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Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9, alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled, phase 2 studies of 8 or 12 weeks' duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, and NCT01288443). Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (−30.3% vs −0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that <5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol. In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering.

In a phase 2 trial, patients with hypercholesterolemia received 80 mg atorvastatin and placebo, 10 mg atorvastatin and an antibody to PCSK9, or 80 mg atorvastatin and an antibody to PCSK9 for 8 weeks. Reductions from baseline in LDL cholesterol were 17.3%, 66.2%, and 73.2%, respectively. Reducing levels of low-density lipoprotein (LDL) cholesterol is a cornerstone of the prevention of cardiovascular disease. 1 , 2 European and U.S. guidelines recommend lowering LDL cholesterol to less than 100 mg per deciliter (2.6 mmol per liter) in persons with established cardiovascular disease and to less than 70 mg per deciliter (1.8 mmol per liter), or by 50% or more, in those at highest risk. 3 , 4 Statins are highly efficacious in lowering LDL cholesterol. However, many patients, especially those with very high initial LDL cholesterol levels and those who have unacceptable side effects with high-dose statins, do not reach recommended target . . .

Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS. This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non–high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred. ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

Background The effect of alirocumab on potentially atherogenic lipoprotein subfractions was assessed in a post ho c analysis using the vertical auto profile (VAP) method. Methods Patients from three Phase II studies with low-density lipoprotein cholesterol (LDL-C) ≥2.59 mmol/L (100 mg/dL) at baseline on stable statin therapy were randomised to receive subcutaneous alirocumab 50–150 mg every 2 weeks (Q2W) or 150–300 mg every 4 weeks (according to study) or placebo for 8–12 weeks. Samples from patients treated with alirocumab 150 mg Q2W ( n  = 74; dose common to all three trials) or placebo ( n  = 71) were analysed by VAP. Percent change in lipoprotein subfractions with alirocumab vs. placebo was analysed at Weeks 6, 8 or 12 using analysis of covariance. Results Alirocumab significantly reduced LDL-C and the cholesterol content of subfractions LDL 1 , LDL 2 and LDL 3+4 . Significant reductions were also observed in triglycerides, apolipoproteins CII and CIII and the cholesterol content of very low-density, intermediate-density, and remnant lipoproteins. Conclusion Alirocumab achieved reductions across a spectrum of atherogenic lipoproteins in patients receiving background statin therapy. Trial registration Clinicaltrials.gov identifiers: NCT01288443 , NCT01288469 , NCT01266876

Background Obesity enhances hemodynamic alterations that predispose to a subsequent increase in left ventricular (LV) wall stress leading to LV hypertrophy. In obese subjects, weight reduction regresses LV mass (LVM), regardless of blood pressure. Sibutramine can increase blood pressure and heart rate, which may attenuate the reductions in LVM associated with weight loss. Methods Outpatients (n = 184, age 18-65 y, body mass index ≥30 to <40 kg/m2) were randomly assigned to 6 months of once daily double-blind treatment with sibutramine 10 mg or 20 mg, or placebo. LV dimensions, status and function of the valves, weight loss, blood pressure, heart rate, and electrocardiogram were assessed. Results For end point data sets, the mean ± SD LVM index (LVM/height) changes were −3.0 ± 11.9 g/m for placebo (n = 56), −4.4 ± 10.7 g/m for sibutramine 10 mg (n = 61), and −4.3 ± 10.9 g/m for sibutramine 20 mg (n = 56). The reductions observed in the sibutramine groups were statistically significant compared with baseline (P <.01), but pairwise comparison results with placebo were not statistically significant. There was no difference in overall status of the cardiac valves. A statistically significant greater weight loss was found in patients on both doses of sibutramine compared with placebo (P <.001). No statistically significant differences between the groups were observed in respect to blood pressure and electrocardiographic intervals, but a statistically significant increase in pulse rate (7 beats/min) was noted for patients with sibutramine treatment. Conclusion A 6-month treatment with sibutramine does not affect ventricular dimensions, heart valves, and electrocardiogram variables. (Am Heart J 2002;144:508-15.)

Background: Anorexigens have been associated with cardiovascular side effects including heart rate (HR), blood pressure (BP) and valvular changes. We assessed the effect of sibutramine (sib), a monoamine reuptake inhibitor, on HR, BP, LV geometry and function and heart valves. Methods: non complicated obese patients (n = 184, 30 ≤ BMI < 40 kg/m2) were randomized double blind to 6 months o.d. sib 10 mg (n = 64) or 20 mg (n = 60) or placebo (n = 60). 2D-Echos were obtained using an ATL Peak 800+ machine, LV mass index (LVMI) was calculated according to Devereux and Reichek and adjusted for height. Heart valves were examined in various axes. Echo data were obtained for 173 patients (10 mg = 61, 20 mg = 56 or placebo = 56). Echo were performed at baseline (twice − poor quality and/or reproducibility echo were excluded) and at 6 months by a single operator. Results: Baseline patients’ characteristics, comparable between the 3 treatment groups, were as follows: age = 38.7 ± 10.8 yrs, 85% female, BMI = 33.8 ± 2.8 kg/m2, SBP/DBP = 121.4 ± 11.7/75.3 ± 8.6 mmHg, LVMI = 60.8 ± 15.9 g/m, LVEF = 65.0 ± 5.4%; grade 1 or 2 valve regurgitation was found in 11% (mitral), 8% (aortic), and 3% (tricuspid) of patients. At 6 months sib decreased BMI (ANOVA) (10 mg: −3.5 ± 2.1 vs 20 mg: −4.4 ± 2.5 vs placebo −1.7 ± 1.6, p < 0.001) and slightly increased HR (+5.7 vs +5.8 vs +0.1bpm, p = 0.001). SBP and DBP and ECG variables, including QT and QTc, were unchanged. Statistically significant differences for LVMI reductions were seen in the sib groups from baseline (p < 0.01) but pairwise comparisons with placebo were not significant (−4.4, −4.3 vs −3.0). Valvular changes were not significant. Conclusion: Obese patients treated with sib 10 mg or 20 mg or placebo for 6 ••• falls in LVM associated with weight loss; these falls were significantly greater for the sib groups from baseline. Also, apart from a slight rise in HR, sib did not affect BP, ECG variables and heart valves.