Metformin

Metformin is a first-line therapy for the treatment of type 2 diabetes, valued for its robust glucose-lowering effects, well-established safety profile, and relatively low cost. ^[1] It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). ^[2] Metformin, a dimethylbiguanide, was first synthesized in 1929 and shown to be a potent hypoglycemic agent. ^[3]

There is a general consensus that the major glucose-lowering effect of metformin in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. ^[1] The discovery that metformin inhibits the mitochondrial respiratory chain complex 1 placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. ^[4] Beyond the liver, increasing evidence points toward other sites of action including the gastrointestinal tract, the gut microbial communities, and tissue-resident immune cells, and the mechanisms appear to vary with the dose used and duration of treatment. ^[5] Metformin is classified among Caloric Restriction mimetics, activating AMP-activated protein kinase to reproduce protective metabolic effects of restricted calorie intake within evidence-based anti-aging strategies ^[6]

Metformin is the first drug to be tested for its age-targeting effects in a large clinical trial, TAME (Targeting Aging with Metformin). ^[7] Clinical trials including MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin) have been designed to determine whether metformin can offset aging and extend lifespan. ^[8] A critical review concluded that, despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial, and that its beneficial effects on aging and healthspan are primarily indirect, arising from its anti-hyperglycemic action, enhancement of insulin sensitivity, reduction of oxidative stress, and protective effects on the endothelium and vascular function. ^[9] In the Diabetes Prevention Program, metformin reduced the 3-year risk of diabetes by 31%, compared with 58% for intensive lifestyle intervention, and was most effective in younger, heavier subjects. ^[10] In a review of prediabetes, metformin decreased the risk of diabetes among individuals with prediabetes by 3.2 cases per 100 person-years over 3 years, while being most effective for women with prior gestational diabetes and for individuals younger than 60 years.

A large proportion of patients cannot tolerate metformin in adequate amounts because of associated gastrointestinal adverse events, which typically include diarrhoea, nausea, flatulence, indigestion, vomiting and abdominal discomfort, with diarrhoea and nausea being the most common. ^[12] Lactic acidosis is the feared adverse effect of the biguanide drugs, but its reported incidence in clinical practice has proved to be very low, at fewer than 10 cases per 100,000 patient-years. ^[13] Because elevated metformin concentrations occur in renal impairment, metformin has been contraindicated in moderate and severe renal impairment, and the mortality rate of metformin-associated lactic acidosis approaches 50%. ^[13] Over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency. ^[14]