Angiotensin receptor-neprilysin inhibitor reduces HbA1c levels

New analysis shows Novartis Entresto improves glycemic control in reduced ejection fraction heart failure patients with diabetes

News - Mar. 21, 2017


Many patients with heart failure (HF) also have diabetes. The prevalence of diabetes is around 35-40% in patients with HF. Diabetes is a major risk factor in HF and is strongly linked to progression of the disease.

Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI) and indicated to reduce the risk of cardiovascular death and hospitalization for heart failure (HF) in patients with chronic HF with reduced ejection fraction (HFrEF). In the PARADIGM-HF study, it showed decreased morbidity and mortality compared to the angiotensin-converting enzyme inhibitor (ACEi) enalapril. Remarkably, the number of patients with new-onset diabetes was very small during the course of the trial.

Therefore, the effect of sacubitril/valsartan on HbA1c was investigated in this post-hoc analysis of the PARADIGM-HF trial, which included 3778 HFrEF patients with diabetes or those who had baseline HbA1c ≥6.5%. Levels were measured after 1, 2 and 3 years of follow-up and compared with these of enalapril-treated patients. Furthermore, the initiation of oral antihyperglycemic or insulin therapy during the study was evaluated.

Main results

  • After 1 year, HbA1c levels were decreased by 0.26% when using sacubitril/valsartan, compared to 0.16% when using enalapril (P=0.0023).
  • No significant relationship between change in HbA1c and the composite primary outcome of cardiovascular death or first hospital admission for HF in the entire cohort of patients with diabetes (HR 0.99, 95% CI 0.91–1.06, P=0.70) was observed.
  • After 3 years, overall HbA1c levels were reduced with 0.14% with sacubitril/valsartan, compared to enalapril (95% CI 0.06-0.23, P=0.0055).
  • Insulin therapy was initiated during the study in 29% fewer patients on sacubitril/valsartan compared to enalapril (HR 0.71, 95% CI 0.56-0.90, P=0.0052).
  • Also fewer patients started oral antihyperglycaemic therapy (HR 0.77, 95% CI 0.58–1.02, P=0.073) in the sacubitril/valsartan group, however the difference did not reach statistical significance.


Treatment of HFrEF diabetes patients with sacubitril/valsartan was associated with greater reductions in HbA1c compared with enalapril treatment. Moreover, fewer sacubitril/valsartan-treated patients needed initiation of insulin therapy. These data suggest that, in addition to providing HF benefit, sacubitril/valsartan helps to tighten glycemic control among HF patients with diabetes. This beneficial metabolic effect is most likely secondary to the inhibition of neprilysin and consequent modulation of its circulating substrates and should be further investigated.


Our coverage of ACC.17 is based on the information provided during the congress.

This study was simultaneously published in The Lancet Diabetes & Endocrinology

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