Diabetes is independently associated with premature death from numerous causes, including several nonvascular causes, according to findings from an analysis of individual-participant data from 97 prospective studies.
The risk of death from any cause was increased in 40,116 patients with diabetes, compared with 674,945 without diabetes (hazard ratio, 1.80), after adjustment for age, sex, smoking status, and body mass index. Similarly, the patients with diabetes also had increased risks of death from cancer (HR, 1.25), vascular causes (HR, 2.32), "other" nonvascular causes not attributed to cancer (HR, 1.73), and deaths of unknown or ill-defined causes (HR, 1.88), investigators reported in the March 3 issue of the New England Journal of Medicine.
Specific cancers that were found in this study to be moderately associated with premature death in diabetes patients vs. nondiabetes patients were liver, pancreas, ovary, colorectum, bladder, lung, and breast cancer (HRs, 2.16, 1.51, 1.45, 1.40, 1.40, 1.27 and 1.25, respectively), reported Dr. Sreenivasa Rao Kondapally Seshasai of the University of Cambridge (England) and colleagues from the Emerging Risk Factors Collaboration (ERFC).
"Other" causes of death in diabetes patients vs. nondiabetes patients included 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, the investigators found (N. Engl. J. Med. 2011;364:829-41).
"These hazard ratios were not appreciably reduced after additional adjustment for systolic blood pressure, lipid levels, C-reactive protein levels, fibrinogen levels, alcohol use, estimated glomerular filtration rate, or indicators of socioeconomic status," the investigators said.
The hazard ratios were, however, reduced considerably after adjustment for fasting glucose or glycated hemoglobin levels, they noted.
Fasting glucose levels exceeding 100 mg/dL – but not levels of 70-100 mg/dL – were associated with excess risk of mortality.
In this study, middle-aged adults with diabetes but without known vascular disease at the time of enrollment generally died earlier than did those without diabetes.
"At 40, 50, and 60 years of age, men with diabetes but without a history of vascular disease would incur about 6.3, 5.8, and 4.5 years of life lost, respectively. The corresponding years of life lost for women with diabetes in middle age were 6.8, 6.4, and 5.4 years, respectively," the investigators wrote. They noted that about 58%, 9%, and 30% of the survival difference at 50 years between those with and without diabetes was attributable to excess vascular, cancer, and noncancer nonvascular deaths, respectively. The number of years of life lost because of diabetes was close to the 7-year reduction in life expectancy among long-term cigarette smokers.
About 40% of the years of life lost as a result of diabetes were attributable to nonvascular conditions, including about 10% attributable to cancer-related death, they said.
The finding of "generally continuous associations" between fasting glucose levels above 100 mg/dL and death suggests that hyperglycemia or a similar factor has direct relevance to the association between diabetes and premature death from these various causes – a finding that is also supported by the "substantial attenuation observed in hazard ratios for death from diabetes after adjustment for markers of glycemia," they added.
In contrast, other risk factors (such as blood pressure, adiposity, inflammation, insulin, and renal function) do not appear to be major mediators of the excess risk of death.
The ERFC is a collaboration that has previously published reports on the associations between lipids, lipoproteins, and inflammatory markers and the risk of vascular disease and cause-specific death. In 2009, the group extended its focus to include analyses of diabetes and other metabolic markers as they relate to incident vascular disease outcomes and cause-specific death. For the current study, the collaboration analyzed individual-participant data from prospective studies with information on diabetes diagnosis or fasting baseline blood-glucose levels. Studies included in the analysis did not select participants on the basis of having previous chronic disease; they did, however, record cause-specific death classified according to clearly defined criteria, and accrued more than 1 year of follow-up data.
The current analysis included 820,900 participants from those studies, of whom 123,205 died. The average age of participants was 55 years, and 48% were women.
The findings of this study have several implications, the investigators said.
For example, the association that was observed between diabetes and deaths resulting from mental and neurologic disease requires further study, with investigation into the possible link between diabetes and onset of depression (especially in light of the association between diabetes and death resulting from intentional self-harm). The findings also reinforce the need for people with diabetes to seek appropriate cancer screenings.