What are the side effects of Metformin (Biguanide)?

From the Guidelines

Metformin is generally well-tolerated, but it can cause gastrointestinal side effects, including bloating, abdominal discomfort, and diarrhea, which can be mitigated by gradual dose titration and/or using extended-release formulation 1. The most common side effects of metformin are gastrointestinal intolerance, which can be minimized by taking the medication with meals and starting with a low dose that gradually increases.

• Gastrointestinal side effects, such as bloating, abdominal discomfort, and diarrhea, affect a significant number of patients, but these can be reduced by using the extended-release formulation or gradual dose titration 1.
• More serious but rare side effects of metformin include lactic acidosis, which is very rare and primarily occurs when the estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m² 1.
• Long-term use of metformin may also cause vitamin B12 deficiency, and periodic testing of vitamin B12 levels is recommended 1.
• It is essential to note that metformin is contraindicated in patients with severe kidney disease, and the risk of lactic acidosis increases when the eGFR is <30 mL/min/1.73 m² 1.
• Overall, the benefits of metformin in reducing microvascular complications, cardiovascular events, and death outweigh the risks of side effects, making it a commonly used and effective medication for the treatment of type 2 diabetes 1.

From the FDA Drug Label

Metformin hydrochloride tablets can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. The following adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis, Vitamin B12 Deficiency, Hypoglycemia. Adverse reactions reported in greater than 5% of metformin hydrochloride tablets treated patients and that were more common than in placebo-treated patients, are listed in Table 1: Diarrhea 53%, Nausea/Vomiting 26%, Flatulence 12%, Asthenia 9%, Indigestion 7%, Abdominal Discomfort 6%, Headache 6%. Additionally, the following adverse reactions were reported in ≥1 % to ≤5% of metformin hydrochloride tablets treated patients and were more commonly reported with metformin hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. Common side effects of metformin hydrochloride tablets include diarrhea, nausea, and upset stomach. About 3 out of every 100 people who take metformin hydrochloride tablets have an unpleasant metallic taste when they start taking the medicine.

Metformin side effects include:

• Lactic acidosis: a rare but serious condition that can cause death
• Gastrointestinal symptoms: diarrhea, nausea, vomiting, flatulence, abdominal discomfort
• Other symptoms: asthenia, indigestion, headache, hypoglycemia, myalgia, lightheaded, dyspnea
• Common side effects: diarrhea, nausea, upset stomach, unpleasant metallic taste 2, 2, 2

From the Research

Metformin Side Effects

• The most common gastrointestinal side effects of metformin include diarrhea, nausea, abdominal pain, and bloating 3, 4, 5, 6.
• These side effects can lead to lower physical and mental health-related quality of life, and may result in patient nonadherence or physician reluctance to optimally titrate the metformin dose 5.
• The risk of gastrointestinal adverse events such as abdominal pain, nausea, and diarrhea is higher in type 2 diabetes patients treated with metformin compared to other antidiabetic drugs 3.
• There is a higher risk of bloating and diarrhea with metformin immediate-release than with metformin extended-release formulation 3, 4.
• Starting at a low dose and titrating slowly may help prevent some gastrointestinal adverse events associated with metformin, but some patients may still be unable to tolerate metformin at all 4.
• The underlying mechanisms of metformin-induced gastrointestinal intolerance are poorly understood, but may involve stimulation of intestinal secretion of serotonin, changes in incretin and glucose metabolism, and bile-salt malabsorption 6.