SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials

Acta Diabetol. 2018 May;55(5):503-514. doi: 10.1007/s00592-018-1116-0. Epub 2018 Feb 27.

Abstract

Aims: There is concern about the infection-related safety profile of sodium-glucose co-transporter 2 (SGLT-2) inhibitors. We aimed to determine the effect of SGLT-2 inhibitors on genitourinary and other infections via systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods: We conducted a systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov to identify double-blinded RCTs enrolling ≥ 50 patients with type 2 diabetes which compared an SGLT-2 inhibitor to placebo or active comparator. Two independent reviewers extracted data and appraised study quality. Data were pooled using random-effects models.

Results: Eighty-six RCTs enrolling 50,880 patients were included. SGLT-2 inhibitors increased the risk of genital infections compared to placebo (relative risk [RR] 3.37, 95% CI 2.89-3.93, I2 0%) and active comparator (RR 3.89, 95% CI 3.14-4.82, I2 0.3%). The risk of urinary tract infection (UTI) was not increased with SGLT-2 inhibitors compared to placebo (RR 1.03, 95% CI 0.96-1.11, I2 0%) or active comparator (RR 1.08, 95% CI 0.93-1.25, I2 22%). In drug-specific analyses, only dapagliflozin 10 mg daily was associated with a significantly increased risk of UTI compared to placebo (RR 1.33, 95% CI 1.10-1.61, I2 0%). SGLT-2 inhibitors were associated with a reduced risk of gastroenteritis (RR 0.38, 95% CI 0.20-0.72, I2 0%) but did not affect the risk of respiratory tract infections.

Conclusions/interpretation: SGLT-2 inhibitors are associated with an increased risk of genital tract infections. Although there is no association overall between SGLT-2 inhibitors and UTI, higher doses of dapagliflozin are associated with an increased risk.

Keywords: Adverse events; Infections; Sodium–glucose co-transporter 2 (SGLT-2) inhibitors; Systematic review and meta-analysis; Type 2 diabetes mellitus.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / therapeutic use
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Drug-Related Side Effects and Adverse Reactions / etiology
  • Glucosides / adverse effects
  • Glucosides / therapeutic use
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Infections / epidemiology*
  • Infections / etiology
  • Randomized Controlled Trials as Topic / statistics & numerical data*
  • Risk Factors
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors*

Substances

  • 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
  • Benzhydryl Compounds
  • Glucosides
  • Hypoglycemic Agents
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors