Baseline characteristics
Baseline characteristics are shown in table 1. 622 018 patients with a mean age of 47.7 (17.9) years were included, of whom 300 979 (48.4%) were men. According to the categorization after the index blood glucose level: 1877 (0.3%) had hypoglycemia, 527 459 (85%) had NGT, 78 416 (13%) had dysglycemia and 14 176 (2%) had hyperglycemia, respectively (Table 1). Patients with hyperglycemia were older and more often male compared to the other groups. The prevalence of hypertension, chronic obstructive pulmonary disease, prior stroke and peripheral arterial disease was more common in patients with hyperglycemia. Patients with dysglycemia and hyperglycemia had the highest prevalence of atrial fibrillation, coronary heart disease, prior revascularization procedure (CABG and PCI) and chronic kidney disease (CDK), compared to the other groups. Patients with dysglycemia were more often treated with statin therapy, aspirin, P2Y12-inhibitors, angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) and oral anticoagulants (OAC) than the other groups.
Early (30-day) outcomes – event, event rates and risk of mortality, myocardial infarction, stroke, and heart failure due to blood glucose level categorization
During the first 30-days a total of 4874 patients died (0.7%): 81 (4.3%) patients with hypoglycemia, 2484 (0.5%) patients with NGT, 1393 (1.8%) patients with dysglycemia and 916 (6.5%) patients with hyperglycemia, respectively. Event, event rates and HRs are all shown in table 2.
Within the first 30-days, after multiple adjustments, patients with hypoglycemia had the highest risk of all-cause mortality HR 9.94 (95% CI 7.95-12:43), followed by patients with hyperglycemia HR 6.92 (95% CI 6.39-7.49), and patients with dysglycemia HR 2.18 (95% CI 2.03-2.33), respectively, compared to patients with NGT. In contrast patients with hyperglycemia had the highest risk of cardiovascular mortality HR 15.22 (95% CI 13.33-17.37) followed by patients with hypoglycemia HR 4.81 (95% CI 2.38-9.70), and patients with dysglycemia HR 2.98 (95% CI 2.62-3.40), compared to patients with NGT (Table 2).
After multiple adjustments, the risk of myocardial infarction, stroke and heart failure was highest among patients with hyperglycemia HR 3.38 (95% CI 3.10-3.69), HR 2.08 (95% CI 1.90-2.26) and HR 2.01 (95% CI 1.75-2.32), respectively, compared to patients with NGT. Corresponding numbers for patients with dysglycemia were HR 1.71 (95% CI 1.61-1.81), HR 1.44 (95% CI 1.36-1.51), and HR 1.21 (95% CI 1.10-1.33), respectively; and for patients with hypoglycemia HR 0.78 (95% CI 0.37-1.65), HR 1.07 (95% CI 0.65-1.78), and HR 0.56 (95% CI 0.21-1.48), respectively, compared to patients with NGT (Table 2).
Long-term outcomes – event, event rate and risk of mortality and myocardial infarction, stroke and heart failure due to blood glucose level categorization
During a mean follow-up time of 3.9 years (maximum 9 years), a total of 45 493 (7.3%) patients died: 218 (12%) with hypoglycemia, 32 127 (6.1%) with NGT, 10 164 (13%) with dysglycemia, and 2 984 (21%) patients with hyperglycemia, respectively. Events, event rate and HRs of mortality, myocardial infarction, stroke and heart failure between categorized groups are shown in table 3. The long-term outcome of mortality is illustrated by a Kaplan Meier curve in figure 1. Long-term outcome of cardiovascular mortality, myocardial infarction, stroke, and hospitalization of heart failure are further illustrated in Kaplan Meier curves (Supplementary material Figure S1).
After multiple adjustments, the relative risk of all-cause mortality was highest among patients with hypoglycemia HR 2.51 (95% CI 2.19-2.87) followed by patients with hyperglycemia HR 1.87 (95% CI 1.80-1.94) and patients with dysglycemia HR 1.23 (95% CI 1.20-1.26), respectively, compared to the reference category of NGT. After multiple adjustments, the relative risk of cardiovascular mortality between groups was much the same as the relative risk for all-cause mortality (Table 3).
For the secondary outcomes, after multiple adjustments, the risk of myocardial infarction, stroke and heart failure were highest among patients with hyperglycemia HR 2.26 (95% CI 2.11-2.41), HR 1.59 (95% CI 1.48-1.70) and HR 1.62 (95% CI 1.49-1.77), respectively, compared to patients with NGT (Table 2). Corresponding numbers were for patients with dysglycemia HR 1.38 (95% CI 1.32-1.44), HR1.21 (95% CI 1.17-1.26) and HR 1.11 (95% CI 1.06-1.17), respectively; and for patients with hypoglycemia HR 0.92 (0.59-1.43), HR 1.17 (0.84-1.64), and 1.08 (0.70-1.66), respectively, compared to patients with NGT (Table 3).
After excluding the first 30-day from the analysis the results were much the same as for the main analysis (Supplementary material Table S2).
Sensitive analysis (competing risk analysis) of long-term outcomes – event, event rate and risk of myocardial infarction, stroke and heart failure due to blood glucose level categorization
The association between blood glucose levels and the relative risk of cardiovascular events with competing risk of death was also investigated. In a competing risk regression analysis, one could see that the sub distribution HRs for myocardial infarction, stroke and heart failure was not statistically affected after this analysis (Supplementary material Table S3).
Mortality and cardiovascular event rates related to sex
Event rates and risk of all-cause mortality, cardiovascular mortality, myocardial infarction, stroke and heart failure due to blood glucose level categorization in women and men, respectively, is presented in table S4 (Supplementary material). Age and sex standardized mortality rate for women was in the hypoglycemia group 57.8 (95% CI 38.0-77.5), NGT group 14.4 (95% CI 13.9-14.8), dysglycemia group 19.5 (95% CI 18.3-20.7) and hyperglycemia group 35.1 (30.6-39.6), calculated per 1000 person-years, respectively. Corresponding numbers for men was in the hypoglycemia group 56.5 (95% CI 37.4-75.6), NGT group 20.3 (95% CI 19.7-20.9), dysglycemia group 24.0 (95% CI 22.7-25.2) and hyperglycemia group 41.6 (95% CI 37.6-45.6) calculated per 1000 person-years, respectively.