Metformin in type 2 diabetes: where is the evidence?

Abstract

Taking into consideration the main evidence available in 2015, Boussageon contest the status of metformin as the first -line treatment for DT2 patients. He contends that as regards macrovascular and microvascular complications, its efficacy has never been proven in a double-blind RCT. This observation leads to a more general interrogation on how anti-diabetes medication is to be assessed. Key messagesEver since the results of the UK Prospective Diabetes Study (UKPDS) 34 were published in 1998, metformin has been considered as the first-line pharmacological treatment for type 2 diabetes.However, from several standpoints the UKPDS was methodologically questionable. The effectiveness of metformin with regard to microvascular and macrovascular complications has never been proven in a randomized double-blind placebo-controlled clinical trial.And upon analysis of published randomized clinical trials taken as a whole, it becomes increasingly apparent that the effectiveness of metformin has not been proven, even when microvascular complications are involved.This observation leads to a more general interrogation on the fact that assessment of the clinical benefits of antidiabetic medication in general is presently lacking. Has the effectiveness of metformin actually been proven?Metformin is an oral antidiabetic drug (OAD) in the biguanide class [1]. It is the recommended first-line treatment for type 2 diabetes (DT2) patients [2]. Its efficacy was supposedly conclusively demonstrated in the UKPDS 34 study published in 1998 (reduction in mortality: RR0.64; CI 95% (0.45 to 0.91) and in myocardial infarction: RR0.61; CI 95% (0.41 to 0.89) [3]. However, these rather impressive results regarding total 10 year mortality (ARR0.07; NNT14) in a small subgroup of obese type 2 diabetes patients (342 in the metformin group vs. 411 patients in the conventional group) have never been reproduced [4]. For instance, the home study [5] years of follow-up, no statistically significant difference was found for total mortality: RR1.48; CI 95% (0.54 to 4.09) or for IDM: RR0.99; CI 95% (0.25 to 3.90). Taking into account all the other randomized clinical trials (RCTs) having evaluated the specific effectiveness of metformin in DT2 patients [6], it becomes evident that metformin has not significantly modified total mortality: RR0.99; CI 95% (0.75 to 1.31), cardiovascular mortality: RR  1.05; CI 95% (0.67 to 1.64), IDM occurrence: RR0.90; CI95% (0.74 to 1.09), cerebrovascular accidents: RR0.76; CI95% (0.51 to 1.14), cardiac insufficiency: RR1.03; CI 95% (0.67 to 1.59), peripheral vascular events: RR0.90; CI 95% (0.46 to 1.78), lower limb amputations: RR1.04; CI 95% (0.44 to 2.44) or microvascular complications: RR0.83; CI95% (0.59 to 1.17). Once an analysis without selection bias has been carried out, it becomes apparent that on the basis of clinical criteria, the efficacy of metformin has not been proven; in science, the reproducibility of results remains an essential validity criterion. The dark side of UKPDSIn point of fact, t...