Effects of food on pharmacokinetics and safety of metformin hydrochloride tablets: A meta-analysis of pharmacokinetic, bioavailability, or bioequivalence studies.

Background: The effects of food on the pharmacokinetics and safety of metformin hydrochloride (MH) are unclear. Objective: To discover the effects of food on the pharmacokinetics and safety of MH, and its influence factors. Methods: English and Chinese databases, and grey (unpublished) literature were searched for eligible studies (registration No. CRD 42022321067 in PROSPERO network). The summary weighted mean difference for continuous variables, and the risk ratio for dichotomous variables was calculated for the main pharmacokinetic parameters. Heterogeneity among the included studies was analyzed using the I2 test. Subgroup analyses, meta-regression, sensitivity analysis, and publication bias test were conducted. Results: Fourteen clinical trials were included, comprising 408 participants. The pooled AUC0→t, AUC0→∞, and Cmax were decreased by about 30.21% (I2 = 16.7%, p = 0.276), 28.00% (I2 = 73.6%, p < 0.001), and 40.38% (I2 = 92.8%, p < 0.001). Tmax was delayed by about 29.42% (I2 = 45.1%, p = 0.034). Subgroup analysis and meta-regression analysis revealed dosage of MH and gender composition as two significant sources of heterogeneity in AUC0→∞ and Cmax. Sensitivity analysis indicated that most of results were stable. The Egger's regression test and the Begg test (p > 0.05) confirmed that there is no publication bias. Conclusions: Pharmacokinetics parameters of MH were affected by food. High-fat, high-calorie diet lowered the extent and rate of absorption while slowing the absorption of metformin. These findings suggest that it is necessary to increase the dosage of MH in order to maintain the same treatment effect when administration of MH after a high fat, high calorie diet.