Association between Insulin Monotherapy versus Insulin plus Metformin and the Risk of All-Cause Mortality and Other Serious Outcomes: A Retrospective Cohort Study

AIMS To determine if concomitant metformin reduced the risk of death, major adverse cardiac events (MACE), and cancer in people with type 2 diabetes treated with insulin. METHODS For this retrospective cohort study, people with type 2 diabetes who progressed to insulin with or without metformin from 2000 onwards were identified from the UK Clinical Practice Research Datalink (≈7% sample of the UK population). The risks of all-cause mortality, MACE and incident cancer were evaluated using multivariable Cox models comparing insulin monotherapy with insulin plus metformin. We accounted for insulin dose. RESULTS 12,020 subjects treated with insulin were identified, including 6,484 treated with monotherapy. 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 (95% CI 39.4-43.6) deaths, 20.8 (19.2-22.5) MACE, and 21.6 (20.0-23.3) cancer events per 1,000 person-years. The adjusted hazard ratios (aHRs) for people prescribed insulin plus metformin versus insulin monotherapy were 0.60 (95% CI 0.52-0.68) for all-cause mortality, 0.75 (0.62-0.91) for MACE, and 0.96 (0.80-1.15) for cancer. For patients who were propensity-score matched, the corresponding aHRs for all-cause mortality and cancer were 0.62 (0.52-0.75) and 0.99 (0.78-1.26), respectively. For MACE, the aHR was 1.06 (0.75-1.49) prior to 1,275 days and 1.87 (1.22-2.86) after 1,275 days post-index. CONCLUSIONS People with type 2 diabetes treated with insulin plus concomitant metformin had a reduced risk of death and MACE compared with people treated with insulin monotherapy. There was no statistically significant difference in the risk of cancer between people treated with insulin as monotherapy or in combination with metformin.