Intolerance to metformin is a common and complex challenge in the treatment of type 2 diabetes, affecting up to 20% of patients using this drug. Metformin is considered the first choice in the therapy of type 2 diabetes because of its proven effects on lowering the glycemic profile, reducing cardiovascular mortality and neutrality in weight. However, intolerance often leads to gastrointestinal side effects such as nausea, abdominal pain, bloating and diarrhea, which can make glycemic control difficult.
Mechanisms of Intolerance
Although the mechanisms of action of metformin are known, increasing evidence suggests that part of its effect comes through the gastrointestinal tract. Recent studies have shown that differences in the absorption, distribution or elimination of metformin are unlikely to contribute to intolerance. Also, no connection was established between intolerance and lactate levels originating from anaerobic glucose metabolism in the intestines, nor with changes in systemic concentrations of bile acids or serotonin.
Metformin is transported from the intestinal lumen by specific transporters, including OCT1, the plasma membrane monoamine transporter (PMAT) and the serotonin transporter (SERT). Genetic variations, especially in the alleles for OCT1 and SERT, can significantly affect the way metformin enters the enterocytes. Research has shown that the concentration of metformin inside enterocytes can be as much as 300 times higher than in the systemic circulation.
Studies of extreme intolerance to metformin suggest that neither Cmax nor tmax of metformin explain the symptoms in patients, indicating that variants of the OCT1 and SERT transporters influence local concentrations of the drug. In addition, increased anaerobic glucose utilization can lead to lactate accumulation, while decreased bile acid absorption can cause osmotic diarrhea, all of which together contribute to the complex nature of metformin intolerance. This highlights the need for further research to better understand these interactions and develop strategies to manage this problem.
Enzyme and Intolerance
One of the key enzymes that can be insufficiently active in patients with intolerance to metformin is methylene-tetrahydrofolate reductase (MTHFR). This enzyme plays an important role in the metabolism of folic acid and, indirectly, in the regulation of homocysteine levels in the blood. Decreased MTHFR activity can lead to the accumulation of toxic metabolites, which can worsen the gastrointestinal symptoms associated with taking metformin. Research suggests that MTHFR genetic variants may influence individual tolerance to metformin, and that further research may focus on their role in this process. In some patients, it may be useful to monitor vitamin B12 and folic acid levels, given the relationship between MTHFR and the metabolism of these nutrients.
Diagnosis of Intolerance
Diagnosing metformin intolerance requires a comprehensive approach that includes:
- History: Talk to the patient about symptoms that occur after taking metformin, including nausea, stomach pain, and diarrhea.
- Physical examination: Exclusion of other potential causes of symptoms.
- Monitoring symptoms: Recording and monitoring symptoms related to metformin dosing can help identify patterns.
- Kidney function tests: Checking creatinine level and evaluating glomerular filtration.
- Laboratory tests: Lactate measurements, bile acid analyses, and genetic testing for MTHFR can provide additional information.
- Gradual Metformin Withdrawal: Temporary withdrawal can help assess whether symptoms are caused by metformin or something else.
Conclusion
Understanding the mechanisms underlying metformin intolerance may not only help develop strategies to manage this problem, but may also improve the quality of life of patients with type 2 diabetes. Further research is needed to elucidate these complex processes and potential individualized therapeutic strategies . With the right approach and support, many patients can continue with metformin therapy and successfully manage their condition.
Written by: mr.pharm. Romana Galin
