Lilly/BI announce real-world EMPRISE data supporting heart failure benefit with Jardiance – November 5, 2018

This morning, Lilly/BI announced initial results from the real-world EMPRISE study (n=35,000), identifying a 44% relative risk reduction in hospitalization for heart failure with Jardiance compared to DPP-4 inhibitors. These findings bolster already-strong RCT and real-world evidence in favor of a heart failure benefit with SGLT-2s.

In the EMPA-REG OUTCOME CVOT, Jardiance demonstrated a 35% risk reduction (HR=0.65, 95% CI: 0.50-0.85) on hospitalization for heart failure vs. placebo. Since then, the heart failure benefit with SGLT-2s has been extended to 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 (topline results only). 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. Also very encouraging is that, according to Brigham and Women’s Hospital’s Dr. Elisabetta Patorno, the reduction in HFF was consistent in people with type 2 regardless of history of CVD.

However, 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 were different from those who received DPP-4s in some way that cannot be controlled for. We’re very interested to learn 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. Presumably, propensity score matching was used in EMPRISE, though we couldn’t find any info on this point. Additionally, it is somewhat limiting that EMPRISE examines only US patients.

EMPRISE considered data from US patients from August 2014 to September 2016. According to Lilly/BI, the study is meant to assess the first five years of Jardiance use (2014-2019) and eventually include >200,000 people, so these are preliminary results. Patients from both Medicare and two commercial systems are/will be included.

Safety data will be presented in the future but aren’t yet available. Of course, we’ll be most interested in data on amputation risk. To our knowledge, the CVD-REAL dataset hasn’t yet been used to examine amputations – Dr. Mikhail Kosiborod emphasized at ACC 2018 that this must be undertaken with a great deal of care. However, J&J’s real-world EASEL study found an increased risk of amputations with all SGLT-2s (as did an independent Karolinska study, presented at ESC 2018), while J&J’s subsequent, larger OBSERVE-4D study did not. These studies also identified CV benefit with SGLT-2s. The question of amputations and SGLT-2s remains very much open, and it is somewhat difficult to imagine real-world data definitively providing an answer.

EMPRISE results will be presented at AHA 2018 in Chicago, which kicks off this Saturday, November 10.

Heart Failure and SGLT-2 Inhibitors

• In the wake of SGLT-2 CVOTs, heart failure has emerged as one of the most exciting disease areas to benefit from this class of agents. As Dr. Mikhail Kosiborod outlined at CODHy 2018 in Tel Aviv, heart failure with preserved ejection fraction (HFpEF) – which is associated with adiposity and insulin resistance – remains a significant area of unmet need. Despite the fact that HFpEF has become more common than heart failure with reduced ejection fraction (HFrEF) – which involves a decreased cardiac output following myocardial insult – most HF therapies continues to target the myocardium. HFpEF, in contrast, is a systemic disease and less responsive to traditional heart failure therapies. Lilly/BI note that ~50% of people with heart failure die within five years, and heart failure is the most common cause of hospitalization among those over 65 years old. Roughly half of people with heart failure have diabetes, and ~26 million people worldwide have chronic heart failure. The hope for SGLT-2 inhibitors, then, is not just that they effectively reduce heart failure hospitalizations and death, but that they more specifically improve outcomes for people with HFpEF. To this end, both Lilly/BI and AZ have initiated dedicated outcomes trials in both types of heart failure. For Jardiance, the EMPEROR-Reduced and EMPEROR-Preserved studies are enrolling people with and without diabetes, as are the Dapa-HF (HFrEF) and DELIVER (HFpEF) trials for AZ’s Farxiga. Moreover, Sanofi/Lexicon have initiated SOLOIST-WHF, investigating SGLT-1/2 dual inhibitor sotagliflozin in those with type 2 diabetes and worsening heart failure. All five trials are scheduled to complete between December 2019 and June 2021. J&J has not expressed interest in a dedicated heart failure trial for Invokana but has noted to us that CREDENCE included heart failure as an endpoint. With these investigations, people with heart failure – with and without diabetes – could gain a highly effective new treatment to reduce the morbidity and mortality associated with heart failure.

--by Ann Carracher and Kelly Close