diastolic BP (72.2 vs. 71.0 mmHg; p<0.0001). While these differences don’t seem all that clinically meaningful in and of themselves (particularly for such a large sample size), the consistency between them paints an interesting pattern.

Exhibit Hall

Amarin

Capitalizing on the buzz around Vascepa and positive REDUCE-IT results (see our full coverage of these results here), Amarin made its first appearance in an exhibit hall we’ve covered. Amarin’s booth was near the entrance of the exhibit hall and featured huge banners touting impressive REDUCE-IT results, describing Vascepa as “A breakthrough in CV risk reduction” and cleverly proclaiming “What does Vascepa do to CV Risk? REDUCE-IT!” Amarin has undertaken a sizeable expansion of its sales force following the release of positive topline results from REDUCE-IT in September, growing from 150 to ~400 sales reps in anticipation of (and to help drive) a boom in sales; from our conversations in the booth, the novelty of the sales reps was fairly evident. The vibe we got from cardiologists visiting the booth was one of curiosity – it seemed as many had (understandably) not heard of Vascepa before. Therein lies the challenge for Amarin, as Vascepa will need to overcome a lack of prescriber familiarity – and build its class alone – while also straightening out confusion among patients over how Vascepa is different from dietary fish oil and EPA supplements. However, there’s no denying the enormous potential that Vascepa now has to become a widely used drug for CV risk reduction. Amarin has repeatedly indicated its desire to utilize a mass marketing approach with Vascepa and aims to minimize cost while attempting to reach as many patients as possible. On this note, we fully expect to see Amarin bring a full-throated presence to future conferences as the company spreads the word on Vascepa.

Amgen

Amgen had a sizable booth near the center of the exhibit hall. PCSK9 inhibitor Repatha (alirocumab) was the obvious focus of Amgen’s exhibit, as the booth touted FOURIER results demonstrating Repatha’s significant CV risk reduction and LDL-C lowering vs. placebo. Representatives in the booth emphasized a new slogan that Amgen has rolled out – “Lower Together” – referencing Repatha’s reductions in LDL-C, CV risk, hassle, and cost. The final is a recent addition, as Amgen just last month announced a significant 60% list price reduction, taken in an attempt to increase access to Repatha, which carried a notoriously high list price for all of its previous time on the market. Access remains a tremendous issue for the PCSK9 inhibitor class: Reps underscored that only 0.2% of patients who could benefit from one of these agents are actually using either Repatha or Praluent currently. A lower list price, if it does improve access, would be a big step toward increasing the number of patients who will actually get Repatha. We’re definitely excited and curious to see what impact this decision will have on uptake; for more granularity on Repatha’s recent commercial performance, see our report on Amgen’s 3Q18 financial update. As an additional side note, we were excited and intrigued to see that Amgen’s booth featured an “Escape Room” that visitors could complete together – Amgen hoped that the activity could increase collaboration between attendees. We loved to see it!

AZ

A sprawling booth in the middle of the hall promoted AZ’s SGLT-2 Farxiga and antiplatelet therapy Brilinta in equal turn – we were quite struck by the level of material dedicated to Farxiga. Indeed, signing called out to attendees, “Welcome to the Farxiga booth,” and it was clear that AZ expected significant interest in the product following readout of full DECLARE results as a Saturday late breaker. Our sense is that AZ and Farxiga benefitted from a very strong focus on heart failure at AHA 2018 (we also think the DECLARE readout drove some of the robust discussion on HF). AZ reps echoed our excitement over a potential first-ever heart failure focused indication, likely including primary prevention, for a diabetes therapy.

We were, however, disappointed not to see any real estate for GLP-1 agonist Bydureon. To be sure, we understand that AZ is not able to promote its GLP-1 for cardioprotection given the narrow statistical miss on superiority for three-point MACE in the EXSCEL CVOT. However, given growing consensus around the idea of cardioprotection as a class effect of GLP-1 agonists, we would love to see more robust promotion of these agents to cardiologists. GLP-1s need to be prescribed more often and become more easily accessible to people with type 2 diabetes, and cardiologists doubtless have a key role to play in promoting their use.

Lilly/BI

The Lilly/BI brought a colossal, two-level (!) booth to AHA, almost exclusively devoted to SGLT-2 inhibitor Jardiance (empagliflozin). In line with AHA’s focus, reps were naturally concentrated on the products’ CV death indication in the US, which was granted based on an impressive 38% relative risk reduction vs. placebo in EMPA-REG OUTCOME. The “crow’s nest” of the booth featured several VR headsets fashioned as binoculars overlooking the exhibit hall floor. Fittingly, these headsets provided users with skyline views of several major US cities, using famous landmarks to illustrate the magnitude of Jardiance’s associated CV death reduction. For example, in Chicago, 25,000 people visit the Willis Tower (formerly the Sears Tower) every day. If every one of those people had type 2 diabetes, established CV disease, and was taking Jardiance, then 550 CV deaths could be prevented over the course of their lifetimes. By the same logic, 2,567 CV deaths could be prevented amongst the 116,667 yearly visitors to Alcatraz, in our home city of San Francisco. While we found this to be a somewhat roundabout way of conveying Lilly/BI’s point, we acknowledge that these numbers are certainly striking and the visualizations stuck with us – we wonder if a similar visualization could help convey Jardiance’s CV death reduction to patients. The lower level of the exhibit was devoted to a coffee bar and social milieu, where we asked a rep for his thoughts on Invokana’s recent US CV indication for reducing risk of full three-point MACE, despite achieving very comparable results in CANVAS as Jardiance achieved in EMPA-REG OUTCOME. We were thrilled to hear the rep express excitement at the indication, stating that it could only help the SGLT-2 class and, most importantly, patients– nice! We are always beyond inspired when companies and reps prioritize the larger picture of diabetes care over in-class competition – hats off to Lilly/BI and this rep.

There was no mention of DPP-4 Tradjenta at the booth, despite the recent readout of the CARMELINA CVOT at EASD. Given that the trial demonstrated only CV safety, and not CV superiority, vs. placebo (as was expected), we find it unsurprising that Lilly/BI prioritized their cardioprotective agent in this display.

J&J

Janssen was split between two booths at AHA; the larger was devoted exclusively to blood-thinner Xarelto while the smaller promoted SGLT-2 inhibitor Invokana’s very recently FDA approved CV indication for reducing three-point MACE in patients with type 2 diabetes and established CV disease in the US. This was certainly a massive win for J&J, and it was clear the company is trying to capitalize commercially. Four large screens repeated flashy infographics promoting Invokana as the first SGLT-2 inhibitor to be recognized for the reduction of all MACE components (Lilly/BI’s Jardiance – the only other SGLT-2 with a CV indication in the US – is only recognized for its impressive 38% reduction in CV death, despite a significant effect on MACE of the same magnitude as Invokana). Particularly impressive to us was how quickly this booth must have been pulled together – Invokana’s CV indication was announced just 10 days ago (we imagine production started before then ; >)! Contrast this to the company’s more defensive booth from AADE 2018, where J&J was mainly promoting its wealth (6.5 years) of safety data on Invokana: This was almost certainly attempt to staunch falling sales attributable to the amputation signal associated with canagliflozin in CANVAS (a signal that we continue to feel is not reflective of the risk faced by most patients). To this end, Invokana’s CV indication is a welcome tailwind for the product’s steadily falling sales; as it stands, the SGLT-2 inhibitor is in dire need of further investment as well as an increase in sales, seeing as the franchise posted its seventh consecutive quarter of double-digit YOY declines in 3Q18. Needless to say, we are beyond thrilled that J&J seems to re-investing in this highly efficacious therapy once again.

Notably, there was no mention of upcoming data from CREDENCE (canagliflozin in CKD), which was stopped a year early this summer due to overwhelming efficacy of Invokana; full results are expected “around Christmastime” or early January. When we asked two company reps about CREDENCE, we were surprised that to hear that neither was aware of the trial’s discontinuation.

Merck

Merck occupied an unassuming and indistinct, single-person booth at AHA, with no promotional material – there were a few logos and charging ports available for attendees (we’ve seen an equivalent presence at other cardiology meetings). This was slightly surprising to us, given that the company heavily advertised DPP-4 inhibitor Januvia (sitagliptin) last year at AHA 2017. While some said that given increasing recognition of cardioprotection as a class effect of SGLT-2 inhibitors, they would have loved to see promotion of Pfizer-partnered Steglatro (ertugliflozin) at the meeting, since the associated CVOT hasn’t reported yet, we imagine that they have to be very careful about this. Results from the VERTIS CV CVOT will be critical to the product’s commercial success, given that Jardiance already has a CV indication, Invokana’s US indication was just approved, and full results from Farxiga’s DECLARE CVOT could support a potential CV indication for heart failure in both primary and secondary populations.

Novo Nordisk

Novo Nordisk brought a smaller booth than we’re used to (at diabetes meetings) to AHA 2018, and it was also located toward the back of the exhibit hall. Still, we were glad to see prominent promotion of both Ozempic and Victoza, the company’s duo of GLP-1 agonists. Booth materials leaned in favor of Ozempic – the product name was emblazoned across the display’s main panel – and we noted that the once-weekly was being promoted as superior to Trulicity on both A1c lowering and weight loss, with panels displaying very positive results from SUSTAIN 7. Reps indicated that there was substantial interest from conference attendees in these results and in learning more about Novo Nordisk’s GLP-1 agonists.

To be sure, however, Victoza was still very prominently featured, and understandably so: The injectable remains the only GLP-1 agonist to hold a CV indication from FDA, for reducing risk of MACE (CV death, non-fatal MI, non-fatal stroke) in people with type 2 diabetes and established CVD (based on LEADER). Of course, that could all change in the next year or so, as Lilly’s Trulicity has also demonstrated CV benefit in the REWIND CVOT, for which topline results were only just announced. We note that Ozempic has also demonstrated CV benefit in the SUSTAIN 6 trial, but that study alone is too small (n=3,297) and short (median FU 2.1 years) to support a CV indication, at least to FDA – in Europe, Novo Nordisk is allowed to promote Ozempic as superior to placebo on three-point MACE. For more on Novo Nordisk’s CVOT plans for Ozempic, see here.

Our understanding is very much that cardiology has been more receptive to the SGLT-2 than the GLP-1 class – and even the former remains underutilized for CV risk reduction (see Dr. Kosiborod, above). We’ve observed that cardiologists find SGLT-2s easier to prescribe than injectable GLP-1s (thought leaders consistently emphasize at cardiology meetings how simple the GLP-1 injection process is), and we also sense that the field has found consistent CVOT results for SGLT-2s somewhat more compelling. We’re glad to see Novo Nordisk continue to target the cardiology community on its mission to get GLP-1s to more patients with CVD who could benefit from them.

Sanofi/Regeneron

Sanofi/Regeneron had a well-sized booth at AHA 2018, with much of the focus on PCSK9 inhibitor Praluent (evolocumab). Praluent’s dosing flexibility was featured prominently throughout the booth, as the companies highlighted that Praluent is the only agent in the (two-member) class to offer two levels of efficacy at varying doses. Regarding patient access to Praluent, representatives in the booth explained that patients can qualify for a $0 copay card for Praluent – however, we do note that this only applies to patients on commercial insurance plans, and not those who are insured through Medicare or Medicaid or are uninsured. Access for PCSK9s continues to be a major point of discussion for both Sanofi/Regeneron and Amgen, especially in light of Amgen’s recent list price cut for Repatha. On this front, however, we imagine that the just-presented cost-effectiveness analysis for Praluent, based on ODYSSEY Outcomes data, will help with identifying patients who can benefit most from this therapy while also increasing justification for broader uptake of PCSK9s in this group.

Next-gen basal insulin Toujeo (insulin glargine) and combination therapy Soliqua (insulin glargine/lixisenatide) were also displayed on hovering screens above the booth, which was great to see; however, it was clear that these products weren’t the focus of the booth’s messaging efforts.

-- by Ann Carracher, Martin Kurian, Peter Rentzepis, Payal Marathe, and Kelly Close