The present study evaluated the association between preoperative hemoglobin A1c (HbA1c) levels and cardiovascular outcomes in patients with type 2 diabetes mellitus (DM) treated with hypoglycemic agents and undergoing coronary revascularization. We conducted a multicenter registry of Japanese patients undergoing first elective coronary revascularization. The present study included 3,571 patients whose HbA1c value at the index hospitalization was available. Of the 3,571 patients, 2,067 did not have DM and 1,504 had type 2 DM. Of the patients with type 2 DM, 202 had a HbA1c level of <6% (very low HbA1c group [VLG]), 426 had a HbA1c level of ≥6% but <7% (low HbA1c group), 405 had a HbA1c level of ‘7% but <8% (intermediate HbA1c group), and 471 had a HbA1c level of ≥8% (high HbA1c group). The patients with type 2 DM treated with diet only were not included in the present study. The VLG had the lowest rate of freedom from major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. On multivariate analyses, the low HbA1c group had the lowest hazard ratio for MACE relative to those without DM (hazard ratio 1.13, 95% confidence interval 0.80 to 1.55). The VLG, intermediate HbA1c group, and high HbA1c group were significantly associated with an increased risk of MACE. On multivariate analyses of patients with DM using the low HbA1c group as a reference, a high HbA1c group level was significantly associated with an increased risk of MACE. The VLG and intermediate HbA1c group tended to be associated with an increased risk of MACE (VLG, hazard ratio 1.54, 95% confidence interval 0.98 to 2.40; intermediate HbA1c group, hazard ratio 1.44, 95% confidence interval 0.98 to 2.13). In conclusion, patients with type 2 DM treated with hypoglycemic agents and undergoing first elective coronary revascularization had significantly worse cardiovascular outcomes than patients without DM, except for patients with DM and a HbA1c of 6% to 7%. In the patients with DM, those with a HbA1c of 6% to 7% tended to have the lowest risk of MACE.
Diabetes mellitus (DM) is associated with worse long-term cardiovascular outcomes after coronary revascularization, including both percutaneous coronary intervention and coronary artery bypass grafting. However, the effect of the preoperative glycemic level on long-term outcomes among patients with DM after coronary revascularization has not been fully studied. The level of hemoglobin A1c (HbA1c), also known as glycosylated hemoglobin, is a marker for the average blood glucose concentrations during the 2 to 3 months before measurement and has strong predictive value for DM complications. The current guidelines of the American Diabetes Association have recommended that the HbA1c goal should be, in general, <7%, which is associated with a lower risk of DM complications. However, it is still controversial whether glucose lowering reduces the risk of cardiovascular disease. Therefore, the purpose of the present study was to evaluate whether the glycemic level, as determined by the HbA1c level at the index procedure, has an effect on cardiovascular disease outcomes after a first elective coronary revascularization in patients with type 2 DM treated with oral hypoglycemic agents or insulin injection in a large-scale multicenter registry in Japan.
Methods
The Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) is a multicenter registry in Japan enrolling consecutive patients who had undergone their first coronary revascularization from January 2000 to December 2002. Patients with acute myocardial infarction within 1 week after study onset were not included. A total of 30 institutions participated in the registry, and baseline and follow-up data were obtained for 9,877 patients. A detailed protocol of CREDO-Kyoto registry has been previously reported. The institutional review boards or ethics committees at all participating institutions approved the present study.
HbA1c levels at the index hospitalization were available for 4,741 patients. Of the 4,741 patients, 497 with untreated DM, 347 with DM treated by diet alone, 74 with malignant disease, and 22 patients with type 1 DM were excluded from the analysis. Shortened red blood cell survival is likely to lower the HbA1c level, because the time needed for glucose to chemically bond with red blood cells is decreased, making it unreliable for assessing glycemic control. Therefore, HbA1c measurement might underestimate long-term glycemic control in patients with hemolytic disease, such as liver cirrhosis, and in patients receiving erythropoietin for end-stage renal disease. Thus, 146 patients with liver cirrhosis and 196 patients undergoing hemodialysis were excluded from the present analysis. Therefore, 3,571 patients (2,067 without DM and 1,504 with type 2 DM treated with oral hypoglycemic agents or insulin injection) were included in the present analyses. These patients were divided into 5 groups according to their DM and baseline glycemic levels: 2,067 patients without DM, 202 with type 2 DM and a HbA1c level <6% (very low HbA1c group [VLG]), 426 with type 2 DM and a HbA1c level of ≥6% but <7% (low HbA1c group [LG]), 405 with type 2 DM and a HbA1c level of ≥7% but <8% (intermediate HbA1c group [IG]) and 471 with type 2 DM and a HbA1c of ≥8% (high HbA1c group [HG]).
The baseline clinical, demographic, and angiographic data of the study patients were collected from the hospital charts or databases at each center by independent clinical research coordinators, according to prespecified definitions, as previously described.
According to the current guidelines in Japan, DM was defined as HbA1c of ≥6.5% or casual plasma glucose of ≥200 mg/dl. Patients who were treated with oral hypoglycemic agents or insulin injection or who had been previously diagnosed with DM and received only dietary therapy were also defined as having DM. All measurements of HbA1c were performed in local laboratories at the discretion of the attending physician.
An independent clinical events committee adjudicated the events. All deaths were confirmed by medical records, telephone, or mail, and death was regarded as cardiovascular in origin unless obvious noncardiovascular causes could be identified. Myocardial infarction was adjudicated according to the definition in the Arterial Revascularization Therapy Study. Within 1 week of the index procedure, only Q-wave myocardial infarction was adjudicated as myocardial infarction. Stroke at follow-up was defined as symptomatic stroke.
The study end point was major adverse cardiovascular events (MACE) defined as the composite of cardiovascular death, myocardial infarction, and stroke.
All continuous variables are presented as the mean ± SD. The statistical significance of differences in baseline demographics among the different groups was assessed using Student’s t test for parametrically distributed continuous variables, Wilcoxon’s test for nonparametrically distributed continuous variables or the Pearson chi-square test for categorized variables. We used Kaplan-Meier estimates to calculate the unadjusted event-free survival curves. Data for patients who were lost to follow-up were censored at the day of the last contact. The log-rank test was used to assess significant differences in unadjusted survival rates. To estimate the hazard ratios for MACE associated with the different categories of HbA1c levels relative to patients without DM, multivariate Cox proportional hazard models were developed using the patients without DM as a reference. Multivariate Cox proportional hazard models among the patients with DM were also developed using the low HbA1c group as a reference. To determine the baseline risk factors for MACE, we conducted log-rank tests for the following variables: age ≥75 years, gender, mode of revascularization, body mass index, history of myocardial infarction, history of congestive heart failure, and history of stroke, peripheral arterial disease, valvular heart disease, current smoker, chronic obstructive pulmonary disease, hypertension, dyslipidemia, chronic kidney disease, anemia, multivessel coronary disease, and use of medications such as statins, antiplatelets, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, β-adrenergic blockers, nitrates, calcium channel blockers, insulin, sulfonylureas, and α-glucosidase inhibitors. All continuous variables were dichotomized to fit proportional assumptions according to the predetermined clinical contexts. We plotted the log (time) versus log [−log (survival)] stratified by each significant risk factor and evaluated whether the plotted lines were parallel, which attested to the proportional assumption. Those variables for which p <0.05 on univariate analyses and for which the proportional assumptions were generally fair were included in the multivariate analysis. Variables common to both models included age ≥75 years, a history of congestive heart failure and stroke, peripheral arterial disease, valvular heart disease, hypertension, chronic kidney disease, anemia, multivessel coronary disease, and the use of antiplatelets. The multivariate models using the patients without DM as a reference also included the mode of revascularization, dyslipidemia, and the use of statins. The multivariate models of the patients with DM using the low HbA1c group as a reference also included the use of insulin, sulfonylureas, and β-adrenergic blockers.
All analyses were conducted using JMP IN, version 5.1 (SAS Institute, Cary, North Carolina). All reported p values were 2-sided, and p <0.05 was considered significant. To adjust for the multiple comparison among the 4 DM groups using the non-DM group as a reference, we used p values <0.0125 (0.05/4) as a significant criterion for the comparisons.
Results
The patients were followed up with respect to mortality for a median of 1,278 days (interquartile range 979 to 1,583), with a 96% follow-up rate at 2 years.
Table 1 lists the baseline characteristics. The patients with DM tended to be younger, women, and noncurrent smokers and to have anemia, dyslipidemia, multivessel coronary disease, and a history of myocardial infarction, stroke, and heart failure. The patients with DM were more likely to have undergone coronary artery bypass grafting and less likely to have valvular heart disease. Table 2 lists the baseline characteristics of the patients with DM. The VLG tended to be older and to have anemia, hypertension, valvular heart disease, chronic kidney disease, and a history of stroke. The intermediate HbA1c group was more likely to have peripheral vascular disease. The high HbA1c group tended to be younger and current smokers. The high HbA1c group was more likely to have undergone percutaneous coronary intervention and less likely to have anemia, hypertension, chronic kidney disease, peripheral vascular disease, or a history of stroke. The proportion of insulin users at admission increased as the HbA1c levels increased.
| Variable | Diabetes Mellitus | p Value | |
|---|---|---|---|
| No (n = 2,067) | Yes (n = 1,504) | ||
| Age (years) | 67.1 ± 10.3 | 66.6 ± 9.1 | 0.14 |
| Patients ≥75 years old | 24.6% | 19.9% | 0.0008 |
| Men | 71.8% | 64.8% | <0.0001 |
| Body mass index (kg/m 2 ) | 23.8 ± 3.3 | 23.9 ± 3.3 | 0.28 |
| Patients with body mass index ≥25 kg/m 2 | 32.0% | 33.0% | 0.49 |
| Percutaneous coronary intervention | 75.0% | 64.9% | <0.0001 |
| Current smoker | 31.2% | 25.7% | 0.0004 |
| Hemoglobin A1c (%) | 5.3 ± 0.4 | 7.5 ± 1.5 | <0.0001 |
| Previous myocardial infarction | 27.7% | 31.9% | 0.008 |
| Previous heart failure | 15.0% | 20.8% | <0.0001 |
| Previous stroke | 13.4% | 19.4% | <0.0001 |
| Peripheral vascular disease | 6.3% | 5.6% | 0.35 |
| Valvular heart disease | 9.3% | 7.1% | 0.016 |
| Hemoglobin <12 g/dl | 20.7% | 29.7% | <0.0001 |
| Chronic obstructive pulmonary disease | 2.4% | 2.5% | 0.93 |
| Hypertension | 67.6% | 67.4% | 0.89 |
| Dyslipidemia (total cholesterol ≥220 mg/dl) | 51.2% | 54.6% | 0.041 |
| Chronic kidney disease (glomerular filtration rate <60 ml/min) | 36.5% | 39.3% | 0.091 |
| Left main trunk disease | 8.3% | 9.3% | 0.30 |
| Multivessel coronary disease | 58.1% | 75.9% | <0.0001 |
| Variable | Hemoglobin A1c (%) | p Value | |||
|---|---|---|---|---|---|
| <6 (n = 202) | ≥6 but <7 (n = 426) | ≥7 but <8 (n = 405) | ≥8 (n = 471) | ||
| Age (years) | 68.2 ± 9.0 | 67.0 ± 8.3 | 66.8 ± 9.0 | 65.5 ± 9.6 | 0.0029 |
| Patients ≥75 years old | 26.7% | 19.0% | 20.5% | 17.2% | 0.039 |
| Men | 62.4% | 68.1% | 64.2% | 63.5% | 0.40 |
| Body mass index (kg/m 2 ) | 23.7 ± 3.2 | 23.9 ± 3.3 | 23.9 ± 3.1 | 24.0 ± 3.4 | 0.64 |
| Body mass index ≥25 kg/m 2 | 30.0% | 36.5% | 30.9% | 33.1% | 0.26 |
| Percutaneous coronary intervention | 60.9% | 60.3% | 67.4% | 68.6% | 0.026 |
| Current smoker | 21.3% | 23.0% | 22.3% | 33.1% | 0.0002 |
| Insulin use | 18.8% | 23.7% | 31.1% | 36.5% | <0.0001 |
| Previous myocardial infarction | 27.7% | 33.1% | 33.3% | 31.2% | 0.50 |
| Previous heart failure | 23.4% | 22.5% | 21.1% | 18.1% | 0.29 |
| Previous stroke | 25.3% | 19.3% | 20.5% | 16.1% | 0.048 |
| Peripheral vascular disease | 6.9% | 5.4% | 7.7% | 3.4% | 0.040 |
| Valvular heart disease | 13.9% | 6.1% | 5.9% | 6.0% | 0.0009 |
| Hemoglobin <12 g/dl | 41.7% | 29.4% | 30.7% | 23.8% | <0.0001 |
| Chronic obstructive pulmonary disease | 4.0% | 2.6% | 2.0% | 2.1% | 0.47 |
| Hypertension | 71.6% | 70.9% | 67.9% | 62.0% | 0.016 |
| Dyslipidemia (total cholesterol ≥220 mg/dl) | 52.0% | 50.8% | 55.6% | 58.4% | 0.12 |
| Chronic kidney disease (glomerular filtration rate <60 ml/min) | 50.3% | 43.9% | 39.4% | 30.4% | <0.0001 |
| Left main trunk disease | 9.9% | 10.8% | 5.9% | 10.6% | 0.054 |
| Multivessel coronary disease | 71.3% | 77.0% | 78.0% | 75.2% | 0.29 |
Table 3 lists the medications prescribed at hospital discharge. The prescription rate for β-adrenergic blockers was significantly lower in the high HbA1c group than in the other groups. No significant difference was found in the prescription rate for oral hypoglycemic agents among the patients with DM.
| Medication | No DM | Patients With DM | p Value | |||
|---|---|---|---|---|---|---|
| Hemoglobin A1c (%) | ||||||
| <6 (n = 202) | ≥6 but <7 (n = 426) | ≥7 but <8 (n = 405) | ≥8 (n = 471) | |||
| Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers | 33.7% | 39.3% | 34.7% | 38.4% | 36.7% | 0.21 |
| β-Adrenergic blockers | 20.1% | 17.4% | 19.7% | 19.3% | 13.4% | 0.020 |
| Calcium channel blockers | 56.7% | 60.7% | 61.0% | 57.2% | 58.6% | 0.45 |
| Antiplatelets | 95.0% | 93.0% | 94.8% | 95.3% | 95.3% | 0.77 |
| Statins | 31.1% | 31.3% | 29.6% | 35.6% | 33.9% | 0.26 |
| Oral hypoglycemic agents | ||||||
| α-Glucosidase inhibitors | — | 23.4% | 24.9% | 28.2% | 29.2% | 0.29 |
| Sulfonylureas | — | 46.3% | 48.8% | 52.5% | 46.1% | 0.25 |
| Thiazolidinediones | — | 0.5% | 2.1% | 2.5% | 1.7% | 0.38 |
| Nateglinides | — | 2.0% | 2.4% | 1.7% | 0.9% | 0.36 |
| Biguanides | — | 1.5% | 2.6% | 3.7% | 2.6% | 0.44 |
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