This systematic review of double-blinded, randomized, controlled trials has separately examined metformin treatment as a stand-alone therapy and as an add-on therapy both to other oral medications and to insulin to quantify its effect on glycemic control. Metformin monotherapy reduced HbA1c
by 1.12%, and metformin in combination with other oral antihyperglycemic treatments or insulin reduced HbA1c
by 0.95 and 0.83%, respectively, for type 2 diabetes, and these effects were sustained at 24 weeks. Of particular interest is that the addition of metformin treatment to insulin treatment improves glycemic control in type 2 diabetes by a clinically significant level despite protocol-permitted insulin dose adjustments in both arms of these trials. Treatment of type 1 diabetic patients with metformin did not reduce HbA1c
. We have also clearly demonstrated that an increase in metformin dose results in a further modest reduction in HbA1c
of 0.26% in trials comparing lower doses to higher doses up to a metformin dose of 2,000 mg. It was not possible to establish whether there is further benefit when metformin dose is increased beyond this level because there were too few trials with higher doses, although the trial on which much of the evidence for cardiovascular benefit is based, the UK Prospective Diabetes Study (UKPDS) (16
), used a median dose of 2,550 mg metformin. Establishing how the dose-effect relationship may vary at different doses and what the maximum effective dose may be is an area for future work.
A previous systematic review found lower rates of cardiovascular mortality in people randomized to metformin in six trials of >11,000 patients (6
). Compared with that review, our analysis has the disadvantage of using the surrogate outcome of glucose lowering, albeit a well-established surrogate on which treatment guidelines are based (4
), but it has the advantage of an estimate based on more trials. This has allowed us to examine subgroups, such as monotherapy, combination oral therapy, and insulin therapy, and to establish a dose-response relationship.
This is the most comprehensive systematic review to date on the effect of metformin treatment on HbA1c
levels. In addition, to our knowledge, this is the first meta-analysis of metformin dose-comparison studies. Significant unexplained heterogeneity observed between the trials, however, is a limitation of this review and, consequently, results need to be treated with caution. Our searches identified 5 times more trials than a previous review, which examined the effect of metformin on glycemic control in seven trials (8
). This is partly explained by the other reviewer’s more stringent inclusion criteria, which included a minimum of 50 subjects in each arm of the trial and an explicit statement that informed consent was obtained. Inclusion of a larger number of trials has made it possible to separately analyze data from metformin monotherapy, oral combination therapy, and insulin trials. The greatest reduction in HbA1c
in our analysis was 1.1%, which is at the low end of the 1–2% estimated by Nathan et al. (3
). The results of our review suggest that these estimated reductions are most likely to be achieved with the highest metformin doses. Previous trials that compared different metformin doses from various trials could not establish a dose-effect relationship of metformin (8
). By including head-to-head trials of metformin in our systematic review, we clearly demonstrate the benefit of using a higher metformin dose to maximize HbA1c
reduction, although there may be an associated increase in gastric side effects. We have not been able to demonstrate a relationship between baseline HbA1c
and change in HbA1c
with treatment observed in other systematic reviews (8
). A previous systematic review of 61 trials of oral glucose-lowering therapy found an association between baseline HbA1c
and the change in HbA1c
on treatment, but metformin was a randomized therapy in only seven of these trials (8
). We were not able to find such a relationship in 15 trials of metformin monotherapy, 12 trials of metformin in combination with oral therapy, and 13 trials of metformin in combination with insulin. However, our analysis is based on metaregression, which compares mean values across trials. The best data to address this question would make comparisons between individuals (20
). These results, therefore, need to be interpreted with caution.
Metformin’s known benefit in reducing cardiovascular mortality (6
), as well as its neutral effects on body weight and low risk of hypoglycemia (16
), has led to wide recommendations for routine prescribing. However, until now, it has not been clear how different patients may respond to treatment. By separately examining the effect of metformin treatment in various groups of patients, depending on their previous antidiabetes medication, we are providing a tool to assist decisions on treatment combinations and optimal doses.
This review demonstrates that metformin treatment can be used to reduce HbA1c
in all patients with type 2 diabetes regardless of prior antihyperglycemic medication or insulin treatment. Use of higher doses of metformin resulted in modestly higher decreases in HbA1c
compared with lower doses. Metformin use in type 1 diabetes may not, however, reduce HbA1c
. Despite this, there may be other indications for treating type 1 diabetic patients with metformin because a reduction in insulin dose required in the metformin arm of these trials was observed consistent with metformin’s role as an insulin sensitizer (21