Aims To determine the effect of the glucagon‐like peptide‐1 analogue liraglutide on left ventricular function in chronic heart failure patients with and without type 2 diabetes. Methods and results LIVE was an investigator‐initiated, randomised, double‐blinded, placebo‐controlled multicentre trial. Patients (n = 241) with reduced left ventricular ejection fraction (LVEF ≤45%) were recruited (February 2012 to August 2015). Patients were clinically stable and on optimal heart failure treatment. Intervention was liraglutide 1.8 mg once daily or matching placebo for 24 weeks. The LVEF was similar at baseline in the liraglutide and the placebo group (33.7 ± 7.6% vs. 35.4 ± 9.4%). Change in LVEF did not differ between the liraglutide and the placebo group; mean difference (95% confidence interval) was −0.8% (−2.1, 0.5; P = 0.24). Heart rate increased with liraglutide [mean difference: 7 b.p.m. (5, 9), P < 0.0001]. Serious cardiac events were seen in 12 (10%) patients treated with liraglutide compared with 3 (3%) patients in the placebo group (P = 0.04). Conclusion Liraglutide did not affect left ventricular systolic function compared with placebo in stable chronic heart failure patients with and without diabetes. Treatment with liraglutide was associated with an increase in heart rate and more serious cardiac adverse events, and this raises some concern with respect to the use of liraglutide in patients with chronic heart failure and reduced left ventricular function. More data on the safety of liraglutide in different subgroups of heart failure patients are needed.

OBJECTIVETo investigate the associations of plasma levels of advanced glycation end products (AGEs) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, and arterial stiffness.RESEARCH DESIGN AND METHODSWe prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, pentosidine and other biomarkers were measured at baseline. The median follow-up duration was 12.3 (interquartile range 7.6–12.5) years.RESULTSDuring the course of follow-up, 82 individuals (24.2%) died; 85 (25.1%) suffered a fatal (n = 48) and/or nonfatal (n = 53) CVD event. The incidence of fatal and nonfatal CVD and of all-cause mortality increased with higher baseline levels of AGEs independently of traditional CVD risk factors: hazard ratio (HR) = 1.30 (95% CI = 1.03–1.66) and HR = 1.27 (1.00–1.62), respectively. These associations were not attenuated after further adjustments for markers of renal or endothelial dysfunction, low-grade inflammation, or arterial stiffness.CONCLUSIONSHigher levels of AGEs are associated with incident fatal and nonfatal CVD as well as all-cause mortality in individuals with type 1 diabetes, independently of other risk factors and of several potential AGEs-related pathophysiological mechanisms. Thus, AGEs may explain, in part, the increased cardiovascular disease and mortality attributable to type 1 diabetes and constitute a specific target for treatment in these patients.

OBJECTIVEGrowth deferentiation factor-15 (GDF-15) is involved in inflammation and apoptosis. Expression is induced in the heart in response to ischemia and in atherosclerotic plaques. The aim of this study was to investigate GDF-15 levels in relation to all-cause mortality, cardiovascular mortality and morbidity, decline in glomerular filtration rate (GFR), and progression toward end-stage renal disease (ESRD).RESEARCH DESIGN AND METHODSThe study was a prospective observational follow-up study including 451 type 1 diabetic patients with diabetic nephropathy (274 men, aged 42.1 ± 0.5 years [means ± SD], diabetes duration 28.3 ± 8.9 years, GFR 76 ± 33 ml/min/1.73 m2) and a control group of 440 patients with longstanding type 1 diabetes and persistent normoalbuminuria (232 men, aged 45.4 ± 11.5 years, duration of diabetes 27.7 ± 10.1 years). The patients were followed for 8.1 (0.0–12.9) years (median [range]).RESULTSAmong normoalbuminuric patients, GDF-15 above the median predicted an adjusted (age, systolic blood pressure [sBP], and estimated GFR) increased risk of all-cause mortality (hazard ratio [HR] 3.6 [95% CI 1.3–10.3]; P = 0.014). Among patients with diabetic nephropathy, higher (fourth quartile) versus lower (first quartile) GDF-15 levels predict all-cause mortality (covariate-adjusted [sex, age, smoking, blood pressure, A1C, cholesterol, GFR, N-terminal prohormone B-type natriuretic peptide, antihypertensive treatment, and previous cardiovascular events]; HR 4.86 [95% CI 1.37–17.30]) as well as fatal and nonfatal cardiovascular events (adjusted HR 5.59 [1.23–25.43] and 3.55 [1.08–11.64], respectively). In addition, higher GDF-15 levels predict faster decline in GFR (P < 0.001) but not development of ESRD.CONCLUSIONSHigher levels of GDF-15 are a predictor of all-cause and cardiovascular mortality and morbidity in patients with diabetic nephropathy. Furthermore, higher levels of GDF-15 are associated with faster deterioration of kidney function.

OBJECTIVETo investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs).RESEARCH DESIGN AND METHODSWe prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of sRAGE and other biomarkers were measured at baseline. The median follow-up duration was 12.3 years (7.6–12.5).RESULTSThe incidence of fatal and nonfatal CVD and all-cause mortality increased with higher baseline levels of log-transformed sRAGE (Ln-sRAGE) independently of other CVD risk factors: hazard ratio (HR) 1.90 (95% CI 1.13–3.21) and 2.12 (1.26–3.57) per 1-unit increase in Ln-sRAGE, respectively. Adjustments for estimated glomerular filtration rate (eGFRMDRD), but not or to a smaller extent for markers of endothelial dysfunction, low-grade inflammation, arterial stiffness, and AGEs, attenuated these associations to HR 1.59 (95% CI 0.91–2.77) for fatal and nonfatal CVD events and to 1.90 (1.09–3.31) for all-cause mortality. In addition, in patients with nephropathy, the rate of decline of GFR was 1.38 ml/min/1.73 m2 per year greater per 1-unit increase of Ln-sRAGE at baseline (P = 0.036).CONCLUSIONSHigher levels of sRAGE are associated with incident fatal and nonfatal CVD and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated renal dysfunction may partially explain this association.