Diabetes mellitus, fasting glucose, and risk of cause-specific death

Abstract

Background: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

Methods: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

Results: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.

Conclusions: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

Figure 1. Hazard Ratios for Death from Cancer and from Noncancer, Nonvascular Causes among Participants with Diabetes as Compared with Those without Diabetes at Baseline

Panel A shows hazard ratios for deaths from cancer, and Panel B shows hazard ratios for deaths from noncancer, nonvascular causes. With the exception of the classifications “site unspecified or other” in Panel A and “other noncancer, nonvascular deaths” in Panel B, causes of death are presented in descending order according to their estimated hazard ratios. All analyses were stratified on the basis of study, sex, and trial group (where applicable) and adjusted for baseline age, smoking status (current smoker vs. any other status), and body-mass index. There was evidence of heterogeneity in hazard ratios among cancer sites and among the noncancer, nonvascular causes of death (P<0.001 for both comparisons). Participants with known preexisting cardiovascular disease at baseline were excluded from all analy ses. The sizes of the data markers are proportional to the inverse of the variance of the log_e hazard ratios. In Panel A, risk estimates for cancer of the colorectum were broadly similar to those for cancer at subsites (i.e., colon cancer vs. cancer of the rectosigmoid and anus). In Panel B, death from endocrine disorders does not include death coded as being due to diabetes. Other noncancer, nonvascular deaths are those that could not be attributed to a major organ or system. COPD denotes chronic obstructive pulmonary disease.

Figure 2. Hazard Ratios for Major Causes of Death, According to Baseline Levels of Fasting Glucose

History of diabetes at baseline was defined according to a self-reported history of diabetes or treatment for diabetes. Glucose levels for participants without a known history of diabetes at baseline were classified as less than 4.0, 4.0 to less than 4.5, 4.5 to less than 5.0, 5.0 to less than 5.5, 5.5 to less than 6.0, 6.0 to less than 6.5, 6.5 to less than 7.0, 7.0 to less than 7.5, and 7.5 mmol per liter or higher. Hazard ratios were plotted against the mean fasting glucose level in each group (reference category, 5.0 to <5.5 mmol per liter). The sizes of the data markers are proportional to the inverse of the variance of the log_e hazard ratios. All analyses were stratified or adjusted for sex and adjusted for baseline age, smoking status (current smoker vs. any other status), and body-mass index. Participants with known preexisting cardiovascular disease at baseline were excluded from all analyses. To convert values for fasting glucose to milligrams per deciliter, divide by 0.05551.

Figure 3. Diabetes and Survival, According to Sex and Diabetes Status

Panel A shows estimated survival curves that were plotted by applying hazard ratios for death from any cause (specific for sex and age at risk) from the present analyses to mortality data for the European Union in 2000. Panel B shows the estimated numbers of years of life lost owing to diabetes. Participants with known preexisting cardiovascular disease at baseline were excluded from both analyses.