Insulin use and increased risk of mortality in type 2 diabetes: a cohort study

Methods: Using the administrative databases of Saskatchewan Health, 12272 new users of oral antidiabetic therapy were identified between 1991 and 1996 and grouped according to cumulative insulin exposure based on total insulin dispensations per year: no exposure (reference group); low exposure (0 to < 3); moderate exposure (3 to < 12) and high exposure (>= 12). Time-varying multivariable Cox proportional hazards models were used to examine the relationship between insulin exposure and all-cause, CV-related and non-vascular mortality after adjustment for demographics, medications and comorbidities. Results: Average age was 65 (s.d. 13.9) years, 45% were female, and mean follow-up was 5.1 (s.d. 2.2) years. In total, 1443 (12%) subjects started insulin, and 2681 (22%) deaths occurred. The highest mortality rates were in the high exposure group; 95 deaths/1000 person-years compared with 40 deaths/1000 person-years in the no exposure group [unadjusted hazard ratio (HR): 2.32; 95% confidence interval (CI): 1.96-2.73]. After adjustment, we observed a graded risk of mortality associated with increasing exposure to insulin: low exposure [adjusted HR (aHR): 1.75; 95% CI: 1.24-2.47], moderate exposure (aHR: 2.18; 1.82-2.60) and high exposure (aHR: 2.79; 2.36-3.30); p = 0.005 for trend. Analyses restricted to CV-related (p = 0.042 for trend) and non-vascular (p = 0.004 for trend) mortality showed virtually identical results. Conclusions: We observed a significant and graded association between mortality risk and insulin exposure level in an inception cohort of patients with type 2 diabetes that persisted despite multivariable adjustment.