Glucose-lowering Drugs and Hospitalization for Heart Failure: A Systematic Review and Additive-effects Network Meta-analysis with More Than 500 000 Patient-years

Abstract

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2is) prevent hospitalization resulting from heart failure (HHF). However, patients with type 2 diabetes mellitus use multiple antihyperglycemic drugs to achieve glycosylated hemoglobin (HbA1c) targets. In these drug combinations, the risk of HHF is unpredictable and so is the parallel effect of glucose-lowering. Purpose: To examine the impact of antihyperglycemic drugs and their association on HHF. Data Sources: Forty randomized controlled trials (RCTs) reporting HHF. Study Selection: Published RCTs were the data source. Data Extraction: Incidence rates of HHF. Data Synthesis: Random additive-effects network meta-analysis showed that metformin (P=0.55), sulfonylureas (P=0.51), glucagon-like peptide-1 receptor-agonist (P=0.16), and dipeptidyl peptidase 4 inhibitors (DPP4is; P=0.54) were neutral on the risk of HHF. SGLT2is and SGLT2is+DPP4is reduced the risk of HHF with a hazard ratio (HR) of 0.68 (95% CI, 0.60-0.76; P<0.0001) and 0.70 (95% CI, 0.60-0.81; P<0.0001), respectively. Increased risk of HHF was associated with thiazolidinediones (TZDs) as monotherapy or in combination with DPP4is (HR: 1.45; 95% CI, 1.18-1.78; P=0.0004) and 1.49 (95% CI, 1.18-1.88; P=0.0008), respectively. Regardless of the therapy, a 1% reduction in HbA1c reduced the risk of HHF by 31.3% (95% CI, 9-48; P=0.009). Limitations: There are no data to verify drug combinations available for clinical use and to discriminate the effect of drugs within each of the therapeutic classes. Conclusions: The risk of HHF is reduced by SGLT2is as monotherapy or in combination with DPP4is and increased by TZDs as monotherapy or in combination. Glucose-lowering provides an additive effect of reducing HHF.