Immune Checkpoints Inhibitors and Diabetes: A Meta-Analysis of Randomized Controlled Trials

Background: Immune checkpoint inhibitors (ICI) exert their therapeutic effect by modulating the immune system and potentiating antitumor immune. ICI have been associated to several immune-related adverse events, such as diabetes. However, no formal metanalysis with this respect has been conducted so far. Aim of the present metanalysis of randomised 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 hyperglycaemia, reported as adverse event. Mantel-Haenszel Odds Ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes. Findings: Out of 42 trials retrieved, 40 reported information on incident diabetes or hyperglycaemia. 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 hyperglycaemia (MH-OR 1.45 [0.99, 2.13], p=0.060), which reached statistical significance in sensitivity analyses and when analysing 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 hyperglycaemia, and an increase in the risk of diabetes cannot be excluded. Clinical Registration: The study has been registered on PROSPERO website (CDR133927). Funding Statement: No funding was received for this study. Declaration of Interests: MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; LN has no conflicts of interest; ID has received speaking fees from Novonordisk; BN is presently employee of Novo Nordisk; GS has received speaking fees from Novo Nordisk, Merck Sharp & Dohme, Sanofi, Boehringer Ingelheim, Eli Lilly, Astra Zeneca, L-Nutra, Theras, Sanofi, Mundipharma, Omikron, and Novartis, and consultancy fees from Servier, Novo Nordisk, Boehringer Ingelheim, Eli Lilly, Astra Zeneca, Merck Sharp & Dohme, Sanofi, Amgem and GlaxoSmithKline; EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. Ethical Approval Statement: Not required.