In patients with diabetes mellitus (DM) in the general population, elevated glycosylated hemoglobin (HbA 1c ) increases the risk for developing heart failure (HF). However, in patients with established HF, the association of HbA 1c level with outcomes is not well established. The aim of this study was to investigate the relation between HbA 1c and outcomes in patients with HF with and without DM. A total of 845 patients with advanced HF followed at the Ahmanson-UCLA Cardiomyopathy Center were studied, stratified by the presence (n = 358) or absence (n = 487) of DM and by DM-specific HbA 1c quartiles (patients with DM: Q1 ≤6.4%, Q2 6.5% to 7.2%, Q3 7.3% to 8.5%, and Q4 ≥8.6%; patients without DM: Q1 ≤5.6%, Q2 5.7% to 6.0%, Q3 6.1% to 6.5%, and Q4 ≥6.6%). The primary outcomes analyzed were death and death or urgent heart transplantation. In the cohort with DM, 2-year event-free survival was 61% and 65% in Q3 and Q4 compared to 48% and 42% in Q1 and Q2 (p = 0.005). In the cohort without DM, there was no difference in outcomes by HbA 1c quartile. Risk-adjusted analysis in the diabetic cohort showed significantly increased hazard ratios for death or urgent heart transplantation in Q1 and Q2 compared to Q4. For every unit HbA 1c increase, there was a 15% decreased hazard ratio of death or urgent heart transplantation and all-cause mortality (p = 0.006 and p = 0.036, respectively). In the cohort without DM, multivariate models revealed similar hazard ratios among HbA 1c quartiles. In conclusion, in this cohort of patients with advanced HF, higher HbA 1c levels were associated with improved outcomes in patients with DM. This relation was not observed in patients without DM. Further investigations into mechanisms underlying the relation between HbA 1c , DM, and survival in advanced HF are warranted.
Diabetes mellitus (DM) is a common co-morbidity in patients with heart failure (HF). The prevalence of DM is approximately 25% in patients with stable HF, compared to only 7% in the general population. This relation may be due in part to pathophysiologic processes that underlie HF and DM, including similar patterns of neurohormonal activation, endothelial dysfunction, and oxidative stress. A useful marker of glycemic control in patients with DM is glycosylated hemoglobin (HbA 1c ). Elevated HbA 1c is a risk factor for the development of HF in patients with DM, with a 10% to 15% increased HF risk for every unit increase in HbA 1c . Although DM and elevated HbA 1c levels are associated with an increased risk for new-onset HF, the data regarding HbA 1c and outcomes in patients with preexisting HF have been conflicting. The aim of this study was to reevaluate the relation between HbA 1c levels and outcomes in a large, well-characterized cohort of patients with advanced HF, including patients with DM and without DM.
Methods
The study population consisted of 845 patients with advanced HF referred to a single university center from January 1, 1999, to July 1, 2010, who had HbA 1c measurements recorded within 6 months of referral. The presence of DM was determined by patient self-report and documentation by physician or documentation of treatment with ≥1 hypoglycemic agent.
Baseline patient characteristics were collected at the time of referral; all testing, including measurement of HbA 1c and other laboratory testing, echocardiography, cardiopulmonary exercise testing, and right-heart catheterization in selected cases, was performed within 6 months of initial referral. Patients were further classified into subgroup-specific quartiles on the basis of HbA 1c levels ( Table 1 ). The cohort was analyzed as a whole and by subgroups on the basis of the presence or absence of DM.
| Quartile | Whole Cohort | DM | |
|---|---|---|---|
| Yes | No | ||
| 1 | ≤5.8 (n = 221) | ≤6.4 (n = 90) | ≤5.6 (n = 130) |
| 2 | 5.9–6.3 (n = 205) | 6.5–7.2 (n = 94) | 5.7–6.0 (n = 120) |
| 3 | 6.4–7.1 (n = 213) | 7.3–8.5 (n = 86) | 6.1–6.5 (n = 143) |
| 4 | ≥7.2 (n = 206) | ≥8.6 (n = 88) | ≥6.6 (n = 94) |
The end points evaluated in this study included (1) death or need for urgent heart transplantation (status 1A) and (2) all-cause mortality, in which all heart transplantations (statuses IA, IB, and II) were coded as nonfatal events. Ventricular assist device placement was not analyzed as a final end point, but rather the subsequent heart transplantation or death after ventricular assist device placement was considered the final outcome. Of 42 subjects who received ventricular assist devices, 24 subsequently received urgent heart transplantation, 5 received nonurgent transplantation, and 13 died.
Baseline characteristics are presented as mean ± SD for normally distributed continuous variables, as medians and interquartile ranges for variables not normally distributed, and as percentages of the total for categorical variables. Statistical methods included independent-samples Student’s t tests, analysis of variance, chi-square tests, and nonparametric tests for comparison of variables as appropriate. Kaplan-Meier survival curves were calculated at 1- and 2-year follow-up. Cox proportional-hazards regression analyses were used to estimate the hazard ratio (HR) of the end points of death or urgent heart transplantation and all-cause mortality. Variables included in the multivariate analysis were patient age, gender, body mass index (BMI), and the left ventricular ejection fraction (LVEF). A p value ≤0.05 was considered significant. PASW version 19 (IBM Corporation, Sommers, New York) was used for analyses.
Results
The cohort was 72% men, with a mean age of 55 ± 12 years. Patients in New York Heart Association class III or IV constituted 78% of the patient population. The mean HbA 1c level was 6.7 ± 1.4% (range 3.6% to 14.3%), and the mean LVEF was 25 ± 12%. Of the patients in the cohort, 42% (n = 358) had DM and 58% (n = 487) did not have DM. In the patients with DM, the mean HbA 1c level was 7.6% (range 4.5% to 14.3%). In those without DM, the mean HbA 1c level was 6.0% (range 4.4% to 8.0%). Table 2 lists characteristics of the cohort stratified by the presence or absence of DM. Patients with DM were older, with higher BMIs but similar LVEFs.
| Variable | DM | p Value | |
|---|---|---|---|
| Yes | No | ||
| Age (years) | 57.3 ± 10.4 | 53.0 ± 13.5 | <0.001 |
| Women | 28.5% | 27.1% | 0.671 |
| Ischemic Etiology | 59.2% | 33.3% | <0.001 |
| HbA 1c (%) | 7.6 ± 1.7 | 6.0 ± 0.6 | <0.001 |
| BMI (kg/m 2 ) | 28.6 ± 5.4 | 26.5 ± 5.7 | <0.001 |
| New York Heart Association class | 0.030 | ||
| I and II | 25.3% | 17.9% | |
| III and IV | 74.7% | 82.1% | |
| LVEF (%) | 25.3 ± 9.6 | 25.3 ± 13.0 | 0.946 |
| Left ventricular end-diastolic diameter index (mm/m 2 ) | 33.6 ± 9.2 | 35.6 ± 11.5 | 0.020 |
| Peak oxygen consumption (ml/kg/min) | 11.6 ± 3.5 | 13.5 ± 4.8 | <0.001 |
| Heart rate (beats/min) | 80.9 ± 15.5 | 81.6 ± 17.2 | 0.566 |
| Mean blood pressure (mm Hg) | 80.7 ± 13.5 | 77.9 ± 12.4 | 0.004 |
| Systolic blood pressure (mm Hg) | 111.5 ± 21.0 | 104.0 ± 18.1 | <0.001 |
| Pulmonary capillary wedge pressure (mm Hg) (n = 560) | 22.3 ± 8.1 | 21.6 ± 8.5 | 0.305 |
| Hemoglobin (g/dL) | 12.7 ± 2.1 | 13.2 ± 2.5 | 0.006 |
| Creatinine (mg/dl) | 1.6 ± 1.7 | 1.4 ± 1.4 | 0.092 |
| Blood urea nitrogen (mg/dl) | 34.8 ± 24.4 | 27.8 ± 18.1 | <0.001 |
| B-type natriuretic peptide (pg/dl) | 597 (253–1,300) | 570 (216–1,410) | 0.876 |
| Total cholesterol (mg/dl) | 154.0 ± 58.2 | 147.6 ± 50.0 | 0.105 |
| Cardiac resynchronization therapy | 31.2% | 40.6% | 0.005 |
| Implantable cardioverter-defibrillator placement | 63.3% | 67.1% | 0.253 |
| Heart failure medications | |||
| β blockers | 83.8% | 81.3% | 0.349 |
| Aldosterone antagonists | 58.1% | 59.5% | 0.673 |
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers | 83.8% | 76.8% | 0.012 |
| Outcomes | |||
| Death or urgent heart transplantation at 2 years | 42.7% | 42.7% | 0.994 |
| All-cause mortality at 2 years | 26.5% | 17.4% | 0.001 |
Baseline patient characteristics of the total cohort by HbA 1c quartile are listed in Table 3 , and baseline patient characteristics of the cohort stratified by HbA 1c in the presence and absence of DM are listed in Tables 4 and 5 , respectively. In the diabetic cohort, patients with higher HbA 1c levels were younger and had higher BMIs, cholesterol, and blood pressure; these trends were not observed in the patients without DM.
| Variable | HbA 1c Level (%) | p Value | |||
|---|---|---|---|---|---|
| ≤5.8 | 5.9–6.3 | 6.4–7.1 | ≥7.2 | ||
| Age (years) | 51.9 ± 12.8 | 55.1 ± 13.3 | 57.0 ± 12.2 | 55.6 ± 10.9 | <0.001 |
| Women | 32.6% | 25.4% | 26.9% | 25.4% | 0.283 |
| Ischemic Etiology | 38.9% | 40.5% | 41.1% | 57.3% | <0.001 |
| BMI (kg/m 2 ) | 26.6 ± 6.2 | 26.6 ± 5.3 | 27.1 ± 5.2 | 29.4 ± 5.6 | <0.001 |
| New York Heart Association class | 0.198 | ||||
| I | 6.4% | 2.5% | 5.2% | 2.7% | |
| II | 20.4% | 20.8% | 14.2% | 16.3% | |
| III | 38.9% | 50.9% | 46.4% | 44.9% | |
| IV | 34.3% | 25.8% | 34.2% | 36.1% | |
| History of DM | 17.6% | 20.5% | 43.0% | 90.3% | <0.001 |
| LVEF (%) | 27.5 ± 14.1 | 24.9 ± 11.9 | 23.9 ± 11.4 | 25.0 ± 8.6 | 0.028 |
| Left ventricular end-diastolic diameter index (mm/m 2 ) | 36.1 ± 11.6 | 36.5 ± 12.0 | 34.4 ± 9.5 | 31.9 ± 8.4 | <0.001 |
| Peak oxygen consumption (ml/kg/min) | 13.5 ± 4.2 | 13.1 ± 5.0 | 12.4 ± 4.3 | 11.6 ± 3.8 | 0.014 |
| Heart rate (beats/min) | 83.5 ± 18.8 | 81.2 ± 17.6 | 83.6 ± 15.6 | 81.5 ± 15.8 | 0.391 |
| Mean blood pressure (mm Hg) | 77.0 ± 12.6 | 75.8 ± 11.5 | 74.9 ± 11.6 | 81.3 ± 14.4 | <0.001 |
| Systolic blood pressure (mm Hg) | 104.7 ± 17.4 | 105.7 ± 17.1 | 103.9 ± 19.2 | 114.6 ± 22.7 | <0.001 |
| Pulmonary capillary wedge pressure (mm Hg) (n = 560) | 20.8 ± 8.6 | 21.5 ± 8.2 | 22.6 ± 8.3 | 22.6 ± 8.1 | 0.173 |
| Hemoglobin (g/dL) | 12.7 ± 3.1 | 13.2 ± 2.0 | 13.1 ± 2.1 | 13.0 ± 2.0 | 0.127 |
| Creatinine (mg/dl) | 1.5 ± 1.2 | 1.4 ± 0.8 | 1.6 ± 1.7 | 1.7 ± 2.1 | 0.296 |
| Blood urea nitrogen (mg/dl) | 26.1 ± 16.1 | 28.1 ± 17.1 | 33.6 ± 22.9 | 35.7 ± 26.2 | <0.001 |
| B-type natriuretic peptide (pg/dl) | 447 (179.7–240.0) | 520.5 (240.5–1,277.5) | 706.0 (316.5–625.0) | 588.0 (251.0–1,300.0) | 0.012 |
| Total cholesterol (mg/dl) | 152.3 ± 54.8 | 147.4 ± 47.4 | 144.9 ± 50.4 | 156.7 ± 60.1 | 0.110 |
| Low-density lipoprotein cholesterol (mg/dl) | 88.3 ± 40.0 | 83.5 ± 35.2 | 83.5 ± 35.0 | 85.4 ± 41.8 | 0.577 |
| High-density lipoprotein cholesterol (mg/dl) | 38.5 ± 16.5 | 36.2 ± 12.5 | 37.7 ± 16.2 | 35.7 ± 13.8 | 0.237 |
| Triglycerides (mg/dl) | 104.0 (69.5–164.5) | 111.0 (77.0–180.0) | 102.0 (71.0–146.0) | 127.0 (76.0–257.0) | 0.001 |
| Heart failure medications | |||||
| β blockers | 76.9% | 83.9% | 82.7% | 86.4% | 0.066 |
| Aldosterone antagonists | 52.5% | 62.4% | 59.3% | 62.1% | 0.126 |
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers | 73.3% | 79.5% | 80.8% | 85.9% | 0.013 |
| HbA 1c Level (%) | |||||
|---|---|---|---|---|---|
| Variable | ≤6.4 | 6.5–7.2 | 7.3–8.5 | ≥8.6 | p Value |
| Age (years) | 58.6 ± 9.6 | 59.0 ± 10.1 | 58.0 ± 10.9 | 53.7 ± 10.0 | 0.001 |
| Women | 28.9% | 29.3% | 24.4% | 31.0% | 0.797 |
| Ischemic Etiology | 61.1% | 58.5% | 67.4% | 50.0% | 0.130 |
| BMI (kg/m 2 ) | 27.5 ± 5.1 | 27.8 ± 5.2 | 28.6 ± 5.1 | 30.7 ± 5.9 | <0.001 |
| New York Heart Association class | 0.678 | ||||
| I | 2.9% | 4.3% | 3.3% | 1.6% | |
| II | 17.4% | 10.1% | 11.5% | 20.6% | |
| III | 43.4% | 47.8% | 54.1% | 38.1% | |
| IV | 36.2% | 37.7% | 31.1% | 39.7% | |
| HbA 1c (%) | 5.8 ± 0.4 | 6.8 ± 0.2 | 7.9 ± 0.4 | 10.0 ± 1.3 | <0.001 |
| LVEF (%) | 26.4 ± 10.5 | 24.5 ± 10.7 | 24.5 ± 8.4 | 25.5 ± 8.5 | 0.501 |
| Left ventricular end-diastolic diameter index (mm/m 2 ) | 35.5 ± 11.0 | 35.1 ± 8.8 | 32.7 ± 8.3 | 30.8 ± 8.0 | 0.014 |
| Peak oxygen consumption (mL/kg/min) | 11.9 ± 2.7 | 11.1 ± 3.6 | 11.6 ± 3.3 | 11.8 ± 4.1 | 0.692 |
| Heart rate (beats/min) | 79.7 ± 16.0 | 78.4 ± 15.1 | 82.5 ± 15.9 | 82.9 ± 14.7 | 0.213 |
| Mean blood pressure (mm Hg) | 76.4 ± 12.1 | 77.5 ± 12.1 | 83.9 ± 13.1 | 85.2 ± 14.7 | <0.001 |
| Systolic blood pressure (mm Hg) | 107.2 ± 16.6 | 107.0 ± 20.1 | 115.4 ± 21.1 | 116.6 ± 24.2 | 0.003 |
| Pulmonary capillary wedge pressure (mm Hg) (n = 560) | 21.4 ± 7.5 | 22.5 ± 8.6 | 22.6 ± 7.6 | 22.7 ± 8.8 | 0.801 |
| Hemoglobin (g/dL) | 12.2 ± 2.3 | 12.8 ± 2.1 | 12.9 ± 1.9 | 13.0 ± 1.9 | 0.096 |
| Creatinine (mg/dl) | 1.5 ± 0.8 | 1.5 ± 0.8 | 1.8 ± 2.6 | 1.6 ± 1.8 | 0.540 |
| Blood urea nitrogen (mg/dl) | 30.1 ± 18.0 | 35.9 ± 23.8 | 41.7 ± 32.8 | 31.8 ± 19.1 | 0.008 |
| B-type natriuretic peptide (pg/dl) | 654.0 (255.0–1,300.0) | 516.0 (252.0–1,220.0) | 743.0 (340.0–1,301.0) | 503.0 (202.5–1,055.0) | 0.557 |
| Total cholesterol (mg/dl) | 151.2 ± 56.1 | 148.2 ± 52.8 | 155.9 ± 64.1 | 161.1 ± 60.0 | 0.507 |
| Low-density lipoprotein cholesterol (mg/dl) | 83.9 ± 44.0 | 83.8 ± 33.1 | 81.5 ± 38.8 | 90.4 ± 45.3 | 0.575 |
| High-density lipoprotein cholesterol (mg/dl) | 35.3 ± 11.7 | 37.6 ± 16.3 | 33.8 ± 9.6 | 37.4 ± 15.5 | 0.266 |
| Triglycerides (mg/dl) | 116.0 (84.0–188.0) | 102.0 (65.0–140.0) | 126.0 (75.0–273.0) | 139.0 (81.0–248.0) | 0.029 |
| Heart failure medications | |||||
| β blockers | 80.0% | 81.9% | 84.9% | 88.6% | 0.425 |
| Aldosterone antagonists | 53.3% | 59.6% | 60.5% | 59.1% | 0.763 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptors blockers | 83.3% | 81.9% | 79.1% | 90.9% | 0.175 |
| Antidiabetic medications | |||||
| Insulin | 33.3% | 21.4% | 35.2% | 48.9% | 0.003 |
| Sulfonylureas | 25.0% | 23.8% | 30.7% | 42.2% | 0.033 |
| Glitazones | 8.3% | 5.1% | 14.8% | 15.4% | 0.276 |
| Metformin | 8.3% | 37.5% | 20.5% | 26.6% | 0.019 |
| Variable | HbA 1c Level (%) | p Value | |||
|---|---|---|---|---|---|
| ≤5.6 | 5.7–6.0 | 6.1–6.5 | ≥6.6 | ||
| Age (years) | 50.1 ± 14.0 | 53.9 ± 13.4 | 54.1 ± 13.7 | 54.2 ± 12.4 | 0.038 |
| Women | 30.8% | 28.3% | 26.2% | 21.7% | 0.500 |
| Myocardial ischemic cause | 35.4% | 35.0% | 34.3% | 26.6% | 0.499 |
| BMI (kg/m 2 ) | 26.2 ± 6.6 | 26.9 ± 5.3 | 26.4 ± 5.9 | 26.6 ± 4.7 | 0.807 |
| New York Heart Association class | 0.783 | ||||
| I | 6.7% | 5.9% | 3.5% | 4.5% | |
| II | 21.3% | 22.4% | 19.1% | 17.9% | |
| III | 38.2% | 42.4% | 52.2% | 44.8% | |
| IV | 33.7% | 29.4% | 25.2% | 32.8% | |
| HbA 1c (%) | 5.3 ± 0.3 | 5.9 ± 0.1 | 6.3 ± 0.1 | 6.9 ± 0.3 | <0.001 |
| LVEF (%) | 27.8 ± 14.5 | 26.8 ± 14.3 | 23.1 ± 11.1 | 23.4 ± 11.1 | 0.009 |
| Left ventricular end-diastolic diameter index (mm/m 2 ) | 36.7 ± 12.8 | 34.7 ± 9.0 | 36.4 ± 12.9 | 34.3 ± 10.3 | 0.380 |
| Peak oxygen consumption (L/kg/min) | 13.8 ± 4.1 | 13.5 ± 5.1 | 13.4 ± 5.5 | 13.4 ± 4.4 | 0.968 |
| Heart rate (beats/min) | 84.3 ± 20.2 | 78.3 ± 15.5 | 82.3 ± 16.5 | 81.3 ± 15.7 | 0.107 |
| Mean blood pressure (mm Hg) | 76.3 ± 11.7 | 79.1 ± 12.9 | 79.1 ± 12.2 | 76.8 ± 12.7 | 0.208 |
| Systolic blood pressure (mm Hg) | 103.2 ± 16.5 | 105.8 ± 17.3 | 104.8 ± 18.0 | 101.9 ± 20.7 | 0.476 |
| Pulmonary capillary wedge pressure (mm Hg) (n = 560) | 20.1 ± 9.3 | 21.6 ± 7.9 | 21.8 ± 8.3 | 22.9 ± 8.3 | 0.257 |
| Hemoglobin (ml/g) | 12.6 ± 2.2 | 13.4 ± 3.6 | 13.4 ± 1.9 | 13.4 ± 2.1 | 0.040 |
| Creatinine (mg/dl) | 1.5 ± 1.4 | 1.3 ± 0.9 | 1.5 ± 0.8 | 1.6 ± 2.4 | 0.656 |
| Blood urea nitrogen (mg/dl) | 24.7 ± 15.3 | 25.9 ± 17.7 | 30.4 ± 19.5 | 30.8 ± 19.2 | 0.017 |
| B-type natriuretic peptide (pg/dl) | 386.0 (135.0–1,093.0) | 402.0 (185.0–838.5) | 687.0 (371.0–1,610.0) | 1,020.0 (477.0–2,150.0) | <0.001 |
| Total cholesterol (mg/dl) | 148.8 ± 49.4 | 152.1 ± 52.3 | 143.2 ± 47.0 | 146.5 ± 50.0 | 0.557 |
| Low-density lipoprotein cholesterol (mg/dl) | 87.4 ± 36.3 | 87.1 ± 36.4 | 81.7 ± 35.1 | 85.8 ± 37.8 | 0.606 |
| High-density lipoprotein cholesterol (mg/dl) | 38.3 ± 15.8 | 39.0 ± 16.0 | 36.8 ± 14.9 | 36.5 ± 16.2 | 0.584 |
| Triglycerides (mg/dl) | 92 (69–141) | 108 (75–174) | 96 (69–142) | 105 (79–170) | 0.236 |
| Heart failure medications | |||||
| β blockers | 76.9% | 80.0% | 82.5% | 87.2% | 0.252 |
| Aldosterone antagonists | 53.8% | 56.7% | 64.3% | 63.8% | 0.236 |
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers | 70.0% | 74.2% | 79.0% | 86.3% | 0.031 |
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