In their comments on our article (1), Drs. Suissa and Azoulay very appropriately emphasized the limitations of observational studies (2). More specifically, they brought to our attention the lack of association between the use of metformin and cancer in recently conducted observational studies looking at metformin exposure as a time-related exposure. There is clearly clinical and epidemiologic data suggesting that metformin has salutary effects on cancers (3–6). However, there are many instances where interventions that were predicted to be beneficial on the basis of observational studies were proven to be ineffective or even harmful when tested in well-designed randomized controlled trials. For example, the Women’s Health Initiative (WHI) study investigated the effect of estrogen and progestin replacement therapy on the risk of coronary heart disease and other cardiovascular diseases in healthy postmenopausal women based on promising results from a large body of observational studies (7). The WHI failed to demonstrate any protective effect of hormone therapy on the heart but showed overall health risks exceeded benefits.
In the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial (1), our exploratory analysis of metformin use (analyzed as a time-varying covariate) suggested that it did not affect cancer outcomes—a finding that supports the current equipoise regarding its effect on cancers and justifies the ongoing randomized controlled trials in this area.
Article Information
Duality of Interest. The ORIGIN trial was funded by Sanofi. H.C.G. received consulting fees from Sanofi, Novo Nordisk, Lilly, Bristol-Myers Squibb, Roche, AstraZeneca, Novartis, GlaxoSmithKline, and Bayer; lecture fees from Sanofi and Bayer; and support for research or continuing education through his institution from Sanofi, Lilly, Merck, Novo Nordisk, Boehringer Ingelheim, Bristol-Myers Squibb, and AstraZeneca. No other potential conflicts of interest relevant to this article were reported.
