Diabetes Mellitus-Related All-Cause and Cardiovascular Mortality in a National Cohort of Adults

Abstract

Background Diabetes mellitus is a risk factor for cardiovascular disease ( CVD ) and has been associated with 2- to 4-fold higher mortality. Diabetes mellitus-related mortality has not been reassessed in individuals receiving routine care in the United States in the contemporary era of CVD risk reduction. Methods and Results We retrospectively studied 963 648 adults receiving care in the US Veterans Affairs Healthcare System from 2002 to 2014; mean follow-up was 8 years. We estimated associations of diabetes mellitus status and hemoglobin A1c (HbA1c) with all-cause and CVD mortality using covariate-adjusted incidence rates and multivariable Cox proportional hazards regression. Of participants, 34% had diabetes mellitus. Compared with nondiabetic individuals, patients with diabetes mellitus had 7.0 (95% CI , 6.7-7.4) and 3.5 (95% CI, 3.3-3.7) deaths/1000-person-years higher all-cause and CVD mortality, respectively. The age-, sex-, race-, and ethnicity-adjusted hazard ratio for diabetes mellitus-related mortality was 1.29 (95% CI, 1.28-1.31), and declined with adjustment for CVD risk factors (hazard ratio, 1.18 [95% CI, 1.16-1.19]) and glycemia (hazard ratio, 1.03 [95% CI, 1.02-1.05]). Among individuals with diabetes mellitus, CVD mortality increased as HbA1c exceeded 7% (hazard ratios, 1.11 [95% CI, 1.08-1.14], 1.25 [95% CI, 1.22-1.29], and 1.52 [95% CI, 1.48-1.56] for HbA1c 7%-7.9%, 8%-8.9%, and ≥9%, respectively, relative to HbA1c 6%-6.9%). HbA1c 6% to 6.9% was associated with the lowest mortality risk irrespective of CVD history or age. Conclusions Diabetes mellitus remains significantly associated with all-cause and CVD mortality, although diabetes mellitus-related excess mortality is lower in the contemporary era than previously. We observed a gradient of mortality risk with increasing HbA1c >6% to 6.9%, suggesting HbA1c remains an informative predictor of outcomes even if causality cannot be inferred.

Keywords: cardiovascular disease; diabetes mellitus; mortality.

Figure 1

Association between diabetes mellitus and mortality. Diabetes mellitus is associated with higher all‐cause and cardiovascular mortality. A, Incidence rate of mortality in unadjusted models and with adjustment for age, sex, race, ethnicity, body mass index (BMI), non–high‐density lipoprotein (non‐HDL) cholesterol, systolic blood pressure, and smoking status. B, Estimated survival probabilities of all‐cause and cardiovascular mortality in individuals without and with diabetes mellitus in models adjusted for age, sex, race, ethnicity, BMI, non‐HDL cholesterol, systolic blood pressure, and smoking status (outcomes occurring in the first 2 years of follow‐up were censored). C, Diabetes mellitus is associated with increased incidence of all‐cause and cardiovascular mortality in individuals without and with prior cardiovascular disease (CVD). D, Adjusted risk difference of mortality, relative to individuals without diabetes mellitus, in individuals with diabetes mellitus with and without prior CVD.

Figure 2

Association between hemoglobin A1c (HbA1c) and mortality. HbA1c is associated with all‐cause and cardiovascular mortality after accounting for modifiable cardiovascular disease (CVD) risk factors. A, Incidence rate of all‐cause and cardiovascular mortality across categories of baseline HbA1c in models adjusted for age, sex, race, ethnicity, body mass index (BMI), non–high‐density lipoprotein (non‐HDL) cholesterol, systolic blood pressure, smoking status, and diabetes mellitus and blood pressure treatment. B, Adjusted risk difference of all‐cause and cardiovascular mortality, relative to individuals with HbA1c 6% to 6.9%, in individuals across categories of baseline HbA1c, stratified by baseline CVD history. Association between HbA1c category and short‐ and long‐term all‐cause and cardiovascular mortality in Cox proportional hazards models, adjusted for age, sex, race, ethnicity, BMI, non‐HDL cholesterol, systolic blood pressure, smoking status, CVD history, and diabetes mellitus and blood pressure treatment (C), and stratified by CVD history (D).

Figure 3

Age‐stratified association between hemoglobin A1c (HbA1c) and mortality. Association between HbA1c and mortality accounting for modifiable cardiovascular disease risk factors and stratified by baseline age (<65 or ≥65 years). A, Incidence rate of all‐cause and cardiovascular mortality across categories of baseline HbA1c in individuals <65 and ≥65 years of age, adjusting for age, sex, race, ethnicity, body mass index (BMI), non–high‐density lipoprotein (non‐HDL) cholesterol, systolic blood pressure, smoking status, and diabetes mellitus and blood pressure treatment. B, Adjusted risk difference of all‐cause and cardiovascular mortality, relative to individuals with HbA1c 6% to 6.9%, in individuals across categories of baseline HbA1c, stratified by age at baseline. C, Association between HbA1c category and short‐ and long‐term all‐cause and cardiovascular mortality in Cox proportional hazards models, adjusted for age, sex, race, ethnicity, BMI, non‐HDL cholesterol, systolic blood pressure, smoking status, cardiovascular disease history, and diabetes mellitus and blood pressure treatment, stratified by baseline age.