Risk of any hypoglycaemia with newer antihyperglycaemic agents in patients with type 2 diabetes: A systematic review and meta-analysis

Objectives: For patients with type 2 diabetes, newer antihyperglycaemic agents (AHA), including the dipeptidyl peptidase IV inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium glucose co-transporter 2 inhibitors (SGLT2i) offer a lower risk of hypoglycaemia relative to sulfonylurea or insulin. However, it is not clear how AHA compare to placebo on risk of any hypoglycaemia. This study evaluates the risk of any and severe hypoglycaemia with AHA and metformin relative to placebo.

Design: A systematic review and meta-analysis was conducted of randomized, placebo-controlled trials ≥12 weeks in duration. MEDLINE, Embase and the Cochrane Library were searched up to April 16, 2019. Studies allowing use of other diabetes medications were excluded. Mantel-Haenszel risk ratio with 95% confidence intervals were used to pool estimates based on class of AHA and number of concomitant therapies used.

Patients: Eligible studies enrolled patients with type 2 diabetes ≥18 years of age.

Results: 144 studies met our inclusion criteria. Any hypoglycaemia was not increased with AHA when used as monotherapy (DPP4i (RR 1.12; 95% CI 0.81-1.56), GLP1RA (1.77; 0.91-3.46), SGLT2i (1.34; 0.83-2.15)), or as add-on to metformin (DPP4i (0.95; 0.67-1.35), GLP1RA (1.24; 0.80-1.91), SGLT2i (1.29; 0.91-1.83)) or as triple therapy (1.13; 0.67-1.91). However, metformin monotherapy (1.73; 1.02-2.94) and dual therapy initiation (3.56; 1.79-7.10) was associated with an increased risk of any hypoglycaemia. Severe hypoglycaemia was rare not increased for any comparisons.

Conclusions: Metformin and the simultaneous initiation of dual therapy, but not AHA used alone or as single add-on combination therapy, was associated with an increased risk of any hypoglycaemia relative to placebo.