European Journal of Heart Failure (2014) 16, 1190–1198 doi:10.1002/ejhf.146
Impaired fasting glucose: a predictor of reduced survival in patients with heart failure Israel Gotsman*, Ayelet Shauer, Chaim Lotan, and Andre Keren Heart Failure Center, Heart Institute, Hadassah University Hospital, POB 12000, Jerusalem, Israel IL-91120 Received 14 March 2014; revised 23 June 2014; accepted 27 June 2014 ; online publish-ahead-of-print 31 July 2014
Aims
Glucose abnormalities are associated with heart failure (HF), are increasingly prevalent, and may have an impact on outcome. Our aim was to evaluate the effect of fasting glucose levels on clinical outcome in patients with HF. ..................................................................................................................................................................... Methods Patients with a diagnosis of HF as coded at a health maintenance organization in Jerusalem, Israel were evaluated and results retrospectively. Impaired fasting glucose (IFG) was defined as fasting plasma glucose levels between 100 and 125 mg/dL. All patients were followed for cardiac-related hospitalizations and death. A total of 6067 HF patients were included. Mean follow-up was 487 days; mean age 75 ± 13 years; 48% of the patients (n = 2,942) had diabetes; and 11.9% (n = 722) had IFG. Overall survival during the follow-up was 82.5%. Cox regression analysis after adjustment for significant predictors including age, gender, ischaemic heart disease, hyperlipidaemia, hypertension, body mass index, glomerular filtration rate, serum urea, sodium, and haemoglobin levels demonstrated that patients with diabetes and IFG had a very similar outcome. Both were significant predictors of reduced survival compared with ‘normal’ glucose levels (fasting glucose levels between 92 and 99 mg/dL) [diabetes, hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.08–1.86, P = 0.01; IFG, HR 1.55, 95% CI 1.13–2.15, P < 0.01]. Diabetes and IFG were also predictors of increased cardiac-related hospitalizations (diabetes HR 1.31, 95% CI 1.16–1.48, P < 0.001; IFG, HR 1.17, 95% CI 1.00–1.35, P < 0.05). ..................................................................................................................................................................... Conclusions Diabetes and IFG are common in patients with HF and have a similar effect on outcome including survival and cardiac hospitalizations. Glucose abnormalities including subclinical diabetes confer significant risk in patients with HF.
.......................................................................................................... Impaired fasting glucose •
Heart failure •
Introduction Heart failure (HF) has emerged as a major epidemic and is now a significant public health burden. It is associated with considerable morbidity and mortality.1 Diabetes is a significant risk factor for the development of HF,2 and poor control of glucose in patients with diabetes increases this risk.3,4 Moreover, glucose abnormalities alone, which can lead to diabetes, also increase the risk of developing HF.5,6 Therefore, it is not surprising that glucose abnormalities and diabetes are common in patients with HF,7 and the prevalence of diabetes in HF patients is high.8 Diabetes is a predictor of a worse outcome in patients with HF compared with patients without diabetes,8 – 11 particularly in patients with ischaemic heart disease.12,13 However, data regarding the clinical
Outcome
.........................................
Keywords
significance of glucose abnormalities and particularly impaired fasting glucose (IFG)14 as a predictor of outcome in HF are limited and not well defined. Glucose abnormalities and diabetes are an epidemic in the western world and are on the way to becoming so in the developing world. Israel, considered a western country, has a very diverse and heterogeneous population with different ethnic as well as cultural backgrounds. The city of Jerusalem exemplifies this diversity, with a large proportion of Jewish immigrants from Europe and Middle Eastern countries as well as a substantial minority of Arab ethnicity. The purpose of the present study was to evaluate the significance of glucose abnormalities on clinical outcome including death and cardiac hospitalization in a large cohort of patients with chronic HF in Jerusalem.
*Corresponding author. Tel: +972 2 6776564, Fax: +972 2 6411028, Email: [email protected]
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
1191
Methods Participants and study design Clalit Health Services is the largest health maintenance organization (HMO) in Israel. It has a central computerized database in which all members have a complete digital record. The database includes demographics, comprehensive clinical data, diagnoses, and all laboratory data undertaken in a single centralized laboratory of the HMO. We identified and retrieved electronically from the computerized database all members with a diagnosis of HF as coded by the database in the city of Jerusalem using the International Classification of Diseases, Ninth Revision (ICD-9) code 428. A total of 6946 patients had a diagnosis of HF. Validation of the diagnosis of HF was performed on a randomly computer-generated 5% of the diagnosed HF patients (n = 338) as previously described.15 Clinical parameters in this group of patients were statistically comparable with those of the whole HF cohort. We reviewed all available data from medical records and hospital admissions. In this group, the majority fulfilled the European Society of Cardiology (ESC) criteria for the diagnosis of HF.17 Only 1% (n = 4) had equivocal clinical data for HF diagnosis. Fasting glucose levels are routinely determined as part of a periodic work-up in all members of the HMO. We identified all the patients in this cohort in whom a fasting glucose level was measured closest to July 2008, the time the database was established. Eighty-seven per cent of the patients (n = 6067) had a fasting glucose level available for analysis. These individuals comprised the study cohort. Echocardiographic data pertaining to left ventricle (LV) function, categorized into preserved (EF ≥50%) and reduced (EF 140/90 mmHg measured on several occasions or administration of antihypertensive treatment, and hyperlipidaemia as low density lipoprotein (LDL) >130 mg/dL, fasting serum triglycerides >200 mg/dL, or administration of lipid-lowering treatment. All hospitalizations in cardiac and internal medicine departments including cardiac and internal intensive care units were retrieved and analysed. Data on mortality were retrieved from the National Census Bureau. The Institutional Committee for Human Studies of the HMO–Clalit Health Services, approved the study protocol.
Laboratory analysis Biochemical analyses were performed at the HMO single centralized core laboratory with routine standardized methodologies on fresh samples of blood obtained after an overnight fast. Glucose levels were measured in plasma, and all other biochemical analyses were performed on serum. The laboratory is authorized to perform tests according to the international quality standard ISO-9001. Periodic assessment of quality control is performed on a regular basis. Serum levels of glucose were measured by the glucose hexokinase G-6-PDH method using an autoanalyser (Beckman Coulter AU analyzer, Fullerton, CA, USA) in the core laboratory of the HMO. Analytical sensitivity was 1 mg/dL, with a range of 10 – 800 mg/dL; the intra-assay coefficient of variance (CV) was 0.5–1%. Normal levels in the HMO laboratory are between 70 and 100 mg/dL. Haemoglobin A1C (HbA1c ) levels were measured by the high-performance liquid chromatography method using the Bio-Rad VARIANT™ II HbA1C analyser (Bio-Rad Laboratories). Normal levels in the HMO laboratory are between 4.0% and 5.7%.
........................................................................................................................................................................
Impaired fasting glucose and outcome in heart failure
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
Statistical analyses SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used in all analyses. Comparison of the clinical characteristics was performed using the Student t-test for continuous variables and the 𝜒 2 test for categorical variables. Log10 was used for logarithmic transformations, with the exception of estimated glomerular filtration rate (eGFR) for which a square root transformation was used. Patients with missing laboratory data were excluded from the analysis. Follow-up time was calculated using the Kaplan–Meier estimate of potential follow-up.18 Kaplan–Meier curves, with the log-rank test, were used to compare survival according to glucose levels. Multivariate Cox proportional hazards regression analysis was used to evaluate independent variables that determined survival. Parameters included in the multivariate Cox regression analysis incorporated age and gender and other significant clinical and laboratory parameters on univariable analysis, with the addition of significant drug therapy in separate models. Proportionality assumptions of the Cox regression models were evaluated by log–log survival curves and with the use of Schoenfeld residuals. An evaluation of the existence of confounding or interactive effects was made between variables and their possible collinearity. A P-value of 125 mg/dL. These patients were considered as having undiagnosed diabetes and were included for this analysis with patients with known diabetes, making a total of 3064 (50.5%) in this group. Patients with fasting glucose levels
Impaired fasting glucose: a predictor of reduced survival in patients with heart failure Israel Gotsman*, Ayelet Shauer, Chaim Lotan, and Andre Keren Heart Failure Center, Heart Institute, Hadassah University Hospital, POB 12000, Jerusalem, Israel IL-91120 Received 14 March 2014; revised 23 June 2014; accepted 27 June 2014 ; online publish-ahead-of-print 31 July 2014
Aims
Glucose abnormalities are associated with heart failure (HF), are increasingly prevalent, and may have an impact on outcome. Our aim was to evaluate the effect of fasting glucose levels on clinical outcome in patients with HF. ..................................................................................................................................................................... Methods Patients with a diagnosis of HF as coded at a health maintenance organization in Jerusalem, Israel were evaluated and results retrospectively. Impaired fasting glucose (IFG) was defined as fasting plasma glucose levels between 100 and 125 mg/dL. All patients were followed for cardiac-related hospitalizations and death. A total of 6067 HF patients were included. Mean follow-up was 487 days; mean age 75 ± 13 years; 48% of the patients (n = 2,942) had diabetes; and 11.9% (n = 722) had IFG. Overall survival during the follow-up was 82.5%. Cox regression analysis after adjustment for significant predictors including age, gender, ischaemic heart disease, hyperlipidaemia, hypertension, body mass index, glomerular filtration rate, serum urea, sodium, and haemoglobin levels demonstrated that patients with diabetes and IFG had a very similar outcome. Both were significant predictors of reduced survival compared with ‘normal’ glucose levels (fasting glucose levels between 92 and 99 mg/dL) [diabetes, hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.08–1.86, P = 0.01; IFG, HR 1.55, 95% CI 1.13–2.15, P < 0.01]. Diabetes and IFG were also predictors of increased cardiac-related hospitalizations (diabetes HR 1.31, 95% CI 1.16–1.48, P < 0.001; IFG, HR 1.17, 95% CI 1.00–1.35, P < 0.05). ..................................................................................................................................................................... Conclusions Diabetes and IFG are common in patients with HF and have a similar effect on outcome including survival and cardiac hospitalizations. Glucose abnormalities including subclinical diabetes confer significant risk in patients with HF.
.......................................................................................................... Impaired fasting glucose •
Heart failure •
Introduction Heart failure (HF) has emerged as a major epidemic and is now a significant public health burden. It is associated with considerable morbidity and mortality.1 Diabetes is a significant risk factor for the development of HF,2 and poor control of glucose in patients with diabetes increases this risk.3,4 Moreover, glucose abnormalities alone, which can lead to diabetes, also increase the risk of developing HF.5,6 Therefore, it is not surprising that glucose abnormalities and diabetes are common in patients with HF,7 and the prevalence of diabetes in HF patients is high.8 Diabetes is a predictor of a worse outcome in patients with HF compared with patients without diabetes,8 – 11 particularly in patients with ischaemic heart disease.12,13 However, data regarding the clinical
Outcome
.........................................
Keywords
significance of glucose abnormalities and particularly impaired fasting glucose (IFG)14 as a predictor of outcome in HF are limited and not well defined. Glucose abnormalities and diabetes are an epidemic in the western world and are on the way to becoming so in the developing world. Israel, considered a western country, has a very diverse and heterogeneous population with different ethnic as well as cultural backgrounds. The city of Jerusalem exemplifies this diversity, with a large proportion of Jewish immigrants from Europe and Middle Eastern countries as well as a substantial minority of Arab ethnicity. The purpose of the present study was to evaluate the significance of glucose abnormalities on clinical outcome including death and cardiac hospitalization in a large cohort of patients with chronic HF in Jerusalem.
*Corresponding author. Tel: +972 2 6776564, Fax: +972 2 6411028, Email: [email protected]
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
1191
Methods Participants and study design Clalit Health Services is the largest health maintenance organization (HMO) in Israel. It has a central computerized database in which all members have a complete digital record. The database includes demographics, comprehensive clinical data, diagnoses, and all laboratory data undertaken in a single centralized laboratory of the HMO. We identified and retrieved electronically from the computerized database all members with a diagnosis of HF as coded by the database in the city of Jerusalem using the International Classification of Diseases, Ninth Revision (ICD-9) code 428. A total of 6946 patients had a diagnosis of HF. Validation of the diagnosis of HF was performed on a randomly computer-generated 5% of the diagnosed HF patients (n = 338) as previously described.15 Clinical parameters in this group of patients were statistically comparable with those of the whole HF cohort. We reviewed all available data from medical records and hospital admissions. In this group, the majority fulfilled the European Society of Cardiology (ESC) criteria for the diagnosis of HF.17 Only 1% (n = 4) had equivocal clinical data for HF diagnosis. Fasting glucose levels are routinely determined as part of a periodic work-up in all members of the HMO. We identified all the patients in this cohort in whom a fasting glucose level was measured closest to July 2008, the time the database was established. Eighty-seven per cent of the patients (n = 6067) had a fasting glucose level available for analysis. These individuals comprised the study cohort. Echocardiographic data pertaining to left ventricle (LV) function, categorized into preserved (EF ≥50%) and reduced (EF 140/90 mmHg measured on several occasions or administration of antihypertensive treatment, and hyperlipidaemia as low density lipoprotein (LDL) >130 mg/dL, fasting serum triglycerides >200 mg/dL, or administration of lipid-lowering treatment. All hospitalizations in cardiac and internal medicine departments including cardiac and internal intensive care units were retrieved and analysed. Data on mortality were retrieved from the National Census Bureau. The Institutional Committee for Human Studies of the HMO–Clalit Health Services, approved the study protocol.
Laboratory analysis Biochemical analyses were performed at the HMO single centralized core laboratory with routine standardized methodologies on fresh samples of blood obtained after an overnight fast. Glucose levels were measured in plasma, and all other biochemical analyses were performed on serum. The laboratory is authorized to perform tests according to the international quality standard ISO-9001. Periodic assessment of quality control is performed on a regular basis. Serum levels of glucose were measured by the glucose hexokinase G-6-PDH method using an autoanalyser (Beckman Coulter AU analyzer, Fullerton, CA, USA) in the core laboratory of the HMO. Analytical sensitivity was 1 mg/dL, with a range of 10 – 800 mg/dL; the intra-assay coefficient of variance (CV) was 0.5–1%. Normal levels in the HMO laboratory are between 70 and 100 mg/dL. Haemoglobin A1C (HbA1c ) levels were measured by the high-performance liquid chromatography method using the Bio-Rad VARIANT™ II HbA1C analyser (Bio-Rad Laboratories). Normal levels in the HMO laboratory are between 4.0% and 5.7%.
........................................................................................................................................................................
Impaired fasting glucose and outcome in heart failure
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
Statistical analyses SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used in all analyses. Comparison of the clinical characteristics was performed using the Student t-test for continuous variables and the 𝜒 2 test for categorical variables. Log10 was used for logarithmic transformations, with the exception of estimated glomerular filtration rate (eGFR) for which a square root transformation was used. Patients with missing laboratory data were excluded from the analysis. Follow-up time was calculated using the Kaplan–Meier estimate of potential follow-up.18 Kaplan–Meier curves, with the log-rank test, were used to compare survival according to glucose levels. Multivariate Cox proportional hazards regression analysis was used to evaluate independent variables that determined survival. Parameters included in the multivariate Cox regression analysis incorporated age and gender and other significant clinical and laboratory parameters on univariable analysis, with the addition of significant drug therapy in separate models. Proportionality assumptions of the Cox regression models were evaluated by log–log survival curves and with the use of Schoenfeld residuals. An evaluation of the existence of confounding or interactive effects was made between variables and their possible collinearity. A P-value of 125 mg/dL. These patients were considered as having undiagnosed diabetes and were included for this analysis with patients with known diabetes, making a total of 3064 (50.5%) in this group. Patients with fasting glucose levels
