Insulin Plus Metformin in Type 2 Diabetes

June 6, 2016

Does insulin in conjunction with metformin have the potential to reduce all-cause mortality in patients with type 2 diabetes?

Patients with type 2 diabetes mellitus (T2DM) treated with insulin plus concomitant metformin have a reduced risk of death and major adverse cardiac events (MACE) compared with people treated with insulin monotherapy, according to the results of a new study.

“In this research we examined insulin dose along with the impact of combining insulin with metformin. We found that there was a considerable reduction in deaths and heart problems when this cheap and common drug was used in conjunction with insulin,” said senior author Professor Craig Currie of the School of Medicine at Cardiff University, Cardiff, UK.

This retrospective cohort study, using data from the UK Clinical Practice Research Datalink, included 12,020 patients with T2DM who progressed to insulin with or without metformin from 2000 onwards, including 6,484 patients treated with insulin monotherapy. The research team tracked the patients for three and a half years, on average, from the time they were first prescribed insulin.

The researchers found that insulin in conjunction with metformin had the potential to reduce mortality and myocardial infarctions. There was no difference in the risk of cancer between those treated with insulin as a single therapy or in combination with metformin.

There were 1,486 deaths, 579 MACE (excluding those with a history of large vessel disease), and 680 cancer events (excluding those in patients with a history of cancer). Corresponding event rates were 41.5 deaths, 20.8 MACE, and 21.6 cancer events per 1,000 person-years.

The adjusted hazard ratios for people prescribed insulin plus metformin versus insulin monotherapy were 0.60 for all-cause mortality, 0.75 for MACE, and 0.96 for cancer.

“Since 1991, the rate of insulin use in type 2 diabetes increased more than six-fold in the UK. In more recent years, metformin has also been used alongside insulin as a treatment,” said Currie. “Previously, our work showed that increased insulin dose is linked with mortality, cancer, and heart attacks. Existing studies have also shown that metformin can attenuate the risks associated with insulin.”

The researchers point out that clinical guidelines recommend that insulin should be added to, rather than replaced by, existing metformin therapy. “Among its purported benefits, metformin may be cardioprotective, an effect that cannot be solely explained by its ability to lower blood glucose,” they stated.

Systematic reviews have reported that insulin plus metformin improves glycemic control, lessens weight gain, and reduces insulin requirements when compared with insulin monotherapy.

The researchers noted that there were potential limitations to the methods used to estimate insulin dose. Also, patients receiving insulin in combination with metformin were, in general, heavier than those receiving insulin as monotherapy and less likely to have a history of large vessel disease.

“While this research indicates the potential of using these treatments together, further studies are needed to determine the risks and benefits of insulin in type 2 diabetes and the possible benefits associated with the administration of metformin alongside insulin," said Currie.

Reference: Holden SE, et al. Association between insulin monotherapy versus insulin plus metformin and the risk of all-cause mortality and other serious outcomes: a retrospective cohort study. PLoS One. 2016 May 6;11(5):e0153594.