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

J Diabetes Sci Technol. 2015 Jul;9(4):808-14. doi: 10.1177/1932296815577425. Epub 2015 Mar 23.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blood Glucose / analysis*
  • Body Mass Index
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Fasting*
  • Female
  • Food, Formulated*
  • Gastrointestinal Microbiome / drug effects*
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Inulin / administration & dosage
  • Male
  • Metformin / administration & dosage*
  • Metformin / adverse effects
  • Middle Aged
  • Pilot Projects
  • Plant Extracts / administration & dosage
  • Plant Extracts / chemistry
  • Polyphenols / administration & dosage
  • Treatment Outcome
  • beta-Glucans / administration & dosage


  • Blood Glucose
  • Hypoglycemic Agents
  • Plant Extracts
  • Polyphenols
  • beta-Glucans
  • Inulin
  • Metformin