Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis

Metformin is among the most frequently prescribed drugs worldwide for a variety of indications. Although metformin has several important advantages, for example being easy to store and administer, it is associated with a high incidence of gastrointestinal side effects. Slower-release formulations of metformin may reduce the incidence of side effects while maintaining efficacy; however, there is a lack of systematic evidence available to guide head-to-head comparisons between different metformin formulations.

PubMed, Web of Science, OVID EMBASE, MEDLINE, The Cochrane database and Clinicaltrials.gov were systematically searched (from inception to 25 January 2021). Trials that randomized adult participants to extended-release formulation of metformin (met-XR), delayed-release (met-DR) or immediate-release metformin (met-IR) were included. Two reviewers independently assessed articles for eligibility and risk-of-bias, with conflicts resolved by a third reviewer. Outcome measures were change in fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), body weight, BMI, lipid profile and side effects. Meta-analyses were conducted using random-effects models.

Fifteen studies (n = 3765) met eligibility criteria. There was no significant difference between the efficacy of met-IR, met-XR or met-DR in changing FPG (p = 0.93). A non-significant reduction in mean body weight was observed in individuals randomized to met-XR vs. met-IR (- 1.03 kg, 95% CI - 2.12 to 0.05, p = 0.06). Individuals randomized to met-XR vs. met-IR had lower low-density lipoprotein (LDL) cholesterol levels (- 5.73 mg/dl, 95% CI - 7.91 to - 3.56, p < 0.00001). Gastrointestinal (GI) side effects were markedly reduced in patients randomised to met-DR vs. met-IR (OR 0.45, 95% CI 0.26-0.80, p = 0.006).

Our results demonstrate equal efficacy of longer-acting formulations (met-XR, met-DR) versus immediate-release metformin formulations in terms of glycaemic control. There were insufficient studies available to compare the efficacy of different metformin formulations outside of diabetes care. However met-XR was associated with reduced serum LDL cholesterol concentrations, while met-DR was strongly associated with reduced GI side effects, which could improve drug compliance.