Biguanides side effects
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Biguanides Side Effects: A Comprehensive Overview
Introduction to Biguanides and Their Use in Diabetes Treatment
Biguanides, particularly metformin, are widely used as oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus. They are known for their efficacy in lowering blood glucose levels without causing significant hypoglycemia. However, their use is associated with several side effects, some of which can be severe.
Lactic Acidosis: The Most Dangerous Side Effect
Incidence and Severity
The most dangerous side effect of biguanides is lactic acidosis, a condition characterized by the buildup of lactate in the body, leading to a decrease in blood pH. This side effect is significantly more frequent with phenformin compared to metformin. Metformin has been reported to cause lactic acidosis in 0.4 cases per 10,000 treatment years, with a mortality rate of about 30%, whereas phenformin-associated lactic acidosis has a mortality rate of 70% .
Mechanism of Action
Biguanides induce lactic acidosis primarily through mitochondrial impairment. They inhibit mitochondrial respiratory complex I, leading to reduced oxygen consumption and increased lactate production from accelerated glycolysis Dykens2008Jangaard1968Wang2003. This mitochondrial dysfunction is a hallmark of biguanide toxicity and is more pronounced in phenformin and buformin compared to metformin Dykens2008Wang2003.
Vitamin B12 Malabsorption
Both phenformin and metformin can cause vitamin B12 malabsorption in about one-third of the cases. However, symptomatic vitamin B12 deficiency is extremely rare . This side effect is due to the interference of biguanides with the absorption mechanisms in the gastrointestinal tract.
Mitochondrial Dysfunction and Cytotoxicity
Biguanides, particularly phenformin, exhibit cytotoxic effects on cells by impairing mitochondrial function. Studies have shown that phenformin is the most cytotoxic, followed by buformin, with metformin showing toxicity only at high concentrations . This cytotoxicity is linked to the inhibition of mitochondrial respiration and the subsequent increase in lactate production.
Role of Organic Cation Transporters
The involvement of organic cation transporters, particularly OCT1 and OCT2, plays a crucial role in the pharmacokinetics of biguanides. These transporters are responsible for the hepatic and renal uptake of biguanides. Phenformin has a higher affinity for these transporters compared to metformin, which may explain the higher incidence of lactic acidosis with phenformin Wang2003Sogame2013.
Conclusion
While biguanides are effective in managing blood glucose levels in type 2 diabetes, their use is associated with significant side effects, particularly lactic acidosis and vitamin B12 malabsorption. The severity of these side effects varies among different biguanides, with phenformin being the most hazardous. Understanding the mechanisms behind these side effects, such as mitochondrial dysfunction and the role of organic cation transporters, is crucial for optimizing the safe use of these drugs.
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