Immune checkpoints inhibitors and hyperglycemia. A Meta-analysis of randomized controlled trials

Background: Immune checkpoint inhibitors (ICI) exert their therapeutic effect by modulating the immune system and potentiating antitumor immunity. ICI have been associated with several immune-related adverse events, such as diabetes. However, no formal metaanalysis with this respect has been conducted so far. Aim of the present metaanalysis of randomized trials is to assess the effects of ICI on incident diabetes and hyperglycemia. Methods: A MEDLINE, Scopus, ISI-WOS, and Cochrane database search was performed to identify trials, enrolling patients with any form of cancer, up to April 23rd, 2019 in which ICI have been compared either with placebo or active comparators. Data were extracted from published reports or, if not available, from clinicaltrials.gov. The principal endpoints were the incidence of diabetes and cases of hyperglycemia, reported as adverse events. Mantel-Haenszel Odds Ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes. The study has been registered on PROSPERO website (CDR133927). Findings: Out of 42 trials retrieved, 40 reported information on incident diabetes or hyperglycemia. No association of ICI with incident diabetes (MH-OR 1.27 [0.66, 2.43], p = 0.47) was observed; whereas there was a trend toward an increased risk of hyperglycemia (MH-OR 1.45 [0.99, 2.13], p = 0.060), which reached statistical significance in sensitivity analyses and when analyzing separately placebo-controlled trials (MH-OR 1.95 [1.10, 3.49], p = 0.020). I2 statistics did not suggest any relevant heterogeneity for all the principal analyses performed. Interpretation: ICI treatment is associated with an increased risk of hyperglycemia, and an increase in the risk of diabetes cannot be excluded.