GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer-free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes.

Cardiovascular safety of metformin and sulfonylureas in patients with different cardiac risk profiles.

OBJECTIVES/BACKGROUND: Based on previous experiences, the Food and Drug Administration and the European Medicines Agency recommend that clinical trials for novel antidiabetic drugs are powered to detect increased cardiovascular risk. In this context, data concerning licensed drugs such as metformin and sulfonylureas are conflicting. The influence of baseline cardiovascular risk on any treatment effect appears obvious but has not been formally proven. We therefore evaluated association of metformin and sulfonylureas with cardiovascular events in patients with different cardiovascular risk profiles indicated by N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels. METHODS: 2024 patients with diabetes mellitus were included in this observational study. The primary endpoint was defined as a combination of cardiovascular events and death. Association of metformin and sulfonylureas was assessed using Cox regression models. Possible differences of these associations in patients with different NT-proBNP levels were studied by stratifying and through interaction analysis. RESULTS: During a median follow-up of 60 months, the primary endpoint occurred in 522 (26%) of patients. The median age was 63 years. A Cox regression analysis was adjusted for site of treatment, concomitant medication, age, gender, body mass index, glycated haemoglobin, duration of diabetes, glomerular filtration rate, cholesterol, and history of smoking and cardiac disease. Metformin was associated with a decreased risk in the cohort with elevated NT-proBNP ≥300 pg/mL (HR 0.70, p=0.014) and a similar association was found for the interaction between metformin and NT-proBNP (p=0.001). There was neither an association for sulfonylureas nor a significant interaction between sulfonylureas and NT-proBNP. CONCLUSIONS: Metformin is associated with beneficial cardiovascular outcomes in patients with diabetes only when (sub)clinical cardiovascular risk defined by NT-proBNP levels is present.

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

OBJECTIVE: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. METHODS: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. CONCLUSIONS: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Association of endostatin with mortality in patients with chronic heart failure.

BACKGROUND: Experimental data imply that in decompensated heart failure (HF), the anti-angiogenic factor endostatin is increased. This study aimed to investigate whether the angiogenesis inhibitor endostatin is related to the risk of all-cause mortality in a prospective cohort study of chronic HF patients. METHODS: In this prospective observational cohort study, endostatin serum concentrations were determined in patients with chronic HF. Mortality data were recorded during a median follow-up of 31 months. RESULTS: One fifty one patients were included. The overall mortality rate was 20%. Baseline endostatin concentrations > 245 ng/mL were associated with higher risk of all-cause mortality [HR 8·7 (95% CI 2·5-30·0); P = 0·001] in the multivariate analysis as compared to endostatin concentrations ≤ 245 ng/mL. When both endostatin and NT-proBNP were above the calculated cut-off of 245 ng/mL and 2386 pg/mL, respectively, the prognostic utility of both biomarkers increased [HR 40·8 (95% CI 4·7-354·6); P = 0·001] compared with values lower than the cut-offs. CONCLUSIONS: Serum endostatin concentrations are independently associated with all-cause mortality. Furthermore, combination of endostatin and NT-proBNP discriminates patients at high risk.

Estimated glomerular filtration rate and albuminuria: true predictors of cardiovascular events in obese patients with type 2 diabetes?

BACKGROUND: The widely used MDRD formula underestimates kidney function in obese patients with diabetes mellitus. Therefore we aimed to evaluate the predictive value of estimated glomerular filtration rate (eGFR) for cardiovascular events in a typical cohort of patients with diabetes mellitus. METHODS: A total of 988 patients were analyzed. Cox regression models including the variables HbA1c, age, duration of diabetes, eGFR and urinary albumin to creatinine ratio (UACR) were run. First the whole collective was analyzed, in a second step the cohort was split into four different groups according to body mass index (BMI) and eGFR (Group 1, 475 Pts: eGFR > 60 ml/min; BMI < 30 kg/m(2), Group 2, 274 Pts: eGFR > 60 ml/min;BMI > 30 kg/m(2), Group 3, 110 Pts,: eGFR < 60 ml/min; BMI > 30 kg/m(2) and Group 4, 129 Pts.: eGFR < 60 ml/min;BMI < 30 kg/m(2)). eGFR was calculated using MDRD, Cockroft-Gault, and CKD-EPI formula. The endpoint was defined as unplanned cardiovascular hospitalization. RESULTS: Patients (571 male, 417 female) were 61 ± 22 years of age, mean duration of diabetes was 14.3 ± 12.3 years. After a median follow-up of 29 months 95 (9.6 %) patients reached the defined endpoint. The first model, including all patients showed that UACR (HR 1.001, p < 0.001) and eGFR (HR 0.957, p < 0.001) were significant predictors of the composite endpoint. In obese patients eGFR completely lost its predictive value for cardiovascular events. The prevalence of normoalbuminuria in patients with an eGFR below 60 ml/min was 59.4 %. CONCLUSION: In obese patients eGFR is not predictive for cardiovascular events.

NT-proBNP as a means of triage for the risk of hospitalisation in primary care.

BACKGROUND: In primary care, identification of patients who are at risk of major adverse events is of great importance. At the same time identifying individuals who are at very low risk and do not need further diagnostic workup and therapy is also important and may help to correctly allocate scarce healthcare resources. AIM: This study evaluated amino-terminal pro B-natriuretic peptide (NT-proBNP) as a risk marker in primary care patients with hypertension, diabetes, clinically suspected heart failure (HF), history of coronary artery disease or myocardial infarction. METHODS AND RESULTS: A prospective observational study was conducted in 1203 primary care patients. The primary endpoint, time to all-cause hospitalisation, was reached in 282 (24%) individuals within 12 months. Of all variables analysed, only NT-proBNP (HR 1.001 [1.000-1.001], p < 0.001) and age (HR 1.018 [1.007-1.028], p = 0.001) were of independent predictive value in a stepwise Cox regression analysis regarding all-cause hospitalisation. Neither systolic dysfunction nor signs and symptoms of HF added independent information to predict outcome. The negative predictive value (NPV) increased depending on the specificity of the endpoint (NPV was 86% for all-cause, 98% for cardiac and 100% for HF-related hospitalisation for 125 pg/ml). Positive predictive value and NPV were superior for NT-proBNP compared to clinical signs and symptoms of HF at every cut-point between 100 and 500 pg/ml. CONCLUSION: NT-proBNP levels predicted clinical events in primary care patients at risk. NPVs were excellent in this high risk population, proving NT-proBNP measurement a safe diagnostic tool.

Differences in the predictive value of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in advanced ischemic and non-ischemic heart failure.

OBJECTIVE: To assess the prognostic value of the pro-apoptotic, but also cell growth-inducing molecule soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) in heart failure (HF). METHODS: We assayed sTWEAK levels in 351 patients with advanced HF (non-ischemic: 130, ischemic: 221). During a median follow-up of 4.9 years, 195 patients (56%) died. RESULTS: sTWEAK concentrations were associated with extended survival in patients with non-ischemic (P=0.022), but not with ischemic HF (P=0.82). The inverse association in non-ischemic HF remained significant in a multivariable Cox regression model (P=0.025) with a hazard ratio of 0.40 (95% confidence interval: 0.21-0.77) comparing the third to the first tertile (P=0.007). CONCLUSION: Low sTWEAK levels independently predict mortality in advanced non-ischemic HF. sTWEAK-induced proliferation of cardiomyocytes may explain its impact on suvival. The different prognostic value of sTWEAK in ischemic and non-ischemic HF may point towards distinct pathogenic pathways determining the course of disease.

Prognostic value of pigment epithelium-derived factor in patients with advanced heart failure.

OBJECTIVE: Whereas angiogenesis, the formation of new blood vessels from preexisting vessels, may be beneficial in restoring failing myocardium, apoptosis may contribute to the progression of heart failure (HF). We investigated the role of pigment epithelium-derived factor (PEDF), a recently discovered antiangiogenic factor with additional proapoptotic effects, in patients with advanced HF. METHODS: We assayed PEDF levels in 351 patients with advanced HF at baseline. During the median follow-up time of 16 months, 50% of patients experienced the composite end point of rehospitalization and/or death. RESULTS: The risk of a clinical event increased with concentrations of the antiangiogenic marker PEDF, with a 1.94-fold higher risk in the third tertile compared with the first tertile (95% CI, 1.33-2.84). This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model (P = .015). Experimental data revealed that PEDF may contribute to the progression of HF by inducing apoptosis in human cardiac myocytes and fibroblasts via activation of caspase 3. CONCLUSIONS: We suggest a role of PEDF in the progression of HF by inducing apoptosis of human cardiac myocytes and fibroblasts. Our clinical data suggest that PEDF concentrations may have the potential to become a valuable marker of the prognosis of HF, in addition to BNP.

Prognostic value of apoptosis markers in advanced heart failure patients.

AIMS: Apoptosis plays an important role in the progression of heart failure (HF). The purpose of this study was to assess whether the pro-apoptotic molecules apoptosis-stimulating fragment (FAS, CD95/APO-1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) predict event-free survival of HF patients. METHODS AND RESULTS: We assayed soluble (s)FAS and sTRAIL levels in 351 patients with advanced HF. During the median follow-up time of 16 months, 175 patients (50%) experienced the composite endpoints: rehospitalization and death. The hazard increased with sFAS concentrations, with a hazard ratio of 2.3 comparing fourth and first quartiles. This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model (P = 0.014). Patients with high sFAS but low BNP had a comparable event-free survival rate with those with elevated BNP only (P = 0.78). Conversely, high sTRAIL concentrations were related to a better prognosis. Particularly, the risk of mortality dropped by 70% in the fourth quartile of sTRAIL (P = 0.001, multivariable Cox regression model). CONCLUSION: sFAS is an independent risk predictor in advanced HF patients. It may be of particular value for the identification of high-risk patients in addition to BNP. Conversely, sTRAIL appears to be protective and could be an interesting therapeutic agent.

NT-proBNP has a high negative predictive value to rule-out short-term cardiovascular events in patients with diabetes mellitus.

AIMS: This study evaluated the predictive value of NT-proBNP for patients with diabetes mellitus and compared the prognostic aptitude of this neurohumoral marker to traditional markers of cardiovascular events. METHODS AND RESULTS: A prospective observational study was conducted in 631 diabetic patients. The composite endpoint consisted of unplanned hospitalization for cardiovascular events or death within the observation period of 12 months. Of all variables analysed (age, gender, history of hypertension, ischaemic heart disease/any cardiac disease, smoking, duration of diabetes, body mass index, blood pressure, New York Heart Association-class, Dyspnoea score, Minnesota Living with Heart Failure Questionnaire, LDL-cholesterol, HbA(1c), creatinine, glomerular filtration rate), the logarithm of NT-proBNP gave the most potent information in a stepwise Cox regression analysis (P < 0.0001). Bootstrapping with 500 samples supports this result in 95% samples. The negative predictive value of a normal value (<125 pg/mL) of NT-proBNP for short-term cardiovascular events in diabetic patients is 98%. CONCLUSION: We have demonstrated a strong and independent correlation between NT-proBNP and short-term prognosis of cardiovascular events for patients with diabetes mellitus. With a high negative predictive value it can identify individuals who are not at intermediate risk for cardiovascular events. NT-proBNP proved to be of higher predictive value than traditional cardiovascular markers, in this unselected cohort.