Associations of three diagnostic glycemic measures with all-cause and cardiovascular mortality in people not on antidiabetic medications: A prospective cohort study

Objective: This study aimed to investigate the value of three diagnostic glycemic measures, i.e., 2-hour plasma glucose (2hPG) during 75-g oral glucose tolerance test, fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c), in predicting risk of all-cause and cardiovascular mortality after adjusting for the influence of these glycemic measures on each other. Methods: A total of 14,013 U.S. adults who were not on antidiabetic medications when recruited were identified from the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES 2005-2016. High blood glucose was defined as 2hPG >= 11.1 mmol/L, FPG >= 7.0 mmol/L, or HbA1c >= 6.5 %, according to the American Diabetes Association 2023 standards. Two approaches were adopted to examine the value of each glycemic measure in predicting mortality risk while controlling the influence of the other two measures: (1) adjusting for 2hPG, HbA1c, and FPG in the same model, and (2) comparing individuals showing isolated elevation of 2hPG, HbA1c, or FPG with those being "normal" for all the three measures. Major non-glycemic risk factors were adjusted for in the multivariable regression analyses. Results: During a median follow-up of 9.8 years, 2869 participants died, and 960 of the deaths were attributed to cardiovascular causes. When included in the model individually, elevated 2hPG, FPG, and HbA1c were all predictive of both all-cause and cardiovascular mortality (adjusted hazard ratios ranging from 1.32 to 1.55, all p values <0.05). After controlling the influence of the other two glycemic measures, elevated 2hPG was still statistically significantly associated with the outcomes (adjusted hazard ratios ranging from 1.04 to 1.33, depending on analytical approaches), whereas elevated FPG was not, and HbA1c was associated with cardiovascular mortality only when treated as a continuous variable and when 2hPG and FPG levels were in the normal range (adjusted hazard ratio 1.27 [1.04-1.55] for 1 % increase in HbA1c). Conclusions: 2hPG, FPG, and HbA1c were all predictive of all-cause and cardiovascular mortality when used alone, but when combined only 2hPG retained its predictive value for both outcomes while HbA1c predicted cardiovascular mortality only when used as a continuous variable and when 2hPG and FPG were in the normal range.