Controversy surrounds the use of metformin in patients with type 2 diabetes mellitus (DM). Intensive blood-glucose control with metformin monotherapy effectively reduces the risk of diabetes-related mortality and morbidity. Based on the strength of these results, metformin is often recommended as first-line therapy, particularly for overweight diabetic patients. However, a subgroup analysis of UKPDS revealed that early addition of metformin to sulfonylurea therapy, so-called “combination therapy” was associated with an increased risk of diabetes-related mortality. Two retrospective, observational studies have also reported an association between combination therapy and an increased risk of mortality. It is not clear whether metformin increases the risk of mortality or if the combination of metformin and sulfonylurea is a marker for more severe DM.
In our study we intend to evaluate the impact of metformin in a population-based cohort of patients with type 2 DM. This is a retrospective cohort study utilizing information from the Saskatchewan Health databases. Our hypothesis is that metformin is not associated with increased mortality.
The primary outcome of this study is mortality. Patients will be grouped according to their exposure status with respect to sulfonylurea, metformin, and combination therapy.
From the Saskatchewan Health database we have identified a cohort of 12,272 new users of oral agents, mean age 64.0 (SD13.6) years, and 45% women. Within this group 12.6% received metformin monotherapy, 36.0% received sulfonylurea monotherapy, and the remainder received some form of combination therapy during the follow-up period. There were 2681 deaths (21.8%) during the follow-up. Analysis of the database is ongoing, with initial results expected by the end of this year.
To our knowledge, this evaluation is the largest study of its kind. Unlike previous analyses, we have information that allows us to control for length of DM prior history of cardiovascular disease, and comorbid disease severity. Upon completion, this evaluation will provide further insight into the contributions metformin has to management of patients with type 2 DM.
Jeff Johnson, Sumit Majumdar, Scot Simpson, Ellen Toth
Institute of Health Economics (Merck Foundation Pharmaceutical Policy Program Grant)
Alberta Heritage Foundation for Medical Research
Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with metformin use compared to sulfonylurea monotherapy in type 2 diabetes mellitus. Diabetes Care 2002;25:2244-2248.
Yee A, Majumdar SR, Simpson SH, McAlister FA, Tsuyuki RT, Johnson JA. Statin use in type 2 diabetes mellitus is associated with a delay in starting insulin. Diab Med 2004;21:962-7.
Johnson JA, Simpson SH, Toth EL, Majumdar SR. Reduced Cardiovascular Morbidity and Mortality Associated with Metformin Use in Subjects with Type 2 Diabetes. Diab Med 2005;22:497–502.