Side Effects of Metformin: It's Not Just a Nocebo Effect?

Introduction

Metformin is one of the most widely used oral antidiabetic drugs, and due to its pleiotropic effects, it is appreciated not only in the treatment of type 2 diabetes. Off-label, it is also used for other conditions, such as polycystic ovary syndrome, metabolic syndrome, or prediabetes.

However, its use can be associated with gastrointestinal and other side effects that make it unusable for 10-20% of patients and can limit the maximum dose for others. The most common complaints from patients include flatulence, dyspepsia, vomiting, and abdominal discomfort. Given the number of patients who can significantly benefit from metformin, understanding these phenomena and managing them is crucial.

Study Objectives

A study published by authors from Weill Cornell Medical College in New York posed interesting questions. To what extent are side effects reproducible? Is the nocebo effect involved? Is intolerance to metformin partially due to its reputation?

To clarify this topic, American researchers conducted a double-blind crossover study on a cohort of patients with a history of intolerance to immediate or extended-release metformin. For the purposes of the study, intolerance was defined as the inability to take metformin or to take a daily dose > 1000 mg despite a doctor's recommendation.

Patients were to take escalating doses of extended-release metformin alternating with placebo, in addition to their baseline medication, and regularly complete questionnaires focused on treatment satisfaction, adherence, and the intensity of side effects. Special attention was given to gastrointestinal effects, which were assessed thoroughly and separately.

Results

Patients indeed reported the presence of side effects, but the results of analyzing their questionnaires were ultimately inconclusive. While exposure to the active ingredient was significantly associated with the patients' reported therapeutic effect (39.42 vs. 51.92; p < 0.05), it was not associated with side effects. Although patients reported lower overall satisfaction scores when unknowingly taking metformin (39.58 vs. 53.75; p < 0.05), the intensity of gastrointestinal or other side effects they reported was not associated with the treatment. In practice, they were unable to distinguish whether they were taking metformin or placebo. Two out of ten participants were able to continue taking metformin despite previous intolerance after the study ended.

Conclusion

This study demonstrated how difficult it is to grasp the side effects of metformin and sometimes raises genuine doubts. Given the clear benefit, it is worth giving patients time to get used to the medication or to work towards increasing tolerance to it in other ways. The study also suggested that around one-fifth of patients who previously could not tolerate metformin due to side effects might even succeed in retrying the medication.

The successful resumption of treatment, or prevention of side effects from the start of therapy, can also be contributed by the use of the XR form (extended-release), which according to available data has better gastrointestinal tolerability. The occurrence of any GI side effects is thus reduced by 50%, and the occurrence of diarrhea even by 75% compared to immediate-release metformin.

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Sources:
1. Orloff J. N., Touhamy S. H., Truong W. et al. Trial of restarting and tolerating metformin (TreatMet). Diabetes Obes Metab 2020 Jul 8, doi: 10.1111/dom.14137 [Epub ahead of print].
2. Hameed M., Khan K., Salman S., Mehmood N. Dose comparison and side effect profile of metformin extended release versus metformin immediate release. J Ayub Med Coll Abbottabad 2017; 29 (2): 225–229.
3. Blonde L., Dailey G. E., Jabbour S. A. et al. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin 2004; 20 (4): 565−572, doi: 10.1185/030079904125003278.