Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with meta-regression of observational studies

Abstract

Introduction: Metformin is the most prescribed medication for type 2 diabetes mellitus (T2DM); there is a well-established link with the elevated incidence of gastrointestinal (GI) adverse events (AE) limiting its administration or intensification.

Objectives: The objective of this systematic review and meta-analysis of observational studies was to evaluate the pooled incidence of GI AE related to metformin use in patients with T2DM.

Materials and methods: PUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 29.07.2024 for observational studies in English describing the frequency of GI AE in patients with T2DM treated with metformin. Random-effects meta-analyses were used to derive effect sizes: event rates.

Results: From 7019 publications, we identified 211 potentially eligible full-text articles. Ultimately, 21 observational studies were included in the meta-analysis. The prevalence of GI AE was as follows: diarrhea 6.9% (95% CI: 0.038-0.123), bloating 6,2% (95% CI: 0.020-0.177), abdominal pain 5,3% (95% CI: 0.003-0.529), vomiting 2.4% (95%: CI 0.007-0.075), constipation 1.1% (95%: CI 0.001-0.100). The incidence of bloating (coefficient -4.46; p < 0.001), diarrhea (coefficient -1.17; p = 0.0951) abdominal pain (coefficient -2.80; p = 0.001), constipation (coefficient -5.78; p = 0.0014) and vomiting (coefficient -2.47; p < 0.001) were lower for extended release (XR) metformin than metformin immediate release (IR) formulation.

Conclusions: This study highlights the prevalence of GI AE in patients receiving metformin, with a diarrhea predominance, followed by bloating, diarrhea, abdominal pain, constipation, and vomiting. The incidence is lower in patients administered with XR metformin.

Trial registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975 , identifier CRD42021289975.

Keywords: Diarrhea; Dose; Formulation; Gastrointestinal adverse events; Meta-analysis; Metformin.

Fig. 1

Study flow chart

Fig. 2

Event rates for abdominal pain in patients treated with metformin

Fig. 3

Regression for ER toward abdominal pain by type of metformin

Fig. 4

Funnel plot of standard error by logit event rate for abdominal pain

Fig. 5

Event rates for bloating in patients treated with metformin

Fig. 6

Regression for ER toward bloating by type of metformin

Fig. 7

Funnel Plot of Standard Error by Logit event rate for bloating

Fig. 8

Event rates for constipation in patients treated with metformin

Fig. 9

Regression for ER toward constipation by type of metformin

Fig. 10

Regression for ER toward constipation by average HbA1c

Fig. 11

Funnel Plot of Standard Error by Logit event rate for constipation

Fig. 12

Event rates for diarrhea in patients treated with metformin

Fig. 13

Regression for ER toward diarrhea by type of metformin

Fig. 14

Funnel Plot of Standard Error by Logit event rate for diarrhea

Fig. 15

Event rates for nausea in patients treated with metformin

Fig. 16

Regression for ER toward diarrhea by type of metformin

Fig. 17

Funnel Plot of Standard Error by Logit event rate for nausea

Fig. 18

Event rates for vomiting in patients treated with metformin

Fig. 19

Regression for ER toward diarrhea by type of metformin

Fig. 20

Regression for ER toward diarrhea by average FBG

Fig. 21

Regression for ER toward diarrhea by average PBG

Fig. 22

Regression for ER toward diarrhea by average HbA1c

Fig. 23

Funnel Plot of Standard Error by Logit event rate for vomiting