Adverse effects of metformin

Gastrointestinal

The most common side effects of metformin are nausea, diarrhea, and abdominal discomfort. Many patients (20–30%) report experiencing at least one of these side effects.19 The gastrointestinal side effects will be less impactful if metformin is taken with a meal and the dose is titrated gradually. Metformin therapy could be initiated at a low dose of 500 mg twice daily and increased by 500 mg daily every 1–2 weeks until the patient reaches the maximum tolerated dose. For those that are unable to tolerate the gastrointestinal (GI) side effects associated with the standard immediate-release formulation, extended-release tablets are available.1 While most patients either tolerate the side effects or switch to the slow-release option, approximately 5% discontinue the drug due to severe GI distress.16 The exact mechanisms of action which result in the common GI side effects are currently unknown. Possible mechanisms may be related to high concentrations of metformin within the GI tract, an increase in serotonin within GI cells, or metformin’s effect on the gut microbiome, leading to opportunistic infections.16,20 Furthermore, it has been proposed that an individual’s unique microbiome might influence metformin tolerance.17,20 Metformin’s relationship with the gut microbiome continues to be a topic of scientific interest.

Lactic acidosis

While the association between metformin and lactic acidosis is notably less significant compared with other biguanides, there is still a slight risk of developing lactic acidosis while taking metformin. Lactic acidosis affects 3–10 per 100,000 persons per year in patients taking metformin.21 Originally, it was thought that people with renal impairment could not take metformin due to an increased risk of developing this potentially lethal side effect. However, in 2016, the FDA deemed the drug safe for people with mild-to-moderate kidney impairment.22 Most current evidence suggests that even in patients with contraindications such as in renal, hepatic, or cardiac failure, lactic acidosis associated with metformin use is considered extremely rare.11

Vitamin B12 deficiency

Malabsorption of vitamin B12 is also linked to metformin use. Several studies have found low vitamin B12 levels in patients taking metformin.1 The major concern with this side effect is its possible association with irreversible neurological consequences.23 Low levels of vitamin B12 could potentially lead to an increased prevalence of peripheral neuropathy.23 As a precaution, regular testing of vitamin B12 levels in patients taking metformin has been suggested.23 In patients with low levels of vitamin B12, an oral supplement may be recommended.1

Ref

Ther Adv Endocrinol Metab. 2021 Jan 13;12:2042018820980225. doi: 10.1177/2042018820980225

Should metformin remain the first-line therapy for treatment of type 2 diabetes?

Chelsea Baker 1,✉, Cimmaron Retzik-Stahr 2, Vatsala Singh 3, Renee Plomondon 4, Victoria Anderson 5, Neda Rasouli 6