By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: In type 2 diabetes mellitus patients with a higher risk of cardiovascular disease, canagliflozin lowered the risk of cardiovascular death or heart failure hospitalization. Patients with pre-existing heart failure may experience even greater benefit.

SOURCE: Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus: Results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018; Mar 11. pii: CIRCULATIONAHA.118.034222. doi: 10.1161/CIRCULATIONAHA.118.034222. [Epub ahead of print].

There is growing evidence of an association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and improved cardiovascular outcomes in diabetic patients. These benefits may be even more pronounced for patients with pre-existing cardiovascular conditions such as heart failure (HF) in whom the risk of adverse cardiovascular events is particularly high. However, few investigators have compared the relationship between SGLT2 inhibitors and cardiovascular events in patients with pre-existing HF vs. those without HF.

The authors of the Canagliflozin Cardiovascular Assessment Study (CANVAS) randomized 10,142 patients with type 2 diabetes mellitus (T2DM) to the SGLT2 inhibitor canagliflozin to placebo. During a mean follow-up of 188 weeks, canagliflozin was associated with a reduced risk of HF hospitalization. In this secondary analysis, Rådholm et al evaluated the association between canagliflozin and the combined outcome of cardiovascular death or hospitalized HF. Also, they compared the effects of canagliflozin in the 14.4% of patients with pre-existing HF to those without HF.

In the overall population, canagliflozin was associated with a reduced risk of cardiovascular death or hospitalized HF (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.91). The observed benefit was even greater among patients with a history of HF (HR, 0.61; 95% CI, 0.46-0.8; P = 0.021 for the comparison to those without HF). Canagliflozin is associated with increased risks of amputation, fracture, and volume depletion. However, this risk was not higher in patients with HF compared to those without. The authors concluded that among patients with T2DM and elevated risk of cardiovascular disease, canagliflozin reduces the risk of cardiovascular death or HF hospitalization. Further, the benefits may be greatest in patients with baseline HF.

COMMENTARY

T2DM and HF coexist frequently. No previous class of glucose-lowering therapy has been shown to reduce the risk of HF hospitalization in this population. The EMPA-REG OUTCOME trial was the first to show a reduction in HF hospitalization with an SGLT2 inhibitor (empagliflozin). The magnitude of the observed benefit was surprising to many observers, but data from CANVAS and a recent large retrospective study have added support for the HF-related benefits of SGLT2 inhibitors. Using data from a large, rigorous, international, clinical trial, Rådholm et al have shown that canagliflozin substantially lowers the risk of a meaningful outcome (cardiovascular death or hospitalized HF). Furthermore, patients with pre-existing HF may derive even greater benefit. The observed HR of 0.61 among patients with pre-existing HF is comparable to long-standing, guideline-recommended therapies for chronic HF. SGLT2 inhibitors produce many cardiovascular effects. The exact mechanism by which they improve outcomes is not understood fully. In CANVAS, the benefits of canagliflozin were observed early, suggesting a hemodynamic or volume-related effect. SGLT2 inhibitors induce natriuresis and osmotic diuresis, lower blood pressure, and reduce arterial stiffness. Longer-term, SGLT2 inhibitors produce anti-atherosclerotic effects and affect cardiac metabolism favorably.

It is important to note that adverse events were no more frequent in HF patients compared to the general population. With everything considered, the growing evidence supporting HF-related benefits of SGLT2 inhibitors makes this a compelling therapy to offer patients with HF and diabetes. There was no left ventricular ejection fraction criteria for defining the HF population within CANVAS. Therefore, it is reasonable to consider SGLT2 inhibitors in patients with HF and preserved ejection fraction (in whom diabetes is common and few effective therapies exist) in addition to those with systolic HF.

The story of SGLT2 inhibitors for reducing cardiovascular outcomes still is in its early stages. The Rådholm et al study was a secondary analysis; therefore, it must be interpreted with caution. With only 14% of the total study population in the HF group, we cannot draw firm conclusions regarding the increased benefit among HF patients. There are multiple ongoing trials that will help us understand the mechanism by which these agents exert their benefit and to identify the patients who will benefit most. There are even trials underway evaluating the benefit of SGLT2 inhibitors in patients with HF but not diabetes. For now, these agents should be strongly considered in diabetic patients with HF (or other cardiovascular disease). Cardiovascular practitioners who are not comfortable prescribing drugs for treatment of diabetes can suggest these agents to their patients’ primary care providers or endocrinologists, highlighting the cardiovascular benefits.