Prevalence and characteristics of diabetic patients in a chronic heart failure population

International Journal of Cardiology 100 (2005) 281 – 287 www.elsevier.com/locate/ijcard

Prevalence and characteristics of diabetic patients in a chronic heart failure population Caroline KistorpT, Sbren Galatius, Finn Gustafsson, Jens Faber, Pernille Corell, Per Hildebrandt Department of Cardiology and Endocrinology, Copenhagen University Hospital, Frederiksberg, 57 Nordre Fasanvej, DK-2000 Frederiksberg, Denmark Received 3 May 2004; received in revised form 11 August 2004; accepted 4 October 2004 Available online 2 March 2005

Abstract Background: Previously, estimates of the prevalence of diabetes mellitus (DM) in patients with chronic heart failure (CHF) have solely been based on history in retrospective studies. The aim of this study was to investigate the prevalence of DM and glucose abnormalities in patients with CHF in accordance with the modern diagnostic criteria of DM. A second aim was to characterize patients with DM with respect to severity of CHF. Methods and results: A prospective study including patients with systolic CHF admitted to a heart failure clinic. Fasting blood glucose (FBG) levels were measured on two occasions, for classification of DM. Severity of CHF was assessed by NYHA class, echocardiography, 6 min walk test and plasma NT-proBNP levels. A total of 195 consecutive patients were included in the study, of these 188 were eligible for classification of DM. A total of 21% had DM by history, 11% of the patients without known DM had FBGz6.1 mmol/l, and a diagnosis of DM was confirmed in half of these patients. There were no differences in severity of heart failure between patients with DM by definition and non-DM patients; however, high body mass index was related to worse CHF symptoms. Conclusion: Twenty six percent of the patients had DM by definition, 20% of these were undiagnosed at the time of admission. One single measurement of FBG is not sufficient to establish a diagnosis of DM. Diabetes was not related to CHF symptoms or to a degree of left ventricular dysfunction. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Chronic heart failure; Diabetes mellitus; Diagnosis; Prevalence; Severity of heart failure; Body mass index

1. Introduction The prevalence of diabetes mellitus (DM), mainly type 2 DM, in heart failure patients is expected to be high. Diabetes mellitus is an independent risk factor for developing chronic heart failure (CHF) [1]. Furthermore, CHF is associated with insulin resistance [2], followed by increased risk of developing type 2 DM [3]. The prevalence of DM in CHF has been evaluated in large clinical heart failure trials and surveys, in which the estimated prevalence of DM has ranged from 10% to more than 30% [4–9]. Thus, most existing data on the

T Corresponding author. Tel.: +45 38164324; fax: +45 38164359. E-mail address: [email protected] (C. Kistorp). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2004.10.024

prevalence of DM in CHF patients have previously been generated from retrospective subgroup analyses, with highly selected patient populations. Furthermore, importantly the diagnosis of DM was made solely by history, except for one study that included fasting blood glucose (FBG), measured once [10]. In this particular study the prevalence of DM and pre-diabetic glucose abnormalities were above 40% [10]. However, according to the diagnostic criteria for DM, FBG should be measured twice in asymptomatic patients [11–13]. Therefore the observed prevalence of DM may be misleading, both in terms of correct diagnosis and in terms of population selections. The correct diagnosis may have important clinical implications with respect to treatment and in particular with respect to prognosis. Furthermore, it has been suggested that DM and pre-diabetic hyperglycaemia, may be asso-

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ciated with increased heart failure symptoms and reduced functional capacity, independent of age and left ventricular ejection fraction (LVEF) [4,10]. Thus, in terms of consecutive patients with CHF referred to a hospital based specialist heart failure clinics without exclusion criteria, no current data on the prevalence and clinical characteristics of diabetic patients exist. Patients with CHF have a severe prognosis [14], and in order to improve quality of life and reduce hospitalisations, many centres have established heart failure clinics operated with cardiologists and specialized nurses [15,16]. These clinics are often based on an open access principle. General practitioners, internists and others are encouraged to refer patients with suspected or known CHF without restrictions, in order to diagnose and optimise treatment of CHF [17]. In this way patients referred to such heart failure clinics may well reflect a more unselected CHF population, than the patients from the large intervention studies [16,17]. We prospectively evaluated the prevalence of DM and the pre-diabetic condition designated impaired fasting glucose (IFG), according to the diagnostic criteria for DM, among consecutive patients admitted with CHF to the heart failure clinic at our hospital. We compared CHF patients with DM and IFG to those without DM with respect to: 1) severity of CHF, as evaluated by NYHA classification, LVEF, functional capacity, and plasma N-terminal pro Brain Natriuretic Peptide (NT-proBNP) levels, and with respect to 2) diabetes related risk markers, as evaluated by fasting plasma insulin, lipid profiles, urinary albumin excretion, and body mass index (BMI).

2.2. Procedure At baseline visit, all the patients were examined by a senior physician with training in cardiology at a specialist level and a specialized nurse, and were evaluated by the following: medical history including medication, a physical examination, NYHA classification based on patient information, an echocardiography (supplemented by an isotopic ventriculography in case the echocardiography was technically insufficient), BMI (kg/m2), resting blood pressure and heart rate and a standardized 6- min walk test were obtained. A resting (20 min) and fasting (overnight, minimum of 8 h) blood sample for the measurement of blood glucose, lipids, haemoglobin A1c (HbA1c), and NTproBNP, and a urine sample (first voided urine in the morning) for the measurement of urinary albumin/creatinine ratio. The diagnostic fasting blood glucose measurements were performed, when the patients were stable, with a median of 15 days from the baseline visit. Patients without previously known DM and with a FBGz5.6 mmol/l were invited for a repeated measurement of FBG. The measurements of FBG levels were repeated in accordance with the 1998 WHO and ADA diagnostic criteria for DM [11–13]. All patients were registered in our heart failure database, based on Microsoft Access software, bHJERTER+b The database serves as a combined medical record and database [18]. The investigations conform to the principles outlined in the Declaration of Helsinki. The study was approved by the local ethics committee, and all patients provided written informed consent. 2.3. Definitions

2. Material and methods 2.1. Study population The heart failure clinic is situated in the centre of Copenhagen, a total of 120,000 inhabitants are living in the referral area and are served by 75 general practitioners. All patients in this area are referred to Frederiksberg University Hospital. Since September 1999, the heart failure clinic at Frederiksberg University Hospital has been operating, the original design of the clinic has been described in detail previously [18]. Briefly, patients with known or suspected systolic CHF is referred to the clinic, either directly from the general practitioners or the departments of internal medicine or cardiology of the hospital, on an open access basis. If systolic CHF is confirmed, the patient is offered referral to the clinic. A total of 195 consecutive CHF patients, with confirmed chronic systolic heart failure, were enrolled in this study. These patients did not differ from the cohort previously described in our heart failure clinic, with respect to age, sex, LVEF, NYHA class, 6-min walk test and duration of CHF [18].

Patients were classified as having known manifest DM on the basis of previous information from a physician or were treated with oral antidiabetic agents or insulin. The diagnosis was confirmed in each case by medical records. Patients without a previous diagnosis of DM were classified with respect to DM according to the 1998 WHO and ADA criteria [11–13]. Newly diagnosed diabetes: Fasting venous whole blood glucose z6.1 mmol/l on two occasions. Impaired fasting glucose (IFG) was defined as: Fasting venous whole blood glucose z5.6 and b6.1 mmol/l on two occasions, without previously known DM. No diabetes: Patients with baseline FBGb5.6 mmol/l, without known DM, were categorized as non-diabetic. Patients with one FBGz5.6 mmol/l, and the following measurements of FBGb5.6 mmol/l were classified as nondiabetic. Patients with FBGz5.6 mmol/l, without completing a second FBG measurement because of death or difficulties in participating in the follow-up remained unclassified (Fig. 1). Systolic CHF was defined, as documented LVEFV45% by echocardiography or ventriculography, in combination with symptoms of CHF.

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Systolic CHF n = 195

Known diabetes n = 39

Previously unknown diabetes n = 156

No DM FBG < 5.6 mmol/l n = 122

FBG ≥ 5.6 mmol/l n = 34

New DM FBG ≥ 6.1 mmol/l measured twice n=9

IFG FBG 5.6-6.1 mmol/l measured twice n = 14

No DM FBG 1 of 2 values < 5.6 mmol/l n=4

Not classified No follow-up n=7

Fig. 1. Flowchart of the patients in the study. No DM=non-diabetic; IFG=impaired fasting glucose; New DM=newly diagnosed diabetes; FBG=fasting blood glucose.

2.4. Measurements Following a minimum of 8 h overnight fast and 20 min of supine rest, venous blood was drawn for measurement of fasting BG, HbA1c and plasma level of NT-proBNP. Blood glucose was measured in venous whole blood, according to the enzymatic amperometric principle with the enzyme glucose oxidase (GOD), using an EPIO 6666 analyser (Eppendorf, Hamburg, Germany). HbA1c was measured with an immuno-turbidimetric assay, using alkaline hematin D-575, on a Cobas Integra analyzer (Roche Diagnostics, Basel, Switzerland). The reference range was 4.6%–6.0% (mean 5.2%), at a confidence interval of 95%. Blood for measurement of plasma levels of NT-proBNP were drawn into EDTA tubes, promptly centrifuged at 4 8C, and frozen at 80 8C until assay. Plasma concentration of NT-proBNP was measured using a double antibody sandwich technique using ElectroChemiLuminescense as signal (Elecsys NT-pro-BNP, Roche Diagnostics). The sensitivity of the assay was b5.9 pmol/l, and the intra and interassay coefficients of variation (CV) were b5.0% [19]. Urine samples were collected as first morning spot urine. Urinary albumin was measured by immunoturbidimetry on a Cobas Bioanalyzer (Roche Products, Basel, Switzerland). Forty microliters of urine was mixed with 225 Al phosphate buffer and 25 Al diluted antibody. Lower detection limit was 1 mg/l and the CV was b4%. Urinary creatinine was measured by a Jaffe´ reaction rate, kinetic principle, thus eliminating pseudocreatines. Urinary albumin excretion was determined as the urinary albumin/ creatinine ratio, upper limit of normal range was 30 mg/g. 2.5. Statistical analysis Values are presented as meanFSD or as median (interquartile range). Differences between the four groups: known DM, newly diagnosed DM, IFG and non DM were

tested by one-way ANOVA followed by Student’s t-test for continuous variables. Statistical analyses of urinary albumin/creatinine ratio, plasma NT-proBNP and duration of CHF were performed using the Kruskal–Wallis tests since the distributions were not Gaussian. The chi square test was used for categorical data. Multivariate logistic regression analyses were used to test the predictive value of DM and Table 1 Patient characteristics Characteristic

Patients (n=195)

Age (years)a Male

69.3 (10.2) 141 (72.4%)

Heart failure etiology Ischemic heart disease Idiopathic cardiomyopathy Hypertension Valvular Others Body mass index (kg/m2)a Fasting blood glucose (mmol/l)a HbA1c (%)a LVEF (%)a NYHA class I II III IV 6-min walk test (m)c NT-proBNP (pg/ml)b Cardiovascular medication ACE inhibitors Angiotensin II blocker h-blocker Statin Spironolactone

108 26 18 7 36 27.3 5.7 6.2 30.0 21 123 49 1 365 1210.2

129 23 60 45 33

(55%) (14%) (10%) (4%) (18%) (5.1) (2.2) (1.2) (8.3) (11%) (63%) (25%) (0.5%) (143) (471.3 3076.6)

(66%) (12%) (31%) (23%) (17%)

a Values are mean (SD). bValues are median (interquartile range). c81 (42%) of the patients did not conduct the 6-min walk test and were not included. Values are numerical (%) if not otherwise stated.

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measurement. Thirty-nine (39/188, 21%) had known DM, most of them were type 2 DM (95%). Of the patients with known diabetes, 21% were treated with diet, 50% were treated with oral antidiabetic medication, 20% with insulin and 9% with insulin in combination with oral antidiabetic medication. The non-classified patients did not differ, with respect to age, duration of CHF or NYHA class, as compared with the classified patients. At baseline 11% (17/ 156) of the patients with no previous diagnosis of diabetes had FBG value z6.1 mmol/l. Of these patients 52% (9/ 17), corresponding to 5% were classified as newly diagnosed DM after a repeated measurement of FBG, and 14 patients (7%) had IFG (Fig. 1). Thus 48 (26%) had DM by definition and a total of 62 (33%) had impaired glucose metabolism. Patient characteristics of the classified CHF patients according to diabetes status are shown in Table 2. Age and sex were similar in the groups. HbA1c was higher in patients with DM by definition than in nonDM, and patients with known DM by history had higher HbA1c than newly diagnosed DM (7.7F1.9% vs. 6.2F0.6 %, p=0.031), whereas the patients with IFG only had a trend towards a higher HbA1c than non-DM ( P=0.059). There was a marked overlap in the HbA1c values among

BMI with respect to functional status. A two-tailed p-value of below 0.05 was considered as statistically significant. The statistical software package SPSS version 10.0 was used for all analyses.

3. Results We included 195 patients, 55 women and 140 men, with a mean age of 69.3F10.2. The mean LVEF for all patients was 30%F(8.3%), range 10%–45%. The majority of the patients (88%) were either NYHA functional class II or III, 11% in NYHA I, and one (0.5%) in NYHA class IV. The median duration of CHF was 6 months with a range of 1– 186 months. Baseline characteristics for the total population are given in Table 1. 3.1. Classification Of the 195 patients, 188 (96%) were eligible for a classification of DM, the remaining 7 patients were not classified, 2 because of death before sampling and 5 because they did not complete in the second FBG

Table 2 Patient characteristics according to diabetes status Pa

Charactertistic

Known diabetes (n=39)

Newly diagnosed diabetes (n=9)

Impaired fasting glucose (n=14)

No diabetes (n=126)

Age (years)b Male (%) Body mass index (kg/m2)b

66.3 (10.2) 80 29.3 (5.7)

69.6 (8.5) 78 29.9 (3.3)

69.5 (12.6) 86 30.5 (5.0)

70.4 (9.7) 68 26.1 (4.8)

0.18 0.287 0.001

Heart failure etiology (%) Ischemic heart disease Idiopathic cardiomypathy Hypertension Others

72 13 6 9

63 11 25 1

67 17 8 8

48 14 10 28

0.087 0.71 0.47 0.088

Metabolic parameters Fasting blood glucose (mmol/l)b HbA1c (%) mean (range) Urinary A/C ratio (mg/g)c Total cholesterol (mmol/l)b LDL-cholesterol (mmol/l)b HDL-Cholesterol (mmol/l)b Triglycerides (mmol/l)b Heart failure parameters CHF duration (month)c LVEF (%)b NYHA class (%) I/II III/IV 6-min walk test (m)b NT-proBNP (pg/ml)c Creatinine clearance (ml/min)b Systolic BP (mmHg) b Diastolic BP (mmHg)b Heart rate (beats per min)b a

8.3 7.7 25 4.6 2.6 1.2 1.7

(3.8) (5.6–13.3) (11–89) (1.1) (0.9) (0.3) (1.4)

8 (3–60) 30 (9) 71 29 327 1079 82 143 80 80

(156) (517–3433) (41) (26) (16) (17)

6.9 6.6 36 4.6 2.6 1.2 1.5

(1.0) (5.6–8.8) (13–122) (1.0) (0.8) (0.3) (0.9)

6 (5–47) 28 (7) 78 22 420 1832 66 136 86 78

(136) (303–3831) (26) (22) (14) (8)

6.0 6.0 9 5.1 3.1 1.2 2.2

(0.4) (5.4–6.8) (6–19) (0.8) (0.6) (0.4) (1.8)

5 (3–25) 36 (7) 85 15 377 495 85 139 80 79

(132) (256–1485) (30) (30) (14) (17)

4.5 5.8 14 5.4 3.3 1.5 1.5

(0.5) (4.6–7.1) (5–29) (1.4) (1.2) (0.5) (0.9)

6 (2–25) 29 (8) 72 28 370 1469 71 138 77 72

(140) (537–3057) (30) (25) (14) (15)

P values for differences between groups. bValues are mean (SD). cValues are median (interquartile range). BP denotes blood pressure.

b0.001 b0.001 0.006 0.009 0.005 0.009 0.079

0.37 0.021

0.78 0.634 0.27 0.107 0.76 0.26 0.024

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the 4 groups of patients, ranges of HbA1c are shown in Table 2. The predictive power of HbA1c for the diagnosis of DM was tested, in patients with no previous history of diabetes and FBGz5.6 mmol/l. Haemoglobin A1c value N6.0% (corresponding to the upper reference range for the laboratory) had a specificity of 47% (8/17) for the diagnosis of DM, with a sensitivity of 67% (6/9). A total of 140 patients were classified as non-diabetic or IFG, of these 35 (25%) had HbA1c values above upper reference range of 6.0%. 3.2. Etiology of CHF There was a trend towards that ischemic heart disease was more often considered the etiology to CHF in patients with DM and IFG as compared the non-diabetics ( p=0.087). No difference in the prevalence of IDC, hypertension or valvular disease was found between the groups (Table 2). 3.3. Diabetes related measurements Total cholesterol and LDL-cholesterol were higher in non-DM than in patients with DM. HDL-cholesterol was lower in the diabetic patients, whereas there was no difference in triglyceride levels between the groups (Table 2). Urinary albumin excretion was markedly increased among patients with known and newly diagnosed DM compared to those with IFG and non-DM. Body mass index was higher in patients with DM and IFG compared to the non-DM patients ( pb0.001) (Table 2). In the total population and among the non-DM patients, there was a significant correlation between FBG and BMI (r=0.27, P=0,001) and (r=0.38, Pb0.0001), respectively. 3.4. Severity of CHF Patients with DM by definition had similar degree of CHF as the non-DM patients, evaluated by mean LVEF, plasma NT-proBNP levels, NYHA class and 6 min walk test as a measure of functional capacity. The patients with IFG had higher LVEF as compared with the DM and the nonDM patients (Table 2). At baseline two thirds of the patients were receiving an ACE-I, and one-third a beta blocker (Table 1). No difference was found in the use of cardiovascular active drugs between the groups. In the non-DM patients, there was a modest correlation between HbA1c (but not with FBG) and NYHA class (r=0.17, p=0.047), but after adjusting for BMI the correlation was no longer significant. BMI was independently correlated with NYHA class (r=0.35, p=0.014), after adjusting for DM, age, LVEF, HbA1c and heart rate, in a multivariate regression model. BMI was higher (28.8F6.4 kg/m2 vs. 26.1F4.5 kg/m2, pb0.05) in patients with NYHA class III/IV symptoms than those with NYHA class I/II.

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4. Discussion The present study is the first study providing prospectively collected data on verified diabetes in consecutive CHF patients, referred to a hospital based heart failure clinic without exclusion criteria. Therefore, we believe that this study provides data reflecting the actual prevalence and characteristic of DM in the general CHF population. The patients in the clinic were approximately 5 years older than in most CHF clinical trial populations, but comparable with respect to NYHA functional class, LVEF, sex, and the prevalence of documented IHD [4,5,9]. In the present population 26% of the patients had DM by definition, and a further 7% IFG. Thus, approximately a third of the patients with systolic CHF had impaired glucose metabolism. Twenty one percent of the patients had a previous diagnosis of DM, which is similar to several previously reported clinical heart failure trials [5,20,21]. Further, the DM prevalence in this study is comparable with the European cohort studies, in which the prevalence was between 18% and 24% [22–24]. But, the prevalence was somewhat less than in the US cohort studies, in which the frequency was approximately 30% [8], and in the US randomised trials with 26%, 27% and 28% observed in the SOLVD, the RESOLVD and the DIGtrial, respectively [4,10,25]. These differences most likely reflect the difference in DM prevalence between Europe and the US, as well as the use of different diagnostic criteria for DM. Although not focusing on DM, several studies from heart failure clinics and different heart failure management programs have reported a DM prevalence, which ranged from 21% to 30% in the European studies [26–28], and with the same pattern of higher frequencies (28%–52%) in the US populations [29–32]. However, most of these previous studies were randomised, with selected populations using different inclusion criteria, as in the study by Rich et al., only including patients N70 years of age [29]. Other studies only included NYHA class III/IV patients [26,28], or used several exclusion criteria [33]. The diagnosis of CHF was often made on a clinical basis [28,29,31], and only some of the studies used echocardiography [15,27,30]. Thus, comparison of the DM prevalence is difficult, due to differences in selection of the patient populations, and use of different diagnostic criteria for CHF. However, the prevalence of diabetes by history in the present study is similar to a recent European, non-randomised, heart failure clinic study, which primarily included CHF patients with systolic dysfunction [27]. More than a fifth of the CHF patients without a previous history of known DM, had elevated fasting blood glucose levels or diabetic range hyperglycaemia after a single measurement of FBG. Thus, of the 195 CHF patients, a total of 37% had either known DM (20%) or abnormal glucose levels (17%), defined as FBGz5.6 mmol/l after a single measurement of FBG. Our cut-off level of FBG is in line with the 1998 WHO and ADA criteria, stating that a

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fasting whole blood glucose level b5.6 mmol/l is an appropriate level for normality [11,12]. This result is in line with previous data from the RESOLVD study, finding 43% of the patients with DM or abnormal glucose metabolism [10]. However, it is important to note that, in the present study only 50% of the patients with single FBGz6.1 mmol/l at baseline met the 1998 WHO and the ADA diagnostic criteria for DM after follow-up measurement. This clearly indicates that a single high FBG in patients with CHF is not reliable in establishing a diagnosis of DM, and overestimates the prevalence. The use of HbA1c as an indicator of DM is controversial, and it is generally believed that this measure does not have the capacity to establish a diagnosis of diabetes in the general population [34]. However, a recent study performed in acutely ill patients, presenting with elevated random blood glucose, HbA1cN6.0% (upper reference level) was always associated with a diagnosis of DM [35]. In contrast, the inability of HbA1c to predict a diagnosis of DM was clearly demonstrated in our study, 20% of the 126 patients finally classified as non-DM had baseline HbA1c levels above the upper normal reference range. Our results are in accordance with recent data from patients with acute myocardial infarction, where 11% were classified as nonDM had HbA1c levels above the upper reference level [36]. HbA1c was measured using an immuno-turbidimetric assay, which is well correlated with the high performance liquid chromatography assay, and recommended as traceable to the DCCT reference method [37]. The present study describes a high prevalence of diabetes and impaired glucose tolerance in a heart failure population. The study population is too small to predict a reliable incidence of de novo diabetes. Further, only three of the patients now classified as newly diagnosed diabetes and none of the patients classified as IFG, had a previous obtainable measurement of FBG, data not shown. However, CHF patients are insulin resistant [2] and previous studies have demonstrated a significant incidence of diabetes, both in patients with normal and impaired glucose tolerance [3,38]. Whether metabolic control will reduce the increased morbidity and mortality in diabetic patients with CHF, remains to be determined in prospective studies. Nevertheless, undiagnosed diabetes is likely to increase the risk of infections and fatigue in these patients. Thus, measurement of FBG on a regulatory basis, preferably once a year, in patients with documented CHF is recommended. Patients with known DM and with less severe glucose abnormalities, as newly diagnosed DM and IFG, had the same risk of severe CHF symptoms (NYHA class III/IV) as patients without DM (RR:1.2, 95% CI: 0.58-2.2, P=0.7), and there were no significant differences in 6-min walk distances. This is not in accordance with the results from the SOLVD and RESOLVD studies, where both manifest DM and pre-diabetic hyperglycaemia were associated with more severe CHF symptoms [4,10]. Therefore, it is interesting that BMI was positively correlated with the NYHA class,

independent of possible confounders as age, LVEF, FBG, and heart rate. Thus, patients with BMIz30 kg/m 2 (corresponding to the 75% quartile of the population) were 2.2 times (95% CI: 1.1–4.7, Pb0.05) as likely to have severe NYHA class III/IV symptoms than patients with BMIb30. To our knowledge, this is the first time that a relationship between high BMI and high NYHA class has been demonstrated in CHF patients. The current study does not allow us to identify the mechanisms responsible for this relationship. However, recently published data from the Framingham study have establishing an observational association between obesity and increased risk of CHF [39]. Limitations: If we had performed an oral glucose tolerance test, a further 5% of the patients might have been classified as DM [40,41]. Another limitation is that our cohort was almost without patients in NYHA class IV, reflecting that the clinic is an outpatient clinic and home visits are not a part of our program. Thus, our results may not apply to the patients with the most severe degrees of CHF. In conclusion, 26% of the patients in this CHF population had DM by definition. Twenty percent of these and 5% of the whole population was undiagnosed at the time of admission. One single raised FBG in combination with HbA1c measurement is not sufficient to establish a diagnosis of DM in patients with CHF. A high BMI, but not a diagnosis of DM, was associated with more severe CHF symptoms.

Acknowledgements We would like to acknowledge the assistance of Inger W7tjen, lab technician, Chemical department, Copenhagen University Hospital Frederiksberg.

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