Wright, R. Scott

Introduction: Excessive bodyweight, often associated with dyslipidemia, may affect the pharmacology of drugs. Inclisiran, a small interfering RNA targeting PCSK9 hepatic mRNA, is an effective LDL-C lowering agent with twice-yearly subcutaneous dosing (after the initial and 3-month doses). Aim: To analyze the efficacy and safety of inclisiran in patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalent across body mass index (BMI) strata. Methods: In this post hoc analysis from ORION-9 (NCT03397121), ORION-10 (NCT03399370) and ORION-11 (NCT03400800), eligible patients were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo at baseline, Day 90 and 6-monthly thereafter. Analyses were stratified by baseline BMI: <25, 25-<30, 30-<35 or ≥35 kg/m 2 . Percentage change in atherogenic lipids from baseline at Day 510 was evaluated. Safety was assessed over 540 days. Results: Baseline demographic and clinical characteristics including atherogenic lipid levels were mostly balanced between the treatment arms and across the BMI strata ( Table ). Percentage change in atherogenic lipids from baseline at Day 510 was significantly greater with inclisiran vs placebo within each BMI stratum ( Table ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms and were reported more frequently with increasing BMI strata (data not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs placebo similarly across strata, but all were mild or moderate. Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained lipid lowering in patients, irrespective of their baseline BMI, and was generally well tolerated.

Introduction: Disorders of glucose metabolism increase in prevalence globally and contribute to excess risk of ASCVD, necessitating intensive lipid lowering. Aim: To analyze efficacy and safety of inclisiran (small interfering RNA targeting hepatic PCSK9 mRNA) across the strata of glycemic disorders. Methods: In this post hoc, pooled analysis of ORION-10 and ORION-11, 3174 patients (pts) with ASCVD/ASCVD risk equivalent (including diabetes mellitus [DM]) were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo (pbo) at baseline (BL), Day (D) 90, and 6-monthly thereafter. Analyses were stratified by BL glycemic status (normoglycemia, pre-DM or DM). LDL-C percentage (%) change from BL to D510 and time-adjusted % change from D90 to D540 were evaluated. Safety was assessed over 540 days. Results: BL characteristics were generally balanced between the treatment arms across the glycemic strata ( Table 1 ). LDL-C % change and time-adjusted % change were greater with inclisiran vs pbo and were similar across all strata ( Table 2 ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms; TEAEs were reported more frequently in pts with vs without glycemic disorders (not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo across the strata but all were mild or moderate ( Table 2 ). Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering irrespective of BL glycemic status, and was generally well tolerated.

BACKGROUND Recent studies have reported that asymptomatic left ventricular dysfunction (ALVD) in humans is characterized by early neurohumoral activation. Specifically, atrial natriuretic factor (ANF) and norepinephrine are activated without activation of the renin-angiotensin-aldosterone system (RAAS). The current study describes hemodynamic and renal function associated with this neurohumoral profile in a canine model of early and presumably "asymptomatic" ventricular dysfunction. We hypothesized that the neurohumoral profile observed in ALVD is associated with preservation of renal function despite significant hemodynamic compromise. METHODS AND RESULTS ALVD was produced by ventricular pacing at 180 beats per minute for 10 days. Intravascular volume expansion was performed before and after producing ALVD in eight conscious dogs. The model of ALVD was characterized by decreases in ejection fraction (48 +/- 2 to 29 +/- 4%), cardiac output (4.64 +/- 0.29 to 2.89 +/- 0.17 L/min), and mean arterial pressure (119 +/- 4 to 108 +/- 4 mm Hg). Atrial pressures and systemic vascular resistance were increased. ANF (60 +/- 19 to 165 +/- 27 pg/mL) and norepinephrine (382 +/- 127 to 690 +/- 211 pg/mL) were activated, whereas the RAAS was not. Creatinine clearance and sodium excretion (UNa V) were unchanged after producing ALVD. The natriuretic response to volume expansion in ALVD was completely intact, with increases in UNa V similar to that observed with volume expansion in ALVD was completely intact, with increases in UNa V similar to that observed with volume expansion before producing ALVD. CONCLUSIONS The current study demonstrates that significant ventricular dysfunction with peripheral vasoconstriction can be associated with normal renal function and thus suggests an important functional role for the neurohumoral profile of ALVD in preserving sodium balance.

Background— After acute myocardial infarction (AMI), diastolic function assessed by Doppler echocardiography provides important prognostic information that is incremental to systolic function. However, Doppler variables are affected by multiple factors and may change rapidly. In contrast, left atrial (LA) volume is less influenced by acute changes and reflects subacute or chronic diastolic function. This may be of importance when one assesses risk in patients with AMI. Methods and Results— Three hundred fourteen patients with AMI who had a transthoracic echocardiogram with assessment of left ventricular (LV) systolic and diastolic function and measurement of LA volume during admission were identified. The LA volume was corrected for body surface area, and the population was divided according to LA volume index of 32 mL/m 2 (2 SDs above normal). LA volume index was >32 mL/m 2 in 142 (45%). The primary study end point was all-cause mortality. During follow-up of 15 (range 0 to 33) months, 46 patients (15%) died. LA volume index was a powerful predictor of mortality and remained an independent predictor (hazard ratio 1.05 per 1-mL/m 2 change, 95% CI 1.03 to 1.06, P <0.001) after adjustment for clinical factors, LV systolic function, and Doppler-derived parameters of diastolic function. Conclusions— Increased LA volume index is a powerful predictor of mortality after AMI and provides prognostic information incremental to clinical data and conventional measures of LV systolic and diastolic function.