Glycemic Control in Type 1 Diabetes and Long-Term Risk of Cardiovascular Events or Death After Coronary Artery Bypass Grafting

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Glycemic Control in Type 1 Diabetes

and Long-Term Risk of

Cardiovascular Events or Death After

Coronary Artery Bypass Grafting

Thomas Nyström, MD, PHD,*yMartin J. Holzmann, MD, PHD,zxBjörn Eliasson, MD, PHD,k Jeanette Kuhl, MD, PHD,{#Ulrik Sartipy, MD, PHD**yy

ABSTRACT

BACKGROUNDPatients with type 1 diabetes mellitus (T1DM) have a high risk of cardiovascular events.

OBJECTIVESThe aim of this study was to investigate whether preoperative hemoglobin A1c(HbA1c) levels could predict cardiovascular events or death after coronary artery bypass grafting (CABG).

METHODSThis was a nationwide population-based observational cohort study that included all patients with T1DM who underwent primary isolated nonemergency CABG in Sweden between 1997 and 2012, according to the Swedish National Diabetes Register and the SWEDEHEART (Swedish Web-system for Enhancement and Develop-ment of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register. We calculated the crude incidence rates and 95% confidence intervals (CIs) and used Cox regression and multivariable hazard ratios (HRs) to estimate the risk of both all-cause mortality and major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, heart failure, or repeat revascularization, in relation to HbA1clevels.

RESULTSIn total, 764 patients with T1DM were included. During a median follow-up of 4.7 years, 334 (44%) patients died or had MACE (incidence rate: 82 events/1,000 person-years). After multivariable adjustment, the HR (95% CI) for death or MACE in patients with HbA1clevels of 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and>10.0% were 1.34 (0.82 to 2.21), 1.59 (1.00 to 2.54), 1.73 (1.03 to 2.90), and 2.25 (1.29 to 3.94), respectively, compared with the reference category. When HbA1cwas used as a continuous variable, the HR for a 1% increase in HbA1clevel was 1.18, and the 95% CI was 1.06 to 1.32.

CONCLUSIONSIn patients with T1DM, poor glycemic control before CABG was associated with increased

long-term risk of death or MACE. (HeAlth-data Register sTudies of Risk and Outcomes in Cardiac Surgery [HARTROCS]; NCT02276950) (J Am Coll Cardiol 2015;66:535–43) © 2015 by the American College of Cardiology Foundation.

From the *Department of Clinical Science and Research, Karolinska Institutet, Stockholm, Sweden;yDivision of Internal Medicine, Södersjukhuset, Stockholm, Sweden;zDepartment of Emergency Medicine, Karolinska University Hospital, Stockholm, Sweden; xDepartment of Internal Medicine, Karolinska Institutet, Stockholm, Sweden; kInstitute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden;{Department of Cardiovascular Medicine, Danderyds Hospital, Stockholm, Sweden; #Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden; **Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden; and theyyDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. This study was supported by grants from the Swedish Society of Medicine to Drs. Holzmann, Kuhl, and Sartipy; Karolinska Institutet Foundations and Funds to Dr. Sartipy; the Mats Kleberg Foundation to Dr. Sartipy, and the Swedish Heart and Lung Foundation to Dr. Nyström. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

Manuscript received January 15, 2015; revised manuscript received May 11, 2015, accepted May 19, 2015.

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A

dvances in treatment for type 1 dia-betes mellitus (T1DM) have improved life expectancy and decreased mor-tality rates over time (1). Despite declining rates of diabetes-associated complications in the past 2 decades(2), the disease persists in large numbers, and the prevalence of cardio-vascular disease (CVD), the most common complication among patients with diabetes, remains very high (3). Abnormal vascular findings associated with atherosclerosis are much more common in patients with T1DM compared with nondiabetic patients(4). The risk of CVD events is high and occurs earlier in patients with T1DM; incidence rates of deaths, even in patients with T1DM who have good glycemic control, are reached at a much younger age compared with the general population(5,6).

Revascularization surgery for patients with multi-vessel coronary heart disease (CHD) is a common procedure; approximately 25% of these patients have diabetes. Patients with diabetes and established CHD often have more complicated atherosclerosis and are at higher risk of developing major adverse CVD events and death than are patients without diabetes(7–10). Revascularization studies have evaluated patients on the basis of various categorizations, including the presence or absence of diabetes(8,9) and the pres-ence of insulin-dependent or not insulin-dependent diabetes(7). In patients with T1DM and CHD, the as-sociation between glycemic control and

cardiovas-cular outcomes after revascularization remains

unclear(11). Because patients with T1DM have a high

risk of CVD events and death (5), we wanted to

investigate whether different levels of glycemic con-trol could predict CVD events after coronary artery bypass graft (CABG) procedures in these patients.

The aim of this study was to analyze the associa-tion between preoperative hemoglobin A1c (HbA1c)

levels and combined all-cause mortality and

myocardial infarction, heart failure, stroke, or repeat revascularization in patients with T1DM who were undergoing primary isolated nonemergency CABG. METHODS

STUDY DESIGN. This was an observational nation-wide population-based cohort study. The study was approved by the regional Human Research Ethics Committee, Stockholm, Sweden.

STUDY POPULATION. The study population was

obtained by cross-referencing patient-level data

from the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Rec-ommended Therapies) register(12)and the National Diabetes Register (13). All patients with T1DM (ac-cording to the Swedish National Diabetes Register) who underwent primary isolated nonemergency CABG in Sweden between 1997 and 2012 were in-cluded. Further information regarding baseline char-acteristics was extracted from the National Patient Register. Cross-referencing was possible through the unique personal identity number assigned to every Swedish citizen(14). The epidemiological definition of T1DM in the Swedish National Diabetes Register is onset of diabetes before the age of 30 years and treatment with insulin only(13).

HEMOGLOBIN A1C. Analyses of HbA1c were carried out at local laboratories with the high-performance liquid chromatography Mono-S method and were quality assured nationwide by regular calibration. We converted all HbA1c values to standard values ac-cording to the National Glycohemoglobin Standardi-zation Program (15). We calculated the mean of all available HbA1c values before the date of CABG for each patient(16). On the basis of their preoperative mean HbA1cvalues, patients were assigned to 1 of the following HbA1c categories: #7.0%, 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and>10.0%.

OUTCOMES. The primary outcome measure was a

combination of all-cause mortality and major adverse cardiovascular event (MACE), defined as rehospitali-zation for a primary diagnosis of myocardial infarc-tion (Internainfarc-tional Classification of Diseases-Tenth Revision [ICD-10] codes: I21 to I21.9), heart failure (ICD-10 codes: I50 to I50.9), stroke (ICD-10 codes: I60 to I69.9), or repeat revascularization (ICD-10 codes: FNG, FNA, FNC). The date and cause of death were obtained from the national Cause of Death Register; the date and cause of rehospitalization were obtained from the National Patient Register. The validity of the diagnoses of myocardial infarction, heart failure, and stroke has been evaluated in the National Patient Register and found to be 95% for a primary diagnosis of heart failure; the positive predictive value is 98% to 100% for myocardial infarction and 98.6% for stroke (17,18). We also assessed death from cardio-vascular and noncardiocardio-vascular causes separately. Finally, the following ICD-10 codes were used to analyze hospitalizations for hypoglycemia: E10.0, E10.6, and E16 to E16.2.

MISSING DATA.We excluded patients with missing information regarding preoperative HbA1c. For the following variables that were used as covariates in the SEE PAGE 544

A B B R E V I A T I O N S A N D A C R O N Y M S

CABG= coronary artery bypass grafting

CHD= coronary heart disease CVD= cardiovascular disease HbA1c= hemoglobin A1c

MACE= major adverse cardiovascular event(s) T1DM= type 1 diabetes mellitus

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multivariable analyses, some data were missing: renal function (7.5%), number of bypass grafts (11%), and left ventricular ejection fraction (34%). We used multiple imputation by chained equations to handle missing data(19). The imputation models included 26 variables, including the event indicator and the Nelson-Aalen estimator of the cumulative baseline hazard(20), under the assumption that the missing values were missing at random. Twenty-five datasets were imputed, and estimates from these datasets were combined according to Rubin’s rules.

STATISTICAL METHODS. Patients’ characteristics were described using frequencies and percentages for categorical variables and using means and standard deviations for continuous variables. The primary outcome measure was death from any cause or hos-pitalization for a MACE (myocardial infarction, heart failure, stroke, or repeat revascularization). Patients contributed person-time in days from the date of the surgical procedure until the date of death from any cause, the date of a MACE, or at the end of the follow-up period (December 31, 2012), whichever occurred first. We calculated the crude incidence rates and 95% confidence intervals (CIs). We used Cox regression to estimate the risk of the combined endpoint all-cause mortality or myocardial infarction, heart failure, stroke, or repeat revascularization according to the following preoperative HbA1c categories: 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and>10.0%, by using HbA1c#7.0% as the reference level. We calcu-lated crude age- and sex-adjusted and multivariable adjusted hazard ratios (HRs) and 95% CIs. All vari-ables listed inTable 1were included as covariates in the final multivariable model. We investigated the potential nonlinear relationship between HbA1c and outcome in a Cox model, where HbA1cwas modeled by restricted cubic splines, and adjusted HRs and 95% CIs were plotted against HbA1c levels. We investi-gated differences in each cause of mortality (cardio-vascular death or noncardio(cardio-vascular causes) by competing risk regression on the basis of the Fine-Gray proportional subhazards model (21), and we calculated subdistribution HRs and 95% CIs. Data management and statistical analyses were performed using Stata version 13.1 (Stata Corp., College Station, Texas) and R version 3.1.2 (R Foundation for Statis-tical Computing, Vienna, Austria).

RESULTS

Baseline patient characteristics are presented in Table 1. The study population included 764 patients, and during a median follow-up time of 4.7 years (interquartile range [IQR]: 1.8 to 8.8 years), 334 (44%)

patients died or had a MACE, for an incidence rate of 82 events per 1,000 person-years (95% CI: 73 to 91). The mean age was highest in the lowest HbA1c cate-gory, and the mean age decreased with increasing preoperative HbA1c level. The proportion of women was highest among those with very poor glycemic control (HbA1c>10.0%). Early mortality (death within 30 days of the surgical procedure) was 4 of 67 (5.6%), 2 of 190 (1.1%), 5 of 296 (1.7%), 2 of 146 (1.4%), and 1 of 65 (1.5%), in the low to high HbA1c categories, respectively.

The age-adjusted freedom from death or MACE is shown inFigure 1. The crude incidence of death or

MACE in patients with preoperative HbA1c

levels #7.0%, 7.1% to 8.0%, 8.1% to 9.0%, 9.1% to 10.0%, and >10.0% was 81 (95% CI: 56 to 116), 76 (95% CI: 61 to 96), 77 (95% CI: 64 to 92), 80 (95% CI: 63 to 103), and 121 (95% CI: 90 to 163) per 1,000 person-years, respectively (Table 2).

No significant association was observed between preoperative HbA1c level and death or MACE in the unadjusted analyses (Table 2). After adjustment for age and sex, patients with high HbA1clevels (i.e., poor glycemic control) had a significantly higher risk of death or MACE compared with patients with low HbA1clevels (#7.0%).

After multivariable adjustment, the HR (95% CI) for death or MACE was 1.34 (0.82 to 2.21) in patients with HbA1cfrom 7.1% to 8.0%, 1.59 (1.00 to 2.54) in patients with HbA1cfrom 8.1% to 9.0%, 1.73 (1.03 to 2.90) in patients with HbA1c from 9.1% to 10.0%, and 2.25 (1.29 to 3.94) in patients with HbA1c>10.0% compared with patients with low HbA1c levels (#7.0%), as shown inTable 2and theCentral Illustration.

The numbers of patients who were hospitalized at least once for hypoglycemia after CABG were 7 of 67 (10%), 15 of 190 (7.9%), 24 of 296 (8.1%), 19 of 146 (13%), and 11 of 65 (17%) in the low to high HbA1c categories, respectively.

DEATH FROM CARDIOVASCULAR AND

NON-CARDIOVASCULAR CAUSES. We also investigated

the relationship between preoperative HbA1c levels

and death from cardiovascular versus

non-cardiovascular causes. In a competing risk regression analysis, we found that the subdistribution HRs for death from cardiovascular and noncardiovascular causes increased with increasing preoperative HbA1c levels. However, because of the relatively low num-ber of events, these risk estimates were not signifi-cant (Figure 2).

NONLINEAR RELATIONSHIP BETWEEN HBA1C AND

PROGNOSIS. We analyzed the potential nonlinear relationship between HbA1clevel and risk of death or

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MACE by entering HbA1cmodeled with restricted cubic splines in an age- and sex-adjusted Cox regression model. As shown in theCentral Illustration, a very small risk increase was found in the HbA1crange from 6.0% to 8.5%. However, a steep increase in the risk of death

or MACE was noted for each 1% increase in HbA1clevel >8.5%. When HbA1cwas used as a continuous variable in a Cox model adjusted for all variables shown in Table 1, the HR for an absolute 1% increase in HbA1c level was 1.18 (95% CI: 1.06 to 1.32; p¼ 0.002). TABLE 1 Baseline Characteristics of 764 Patients With Type 1 Diabetes Who Underwent Primary Isolated Coronary Artery Bypass Grafting, According to Baseline HbA1cLevel

HbA1c#7.0, 67 (8.8%) HbA1c7.1–8.0, 190 (25%) HbA1c8.1–9.0, 296 (39%) HbA1c9.1–10.0, 146 (19%) HbA1c>10.0, 65 (8.5%) p Value Age, yrs 60.5 9.7 59.9 8.8 56.6 9.2 55.3 8.2 50.2 8.5 <0.001 Female 24 (35.8) 89 (46.8) 127 (42.9) 64 (43.8) 35 (53.8) 0.28

Body mass index, kg/m2 24.0 3.9 25.4 3.7 26.2 3.9 26.5 3.9 25.7 4.4 <0.001

eGFR <0.001

>60 ml/min/1.73 m2 36 (57.1) 109 (62.6) 178 (65.2) 87 (64.0) 29 (47.5)

45–60 ml/min/1.73 m2 8 (12.7) 26 (14.9) 44 (16.1) 17 (12.5) 4 (6.6)

30–45 ml/min/1.73 m2 6 (9.5) 11 (6.3) 16 (5.9) 17 (12.5) 13 (21.3)

15–30 ml/min/1.73 m2 0 (0.0) 10 (5.7) 5 (1.8) 4 (2.9) 4 (6.6)

End-stage renal disease 12 (17.9) 17 (8.9) 29 (9.8) 10 (6.8) 11 (16.9) 0.048

Duration, yrs 47.5 10.4 45.5 10.0 42.6 10.8 39.3 9.3 35.9 9.6 <0.001

Hypertension 30 (44.8) 76 (40.0) 134 (45.3) 55 (37.7) 27 (41.5) 0.57

Hyperlipidemia 12 (17.9) 46 (24.2) 83 (28.0) 40 (27.4) 22 (33.8) 0.26

Peripheral vascular disease 17 (25.4) 35 (18.4) 54 (18.2) 23 (15.8) 17 (26.2) 0.28

Earlier PCI 12 (17.9) 21 (11.1) 42 (14.2) 21 (14.4) 4 (6.2) 0.25

COPD 0 (0.0) 5 (2.6) 13 (4.4) 8 (5.5) 4 (6.2) 0.24

Earlier myocardial infarction 39 (58.2) 99 (52.1) 147 (49.7) 80 (54.8) 37 (56.9) 0.62

Heart failure 9 (13.4) 36 (18.9) 48 (16.2) 29 (19.9) 16 (24.6) 0.41

Stroke 6 (9.0) 21 (11.1) 33 (11.1) 20 (13.7) 8 (12.3) 0.87

Atrialfibrillation 3 (4.5) 6 (3.2) 9 (3.0) 4 (2.7) 2 (3.1) 0.98

Left ventricular ejection fraction 0.23

>50% 32 (71.1) 88 (67.2) 141 (72.3) 63 (64.9) 21 (58.3) 30%–50% 9 (20.0) 38 (29.0) 44 (22.6) 29 (29.9) 15 (41.7) <30% 4 (8.9) 5 (3.8) 10 (5.1) 5 (5.2) 0 (0.0) EuroSCORE 3.7 2.9 3.8 2.4 3.3 2.6 3.2 2.3 3.6 1.9 0.22 Alcohol dependency 0 (0.0) 2 (1.1) 4 (1.4) 2 (1.4) 0 (0.0) 0.77 Birth region 0.015 Nordic countries 66 (98.5) 187 (98.4) 293 (99.0) 138 (94.5) 65 (100.0) Other 1 (1.5) 3 (1.6) 3 (1.0) 8 (5.5) 0 (0.0) Education 0.22 <10 yrs 23 (34.8) 56 (29.6) 97 (33.2) 50 (34.5) 20 (30.8) 10–12 yrs 29 (43.9) 87 (46.0) 135 (46.2) 66 (45.5) 40 (61.5) >12 yrs 14 (21.2) 46 (24.3) 60 (20.5) 29 (20.0) 5 (7.7) Marital status 0.024 Married 35 (52.2) 129 (67.9) 170 (57.4) 87 (59.6) 31 (47.7) Other 32 (47.8) 61 (32.1) 126 (42.6) 59 (40.4) 34 (52.3) Off-pump CABG 4 (6.0) 10 (5.3) 16 (5.4) 4 (2.7) 6 (9.2) 0.40 Number of grafts 0.048 1–2 13 (20.0) 20 (12.0) 55 (21.0) 22 (17.7) 9 (15.3) 3–4 46 (70.8) 129 (77.2) 171 (65.3) 80 (64.5) 36 (61.0) >4 6 (9.2) 18 (10.8) 36 (13.7) 22 (17.7) 14 (23.7) Type of graft

Internal mammary artery 60 (89.6) 182 (95.8) 280 (94.6) 137 (93.8) 62 (95.4) 0.42

Bilateral internal mammary arteries 0 (0.0) 0 (0.0) 2 (0.7) 5 (3.4) 1 (1.5) 0.024

Radial artery 3 (4.5) 7 (3.7) 11 (3.7) 4 (2.7) 5 (7.7) 0.54

More than 1 arterial graft 3 (4.5) 7 (3.7) 11 (3.7) 9 (6.2) 6 (9.2) 0.31

Values are mean SD or n (%).

CABG¼ coronary artery bypass grafting; COPD ¼ chronic obstructive pulmonary disease; eGFR ¼ estimated glomerular filtration rate; HbA1c¼ hemoglobin A1c; PCI¼ percutaneous coronary intervention.

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DISCUSSION

The mainfinding in this long-term (median, 4.7 years) follow-up study was that high preoperative HbA1c levels were significantly associated with an increased risk of death or MACE in patients with T1DM who were undergoing primary isolated nonemergency CABG in Sweden between 1997 and 2012. The associ-ation between higher pre-operative HbA1clevels and worse cardiovascular prognosis was independent of a number of clinical characteristics and previously identified risk factors. In patients with very poor glycemic control, the risk of death or MACE was more than twice that of patients with lower preoperative HbA1clevels (<7.0%).

Chronic hyperglycemia affects several target

organs, including the heart, brain, and kidney, and it contributes to organ damage. Although the devel-opment of atherosclerosis is multifactorial, evidence indicates that chronic hyperglycemia is a culprit in

macrovascular complications(22). Coronary atheroma is more common among diabetic patients, and HbA1c level is associated with progression of atherosclerosis and CHD(23). In the follow-up of patients with T1DM in the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Control, intensive glycemic control reduced the risk of CVD events(24). Recent epidemiological data also support a relationship be-tween hyperglycemia and CVD mortality in patients with T1DM(5,25–28). CVD events occur as much as 10 to 15 years earlier in patients with T1DM compared with nondiabetic patients(6). In our study, there was a robust association between preoperative HbA1c levels and all-cause mortality or MACE that confirmed hyperglycemia as a major risk factor in T1DM. Chronic hyperglycemia is generally thought to be the most important modifiable risk factor for long-term com-plications in T1DM (29). As HbA1c rises, other risk factors for CVD events also tend to increase. Blood pressure, hyperlipidemia, body mass index, and renal failure can all modify the risk of CVD events. Age, sex, and diabetes duration are additional risk factors for CVD events. After adjustment for age and sex, pa-tients with poor glycemic control and high HbA1c levels had a significantly higher risk of death or MACE. Multivariable adjustment for a number of other risk factors did not attenuate the HRs for death or MACE. In fact, the relationship between HbA1c level and death or MACE was already significant at HbA1clevels of 7.1% to 8.0%, and it increased further by 18% for every 1% absolute increase in HbA1clevels. In a recent large study from the Swedish National Diabetes Register, patients with T1DM, even those with very good glycemic control (HbA1c<6.9%), had more than double the risk of death compared with the general population. This risk increased further for every 1% absolute increase in HbA1clevel, with a more than 5-fold increased risk of death from cardiovas-cular causes in patients with the highest HbA1clevels (5). Patients in our study all had manifest severe CHD,

TABLE 2 Event Rates and Relative Risks for a Combination of All-Cause Mortality or Major Adverse Cardiovascular Events*After Primary Isolated Coronary Artery Bypass Grafting in 764 Patients With Type 1 Diabetes, According to Baseline HbA1c

HbA1c Events/Person-Years

Rate per 1,000 Person-Years

(95% CI)

Crude Hazard Ratio (95% CI)

Age- and Sex-Adjusted Hazard Ratio (95% CI)

Multivariable Adjusted† Hazard Ratio (95% CI)

#7.0 (Ref) 29/358 81 (56–116) 1.00 1.00 1.00

7.1–8.0 76/993 76 (61–96) 0.92 (0.60–1.41) 1.10 (0.71–1.71) 1.34 (0.82–2.21)

8.1–9.0 122/1,588 77 (64–92) 0.94 (0.63–1.42) 1.23 (0.81–1.87) 1.59 (1.00–2.54)

9.1–10.0 64/796 80 (63–103) 0.98 (0.63–1.53) 1.34 (0.85–2.11) 1.73 (1.03–2.90)

>10.0 43/355 121 (90–163) 1.50 (0.94–2.40) 2.23 (1.36–3.66) 2.25 (1.29–3.94)

*A major adverse cardiovascular event was defined as rehospitalization for myocardial infarction, heart failure, stroke, or repeat revascularization. †Multivariable adjustment was made for all variables inTable 1.

CI¼ confidence interval; HbA1c¼ hemoglobin A1c; Ref¼ reference category.

FIGURE 1 Freedom From Death or MACE

1 .8 .6 .4 .2 0 0 2 Time (Years)4 6 8 10 HbA1c ≤7.0 HbA1c 7.1-8.0 HbA1c 8.1-9.0 HbA1c 9.1-10.0 HbA1c >10.0 Age-Adjus ted F reedom F rom Death or MA CE

Age-adjusted freedom from death or major cardiovascular events (MACE) in patients with type 1 diabetes who underwent primary isolated coronary artery bypass grafting, according to baseline hemoglobin A1c(HbA1c) level.

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they were old, and they had diabetes of long duration. These patients were therefore at high risk for death or MACE, as confirmed by the high incidence of these outcomes, an incidence higher than that reported in another recently published study(30). However, in that study, no distinction was made between the types of diabetes. Patients with earlier CHD have an increased incidence of new CVD events. Patients with type 2 diabetes mellitus (T2DM) have the same increased risk of myocardial infarction as nondiabetic

patients who have had an earlier myocardial infarc-tion(31). Findings of this 1998 index study resulted in the recommendation that patients with T2DM should be regarded as CHD equivalent(31). Intensi-fied intervention against multiple risk factors in pa-tients with T2DM strongly reduces the risk of CVD events(32). Whether this reduced risk is seen in pa-tients with T1DM is not fully understood(4). Standard CHD risk factors (e.g., lipids, blood pressure, and obesity) are clearly operational in T1DM. However, CENTRAL ILLUSTRATION HbA1cand Prognosis After CABG in Type 1 Diabetes

Nyström, T. et al. J Am Coll Cardiol. 2015; 66(5):535–43.

Thisfigure shows the relationship (event rates and adjusted relative risks for the association) between pre-operative hemoglobin A1c(HbA1c) level

(in clinically relevant categories above and also as a continuous variable below) and all-cause mortality or a major cardiovascular event (MACE). The graph

shows the adjusted hazard ratio (solid salmon line) and 95% confidence intervals (dashed blue lines) for the association between baseline HbA1cand

combined all-cause mortality and major cardiovascular event occurrence. The baseline HbA1clevel was modeled with restricted cubic splines with 3

knots (at 7.1%, 8.5%, and 9.8%) in a Cox regression model. The reference level was set at 7.0% for the estimation of hazard ratios. The Cox model was adjusted for age and sex. The mainfinding of our study was that higher preoperative HbA1clevels were significantly associated with an increased risk

of death or MACE in patients with type 1 diabetes who underwent coronary artery bypass grafting. CI¼ confidence interval; PY ¼ person-years;

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management approaches to CHD reduction have been extrapolated from T2DM studies and are therefore not easily applied to patients with T1DM. In the present study, HRs did not change after adjustments for well-known CVD risk factors, including chronic kidney disease, afinding suggesting glycemic control as the most important risk factor for death or MACE.

A recent study examined whether preoperative HbA1clevels can help predict mortality and morbidity after CABG (11). Some studies (33–35), but not all (36–38), have demonstrated an association between HbA1clevels and CVD outcome in patients after CABG. Earlier studies that examined the impact of preoper-ative HbA1c as a risk factor for long-term mortality

after CABG (39,40) found that patients with

HbA1c higher than 7% had lower 5-year survival

compared with patients with HbA1c lower than 7%. After adjustment, higher HbA1cwas associated with reduced long-term survival(39). Recently, it was also

demonstrated that HbA1c levels predict insulin

sensitivity during cardiac surgical procedures and

possibly outcome in diabetic patients(41). However, none of these studies(39–41)distinguished between T1DM and T2DM. Studies investigating the prognostic impact of diabetes in patients after CABG are even more ambiguous (7–10). Results from these studies have been conflicting, demonstrating either an asso-ciation with adverse outcome (9) or no association with outcome (8). Importantly, categorization into T1DM and T2DM in these studies is lacking(8,9). To the best of our knowledge, only one study categorized CABG-treated patients into T1DM and T2DM. In that study, the investigators found an increased risk of death or myocardial infarction for both T1DM and T2DM(42). However, that study was conducted more than 3 decades ago, and considering that the risks of death and CVD events associated with diabetes have been reduced by more than one-half during the last 2 decades(2), those results should be interpreted with caution in a contemporary population. Our find-ings are in line with those of a recent study of dia-betic patients who underwent percutaneous coronary FIGURE 2 Incidence Rate and Relative Risks According to Baseline HbA1c

Outcome

Death+MACE

CV death

Non-CV death

No. events/PY Crude rate [95% CI]

per 1,000 PY

Adjusted hazard ratio [95% CI] ≤7.0 (Ref) 7.1-8.0 29/358 81 [56 - 116] 1.00 1.34 [0.82 - 2.21] 1.59 [1.00 - 2.54] 1.73 [1.03 - 2.90] 2.25 [1.29 - 3.94] 1.00 1.46 [0.56 - 3.78] 1.62 [0.64 - 4.13] 1.32 [0.46 - 3.79] 2.15 [0.73 - 6.32] 1.00 1.09 [0.48 - 2.46] 1.46 [0.68 - 3.16] 1.55 [0.70 - 3.45] 2.13 [0.85 - 5.34] 0.5 1 1.5 2 2.5 3 3.5 4 76 [61 - 96] 77 [64 - 92] 80 [63 - 103] 121 [90 - 163] 19 [9.7 - 39] 20 [13 - 30] 19 [13 - 26] 13 [7.7 - 23] 25 [14 - 45] 22 [11 - 42] 18 [12 - 28] 20 [14 - 27] 21 [14 - 33] 34 [21 - 57] 76/993 122/1,588 64/796 43/355 8/411 13/982 11/440 9/411 21/982 15/440 21/1,167 37/1,871 23/1,167 35/1,871 8.1-9.0 9.1-10.0 >10.0 ≤7.0 (Ref) 7.1-8.0 8.1-9.0 9.1-10.0 >10.0 ≤7.0 (Ref) 7.1-8.0 8.1-9.0 9.1-10.0 >10.0

Crude incidence rates and adjusted hazard ratios for 3 outcomes: 1) combined all-cause mortality and major adverse cardiovascular events; 2) cardiovascular death; and 3) noncardiovascular death, in patients with type 1 diabetes who underwent primary isolated coronary artery bypass grafting, according to baseline HbA1clevel. Hazard ratios for cardiovascular (CV) death and non-CV death are subdistribution hazard ratios from

competing risk regression models that were adjusted for age, sex, left ventricular ejection fraction, and renal function. PY¼ person-years;

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intervention procedures and were categorized ac-cording to HbA1clevels. Patients with poor glycemic control had higher long-term mortality than did pa-tients with good glycemic control (HbA1c<7.0%)(28). In that study, there was no attempt to distinguish be-tween types of diabetes; therefore, the results cannot be translated to patients with T1DM(28).

This study investigated the incidence of death and MACE in T1DM patients after CABG. The information used to categorize patients as T1DM has been shown to have a high validity(43). Other strengths of this study were its nationwide population-based design, the long follow-up period, and the accurate determi-nation of mortality and MACE because of the high-quality national Swedish health data registers.

STUDY LIMITATIONS.We lacked information

re-garding CVD medications and insulin doses. Within the scope of this study, we cannot rule out the role of underlying microvascular complications. However, we considered estimated glomerularfiltration rate as a proxy for microvascular disease, which could be controlled for in the multivariable models. As in any observational study, we cannot rule out that residual confounding factors affected ourfindings.

CONCLUSIONS

Our study found that patients with T1DM who were undergoing CABG were at high risk for death or MACE during a median follow-up period of 4.7 years, and we also found that elevated preoperative HbA1c levels were significantly associated with an increased risk for all-cause mortality or MACE. In patients with

T1DM with very poor glycemic control before CABG, the long-term risk of death or MACE was more than double that in patients with T1DM who had adequate glycemic control.

ACKNOWLEDGMENTSThe authors are grateful to

the steering committee of SWEDEHEART and the National Diabetes Register for providing data for this study.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

Ulrik Sartipy, Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, SE-171 76, Stockholm, Sweden. E-mail:Ulrik.Sartipy@ karolinska.se.

R E F E R E N C E S

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PERSPECTIVES

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS:Although CABG surgical intervention is the preferred method of revasculari-zation for patients with diabetes and multivessel coronary artery disease, patients with T1DM who had poor glycemic control before CABG faced risks of death or MACE over the ensuing 5 years that were more than twice as high as risks in patients with T1DM who had adequate glycemic control.

TRANSLATIONAL OUTLOOK:Interventions to achieve better control of blood glucose concentra-tions and other cardiovascular risk factors in patients with T1DM should be evaluated in prospective trials.

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34.Hudson CC, Welsby IJ, Phillips-Bute B, et al. Glycosylated hemoglobin levels and outcome in non-diabetic cardiac surgery patients. Can J Anaesth 2010;57:565–72.

35.McGinn JT Jr., Shariff MA, Bhat TM, et al. Prevalence of dysglycemia among coronary artery bypass surgery patients with no previous diabetic history. J Cardiothorac Surg 2011;6:104.

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37.Knapik P, Ciesla D, Filipiak K, Knapik M, Zembala M. Prevalence and clinical significance of elevated preoperative glycosylated hemoglobin in diabetic patients scheduled for coronary artery surgery. Eur J Cardiothorac Surg 2011;39:484–9. 38.Tsuruta R, Miyauchi K, Yamamoto T, et al. Effect of preoperative hemoglobin A1c levels on long-term outcomes for diabetic patients after off-pump coronary artery bypass grafting. J Cardiol 2011;57:181–6.

39.Halkos ME, Lattouf OM, Puskas JD, et al. Elevated preoperative hemoglobin A1c level is associated with reduced long-term survival after coronary artery bypass surgery. Ann Thorac Surg 2008;86:1431–7.

40.Alserius T, Anderson RE, Hammar N, Nordqvist T, Ivert T. Elevated glycosylated haemoglobin (HbA1c) is a risk marker in coronary artery bypass surgery. Scand Cardiovasc J 2008; 42:392–8.

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KEY WORDS coronary artery bypass grafting, diabetes mellitus type 1, glycosylated hemoglobin A, prognosis

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References

  1. NCT02276950)
  2. Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster
  3. h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 5 . 0 5 . 0 5 4
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