Metformin reduces the risk of adverse cardiovascular outcomes in patients with type 2 diabetes compared with sulfonylurea monotherapies, a study shows.
The review, which sought to differentiate between the various diabetes treatments available, found that metformin was associated with a 30–40% reduction in the relative risk of cardiovascular death compared with sulfonylureas. Metformin also seemed to have a greater impact on all-cause mortality and cardiovascular morbidity, though the evidence was less conclusive than that available for cardiovascular death.
“Metformin looks like a clear winner,” says lead author Nisa Maruthur, assistant professor at the Johns Hopkins University School of Medicine in Baltimore, Maryland. “Our results support metformin as the first-line drug for type 2 diabetes given its beneficial effects on haemoglobin (Hb)A1c and cardiovascular mortality (relative to sulfonylureas) and track record of safety.”
The researchers, who published their results in the Annals of Internal Medicine
(online, 19 April 2016), analysed results from 179 randomised trials and 25 observational studies to compare the efficacy and safety of thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase (DPP)-4 inhibitors, sodium glucose cotransporter (SGLT)-2 inhibitors, and glucagon-like peptide-1 receptor agonists given as monotherapy. They also included some metformin combinations in their comparisons.
The review found that most therapies approved by the US Food and Drug Administration (FDA) had comparable effects on HbA1c levels. However, DPP-4 inhibitors – a more recent class of antidiabetic drugs – were less effective at lowering blood sugar levels compared with metformin and sulfonylureas.
Compared with antidiabetic drugs that reduced or maintained weight, thiazolidinediones, sulfonylureas and insulin were associated with clinically significant weight gain (up to 5kg). Sulfonylureas increased hypoglycaemia risk; metformin and GLP-1 receptor agonists increased gastrointestinal side effects; and thiazolidinediones increased risk for congestive heart failure. SGLT-2 inhibitors, the newest class of antidiabetic drugs, increased risk for genital mycotic infections.
The authors note that the newer drug classes are not necessarily safer than older drugs and less is known about their potential complications.
“Medications other than metformin should be considered in light of their known weight and side effects as well as uncertainty in long-term risks,” says Maruthur. “Patient preferences are extremely important in selecting medications others than metformin (either in place of metformin or for add-on therapy to metformin).”
The analysis was carried out on behalf of the US Agency for Healthcare Research and Quality, which previously published a report comparing diabetes therapies in 2011. Since then, the FDA has approved several new drugs and more than 100 studies have been published, many of which were included in the current review.
In the UK, National Institute for Health and Care Excellence guidelines, which were updated in 2015, recommend metformin as first-line therapy in type 2 diabetes, with sulphonylureas, DPP-4 inhibitors or pioglitazone suggested as add-ons when metformin alone fails to result in glycaemic control.
Emily Burns, research communications manager at Diabetes UK, says the review’s findings support current guideline recommendations for the use of metformin as first-line therapy. “The reduced risk in cardiovascular disease that was associated with metformin is a welcome finding, after a potential link was first noted in the UK Prospective Diabetes Study in 1999,” she says.
“This research highlights the importance of long-term observational studies that can really help us to understand the comparative effects of type 2 diabetes medications available today.”
 Maruthur NM, Tseng E, Hutfless S et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Annals of Internal Medicine 2016. doi: 10.7326/M15-2650