Metformin — A “Wonder Drug” Beyond type 2 Diabetes

Metformin has proven to be a “magic drug” beyond its application in treating diabetes. Over the past 20 years, metformin has become the mainstay of type 2 diabetes treatment and is now the drug of first choice in the United States and around the world for the treatment of this condition. Since its marketization in the United States in 1995, metformin has caught attention from both clinicians and patients. This drug was found to be safe and effective, and the one-month generic drug supply price was around $ 4, which is affordable for nearly all people.


According to a series of new studies, metformin may also have benefits in protecting against cardiovascular disease, cancer, stroke, and dementia except for its anti-diabetic effects. “Metformin is the first drug of choice, by all standards,” professor and clinical pharmacist at Howard University School of Pharmacy told Endocrine Today. “It’s a rarity that all experts agree on something. It is time-tested to have good efficacy and a good safety profile. Plus, it’s cheap. Metformin has been around long before it came to the United States. That’s why I find it amazing that we only have one drug in that class.”


New research is suggesting that metformin may hold promise in treating or preventing a whole host of conditions in patients with and without type 2 diabetes. Studies show metformin may be cardioprotective in patients with diabetes and beneficial in the presence of stable congestive heart failure. The agent also may help to increase pregnancy rate in polycystic ovary syndrome, provide breast and prostate cancer benefits, and offer neuroprotection that may reduce dementia and stroke risk. Currently researchers are exploring whether metformin can target and delay aging so as to reduce the incidence of age-related diseases.


An endocrinologist and director of the Institute for Aging Research at the Albert Einstein College of Medicine said he hopes to work with the FDA to conduct an NIH/American Federation for Aging Research metformin trial later this year — Targeting Aging with Metformin (TAME) — that will demonstrate the agent’s ability to delay the onset of comorbidities related to aging, thereby reducing the period of morbidity at the end of life. “If metformin can target and delay aging, its administration should be associated with fewer age-related diseases in general, rather than merely the decreased incidence of a single disease.”

the history and theories behind possible mechanisms

Now let’s take a quick review on the history and theories behind possible mechanisms. The use of the so-called metformin could be traced back to the Middle Ages, when herbalists first derived extracts from Galega officinais, a plant known alternatively as French lilac, false indigo and Spanish sainfoin, to treat frequent urination. The plant’s active ingredient — guanidine — was later synthesized as metformin with low toxicity. The drug was approved in France and the United Kingdom in 1957 and 1958 respectively, but it would be another 37 years before the FDA approved the agent for use in the United States. Despite the initial resistance to the drug, the FDA is more inclined recently to consider studies that could examine other indications for metformin through trials.
Studies show that metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not cause hypoglycemia or hyperinsulinemia. Insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. Metformin is most commonly used to treat type 2 diabetes, either alone or combined with other agents, but is also used off-label as a treatment for prediabetes, gestational diabetes and PCOS.


“There are some other off-label uses for metformin that we don’t have strong evidence for, but where there may be potential, such as HIV-related lipodystrophy,” said one of the researchers. For patients on atypical antipsychotic medications, they may experience some side effects related to insulin resistance. For that reason, those patients may consider using metformin. Besides, metformin may also have a role in metabolic syndrome, and it’s been studied intensely in nonalcoholic fatty liver disease, although pioglitazone may have a stronger role in such a case.


Then what are the unexpected off-label uses for metformin?



Treatment for obesity

Researchers from Massachusetts General Hospital in Boston recalled patients with obesity in recent years who struggled to lose weight via different approaches including attempting lifestyle modification and multiple weight-loss medications. Ultimately, a combination of metformin and lorcaserin worked for the patient and help lose 50 pounds in weight. All these results show that metformin is effective in counteracting weight gain from antipsychotic agents for a certain patients. Still, the weight-loss effects of metformin are sometimes a welcome surprise.


Treatment for cognitive dysfunction

Other emerging evidence suggests that metformin may preserve cognitive function and reduce mortality. In an analysis of 365 adults aged over 55 years participating in the Singapore Longitudinal Aging Studies, the researchers assessed the association of metformin use versus nonuse with cognitive impairment. And the results showed that metformin use was inversely associated with cognitive impairment in longitudinal analysis, and that the lowest risk for cognitive impairment was associated with use of the drug for more than 6 years.


Treatment for cancer-related mortality

Epidemiologic studies suggest that metformin use may be associated with both reduced cancer incidence and mortality. Although patients with diabetes had a higher risk for developing colon cancer, those patients who assigned metformin had a 27% reduced risk, according to researchers. The reason is that: metformin clearly affects AMP-activated protein kinase, which effects mitochondrial energy generation and may deprive malignant, inefficient cells of energy and therefore reduce their potential growth rate. Although no observations clearly prove that metformin can prevent the progression of cancer for now, its preventive effects are already specified.