Effects of Sacubitril/Valsartan on Glycaemia in Patients with Diabetes and Heart Failure: The PARAGON-HF and PARADIGM-HF Trials

• Compared with enalapril, sacubitril/valsartan has been seen to lower HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial
• This analysis aimed to assess the glycaemic effects of sacubitril/valsartan across the rest of the left ventricular ejection fraction (LVEF) spectrum in heart failure and diabetes
• Sacubitril/valsartan reduced HbA1c and new insulin therapy across the LVEF spectrum

This secondary analysis pooled data from two sources. PARAGON-HF (NCT01920711) a randomised, double-blind, active controlled event driven clinical trial that compared the efficacy and safety of sacubitril/valsartan with that of valsartan in patients with symptomatic heart failure with preserved ejection fraction (HFpEF). PARADIGM-HF a randomised clinical trial that compared the efficacy and safety of sacubitril/valsartan with that of enalapril in patients with HFrEF.

• Changes in HbA1c
• New use of antihyperglycemic medications
• Hypoglycemia

• Patients were required to be ≥50 years
• Have a LVEF of at least 45% within 6 months of screening
• Have NYHA class II-IV symptoms of heart failure
• Have required diuretic therapy for at least 30 days before screening
• Have elevated levels of NT-proBNP and echocardiographic evidence of either left ventricular hypertrophy or left atrial enlargement or both
• Patients were then identified as diabetic if they had a self-reported history at screening, used antihyperglycemic medication or had HbA1c of 6.5% or higher

• Total of 4796 patients from PARAGON and 8399 from PARADIGM

• The reduction in mean HbA1c was larger in the sacubitril/valsartan group than control. Difference of -0.19% (95% confidence interval [CI] -0.25% to -0.13%, p <0.001)

• LVEF did not significantly change the treatment effect of sacubitril/valsartan on HbA1c (Pinteraction= 0.56)

• Initiation of insulin in follow-up was significantly lower in sacubitril/valsartan than control (9.3% vs. 12.4%; hazard ratio [HR] 0.75, 95% CI 0.63–0.89, P = 0.001).
• This was not significantly changed by LVEF (Pinteraction = 0.40)

• Initiation of non-insulin antihyperglycaemic medications was only numerically lower for sacubitril/valsartan vs control (11.5% vs. 14.3%; HR 0.80, 95% CI 0.64–1.01, P = 0.06)
• Not significantly modified by LVEF (Pinteraction = 0.93)

• Incidence of hypoglycaemia, in diabetics, was significantly higher in sacubitril/valsartan than control (3.3% vs. 2.5%; HR: 1.37, 95% CI 1.02–1.84, P = 0.038)

• For all patients (with or without diabetes) not taking antihyperglycaemics at baseline, there was no significant increased risk of hypoglycaemia in sacubitril/valsartan group (0.2% vs. 0.1%; HR 1.81, 95% CI 0.67–4.90, P = 0.24)

Sacubitril in combination with valsartan had small but significant reduction in HbA1c and in new use of insulin across the whole spectrum of LVEF. For clinicians, the possibility of improved glycaemic control is worth considering when starting sacubitril/valsartan in diabetics.

• The PARAGON-HF trial was not designed for the primary outcomes of this analysis
• Changes in HbA1c recorded in this study occurred on the background of external clinical decisions
• Hypoglycemia adverse events were investigator reported
• Low number of adjudicated cases of new diabetes
• No differentiation between type 1 and type 2 diabetes
• Dose adjustments and changes between antihyperglycemic medication were not analysed