Addition of a Gastrointestinal Microbiome Modulator to Metformin Improves Metformin Tolerance and Fasting Glucose Levels

Abstract

Background: Adverse effects of metformin are primarily related to gastrointestinal (GI) intolerance that could limit titration to an efficacious dose or cause discontinuation of the medication. Because some metformin side effects may be attributable to shifts in the GI microbiome, we tested whether a GI microbiome modulator (GIMM) used in combination with metformin would ameliorate the GI symptoms.

Methods: A 2-period crossover study design was used with 2 treatment sequences, either placebo in period 1 followed by GIMM in period 2 or vice versa. Study periods lasted for 2 weeks, with a 2-week washout period between. During the first week, type 2 diabetes patients (T2D) who experienced metformin GI intolerance took 500 mg metformin along with their assigned NM504 (GIMM) or placebo treatment with breakfast and with dinner. In the second week, the 10 subjects took 500 mg metformin (t.i.d.), with GIMM or placebo consumed with the first and third daily metformin doses. Subjects were permitted to discontinue metformin dosing if it became intolerable.

Results: The combination of metformin and GIMM treatment produced a significantly better tolerance score to metformin than the placebo combination (6.78 ± 0.65 [mean ± SEM] versus 4.45 ± 0.69, P = .0006). Mean fasting glucose levels were significantly (P < .02) lower with the metformin-GIMM combination (121.3 ± 7.8 mg/dl) than with metformin-placebo (151.9 ± 7.8 mg/dl).

Conclusion: Combining a GI microbiome modulator with metformin might allow the greater use of metformin in T2D patients and improve treatment of the disease.

Keywords: GI adverse events; NM504; glucose; metformin; metformin intolerance; microbiome modulator.

Figure 1.

Metformin is better tolerated when combined with GIMM than placebo. Tolerability is a composite score of GI symptoms. A greater tolerability score indicates a better metformin tolerance.

Figure 2.

Fasting blood glucose levels. Subjects were assigned GIMM (A) or placebo (B) for the initial period. Subjects were instructed to take 500 mg metformin b.i.d. during the initial week of each period and 500 mg metformin t.i.d. during the second week. Subjects were permitted to discontinue metformin dosing if symptoms became intolerable. Days metformin was taken are indicated by the solid symbols. Subject number is indicated in the upper left as well as in Table 1.

Figure 3.

Mean observed fasting glucose for subjects taking GIMM during period 1. Bars represent the mean ± SEM.