Retinopathy Is Associated With Cardiovascular and All-Cause Mortality in Both Diabetic and Nondiabetic Subjects: The Hoorn Study

Diabetic retinopathy has been associated with increased cardiovascular and all-cause mortality risks among diabetic populations (1). The exact mechanism of this association, however, still remains unclear (1). Recently, we reported (2) that hypertension, dyslipidemia, and obesity are associated with retinopathy in diabetic and nondiabetic individuals. Conceivably, these associations with cardiovascular risk factors, which explain the occurrence of retinopathy in a nondiabetic population, may also explain the association of retinopathy and mortality. Therefore, the purpose of this population-based, prospective cohort study was to describe the association of retinopathy with cardiovascular and all-cause mortality in diabetic and nondiabetic individuals. Further investigation was directed toward the contribution of cardiovascular risk factors and risk factors of retinopathy to the association of retinopathy and mortality risk. The study population consisted of an age-, sex-, and glucose tolerance-stratified random sample of the Hoorn Study (n = 631), a study of diabetes and diabetes complications. At baseline, the years 1989–1990, extensive physical and ophthalmological examinations were performed (2). Follow-up on mortality until January 2002 was available (median duration 10.7 years; range 0.5–12.2). Cox proportional hazards analyses were conducted to assess mortality risks and independent contributions of cardiovascular risk factors to the association of retinopathy with mortality. Retinopathy was detected in 85 (44 nondiabetic and 41 diabetic) subjects (13.6%), 88% of whom had nonproliferative retinopathy. During the follow-up period, 157 (25.1%) participants died, 62 (9.9%) of whom had a cardiovascular cause of death. The cardiovascular mortality risks for subjects with retinopathy adjusted for age and sex were 1.75 (0.60–5.08) and 2.20 (1.03–4.70) in nondiabetic and diabetic subjects, respectively. The all-cause mortality risks were 1.43 (0.74–2.79) and 2.05 (1.23–3.44) in nondiabetic and diabetic subjects, respectively. After adjustment for diabetes and diabetes duration, the mortality risks in diabetic subjects were 1.67 (0.72–3.86) for cardiovascular mortality and 1.61 (0.92–2.81) for all-cause mortality. BMI, prior cardiovascular disease, and triglycerides explained smaller portions of the association in diabetic subjects, whereas the mortality risk was only lowered by glycated hemoglobin in nondiabetic subjects. Adjustment for other cardiovascular risk factors, such as hypertension, smoking, and homocysteine, did not considerably change the estimates. Finally, after adjustment for all explanatory risk factors in diabetic and nondiabetic subjects together, a 1.4-fold (0.7–2.8) higher risk for cardiovascular mortality and a 1.4-fold (0.9–2.1) higher risk for all-cause mortality in subjects with retinopathy remained unexplained. The contribution of several cardiovascular risk factors to the increased risk of (cardiovascular) mortality might suggest shared pathophysiological mechanisms in microvascular and macrovascular disorders. Other mechanisms that could possibly contribute to the unexplained 40% increased mortality risk include inflammation, endothelial dysfunction, or advanced glycation end products.