National Institutes of Health.

Summary Background Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. Methods In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA1c≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Times to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups. Findings There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05–0·22, p=0·0023). HbA1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06–0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56–0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58–1·02, p=0·073) in the sacubitril/valsartan group. Interpretation Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.

Background Narrower retinal arterioles and wider retinal venules have been associated with negative cardiovascular outcomes. We investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up and provide incremental value over the 2013 American College of Cardiology/American Heart Association pooled cohort equations (PCE) in predicting Atherosclerotic Cardiovascular Disease Events (ASCVE). Methods 10,470 men and women without prior ASCVE or heart failure (HF) in the Atherosclerosis Risk in Communities (ARIC) study underwent retinal photography at visit 3 (1993–1995). Results During a mean follow up of 16 years, there were 1779 incident CHD events, 548 ischemic strokes, 1395 HF events and 2793 deaths. Rates of all outcomes were higher in those with wider retinal venules and narrower retinal arterioles. Subjects with wider retinal venules [hazard ratio (HR) 1.13 (95% CI: 1.08–1.18), HR 1.18 (1.07–1.31) and HR 1.10 (1.00–1.20) per standard deviation (SD) increase] and narrower retinal arterioles [HR 1.06 (1.01–1.11), HR 1.14 (1.03–1.26) and HR 1.13 (1.03–1.24) per SD decrease] had a higher risk of death and stroke in both sexes as well as incident CHD in women but not men (interaction p=0.02) after adjustment for the PCE risk-score variables. The association between retinal vessel caliber and HF was non-significant after adjustment for systolic blood pressure. Among women with PCE-predicted 10-year ASCVE risk <5% (overall risk 3.9%), women in the narrowest arteriolar quartile had a 10-year event-rate of 5.6% compared to 2.8% for the widest quartile (5.0% vs. 3.4% for wider vs. narrower venules). Retinal vessel caliber reclassified 21% of low-risk women (11% of all women) as intermediate-risk (>5%). Conclusions Narrower retinal arterioles and wider retinal venules conferred long-term risk of mortality and ischemic stroke in both genders and CHD in women. These measures serve as an inexpensive, reproducible biomarker that added incremental value to current practice guidelines in ASCVE risk prediction in low-risk women.

Background It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows comprehensive evaluation of patients with known or suspected stable coronary artery disease. As management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. Methods MBF and CFR were quantified in 4,029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF<1.8 ml·g-1·min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. Results A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure-product, type of radiotracer or stress agent used, and revascularization post-scan (adjusted Hazard Ratio, HR [95% Confidence-Interval, CI]: 1.79 [1.38-2.31], p<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates, and 1.03 [0.84-1.27], p=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95%CI: 2.9-3.7%) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI: 1.3-2.1%) per year; these patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI: 0.6-1.6%) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95% CI: 0.3-0.6%) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the four concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. Conclusions CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.