3.3.1 Effect of metformin in cancer
To further investigate the anti-aging benefits of metformin seen in animal models, numerous studies have been conducted to replicate these results in humans 89. In 2005, a case-control study first suggested that the use of metformin in diabetic patients was associated with reduced risk of cancer 91. Since then, the anti-tumor effect of metformin has been extensively investigated in multiple observational studies. In particular, Libby et al. and his colleagues compared new users of metformin and those who were taking sulfonylurea, insulin, or other anti-diabetic drugs. Their results showed that in patients with T2DM, metformin users (n= 4,085) have a significant lower risk of cancer than non-users (n= 4,085 ) do after adjusting for covariates (Hazard Ratio [HR] 0.63, 95% Confidence Interval [CI] [0.53-0.75]) 92.
Although a large body of subsequent observational studies have supported the positive relationship between metformin use and its anti-cancer effect, the evidence from Randomized Control Trials (RCTs) has been largely inconclusive 93, 94. For instance, Home and his colleagues compared the malignancy rates among diabetic patients who were initially treated with different glucose lowering medications. Their results did not support the view that metformin had a protective effect against cancer compared with rosiglitazone and sulfonylureas95. Consistently, multiple meta-analysis did not find any evidence showing metformin treatment being associated with a reduction of cancer incidence 96, 97.
Taken together, metformin use in animal studies and some observational studies have indicated its great potential as a cancer protective agent, which has sparked great interest for expansion to human clinical trials. Encouragingly, multiple RCTs that aim to investigate the anti-aging properties of metformin in non-diabetic individuals are on the horizon. In particular, the Targeting Aging with Metformin (TAME) trial, a large placebo-controlled trial that has been designed to enroll 3000 subjects, was launched in 2017. This study intends to compare the metformin users with placebo controls, and might offer stronger evidence for the protective role of metformin in cancer, cardiovascular disease and other age-related diseases 98, 99.