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

Abstract

Introduction: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: Diabetes; Efficacy; Metformin; Polycystic ovarian syndrome; Side effects.

Fig. 1

Effect of metformin formulations (met-XR, met-IR and met-DR) upon mean fasting plasma glucose concentrations (mg/dl) measured at the start and at the end of the study. Metformin doses range between 600 mg per day to 2000 mg. Summary measures expressed as doses between 1000 and 1500 mg per day. Mean difference and 95% confidence intervals

Fig. 2

Meta-regression of the effect of metformin formulations (met-XR, met-IR and met-DR) upon the change in fasting plasma glucose concentrations

Fig. 3

Effect of metformin formulations (met-XR, met-IR and met-DR) upon mean HbA1c concentrations (%) measured at the start and at the end of the study. Metformin doses range between 600 mg per day to 2000 mg. Summary measures expressed as doses between 1000 and 1500 mg per day. Mean difference and 95% confidence intervals

Fig. 4

Effect of metformin formulations upon a mean body weight (kg) and b mean BMI (kg/m²). Only comparisons available were met-XR versus met-IR. Mean difference and 95% confidence intervals

Fig. 5

Effect of metformin formulations upon overall gastrointestinal side effects in a met-XR versus met-IR, b met-DR vs. met-IR and c met-DR versus met-XR. Odds ratio and 95% confidence interval