Phenformin is an oral medication categorized as a biguanide, a class of drugs historically used to manage type 2 diabetes. Developed in 1957, it was introduced to lower elevated blood glucose levels in patients. While initially considered an effective treatment, phenformin was later withdrawn from the market in many countries due to safety concerns.
Historical Use in Diabetes Management
Phenformin played a significant role in diabetes therapy during the mid-20th century. Its primary function involved reducing the amount of glucose produced by the liver, a process known as hepatic gluconeogenesis. The medication also enhanced glucose uptake by peripheral tissues, such as muscle cells, helping remove sugar from the bloodstream, making cells more efficient at utilizing glucose.
Phenformin influenced the digestive system by decreasing glucose absorption from the intestines. By acting on these pathways—liver production, tissue uptake, and intestinal absorption—phenformin lowered blood sugar levels. Its mechanism involved activating AMP-activated protein kinase (AMPK), an enzyme that helps regulate cellular energy.
The Risk of Lactic Acidosis and Market Withdrawal
Despite its effectiveness in managing blood sugar, phenformin carried a serious side effect: lactic acidosis. This condition occurs when excessive lactic acid builds up in the bloodstream, leading to a dangerous drop in pH. In severe cases, lactic acidosis can be fatal, with a fatality rate as high as 50%.
Phenformin’s structure made it more lipid-soluble and gave it a higher affinity for mitochondrial membranes. This led to a potent inhibition of mitochondrial respiration, specifically affecting Complex I of the electron transport chain. This inhibition disrupted the body’s normal energy production, leading to lactate accumulation.
Reports of lactic acidosis increased, prompting regulatory action. In October 1976, the U.S. Food and Drug Administration (FDA) Endocrinology and Metabolism Advisory Committee recommended the drug’s removal. The FDA initiated formal proceedings in May 1977, leading to phenformin’s withdrawal in the U.S. by November 15, 1978. While banned in many regions, phenformin remained available in some countries, such as China, Brazil, and Italy.
Comparison with Metformin
Phenformin and metformin are both biguanide drugs. Both medications decrease glucose production in the liver, enhance insulin sensitivity in body tissues, and reduce glucose absorption from the intestines. They also activate AMP-activated protein kinase (AMPK), an enzyme involved in energy regulation.
Significant differences exist between the two compounds, particularly concerning their safety profiles. Phenformin is more potent than metformin in inhibiting mitochondrial complex I, leading to a higher risk of lactic acidosis. Phenformin’s higher lipid solubility allows it to enter cells more readily without requiring specific transport proteins, unlike metformin which relies on organic cation transporters (OCTs). This difference in cellular uptake contributes to phenformin’s greater accumulation and more pronounced effect on lactate production, leading to an 8-fold higher incidence of lactic acidosis compared to metformin. Metformin, while still carrying a small risk of lactic acidosis, especially in patients with impaired kidney function, is much safer, with a reported rate of about 3 cases per 100,000 patient-years, compared to 64 cases per 100,000 patient-years for phenformin.
Modern Research and Potential Applications
Despite its withdrawal from diabetes treatment, phenformin has seen renewed scientific interest, primarily in oncology. Researchers are investigating whether its potent metabolic disruption could be harnessed to target cancer cells. Cancer cells often exhibit altered metabolism, relying on specific energy pathways for rapid growth.
Phenformin’s inhibition of mitochondrial respiration, particularly Complex I, disrupts these energy pathways, leading to energy and oxidative stress. This action can activate pathways like AMPK and inhibit mTOR, involved in cell growth and survival, potentially leading to cell cycle arrest and tumor growth inhibition. Preclinical studies have explored phenformin as a potential anti-cancer agent in various tumor types, including breast, lung, ovarian, and prostate cancers. This research remains experimental, and phenformin is not an approved cancer treatment, but it highlights how understanding a drug’s precise mechanisms can lead to unexpected new avenues of investigation.