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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 HbA1c 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 HbA1c ≥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 HbA1c, 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 HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1cconcentrations 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 ). HbA1c 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 HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF. Funding: Novartis.


Mary MacKillop Institute for Health Research

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