Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial

Abstract

Background: Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA_1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.

Methods: In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA_1c ≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA_1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups.

Findings: There were no significant differences in HbA_1c concentrations between randomised groups at screening. During the first year of follow-up, HbA_1c concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05-0·22, p=0·0023). HbA_1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06-0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56-0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58-1·02, p=0·073) in the sacubitril/valsartan group.

Interpretation: Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA_1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.

Funding: Novartis.