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Tolerance to Metformin through the Use of Gastrointestinal Microbiome

Gastrointestinal microbiome modulator may help alleviate the side effects of metformin and improve glucose control in patients with type 2 diabetes…

Metformin’s main side effects are gastrointestinal and this limits the use of the medication either by not reaching the maximum dose or discontinued use altogether. The most common adverse effects are diarrhea, heartburn, nausea, abdominal pain, bloating, and retching. The side effects are caused from a shift in microbiome in the GI. This study tested whether a GI microbiome modulator (GIMM) could relieve the symptoms when used in combination with metformin.

The study design was a double-blinded, randomized, 2-period crossover with 2 treatment sequences between June 2013 and June 2014 and included a total of 10 patients (eight women) aged 29 to 71 years with type 2 diabetes who were experiencing metformin adverse effects. Period 1 was placebo followed by period 2 with the use of GIMM or vice versa. The study lasted for 2 weeks with a period of 2 weeks in between for washout. In the first week, type 2 diabetes patients who have experienced GI side effects took 500 mg of metformin along with their assigned GIMM or placebo with breakfast and with dinner. In the second week, patients took metformin 500 mg three times a day with GIMM in the first and third daily metformin doses or placebo. Patients were allowed to discontinue metformin if the side effects became intolerable. An adapted questionnaire about irritable bowel syndrome was used to evaluate GI symptoms. Fasting blood glucose was also measured with a glucometer. The ratings of the severity of four GI symptoms were combined into a single score using a weighted sum, which was considered a composite tolerability score.

GIMM treatment with metformin showed significantly better tolerance score versus placebo (6.78 +/- 0.65 versus 4.45 +/- 0.9, p=0.0006). Fasting blood glucose was also significantly lowered with GIMM and metformin treatment versus placebo and metformin treatment (121.3 +/- 7.8 mg/dl versus 151.9+/-7.8 mg/dl, p<0.02).

The study suggested that GIMM treatment, which stimulates microbiota and generates short chain fatty acids instead of lactic acid, allows patients to better tolerate metformin use in type 2 diabetes, increases the use of metformin, and therefore improves the treatment of the disease. However, further research is necessary to confirm these findings. “The principal limitation for chronic metformin therapy in some patients is presentation of persistent adverse GI symptoms that may cause patients to discontinue metformin use,” the authors wrote. “The data observed in this pilot clinical trial suggest that a modulator of the GI microbiome could both alleviate metformin-mediated GI symptoms and may improve glucose regulation.”

Practice Pearls:

  • GIMM treatment with metformin showed significantly better tolerance score vs placebo.
  • Fasting blood glucose was also significantly lowered with GIMM and metformin treatment versus placebo and metformin treatment.
  • GIMM treatment allows patients to better tolerate metformin use in type 2 diabetes.

Jeffrey Burton H et al. Addition of a Gastrointestinal Microbiome Modulator to Metformin Improves Metformin Tolerance and Fasting Glucose Levels. J Diabetes Sci Technol. 2015;doi:10.1177/ 1932296815577425.