Extended-Release Formulation of Metformin Reduces Digestive Discomfort

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Although gastrointestinal adverse events are common in patients with type 2 diabetes mellitus treated with metformin, extended-release (XR) metformin is associated with significantly fewer gastrointestinal side effects compared with immediate-release (IR) formulations, with lower incidences of diarrhea, bloating, abdominal pain, constipation and vomiting.

Metformin is considered a first-line treatment for type 2 diabetes according to the International Diabetes Federation (IDF) recommendations. The well-studied drug is known for its good metabolic control and affordable price, making it a popular treatment option worldwide, despite its known gastrointestinal side effects.

“Metformin administration may be linked to the side effects limiting its use, specifically gastrointestinal related ones, which are common and were found to affect up to 20%-30% of patients of which approximately 5% discontinued the treatment which was evaluated in a study conducted 20 years ago,” wrote a team of investigators led by Katarzyna Nabrdalik MD, PhD, associated with the Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze at the Medical University of Silesia in Poland.

To determine the link between the incidence of gastrointestinal adverse events related to metformin use among this patient population, investigators conducted a systematic review and meta-analysis of observational studies. The database search included studies published in PubMed, Web of Science, Scopus and CINAHL from inception through July 2024. Eligible studies were those that recruited patients with type 2 diabetes who were treated with metformin without concurrent glucose-lowering medications.

Investigators assessed adverse events including abdominal pain, constipation, diarrhea, bloating, nausea, vomiting and treatment discontinuation due to side effects.

Of the 7,019 publications initially identified, 211 were eligible for inclusion and 21 were ultimately analyzed. The studies included a total of 25,206 patients with a variety of ethnic backgrounds. Approximately half (45.13%) of patients were male and the mean age was 57.4 years.

The most common gastrointestinal symptoms were diarrhea (6.9%), followed by bloating (6.2%), abdominal pain (5.3%), vomiting (2.4%) and constipation (1.1%). However, the incidence of adverse events were lower among patients prescribed the XR formulation compared with the IR formulation. Currently, United Kingdom’s National Institute for Health and Care Excellence (NICE) guidelines recommend the metformin XR in patients who are intolerant to the IR version. These improvements could be due to the tablet design, which releases the drug slowly and therefore decreases gastrointestinal exposure to metformin.

The prevalence of gastrointestinal symptoms was not linked to the dosage of metformin or previous metformin therapy, age, gender and body mass index (BMI). However, previous research published by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) stated gastrointestinal symptoms are dose dependent, can improve with a reduction in dosage and should be increased as tolerated to an optimal dose for each individual patient. Investigators hypothesized that the dose of the drug and incidence of gastrointestinal adverse events could be influence by other factors such as a genetic predisposition to metformin intolerance.

The systematic review was the first to study gastrointestinal adverse events among this patient population and use observational data to complement previous meta-analysis.

“Observational studies offer an expanded purview of real-world clinical outcomes, capturing a diverse range of patients often excluded from randomized controlled trials (RCTs) due to stringent inclusion and exclusion criteria,” investigators said. “This is particularly relevant given the routine practice of ‘run-in’ periods in RCTs, which effectively screen out participants who do not initially tolerate the drug, thus potentially underrepresenting the true incidence of gastrointestinal adverse events in the general population of patients with type 2 diabetes.”