Metformin is a medication belonging to the biguanide class, primarily used in the treatment of type 2 diabetes. Its origins date back to the early 20th century when it was synthesized from galegine, a compound extracted from Galega officinalis, a plant used in traditional medicine. However, its clinical use only truly developed from the 1950s onward.
Today, metformin is one of the most widely prescribed antidiabetic drugs worldwide and is the first-choice treatment following a diagnosis of type 2 diabetes. The study we are analyzing focuses on preventing the gastrointestinal side effects of metformin. Despite its effectiveness, metformin is often associated with digestive disorders (diarrhea, abdominal pain, bloating, etc.), which may lead some patients to discontinue treatment. To address this issue, the dosage is typically increased gradually, and if necessary, an extended-release formulation can be used. This study explores the impact of a gut microbiota modulator, a blend of prebiotic fibers and natural antioxidants, as a means to improve metformin tolerance. A prebiotic is a substance that nourishes the gut flora and helps maintain its proper function.
Study Methodology
The study is based on a small-scale randomized trial involving 10 patients, randomly assigned to two groups. The selection criteria were clear, and the individuals were representative of the general diabetic population. At the time of recruitment, all participants had experienced or were experiencing metformin intolerance.
The two groups alternately received one of the following two combinations:
Combination 1: Metformin + microbiota modulator
Combination 2: Metformin + placebo
Participants followed a structured protocol consisting of three phases:
Phase 1: 2 weeks of treatment with either combination 1 or combination 2
Phase 2: 2 weeks of washout (no treatment)
Phase 3: 2 weeks of treatment, switching to the other combination
This type of design, known as a crossover trial, allows each patient to receive both the treatment and the placebo, thus minimizing biases related to individual differences among participants.
Hypothesis and Biological Basis
The study is based on previous research showing that the interaction between gut microbiota and metformin could influence its side effects through the following mechanism:
Due to its pharmacological effect, metformin promotes the production of D-lactate by bacteria in the gut.
Increased D-lactate levels may be responsible for the digestive issues associated with metformin.
The production of D-lactate is exacerbated in individuals who consume diets rich in starch and sugar (cereals, legumes).
Additionally, through its effects on the liver, metformin may increase the presence of bile acids in the intestines, further raising the risk of diarrhea.
Although not explicitly stated, the researchers clearly aim to validate the effectiveness of a microbiota modulator—composed of inulin, beta-glucan, and anthocyanins—in restoring gut flora balance, reducing D-lactate production, and protecting the intestines from excessive bile acid levels. This would, in turn, reduce metformin-related digestive side effects. These modulating elements are naturally present in several fresh foods, including garlic, leeks, onions, oats, apples, and blueberries. In the study, both the microbiota modulator and the placebo were provided as a powdered supplement to be mixed with water.
Measurements and Evaluation Tools
The effectiveness of the treatment was assessed using three measures:
A questionnaire evaluating the presence and intensity of gastrointestinal symptoms.
A stool assessment scale measuring stool volume and consistency.
A daily fasting capillary blood glucose test conducted at home by participants.
Since blood glucose measurements were performed independently by participants, verification of the presented results was not possible (uncertainty about the type of device used, method applied, and supervision of results). Therefore, the main focus was on the impact of the treatment on side effects.
Statistical Analysis and Validity of Results
Strengths of the Study
A randomized trial helps reduce biases related to individual differences and establish a causal relationship, making it a reference method for evaluating treatment effectiveness. Additionally, the crossover design improves the comparison of effects by ensuring that each patient serves as their own control, thereby reducing inter-individual variability.
Weaknesses and Limitations
A statistical power issue may arise when the sample size is too small, limiting the ability to detect a significant difference between groups. Furthermore, the detailed results of the side effect evaluation questionnaire were not presented: although the authors claim that the microbiota modulator significantly reduces metformin intolerance, they do not provide precise calculations to support this conclusion.
Analysis of Results
The study presents an interesting hypothesis regarding the link between the gut microbiota and metformin tolerance. While it is not possible to confirm the significant effect reported by the authors, the addition of a dietary supplement beneficial to gut bacteria could improve metformin tolerance, allowing more people with type 2 diabetes to benefit from this effective and affordable treatment. Beyond supplementation, it is worth noting that a diet rich in fruits and vegetables and a reduction in the consumption of starch-rich and refined sugar foods could have a similar effect.
The authors also mention a significant effect of the microbiota modulator in reducing participants’ blood glucose levels. However, a longer study with controlled blood glucose measurements through blood tests would be necessary to confirm this effect. Once again, a diet high in fruits and vegetables and low in starch and refined sugars would likely have a positive impact on blood glucose regulation.
To strengthen the validation of these results, several improvements could be made:
Increasing the sample size would enhance statistical power and the reliability of the findings.
Controlling confounding factors such as diet, baseline stool frequency before recruitment, or inter-individual microbiota variations would help limit bias and refine conclusions.
Ultimately, this study suggests that modifying dietary habits could further improve metformin tolerance, providing additional benefits for patients with type 2 diabetes.