Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure

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1 Diabetes, lipids and metabolism Downloaded from on September 19, Published by group.bmj.com Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure C Berry, 1 M Brett, 1 K Stevenson, 1 J J V McMurray, 1 J Norrie 2 1 Department of Cardiology, Western Infirmary, Glasgow, Scotland; 2 Centre for Healthcare Randomised Trials (CHaRT), Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland Correspondence to: Professor John J V McMurray, MD FRCP FESC FACC FAHA, Department of Cardiology, Western Infirmary, Glasgow and Faculty of Medicine, University of Glasgow, Glasgow G11 6NT, United Kingdom; j.mcmurray@ bio.gla.ac.uk Accepted 19 June 2007 Published Online First 30 July 2007 ABSTRACT Objective: To investigate the nature and importance of blood glucose abnormalities in an unselected heart failure (HF) population. Design: Cohort study. Setting: Urban University hospital. Patients: All index emergency HF admissions to one University hospital during the year 2000 were studied. Results: 454 consecutive index admissions had blood chemistry, diabetic status and follow-up information recorded. 390 (86%) patients had an echocardiogram, of whom 117 (30%) had preserved left ventricular systolic function and 110 (24%) had diabetes. Sixty (13%) patients had abnormal glucose tolerance ( mmol/l), and 284 (63%) patients had a normal admission blood glucose (,8 mmol/l). 51 (11.2%) patients died in hospital. After adjustment for other prognostic attributes, abnormal glucose tolerance (Cox hazard ratio HR, 95% CI: 5.920, 1.03 to 34.00; p = 0.046) but not diabetes (HR 3.46, 0.75 to 16.02; p = 0.112) predicted in-hospital mortality. During follow-up (median 812 (range ) days), 104 (36.6%), 30 (50.0%) and 55 (50%) patients with a normal admission blood glucose concentration, abnormal glucose tolerance and diabetes, respectively, died (log rank test p = , adjusted p = 0.075). Compared with patients with normal admission blood glucose, abnormal glucose tolerance (adjusted HR: 1.41 (0.92 to 2.16); p = 0.12) and diabetes (adjusted HR: 2.02 (1.41 to 2.88); p = ) predicted mortality. Considering glucose on admission as a continuous covariate, a 2 mmol/l increase was associated with a HR of 1.08 (1.03 to 1.13), p = , which after adjustment for the above covariates became 1.08 (1.03 to 1.13), p = Conclusions: Admission blood glucose concentration and diabetes are prognostically important in HF and could help target some patients for more intensive therapy. Although patients with heart failure (HF) and diabetes are recognised to have a poorer prognosis than those with HF and no diabetes, 1 4 many questions remain unanswered about the relationship between glycaemic abnormalities, HF and clinical outcomes. Whilst the relationships between blood glucose and fasting insulin concentrations and outcome have been assessed in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study, 2 the nature and importance of glycaemic abnormalities in an unselected, contemporary HF population have not been well described. Similarly, the prevalence of important comorbidities, such as anaemia and renal dysfunction, in patients with diabetes and other glycaemic abnormalities has not been reported. It is conceivable that some of the increased risk related to diabetes could be accounted for by an increased prevalence of these comorbidities. To date the majority of information about diabetes in HF has been obtained from studies restricted to patients with reduced left ventricular systolic function. Up to half of patients with HF may have preserved systolic function yet there is little information about diabetes in patients with that type of HF, 5 and none of the existing reports has included blood glucose information. Whether patients with HF and diabetes or other glycaemic abnormalities are more or less likely to have preserved systolic function is unknown. Finally, whilst the prognostic importance of diabetes in HF patients is well described, the prognostic implications of subclinical glycaemic abnormalities and blood glucose concentration per se are not understood. We retrieved the blood glucose concentration and diabetic status of consecutive index emergency admissions of patients with HF to our hospital. We then investigated the relationship between blood glucose concentrations and diabetic status, and comorbidity and outcomes, in this population. METHODS Identification of patients All patients discharged from the Western Infirmary are supplied with an immediate discharge letter and prescription. As part of an audit of the investigation, treatment and outcome of patients with heart failure, all discharged letters issued in the calendar year 2000 were reviewed for either a discharge diagnosis of HF or treatment with a combination of a diuretic and an ACE inhibitor. Case note review was performed for patients with a secondary diagnostic coding of HF, or in whom HF was suggested by treatment with a loop diuretic/ace inhibitor. In this case, a radiological description of interstitial oedema on the formal CXR report, in conjunction with supportive statements of typical symptoms and signs of fluid retention, was required for inclusion in this study. If these radiological and clinical features were not evident in the case record, then the patient was removed from the database. 6 7 Acute HF was a requirement for entry into this cohort. Patients with chronic heart failure who were electively admitted to the cardiology ward (such as for HF drug therapy adjustment, or for investigations) have this type of admission classified and recorded on the discharge letter. Therefore, these patients were not included in this analysis. 296 Heart 2008;94: doi: /hrt

2 Downloaded from on September 19, Published by group.bmj.com Diabetes, lipids and metabolism Electronic death records were also searched in order to identify patients admitted with HF who did not survive to discharge. Only the first emergency admission for each patient was included in this analysis. 67 Patients with a primary or secondary diagnosis of acute myocardial infarction were not included in this analysis. Discharge information was used to define diabetic status. A patient was said to have diabetes if there was 1) a discharge diagnosis of diabetes or 2) treatment with anti-diabetic therapy or 3) an admission blood glucose concentration of >11.0 mmol/ l. 8 Patients without diabetes were described as having either a) normal glycaemia (blood glucose concentration,8 mmol/l) or b) abnormal glucose tolerance (glucose concentration was mmol/l) Biochemical and haematological measurements Biochemical and haematological measurements made during the first 24 hours of admission were analysed. Blood glucose concentration obtained from the first admission blood sample was quantified using the glucose oxidase method. 6 7 Estimation of glomerular filtration rate (GFR) Estimated GFR (egfr) was calculated using the Modification of Diet in Renal Disease equation, egfr = 1706 [serum creatinine] [age] [0.762, if the patient is female] 6[1.180 if the patient is black] 6 [serum urea] [albumin] Echocardiography Left ventricular systolic dysfunction was defined as either a left ventricular ejection fraction,0.40 or a qualitative report of depressed systolic function. Follow-up for death and readmission All patients were followed, using national electronic records, from their date of admission until death or 30 September Statistical analysis Admission characteristics, including demographics, comorbidities, laboratory measurements, cardiac medications, egfr, haemoglobin and haematocrit, and echocardiogram covariates, were tabulated and compared for normal glucose tolerance, abnormal glucose tolerance, and diabetes (either clinically diagnosed, or blood glucose.11 mmol/l) using ANOVA F-tests (or Kruskal Wallis tests for skewed covariates), and Fisher Exact Tests for categorical data. Kaplan Meier time to event curves were plotted with logrank tests. Univariate Cox proportional hazards models were fitted for time to (i) death (first, in hospital, defined as within 30 days of admission; second, at 1 year; and third, at any time), and (ii) death or any hospital admission for HF. Multivariate Cox proportional hazards regression models were then fitted to adjust the influence of abnormal glucose tolerance and diabetes for other covariates which (a) were univariately significant at p,0.05 and (b) had data available on at least 95% of the subjects. These covariates were allowed to enter a stepwise Cox model with the abnormal glucose tolerance and diabetes covariates forced into the model, and with a p-to-enter and a p-to-stay both set at To further assess the incremental prognostic value of abnormal glucose tolerance and diabetes, a hierarchy of multivariable Cox models was fitted to assess the additional prognostic capacity for death, having adjusted for other factors of prognostic importance. Classes of significant univariate predictors were added to this hierarchy of models first, demographics, then anaemia, then lymphopaenia, then renal function, then hepatic function, then albumin, then cardiac drugs, then echocardiography data. C-reactive protein (CRP), as a marker of inflammation, was also added in the subset of patients in whom this was available. Finally, some of these analyses were repeated to investigate the prognostic influence of admission glucose level. All statistical analyses were undertaken using StatacorpH version 7 and SAS 9.1 for Windows. Significance was taken at p,0.05 throughout and no adjustments were made for multiple testing. RESULTS There were 528 first admissions with HF between 1 January and 31 December Four hundred and fifty-four patients (86%) had blood chemistry, diabetic status and follow-up information available (table 1). Eighty-four of those 454 patients (19%) had a history of diabetes and 58 of them (69%) were treated with antidiabetic therapy. An additional 26 of the 454 patients (6%) had an admission blood glucose concentration >11 mmol/l consistent with new diabetes; therefore the percentage of patients with diabetes was 25%. Sixty of the 454 patients (13%) had abnormal glucose tolerance ( mmol/l), and 284 (63%) patients had a random blood glucose,8 mmol/l (fig 1). The characteristics of patients with known or unrecognised diabetes (blood glucose >11 mmol/l) were similar and for this reason they were grouped together (n = 110 (24%)). Blood chemistry and renal function There were no clinically important differences in electrolytes, albumin or cholesterol between the groups. Urea and creatinine concentrations (table 1) and estimated GFR (table 2) were similar in each patient group. Thyroid function and CRP were also similar in all three groups. Haematology Haemoglobin and haematocrit values in men and women are shown in table 1. Anaemia was present in about half of all patients and its prevalence was similar in patients with and without diabetes. Lymphopaenia was also very common, but occurred less frequently in patients with diabetes. Echocardiography A report of LV function was available in 390 of the 454 (86%) patients with complete information on blood chemistry, diabetic status and follow-up. A similar proportion of patients Figure 1 Distribution of plasma glucose concentration (mmol/l; n = 454) obtained from the first admission blood sample. Heart 2008;94: doi: /hrt

3 Diabetes, lipids and metabolism Downloaded from on September 19, Published by group.bmj.com Table 1 Characteristics according to glucose tolerance and diabetes Heart failure primary Heart failure secondary p Value{ All, n = 454 (100%) Normal glucose tolerance, n = 162 (63%) Abnormal glucose tolerance, n = 29 (11%) New diabetes, n = 49 (19%) Diabetes,* n = 17 (7%) Normal glucose tolerance, n = 122 (62%) Abnormal glucose tolerance, n = 31 (16%) New diabetes, n = 35 (18%) Diabetes,* n = 9 (5%) All HF primary HF secondary Male (n (%)) 222 (49) 75 (46) 13 (45) 31 (63) 8 (47) 54 (44) 18 (58) 20 (57) 3 (33) Mean (SD) age (years) 72 (13) 73 (14) 79 (10) 66 (14) 68 (8) 71 (12) 75 (10) 72 (11) 72 (16) Comorbidity (n (%)) Atrial fibrillation 137 (30) 66 (41) 9 (31) 16 (33) 5 (29) 19 (16) 7 (23) 11 (31) 4 (44) Angina or MI 170 (37) 25 (15) 10 (34) 9 (18) 3 (18) 81 (66) 15 (48) 24 (69) 3 (33) COPD 49 (11) 16 (10) 5 (17) 3 (6) 1 (6) 15 (12) 4 (13) 3 (9) 2 (22) Anaemia{ 199 (44) 67 (42) 15 (54) 24 (49) 7 (41) 49 (40) 17 (55) 17 (49) 3 (33) Valve disease 19 (4) 12 (7) 2 (7) 2 (4) 0 1 (1) 1 (3) 1 (3) Blood chemistry (mean (SD)){ Sodium (mmol/l) 139 (5) 140 (4) 139 (4) 138 (5) 140 (3) 140 (4) 138 (3) 138 (4) 135 (8), Potassium (mmol/l) 4.2 (0.6) 4.2 (0.6) 4.2 (0.6) 4.4 (0.6) 4.0 (0.6) 4.3 (0.6) 4.2 (0.6) 4.4 (0.7) 4.1 (0.6) Urea (mmol/l) 10.6 (7.5) 10.8 (7.1) 12.2 (8.3) 11.6 (8.6) 8.4 (4.5) 9.4 (6.8) 11.0 (6.4) 12.7 (12.0) 8.9 (4.7) Creatinine (micromol/l) 132 (85) 131 (69) 136 (64) 132 (73) 113 (50) 125 (84) 143 (72) 151 (162) 152 (155) Albumin (mmol/l) 38 (5) 38 (5) 36 (6) 37 (5) 41 (7) 38 (4) 38 (4) 39 (3) 35 (4) Glucose (mmol/l) 8.0 (4.9) 5.7 (1.0) 8.8 (0.8) 12.7 (7.8) 15.5 (6.1) 5.9 (1.0) 9.2 (1.0) 11.3 (5.0) 17.2 (11.6) Treatment (n (%))1 Loop diuretic 392 (86) 145 (90) 25 (86) 43 (88) 15 (88) 99 (81) 26 (84) 32 (91) 7 (78) ACE inhibitor 323 (71) 105 (65) 18 (62) 37 (76) 11 (65) 95 (78) 22 (71) 29 (83) 6 (67) b-blocker 152 (33) 41 (25) 7 (24) 11 (22) 7 (41) 57 (47) 8 (26) 19 (54) 2 (22) Spironolactone 79 (17) 29 (18) 5 (17) 15 (31) 4 (24) 14 (11) 6 (19) 4 (11) 2 (22) Digoxin 96 (21) 44 (27) 3 (10) 13 (26) 3 (18) 16 (13) 6 (19) 8 (23) 3 (33) Aspirin 274 (60) 83 (52) 18 (64) 33 (70) 9 (56) 81 (67) 16 (53) 29 (83) 5 (62) Warfarin 96 (21) 40 (25) 7 (24) 6 (12) 4 (24) 26 (21) 6 (19) 6 (17) 1 (11) HMG CoA reductase inhibitor 137 (30) 33 (20) 10 (34) 15 (31) 6 (35) 50 (41) 2 (6) 20 (57) 1 (11) Antidepressant 55 (12) 17 (10) 2 (7) 14 (29) 4 (24) 9 (7) 2 (6) 4 (11) 3 (33) *Diabetes is defined by a history of diabetes or treatment with antidiabetic therapy. New diabetes is defined as a blood glucose >11 mmol/l without existing diabetes; abnormal glucose tolerance is defined by a glucose concentration mmol/ l; normal glucose tolerance,8 mmol/l. Five patients had a blood glucose of,4 mmol/l (minimum 2.8 mmol/l). {x 2 test for linear trend across level of glycaemic status for categorical data and ANOVA test for linear trend of means for continuous data. {Anaemia is defined by a haemoglobin concentration,13 g/dl in men or,11.5 g/dl in women; haematology results were available in 451 (99%) patients. One hundred and ninety-nine (44%) patients were defined as anaemic by haemoglobin criteria. {, all values given as mean (SD) except thyroid stimulating hormone and CRP, which are given as median (IQR). 1 at discharge. ACE, angiotensin converting enzyme; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; HF, heart failure; HMG CoA reductase, hydroxymethylglutaryl Coenzyme A reductase; MI, myocardial infarction; TSH, thyroid stimulating hormone. 298 Heart 2008;94: doi: /hrt

4 Downloaded from on September 19, Published by group.bmj.com Diabetes, lipids and metabolism Table 2 Relationships between diabetes and estimated GFR Estimated GFR (egfr) ml/min/1.73 m 2 * All, n = 408 Normal glucose tolerance, n = 258 (63%) Abnormal glucose tolerance, n = 51 (13%) Diabetes, n = 99 (24%) Mean (SD)* 52 (22) 53 (23) 47 (20) 52 (22) >90 (n (%)){ 20 (5) 15 (6) 1 (2) 4 (4) 60 to,90 (n (%)){ 123 (30) 78 (30) 13 (25) 32 (32) 30 to,60 (n (%)){ 198 (48) 124 (48) 26 (51) 48 (48),30 (n (%)){ 67 (16) 41 (16) 11 (22) 15 (15) *Serum creatinine and serum urea concentrations were available in 453 (99%) subjects, of whom 408 (90%) (218 (53%) women and 190 (47%) men) had an estimate of GFR. An estimate of GFR was available in 258 (91%), 51 (85%) and 99 (90%) patients with normal glucose tolerance, abnormal glucose tolerance, or diabetes, respectively. {Age was not recorded in 10 patients. Table 3 Echocardiographic characteristics of patients with or without diabetes All, n = 390 Normal glucose tolerance, n = 241 (62%) Abnormal glucose tolerance, n = 55 (14%) Diabetes, n = 94 (24%) p Value Left ventricular systolic function Preserved (n* (%)) 117 (30) 69 (29) 22 (40) 26 (28) Reduced (n* (%)) 273 (70) 172 (71) 33 (60) 68 (72) Left ventricular dilatation 150 (38) 93 (39) 16 (29) 41 (44) (LVEDD.5.5 cm) (n* (%)) Left ventricular hypertrophy 136 (35) 79 (33) 23 (42) 34 (36) (.1.1 cm), (n* (%)) Mitral regurgitation (n* (%)) 296 (76) 196 (81) 36 (65) 64 (68) An echocardiographic assessment of LV function was available in 390 (86%) patients. A similar proportion of diabetic (n = 94 (87%)) and non-diabetic (n = 296 (86%)) patients had an echocardiogram. Sixty-four patients did not have an echocardiogram, of whom 15 (23%) were diabetic. *Denominator is number of patients with a measurement of relevant variable. LVSF, left ventricular systolic function. Table 4 Univariate Cox models for mortality Variable Patients (n) Deaths (n) Hazard ratio (95% CI) p Value Glucose (2 mmol/l) (1.03 to 1.13) Glycaemic status Normal blood glucose concentration (1.12 to 2.53) Abnormal glucose tolerance (1.18 to 2.27) Diabetes Age (10 years) (1.24 to 1.62),0.001 Anaemia (Y/N) (1.41 to 2.50),0.001 Lymphopaenia (Y/N) (1.24 to 2.29) Hb (2.0 g/dl) (0.60 to 0.78),0.001 Albumin (5 g/l) (0.48 to 0.67),0.001 Alkaline phosphatase (100 IU) (1.07 to 1.22),0.001 CRP (50 mg/l) (1.21 to 1.53),0.001 Creatinine (100 mmol/l) (1.21 to 1.57),0.001 GFR (20 ml/min/1.73 m 2 ) (0.54 to 0.73),0.001 Sodium (4 mmol/l) (0.74 to 0.98) Lymphocyte count ( /l) (0.62 to 0.90) White cell count ( /l) (1.12 to 1.35),0.001 Leucocytosis (Y/N) (1.69 to 2.99),0.001 Neutrophil count ( /l) (1.17 to 1.40),0.001 Aortic valve gradient (10 mm Hg) (1.18 to1.38),0.001 Aortic valve disease (1.63 to 3.86),0.001 Mitral regurgitation (0.96 to 2.23) Mitral valve flow velocity (0.5 m/s) (1.22 to 1.80),0.001 b-blocker (Y/N) (0.48 to 0.92) ACE inhibitor (Y/N) (0.37 to 0.66),0.001 Spironolactone (Y/N) (1.26 to 2.46),0.001 ACE, angiotensin converting enzyme; CRP, C-reactive protein; GFR, glomerular filtration rate; Hb, Haemoglobin. Univariate hazard ratios with 95% confidence intervals (CI) and associated p values for outcome of death from Cox proportional hazard models. The hazard ratio for continuous variables is stated for 1 standard deviation, for example an increase in age of 12.7 years. Heart 2008;94: doi: /hrt

5 Diabetes, lipids and metabolism Downloaded from on September 19, Published by group.bmj.com Table 5 Model Multivariate Cox models for mortality Deaths/subjects (% deaths) Hazard ratio for diabetes (yes vs no) (95% CI) p Value A: Normal glucose tolerance 104/284 (37%) 1 Abnormal glucose tolerance 30/60 (50%) 1.68 (1.12 to 2.53) Diabetes 55/110 (50%) 1.64 (1.18 to 2.27) B: Model A plus age 10/277 (36%) 1 30/57 (52%) 1.52 (1.01 to 2.29) /110 (50%) 1.89 (1.35 to 2.65),0.001 C: Model B plus anaemia 102/275 (37%) 1 29/56 (52%) 1.43 (0.94 to 2.16) /110 (50%) 1.89 (1.35 to 2.65),0.001 D: Model C plus lymphopaenia 102/275 (37%) 1 29/56 (52%) 1.40 (0.92 to 2.12) /110 (50%) 2.02 (1.43 to 2.84),0.001 E: Model D plus creatinine 102/275 (36%) 1 29/56 (48%) 1.47 (0.97 to 2.23) /109 (49%) 2.06 (1.46 to 2.91),0.001 F: Model E plus alkaline phosphatase 96/261 (37%) 1 24/50 (48%) 1.43 (0.91 to 2.25) /101 (48%) 1.91 (1.33 to 2.75),0.001 G: Model F plus albumin 95/254(37%) 1 24/49 (49%) 1.41 (0.89 to 2.21) /98 (49%) 1.84 (1.27 to 2.65) H: Model G plus cardiac drugs (ACE inhibitor, b-blocker, spironolactone) 95/177 (54%) 1 24/35 (68%) 1.43 (0.91 to 2.26) /72 (67%) 1.87 (1.29 to 2.71) I: Model H plus valve disease (aortic valve disease, mitral regurgitation) 61/156 (39%) 1 18/35 (51%) 1.74 (0.99 to 3.05) /53 (51%) 1.63 (0.99 to 2.67) J: Model I plus inflammation (CRP) 44/115 (38%) 1 12/25 (48%) 1.98 (0.94 to 4.04) /40 (50%) 2.38 (1.30 to 4.37) Cox multivariable model for mortality in relation to the presence or absence of abnormal glucose tolerance (random blood glucose concentration mmol/l) or diabetes (a history of diabetes or blood glucose concentration >11.0 mmol/l). with normal glucose tolerance (241 (85%)), abnormal glucose tolerance (55 (92%)) and prior or new diabetes (94 (87%)) had an echocardiogram (p = 0.32). The proportions of patients in each group with reduced and preserved left ventricular systolic function did not differ (table 3). Drug treatment Of the patients with known diabetes (n = 84), 58 (69%) were treated with antidiabetic drugs. Of the patients with a history of diabetes (n = 84), 14 (17%) received insulin monotherapy, 38 (45%) received oral hypoglycaemic agent (OHA) monotherapy; of these 33 (39%) were treated with a sulphonylurea alone, three (4%) received metformin, two (2%) were treated with acarbose; seven (8%) were treated with a combination of oral hypoglycaemic agents (OHA), and two (2%) patients received a combination of insulin and OHA. Aspirin, HMG CoA reductase inhibitors and antidepressants were used more often in patients with known diabetes (table 1) than in other patients. Clinical outcomes The median (interquartile range (IQR)) follow-up time in survivors was 812 days ( days). The duration of Table 6 diabetes Crude mortality rates according to glucose tolerance and Normal glucose tolerance Abnormal glucose tolerance n = 284 (63%) n = 60 (13%) Diabetes n = 110 (24%) p Value Mortality, n (%) In-hospital 21 (7.4) 12 (20.0) 18 (16.4) year 68 (24) 22 (37) 43 (39) Long-term 104 (37) 30 (50) 55 (50) Mortality and readmission with heart failure, n (%) 1-year 97 (31) 36 (46) 32 (48) Long-term 126 (44) 37 (62) 60 (63) Median long-term follow-up was 812 (range ) days. hospital admission was similar in all patient groups: diabetic patients 7.0 (SD 6.1) days, abnormal glucose tolerance 7.2 (SD 6.5) days and normal glucose tolerance: 6.9 (SD 5.9) days; p = 0.9. Mortality Relationship between survival, glucose tolerance and diabetes The crude in-hospital, 1-year and longer-term mortality rates are shown in table 6. Abnormal glucose tolerance and diabetes predicted mortality at 1 year (tables 4 and 6) and in the longer term, even after adjustment for age, urea, sodium, white cell count, ACE inhibitor use, spironolactone, anaemia, and creatinine (tables 5 and 7). Relationship between survival and blood glucose concentration on admission A striking relationship existed between blood glucose concentration and mortality. The mortality rates according to glucose category during the entire follow-up period are shown in table 8 and fig 2, and the adjusted hazard ratios are shown in table 9. The Kaplan Meier survival estimates for patients stratified according to glycaemic status on admission and admission blood glucose category are shown in figs 3 and 4, respectively. Considering glucose on admission as a continuous covariate, a 2 mmol/l increase was associated with a HR of 1.08 (1.03 to 1.13), p = , which after adjustment for the above covariates became 1.08 (1.03 to 1.13), p = Death and readmission for heart failure The crude in-hospital, 1-year and longer-term mortality and readmission with heart failure according to glucose tolerance Table 7 Adjusted hazard ratios for clinical outcomes according to glucose tolerance and diabetes, where normal glucose tolerance (glucose,6 mmol/l) represents no hazard Abnormal glucose tolerance Diabetes Mortality Adjusted HR (95% CI) p Value Adjusted HR (95% CI) p Value 1-year 1.42 (0.85 to 2.39) (1.42 to 3.36),0.001 Long-term 1.41 (0.92 to 2.16) (1.41 to 2.88),0.001 Mortality and readmission with heart failure 1-year 1.61 (1.07 to 2.41) (1.22 to 2.88) Long-term 1.69 (1.15 to 2.48) (1.14 to 2.19) *Multivariate Cox models included age, urea, neutrophil count, spironolactone, ACE inhibitor use, anaemia, and creatinine. 300 Heart 2008;94: doi: /hrt

6 Downloaded from on September 19, Published by group.bmj.com Diabetes, lipids and metabolism Figure 2 Mortality rate according to admission glucose concentration range category,4 mmol/l (n = 5), mmol/l (n = 185), mmol/l (n = 120), mmol/l (n = 78), >11.0 mmol/l (n = 66). and diabetes, and for glucose category, are shown in tables 6 and 7, respectively. Increasing levels of admission blood glucose were associated with a progressively greater hazard ratio for death or readmission with heart failure, even after adjustment for other prognostically important attributes (table 9). When considered as a continuous covariate, a 2 mmol/l increase in admission glucose had a HR of 1.06 (1.02 to 1.10), p = , which after adjustment for the listed covariates became 1.06 (1.01 to 1.11), p = DISCUSSION Diabetes and elevated blood glucose concentrations on admission were very common in this population. Furthermore, one in 14 (7%) patients discharged without a diagnosis of diabetes had an admission blood glucose concentration consistent with new diabetes, suggesting under-recognition of this problem. We found that in-hospital mortality and mortality, and morbidity in the longer term, were higher in patients with abnormal glucose tolerance or diabetes. Additionally, blood glucose was a predictor for mortality (and mortality morbidity) after adjustment for other attributes of prognostic importance in diabetic and non-diabetic subjects, and even mild elevations of blood glucose predicted mortality. The prevalence of diabetes in this population was 18% based on a known history and 24% when a blood glucose >11 mmol/l was taken into account. In the Danish Investigation of Arrhythmia and Mortality On Dofetilide (DIAMOND) Heart Failure Trial, which included consecutive admissions to 34 Danish hospitals between November 1993 and December 1995 with new or worsening HF, a diagnosis of diabetes was based on a self-report by the patient or by documentation in the patient s medical records. 3 In that population, 16% of patients were diabetic. In two other European cohort studies of unselected, unplanned HF admissions, the prevalence of diabetes ranged between 21% in a French cohort 12 and 34.7% in a Spanish cohort. 4 However, the criteria for a diagnosis of diabetes and blood glucose concentrations were not reported in those European cohorts. The proportion of HF patients with diabetes in North American hospital cohorts has generally been higher (30% to 50%) In a Japanese study, diabetes was reported in 25% of admissions with HF. 19 In each of these non-european cohorts, a diagnosis of diabetes was based on a history of diabetes as recorded by the admitting physician. As in the European studies, however, blood glucose concentrations were not described. The reasons for these apparent geographic differences in the prevalence of diabetes are unclear. Possible explanations include a higher prevalence of diabetes in North American subjects and differences in the aetiology of HF in these populations. For example, diabetes may be more common in patients with ischaemic heart disease than in those with HF due to other causes. In the Studies Of Left Ventricular Systolic Dysfunction (SOLVD), diabetes occurred in 19% of patients with ischaemic HF and 15% of non-ischaemic HF (p = 0.03). 20 Differences in definitions or methods of diagnosis may also explain geographic variation. Figure 3 Kaplan Meier survival curves for patients hospitalised with heart failure. Survival is shown according to normal glycaemic status (no diabetes and an admission blood glucose,8 mmol/l) (n = 284), reduced glucose tolerance (glucose mmol/l) and diabetes (a history of diabetes or blood glucose.11 mmol/l). Heart 2008;94: doi: /hrt

7 Diabetes, lipids and metabolism Downloaded from on September 19, Published by group.bmj.com Figure 4 Kaplan Meier survival curves for patients hospitalised with heart failure. Survival is shown according to admission (first blood sample) glucose concentration. In the present study, diabetic patients were younger than non-diabetic patients, and a higher proportion were male. We found that the proportions of diabetic and non-diabetic patients with preserved and reduced systolic function were similar. In DIAMOND, a higher proportion of diabetic patients had reduced systolic function, 3 whereas in the VMAC trial population, diabetic patients had had a higher mean ejection fraction (29% (SD 15%)) than non-diabetic patients (25% (SD 13%)). The explanation for this discrepancy is unclear. In the Acute Decompensated Heart Failure National Registry (ADHERE), which enrolled consecutive admissions with acute heart failure in 282 North American hospitals, the overall prevalence of diabetes was 44%. 21 The lower prevalence of diabetes in our study (25%) may be explained by differences in the populations of patients. For example, 20% of patients in ADHERE were African American (in whom the prevalence of diabetes is relatively high) whereas all but one patient in our study were Caucasian. Furthermore, ADHERE included patients with multiple admissions, which may have contributed to the differences in our populations, as we simply included index heart failure admissions. Perhaps surprisingly, the prevalence of differing severities of renal dysfunction, assessed using serum creatinine or estimated GFR, was similar in patients with normal glycaemia, abnormal blood glucose tolerance and diabetes. We also observed a similar frequency of anaemia in the three groups. Whilst anaemia and renal dysfunction are important prognostic markers in both diabetes and HF, our findings suggest that the adverse prognosis of patients with abnormal glycaemic control and frank diabetes cannot be explained by those other systemic abnormalities. 22 We found a striking relationship between random blood glucose concentration on admission and total mortality (fig 2). We included a comprehensive range of comorbid predictors of prognosis in our multivariable models, including haematology (haemoglobin, lymphopaenia), liver function (alkaline phosphatase), protein anabolism (albumin), valve disease, and inflammation (CRP), which have not been included in other investigations of prognosis. 1 2 Despite this extensive adjustment for other predictors of mortality, glycaemic status and diabetes remained predictors of outcome. Although the prognostic implications of diabetes in HF are well described, 1 2 only the RESOLVD report has provided information about other indices of abnormal glycaemic control in HF patients. 2 Blood glucose (6.3 (SD 0.2) vs 5.6 (SD 0.1) mmol/l, p,0.005) and insulin (19.6 (SD 2.3) vs 10.2 (SD 0.6) mu/l, p,0.005) concentrations, and fasting insulin resistance index (6.2 (SD 1.0) vs 2.4 (SD 0.2), p,0.005), were higher in patients with NYHA functional class III/IV than in those with functional class I/II. Non-diabetic patients with an elevated blood glucose concentration (.6.1 mmol/l), elevated insulin concentration (.11.2 mu/l), or an increased fasting insulin resistance index (.2.7) had a shorter 6-minute walk distance than those with normal values (368 (SD 8) vs 389 (SD 4) m, p = 0.02; 369 (SD 7) vs 393 (SD 5) m, p,0.005; 372 (SD 7) vs 391 (SD 5) m, p = 0.02), respectively. Furthermore, there was an inverse correlation between brain natriuretic peptide and plasma glucose Table 8 Crude outcome rates according to admission glucose concentration Glucose category,4 mmol/l mmol/l mmol/l mmol/l >11 mmol/l n = 5 (1%) n = 185 (41%) n = 120 (26%) n = 78 (17%) n = 66 (14%) Log rank adjusted p value Long-term mortality, n (%) 1 (20) 62 (34) 51 (43) 38 (53%) 34 (53) Long-term mortality and readmission with heart failure, n (%) 2 (40) 76 (41) 61 (51) 47 (60) 37 (66) The median long-term follow-up was 812 (range ) days. 302 Heart 2008;94: doi: /hrt

8 Downloaded from on September 19, Published by group.bmj.com Diabetes, lipids and metabolism Table 9 Adjusted hazard ratios for clinical outcomes according to glucose category, where normal glucose concentration (,6 mmol/l) represents no hazard for follow-up during the entire study period Glucose category mmol/l mmol/l >11 mmol/l Adjusted HR (95% CI) p Value Adjusted HR (95% CI) p Value Adjusted HR (95% CI) p Value Long-term mortality 1.21 (0.83 to 1.76) (0.99 to 2.27) (1.50 to 3.68),0.001 Long-term mortality and 1.25 (0.89 to 1.76) (1.18 to 2.50) (1.21 to 2.80) readmission with heart failure Multivariate Cox models included age, urea, neutrophil count, spironolactone, ACE inhibitor use, anaemia, and creatinine. (R = 20.17, p,0.001) and insulin resistance index (R = 0.28, p,0.001). Impaired insulin sensitivity correlates with the severity of heart failure 23 and is an independent predictor of mortality in heart failure patients with ischaemic heart disease 24 or valve disease. 25 The mechanisms for reduced glucose disposal may be due to excess sympathoadrenal activation, 25 which also correlates with disease severity. 26 While we do not provide mechanistic information in the present study, it is interesting to speculate that prognostically important glucose elevations in patients with worsening heart failure may be explained by neurohormonal activation, which is also prognostically important in this setting. 27 In RESOLVD, diabetic patients had an increased mortality rate, whereas non-diabetic patients with abnormal blood concentrations had a similar prognosis to patients with normal blood glucose concentrations. 2 This latter finding from RESOLVD is in contrast to those of the current study where we found that even a mild elevation in blood glucose was prognostically important. This suggests that a cut-off for diabetes or no diabetes may be too simplistic. Newton et al 28 retrospectively reviewed the charts of 528 hospitalised patients who had a new diagnosis of heart failure. They found that a glucose concentration of.10 mmol/l predicted all-cause mortality, whereas lower concentrations of glucose did not. Furthermore, blood glucose did not predict allcause mortality in non-diabetic patients. Newton et al 28 reported that glucose concentrations did not influence survival in diabetic subjects. By contrast, we found that glucose concentration predicted mortality independent of a history of diabetes. Comparison with Newton s study is clouded by the fact that patients with an admission glucose.11 mmol/l were not ascertained as being diabetic. As a high proportion, if not all, of these patients were likely to be diabetic and have impaired glucose metabolism, an interaction test for diabetes status was, in our view, inappropriate. Undertreatment of diabetic patients 29 does not seem to be an explanation for the relationship between glycaemic abnormalities and outcome. We found that diabetic and non-diabetic patients were treated equally commonly with evidence-based drug therapies, such as ACE inhibitors and b-blockers. 30 CONCLUSION We found that, in a contemporary, unselected population of consecutive hospitalised HF patients, abnormal glucose tolerance and diabetes were associated with an increased risk of death in hospital and in the longer term, and were also comparable predictors for these outcomes. Use of evidencebased drug therapies was greater in diabetic patients, yet despite this, outcomes were much worse in this group. The explanation for the poor prognosis of patients with HF and diabetes requires further investigation. HF patients with abnormal glucose tolerance should receive intensive medical management in order to improve prognosis. Competing interests: None declared. REFERENCES 1. 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9 Diabetes, lipids and metabolism Downloaded from on September 19, Published by group.bmj.com 23. Swan JW, Anker SD, Walton C, et al. Insulin resistance in chronic heart failure: Relation to severity and etiology of heart failure. J Am Coll Cardiol 1997;30: Doehner W, Rauchaus M, Ponikowski P, et al. Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure. JAm Coll Cardiol 2005;46: Paolisso G, Tagliamonte MR, Rizzo MR, et al. Prognostic importance of insulinmediated glucose uptake in aged patients with congestive heart failure secondary to mitral and/or aortic valve disease. Am J Cardiol 1999;83: Anker SD, Chua TP, Ponikowski P, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 1997;96: Staroukine M, Devriendt J, Decoodt P, et al. Relationships between plasma epinephrine, norepinephrine, dopamine and angiotensin-ii concentrations, renin-activity, hemodynamic state and prognosis in acute heart-failure. Acta Cardiol 1984;39: Newton JD, Squire IB. Glucose and haemoglobin in the assessment of prognosis after first hospitalisation for heart failure. Heart 2006;92: Everly MJ, Heaton PC, Cluxton RJ. Beta-blocker underuse in secondary prevention of myocardial infarction. Ann Pharmacother 2004;38: Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status - A meta-analysis of major clinical trials. J Am Coll Cardiol 2003;41: BMJ Clinical Evidence Call for contributors BMJ Clinical Evidence is looking to recruit new contributors to update the Secondary Prevention of Ischaemic Cardiac Events and the Acute Myocardial Infarction reviews. However, we are always looking for new contributors, so do get in touch if you are interested in contributing to another review. Contributors are clinicians or epidemiologists with experience in evidence-based medicine and the ability to write in a concise and structured way. They can be UK or internationally based. If you require more information about what contributing to BMJ Clinical Evidence involves see www. clinicalevidence.com/ceweb/contribute/contributor.jsp and send your CV, clearly stating the clinical area you are interested in, to CECommissioning@bmjgroup.com. 304 Heart 2008;94: doi: /hrt

10 Downloaded from on September 19, Published by group.bmj.com Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure C Berry, M Brett, K Stevenson, J J V McMurray and J Norrie Heart : originally published online July 30, 2007 doi: /hrt Updated information and services can be found at: References alerting service These include: This article cites 30 articles, 6 of which you can access for free at: Receive free alerts when new articles cite this article. Sign up in the box at the top right corner of the online article. Topic Collections Articles on similar topics can be found in the following collections Epidemiology (3714) Drugs: cardiovascular system (8765) Diabetes (837) Notes To request permissions go to: To order reprints go to: To subscribe to BMJ go to: