CANVAS Analysis Provides Heart Failure Reassurances for Canagliflozin

ORLANDO, FL—Patients with type 2 diabetes and an increased risk of cardiovascular disease treated with a sodium cotransporter-2 (SGLT-2) inhibitor had a significantly reduced risk of heart failure when compared with patients treated with placebo, a new analysis shows.  

Moreover, the benefit of canagliflozin (Invokana; Janssen) appeared to be greatest among individuals at highest risk, specifically diabetic patients with a prior history of heart failure.

Gemma Figtree, MBBS (Royal North Shore Hospital, St. Leonard’s, Australia), who presented the results at the American College of Cardiology (ACC) 2018 Scientific Session, said that in those with a history of heart failure, physicians “can be reassured that there is certainly no worse effect with canagliflozin in those patients and the effect might possibly be greater in these individuals.” 

Heart failure, she added, “is a major problem for our patients with diabetes,” and is largely attributed to macrovascular and microvascular dysfunction, volume overload, impaired renal function, and the direct effects of insulin resistance on cardiac myocytes, she said.

Moreover, there are risks of heart failure with antidiabetic medications, particularly thiazolidinediones and dipeptidyl peptidase-4 (DPP-4) inhibitors. In 2016, the US Food and Drug Administration added a warning about the risks of heart failure, particularly in patients with cardiovascular and renal disease, to the label of saxagliptin (Onglyza; AstraZeneca) and alogliptin (Nesina; Takeda).

The results of the analysis were published simultaneously March 11, 2018, in Circulation to coincide with the ACC presentation.  

Heart Failure: a Deep Dive

In CANVAS, which was published last year in the New England Journal of Medicine, treatment with canagliflozin reduced the risk of cardiovascular events and slowed renal decline, but was associated with a twofold increased risk of amputations, primarily of the toe or metatarsal.

During the featured clinical research session, Figtree took a deeper dive into the heart failure data. The study included 1,461 patients with heart failure at baseline and 8,681 patients without heart failure. Those with heart failure were more frequently women, white, hypertensive, and had a history of prior cardiovascular disease. They were also more likely to be treated with inhibitors of the renin angiotensin aldosterone system, diuretics, and beta-blockers.

Overall, treatment with canagliflozin (Invokana, Janssen Pharmaceuticals) reduced the risk of cardiovascular mortality and heart failure hospitalizations by 22% compared with placebo-treated patients, as well as reduced the risk of fatal or hospitalized heart failure by 30%. The event curves for the primary endpoint of cardiovascular death or hospitalized heart failure “diverged very early on,” said Figtree. “A similar pattern was observed for fatal or hospitalized heart failure.”

The benefit of canagliflozin appeared to be stronger in patients with prior heart failure. Among these patients, there was a 39% reduction in the risk of cardiovascular mortality or heart failure compared with a 13% reduction in patients without heart failure at baseline (P = 0.021 for interaction). For those with heart failure treated with canagliflozin, there were 106.97 fewer primary endpoint events per 1,000 patient-years compared with placebo-treated patients. Among those without heart failure, there were 8.36 fewer primary endpoint events per 1,000 patient-years (P = 0.003 for interaction). 

“The key point, which we know clinically, is that a person with a history of heart failure is much more likely to have an event,” said Figtree. “So the absolute event rate was much higher, such that by the end of the follow-up period over 25% had had an event in the placebo group.”

In further subgroup analyses, the researchers did not observe any significant interactions, with canagliflozin reducing the risk of cardiovascular mortality and heart failure hospitalizations in those with renal disease, atrial fibrillation, and those treated with different background medications, among others.

CVD-REAL 2 Study

In addition to the CANVAS analysis, Mikhail Kosiborod, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), presented a real-world look at more than 400,000 patients treated with SGLT-2 inhibitors in South Korea, Japan, Israel, Australia, and Canada. In the analysis, 75% of patients were treated with dapagliflozin (Farxiga; AstraZeneca), 9% with empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), 8% with ipragliflozin (Suglat; Astellas/Kotobuki Pharmaceuticals), and 4% with canagliflozin.

Overall, treatment with an SGLT-2 inhibitor as compared with any other glucose-lowering agent reduced the risk of heart failure hospitalization by 28%, all-cause mortality by 53%, MI by 13%, and stroke by 15%.

Speaking during the session, Kosiborod said previous analysis of the SGLT-2 inhibitors largely involved US and European subjects and focused on primarily on all-cause mortality and heart failure outcomes. “There are important differences in patient characteristics, treatment patterns, and types of adverse cardiovascular events experienced by patients in these [different] regions,” he said. “As an example, stroke is much more common in Asia.”    

Photo Credit: © ACC/Luke Franke 2018. Used with permission.