Lilly/BI announce topline results from EMPA-REG OUTCOME demonstrating CV risk reduction with Jardiance (empagliflozin) – August 20, 2015

Lilly/BI announced topline results today from the EMPA-REG OUTCOME cardiovascular outcomes trial (CVOT) demonstrating cardiovascular risk reduction with their SGLT-2 inhibitor Jardiance (empagliflozin) compared to placebo in high-risk patients with type 2 diabetes. EMPA-REG OUTCOME is the first CVOT for an SGLT-2 inhibitor to report results and the first CVOT for any type 2 diabetes drug to demonstrate cardioprotection. Full results will be presented on September 17 at EASD. The trial involved 7,034 patients with type 2 diabetes and high cardiovascular risk, had a median duration of 3.1 years, and had a standard primary composite endpoint of cardiovascular death, non-fatal MI, and non-fatal stroke. While the majority of participants had fairly longstanding diabetes – 57% had a disease duration of at least 10 years – 18% of the study population had a duration of less than five years, perhaps enhancing the generalizability of the results to some extent. The press release stated that Jardiance’s safety profile was consistent with previous studies, presumably meaning there was no significant increased risk of ketoacidosis or any other unpleasant surprises with regard to the secondary endpoints. It will be very important to learn the magnitude of the effect, whether it is consistent across subgroups (especially the more recently diagnosed patients), and the degree to which it is explained by any observed changes in conventional cardiovascular risk factors, e.g. blood pressure, glycaemia, weight, lipid profiles. As well, we are interested to know more about the results for enrolled subgroups, as well as details of what endpoints are driving the result in what subpopulations. It will also be key to better understand the mechanism as well as safety and side effect profile related to DKA – many KOLs have characterized this as a manageable risk, though we don’t necessarily know the details. No matter what the magnitude, we are also keen to know what is possible to have in the PI. We’ve heard FDA wants two trials showing results before it will allow information in the PI.

While we will have to wait for the detailed results to fully understand the full implications of this striking news, these findings could potentially have an enormous impact on the treatment of type 2 diabetes. Particularly if results from the other SGLT-2 inhibitor CVOTs (CANVAS for J&J’s Invokana [canagliflozin] is expected to complete in 2017 and DECLARE for AZ’s Farxiga [dapagliflozin] in 2019) are also positive, we imagine that the class could become the standard second-line  treatment option after metformin and depending on the magnitude of CV risk reduction, possibly even first-line therapy standard of care. While we expect that most clinicians and payers will view these results as suggestive of a class effect given the homogeneity of the SGLT-2 inhibitor class, the findings should certainly help the third-to-market Jardiance pick up some steam vs. its competitors. We will be waiting on the edge of our seats for the next month for the full results! Most of all, we await news on the magnitude of the benefit; while we do not expect it to be as dramatic as that seen with drugs like statins, even a ~10% risk reduction would be very clinically meaningful given the number of patients affected. We are also very curious to see how these results influence the broader debate over the benefits and costs of the 2008 CV Guidance – read on below for more, especially on what key diabetes experts said.

• EMPA-REG OUTCOME investigated the effect of Jardiance vs. placebo, both in addition to standard of care, in ~7,000 high-risk patients with type 2 diabetes. A 2014 article in Cardiovascular Diabetology provides detailed information on the design and baseline characteristics of the study. The trial randomized 7,042 patients (7,034 of whom were treated) to receive one of two doses of Jardiance (10 mg and 25 mg) or placebo in addition to standard of care. It was an event-driven study that continued until ≥691 confirmed primary outcome events occurred (the study completed ahead of schedule due to a higher than expected event rate). Patients were followed for up to five years, with a median duration of follow-up of 3.1 years. It had 90% power to rule out a hazard ratio of 1.3 for the primary endpoint and at least 80% power to detect a 25% risk reduction. Study participants had a mean baseline A1c of 8.1%, and 57% had a duration of diabetes >10 years (18% had a duration ≤5 years). Almost all patients had a prior history of CVD and many were taking multiple glucose-lowering and cardiovascular medications (45% on multiple glucose-lowering therapies, 77% on a statin, 94% on blood pressure-lowering drugs).
• We eagerly await the EASD presentation to better understand the magnitude of the benefit and the results for the numerous secondary endpoints. Our expectation is that the effect will be relatively minor compared to the benefit with drugs like statins that target more direct CV risk factors. However, even a ~10% risk reduction would be very clinically meaningful considering the number of patients affected. Key secondary endpoints include an expanded MACE composite (including hospitalization for unstable angina), individual adverse CV events, hospitalization for heart failure, all-cause mortality, and renal outcomes. We are also very eager to see the rates of ketoacidosis given the recent concerns about this issue. While much of the concern has related to off-label use of SGLT-2 inhibitors in type 1 diabetes, this trial and others in type 2 diabetes should help to clarify whether this is a truly rare and manageable risk in this population.
• It will be interesting to see to what extent these positive results act to boost Jardiance individually relative to the SGLT-2 inhibitor class as a whole. In response to a question along these lines during Lilly’s 2Q15 update, Lilly Diabetes head Mr. Enrique Conterno suggested that a positive outcome would lift the entire class but that Jardiance would likely get some level of disproportionate benefit. Our expectation is that these results are more likely indicative of a class effect rather than a drug-specific effect given the homogeneity of the SGLT-2 inhibitor class. However, the attention surrounding the announcement should certainly help give Jardiance somewhat of a boost with clinicians and payers relative to other agents. These results do increase our confidence that the ongoing trials for Invokana and Farxiga will also produce positive results, as both programs have larger study populations and longer durations compared to EMPA-REG OUTCOME and aimed to enroll a similarly broad high-risk population – see the table below for more details.

Table 1: CVOTs for SGLT-2 inhibitors

• These results could have broader implications for type 2 diabetes treatment guidelines in the future. Particularly if the other SGLT-2 inhibitor CVOTs also report positive results, the class could become the standard second-line treatment option for type 2 diabetes (and perhaps eventually even the first-line option depending on level of magnitude – and particularly once they are generic). The situation could of course become more complicated if one of the ongoing GLP-1 agonist CVOTs also demonstrates cardioprotection – Novo Nordisk Chief Scientific Officer Dr. Mads Thomsen expressed cautious optimism during the company’s recent 2Q15 update regarding the potential for a superiority finding from the LEADER trial for Victoza (liraglutide). In the meantime, we imagine that these results will at least help SGLT-2 inhibitors continue to make gains relative to DPP-4 inhibitors, for which outcomes results have been resoundingly neutral.
• The findings add a new wrinkle to the debate over the broader costs and benefits of the 2008 CV Guidance. Proponents of the current CVOT paradigm can now convincingly argue that at least one of these trials has revealed a clinically meaningful benefit that might otherwise have remained unknown – however, we doubt it would be unknown since presumably the companies would’ve done these trials – but on their own timeline. However, for a class like the DPP-4 inhibitors for which there was little suggestion that the results would be anything other than neutral, it is far from clear that the benefit was worth the enormous investment – moreover, since safety was so key to establish, most manufacturers invested in safety, rather than both safety as well as efficacy, as has been seen with the EMPA-REG OUTCOME trial.  Our sense remains that incentivizing companies to conduct outcomes trials for drugs where there is a plausible chance of cardiovascular benefit (and of course requiring safety studies where there is a clear potential for increased risk) would be more reasonable than the current across-the-board policy for type 2 diabetes drugs.
• We consider this a very big result for EMPA as well as potentially the entire SGLT-2 class and look so forward to learning more! In the meantime, here are some views by highly regarded advisors (many more have been asked and we’ll be expanding this list:
  
  • Dr. John Buse: “At face value this is great news for people with diabetes; I cannot wait to see the full results.”
  • Dr. Dan Drucker: “Demonstration of a reduction of MACE events through addition of empagliflozin to a standard regimen of anti-diabetic agents represents a breakthrough in management of patients with type 2 diabetes with increased cardiovascular risk and resets our standards and expectations higher for the actions of newer anti-diabetic agents going forward… Your premise about first line therapy for SGLT2/empagliflozin is reasonable, and let's see the full results of the study in 5 weeks then revisit this metformin vs. SGLT2i discussion.”
  • Dr. Irl Hirsch: “It obviously is a big deal and there are some key questions…”
  • Dr. Rury Holman: "Having a second glucose-lowering drug shown to impact positively on cardiovascular risk is a pivotal result and a welcome finding for people with type diabetes."
  • Professor Philip Home: "I welcome the announcement, but can only accept it with caution without seeing the scientific basis, including numbers of events, confidence intervals, analysis of components, sight of the time-to-first-event curves, duration of exposure, participant retention and the like."

-- by Emily Regier and Kelly Close