Effect of sacubitril/valsartan and ACEI/ARB on glycaemia and the development of diabetes: a systematic review and meta-analysis of randomised controlled trials
Authors: Wang Ruxin , Ye Haowen , Zhao Yongting , Wei Jinjing , Wang Ying , Zhang Xiaofang , Wang Lihong 
Published: December 2022

Abstract
Background
Sacubitril/valsartan and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) therapies were reported to affect glycaemic control and the development of diabetes mellitus (DM), but the findings are inconsistent. We examined the evidence for the effects of sacubitril/valsartan and ACEI/ARB in DM by conducting a meta-analysis.

Methods
The Cochrane Central Register of Controlled Trials (The Cochrane Library), Embase, PubMed, and ClinicalTrials.gov were searched for data from randomised clinical trials (RCTs) that evaluated the efficacy of sacubitril/valsartan and ACEI/ARB in patients, as of May 25, 2022. Patients were grouped by their disease background at baseline. The main outcomes were the number of new-onset DM and hypoglycaemia, elevated glycaemia, inadequate DM control, diabetes treatment, and diabetic complications, from baseline to the end of the trials. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (ROB 2). The quality of the evidence was evaluated according to the Recommendations for Assessment, Development, and Evaluation guidelines. The meta-analysis of the incidence of various outcomes was conducted using fixed or random effects models. The results are expressed as binary risk, 95% confidence interval (CI), and relative risk (RR). The Mantel-Haenszel method and Z test were used to determine the overall results and determine the significance of the RR.

Results
This study included 31 RCTs and 86,809 subjects. Compared with placebo, sacubitril/valsartan treatment significantly reduced the risk of new-onset DM among all patients (RR = 0.78, 95% CI: 0.64–0.95), patients with heart failure (HF) (RR = 0.24, 95% CI: 0.12–0.48), HF with reduced ejection fraction (HFrEF) (RR = 0.24, 95% CI: 0.12–0.50), and HF with preserved ejection fraction (HFpEF) (RR = 0.54, 95% CI 0.34–0.85). In contrast, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among all patients (RR = 1.91, 95% CI: 1.05–3.47), patients with not all-DM (defined as part of the study population having DM at baseline) (RR = 5.71, 95% CI: 2.02–16.21), and patients with HFpEF (RR = 7.06, 95% CI: 2.10–23.76). Compared with ACEI/ARB, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among patients with HF (RR 1.85, 95% CI 1.12–3.06, p = 0.02) and HFpEF (RR 3.59, 95% CI 1.51–8.55, p = 0.004). Compared with placebo, ACEI/ARB treatment did significantly reduce the risk of new-onset DM among all patients (RR 0.85, 95% CI 0.77–0.93, p = 0.0007) and patients with not all-HF (defined as part of the study population having HF at baseline) (RR 0.87, 95% CI 0.82–0.93, p<0.0001) and HFpEF (RR 0.60, 95% CI 0.44–0.83, p = 0.002), diabetes complications among patients with non-HF (/not all-DM) (RR 0.87, 95% CI 0.76–0.99, p = 0.04), and subsequent diabetes treatment among patients with new-onset DM (RR 0.70, 95% CI 0.58–0.84, p = 0.0002) and significantly increased the risk of hypoglycaemia among patients with not all-DM (RR 2.06, 95% CI 1.172–3.61, p = 0.01).

Conclusions
The results of our study, especially in reducing glycaemia and new-onset DM, revealed that sacubitril/valsartan had a positive effect on the control of glycaemia and the development of DM. ACEI/ARB also had a beneficial effect but the effect was weaker than that of sacubitril/valsartan. The above effects varied across diseases but the evidence was strongest in patients with HF.

Trial registration
CRD42022336311.