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 extendedrelease 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.

An Update to the Article “Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis”

“…This is an updated version of Fig. 5a within our previous publication [2], now including additional data from the study by Fujioka et al [4] that has not previously been published but was subsequently made available outside of our pre-specified search strategy by kind permission of Merck Healthcare KGaA. The addition of this extra data does not alter the substantive conclusions of the meta-analysis previously presented.…”

“…To tackle this evidence gap, we recently performed a systematic review and meta-analysis of all studies that compared different formulations of metformin, i.e. immediate release (IR), sustained release (also known as long-acting or extended release; XR), or delayed release (DR) [2]. Delayed release metformin is a new formulation, with all global rights owned by Anji Pharmaceuticals; it is currently available only to participants in clinical studies.…”

“…Prior Presentation. This editorial is based on work that has been previously presented/published [2].…”

“…Data Availability. All data generated or analyzed during this study are included in our previously published article/as supplementary information files [2].…”

Commentary: In Utero Exposure to Metformin Reduces the Fertility of Male Offspring in Adulthood

“…In general, and as reported in the Faure et al references, metformin is usually used at doses of approximately 20 to 30 mg/kg in humans for the treatment of diabetes or polycystic ovary syndrome (PCOS), both conditions being associated with female infertility and several pregnancy complications. Pregnant women affected by obesity, diabetes and/or PCOS have an increased risk for the hypertensive disorders of pregnancy, including preeclampsia, and metformin can reduce such risk (3,4). A recent systematic review of human studies demonstrates that metformin mediates several molecular pathways implicated in the pathogenesis of pre-eclampsia and intrauterine growth retardation (5).…”