Spotlight on SGLT-2 inhibitors and heart failure
The effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on heart failure, in patients with and without diabetes, were the focus of three analyses published in the past month, two on dapagliflozin and one on canagliflozin.
Several recent industry-funded studies looked at the effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors as treatment for heart failure.
The DAPA-HF study, published by the New England Journal of Medicine on Sept. 19, was a phase 3 trial of 4,744 patients with New York Heart Association (NYHA) class II, III, or IV heart failure and an ejection fraction of 40% or less, 45% of them with type 2 diabetes. They were randomized to either dapagliflozin, 10 mg/d, or placebo in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in IV therapy for heart failure) or cardiovascular death. After a median of 18.2 months, the composite outcome had occurred in significantly fewer patients in the intervention group (16.3% vs. 21.2%; hazard ratio [HR], 0.74 [95% CI, 0.65 to 0.85]; P<0.001), as had each of the individual component outcomes. The number needed to treat to prevent one event was 21. Results were similar in patients with or without diabetes. The study supports previous evidence that SGLT-2 inhibition has beneficial effects on heart failure through mechanisms other than glucose lowering, the authors said. The study's limitations included having few patients who were black or elderly with multiple comorbidities. An accompanying editorial said that more data is also needed in patients with more severe heart failure and those taking sacubitril-valsartan. There are also barriers to putting the study's findings into practice, including concerns about polypharmacy, cost and administrative barriers, and the intimidating complexity and variety of new diabetes medication classes, the editorial noted.
The DEFINE-HF trial, published by Circulation on Sept. 16, included 263 patients with an ejection fraction of 40% or less, NYHA class II or III heart failure, and elevated natriuretic peptides, 62% of them with type 2 diabetes. They were randomized to dapagliflozin, 10 mg/d, or placebo for 12 weeks. The study's primary outcomes were 1) mean N-terminal pro b-type natriuretic peptide (NT-proBNP) and 2) proportion of patients with a five-point increase in heart failure health status on the Kansas City Cardiomyopathy Questionnaire or at least a 20% decrease in NT-proBNP. At both six and 12 weeks, there was no difference between groups in the first outcome. However, at 12 weeks, the dapagliflozin group did better on both components of the second outcome: 42.9% versus 32.5% (adjusted odds ratio [OR], 1.73; 95% CI, 0.98 to 3.05) and 44.0% versus 29.4% (adjusted OR, 1.9; 95% CI, 1.1 to 3.3), respectively. Results were similar in patients with or without diabetes and among other studied subgroups. The trial may not have had sufficient power to find a difference on the first outcome, study authors said. Strengths include that a substantial proportion of patients were African-American and that a third of patients were taking sacubitril-valsartan. Limitations include the lack of data on the outcomes of hospitalization and mortality and the short duration of follow-up.
A third study, published by JACC: Heart Failure on Oct. 9, explored potential mediators of the effect of canagliflozin on heart failure, using data from the CANVAS trial. Researchers measured the effect of 19 biomarkers by comparing the HRs for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. They found early changes in three biomarkers: urinary albumin/creatinine ratio, serum bicarbonate, and serum urate. An additional 11 biomarkers were identified as significant mediators based on averages after randomization: systolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, and erythrocyte concentration. The biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin/creatinine ratio maximized cumulative mediation. Some of these mediators were anticipated and some were not, according the study authors. The findings support “existing and novel hypothesized mechanisms for the prevention of heart failure with SGLT2 inhibitors,” they concluded.