Baseline In Low-density Lipoprotein Cholesterol Research Articles

PCSK9 Inhibitors: Is the Time Ripe for the "Fast Track" Use Independently on the LDL-C Baseline Values in Acute Coronary Syndrome?

The low-density lipoprotein cholesterol (LDL-C) lowering decreases the risk to develop major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS). Therefore, the "fast track" use of PCSK9 inhibitors (PCSK9i) has been introduced in ACS patients not achieving LDL-C target (70mg/dl) despite an ongoing lipid lowering therapy with statin at maximum tolerated dosage plus ezetimibe or stain-naïve (LDL-C > 130mg/dl). PCSK9i "fast track" use has shown to achieve the regression of "non-culprit" atherosclerotic plaques leading to a further MACE decrease. Interestingly, it has been also hypothesized a role of PCSK9i beyond the LDL-C lowering in ACS. PCSK9i have been demonstrated to decrease the inflammation of atherosclerotic plaques and myocardium, inhibit platelet aggregation, and improve the cardiomyocyte survival against the reperfusion injury. All these findings may positively impact on the prognosis and suggest the PCSK9i use in the acute phase of ACS independently on the baseline LDL-C values.

Efficacy and Safety of Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease

Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial. To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti-PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C-lowering treatment. This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg/dL or greater with CVD or 100 mg/dL or greater if at high risk of CVD were included. Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo for 52 weeks. The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets. Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C-lowering efficacy. In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone. ClinicalTrials.gov Identifier: NCT04806893.

Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial.

Lerodalcibep, a novel small recombinant fusion protein of a PCSK9-binding domain (adnectin) and human serum albumin demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 ml SC dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep was evaluated in heterozygous familial hypercholesterolaemia (HeFH) patients requiring additional LDL-C lowering. Patients were randomized 2:1 to monthly SC injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the percent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. In 478 randomized subjects [mean age (range); 53 (18-80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L] lerodalcibep reduced LDL-C, compared to placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean(SE); 95% CI -2.30 to -1.87] with a percentage difference of -58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% CI -2.47 to -2.09) with a percentage difference of -65.0 (2.87)% at the mean of Weeks 22 and 24 (P < 0.0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended ESC LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo. Lerodalcibep, a novel anti-PCSK9 small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with HeFH with a safety profile similar to placebo.

Population pharmacokinetic and pharmacokinetic-pharmacodynamic modeling of bempedoic acid and low-density lipoprotein cholesterol in healthy subjects and patients with dyslipidemia

Population pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve. Mild (estimated glomerular filtration rate (eGFR) 60 to < 90 mL/min vs. ≥ 90 mL/min) and moderate (eGFR 30 to < 60 mL/min vs. ≥ 90 mL/min) renal impairment, female sex, low (< 70 kg vs. 70–100 kg) and high (> 100 kg vs. 70–100 kg) body weight were predicted to have a 1.36-fold (90% confidence interval (CI) 1.32, 1.41), 1.85-fold (90% CI 1.74, 2.00), 1.39-fold (90% CI 1.34, 1.47), 1.35-fold (90% CI 1.30, 1.41), and 0.75-fold (90% CI 0.72, 0.79) exposure difference relative to their reference populations, respectively. An indirect response model described changes in serum LDL-C with a model-predicted 35% maximal reduction and bempedoic acid IC50 of 3.17 µg/mL. A 28% reduction from LDL-C baseline was predicted for a steady-state average concentration of 12.5 µg/mL after bempedoic acid (180 mg/day) dosing, accounting for approximately 80% of the predicted maximal LDL-C reduction. Concurrent statin therapy, regardless of intensity, reduced the maximal effect of bempedoic acid but resulted in similar steady-state LDL-C levels. While multiple covariates had statistically significant effects on PK and LDL-C lowering, none were predicted to warrant bempedoic acid dose adjustment.

The efficacy of PCSK9 inhibitors on major cardiovascular events and lipid profile in patients with diabetes: a systematic review and meta-analysis of randomized controlled trials.

To evaluate the specific effects of PCSK9 inhibitors (i.e. alirocumab and evolocumab) on major cardiovascular events (MACE) and lipid profile in patients with diabetes. We conducted a systematic review of literature according to the PRISMA statement. A total of eight randomized control trials (RCTs) enrolling 20651 patients with diabetes were included. The mean follow-up was 51 weeks. We included RCTs that had compared the subtilisin-kexin type 9 inhibitors (PCSK9i) alirocumab and evolocumab with placebo in subjects with hypercholesterolaemia and diabetes mellitus.MACE occurred in 8.7% of patients with diabetes randomized to PCSK9i vs.11.0% of those randomized to placebo. Thus, the use of alirocumab or evolocumab reduced MACE by 18% [odds ratio (OR): 0.82; 95% confidence interval (CI): 0.74-0.90]. Compared with control group, the use of PCSK9 inhibitors was associated with a significant percentage change from baseline in low-density lipoprotein cholesterol [mean difference (MD) -58.48%; 95% CI: -63.73 to -53.22%, P<0.0001], high-density lipoprotein cholesterol (HDL-C) (MD 5.21%; 95% CI: 3.26-7.17%), triglycerides (MD -14.59%; 95% CI: -19.42 to -9.76%), non-HDL-C (MD -48.84%; 95% CI: -54.54 to -43.14%), and total cholesterol (MD -33.76%; 95% CI: -38.71 to -28.8%). Moreover, a significant reduction of lipoprotein(a) (MD -32.90%; 95% CI: -38.55 to -27.24%) and apolipoprotein B (MD -46.83%; 95% CI: -52.71 to --40.94%) were observed in PCSK9i group compared with placebo. PCSK9i appear to be effective in reducing the risk of MACE and in improving lipid profiles of subjects with diabetes and dyslipidaemia.

Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616

BackgroundMK-0616 is an oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of hypercholesterolemia. ObjectivesThis Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia. MethodsThis trial was planned to include 375 adult participants with a wide range of atherosclerotic cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The primary endpoints included percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the 8-week treatment period. ResultsOf the 381 participants randomized, 49% were female, and the median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: –41.2% (6 mg), –55.7% (12 mg), –59.1% (18 mg), and –60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group. ConclusionsMK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia [MK-0616-008]; NCT05261126)

Translational Population-Pharmacodynamic Modeling of a Novel Long-Acting siRNA Therapy, Inclisiran, for the Treatment of Hypercholesterolemia.

Inclisiran is a novel N-acetylgalactosamine (GalNAc) conjugated small-interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half-life, but long duration of effects on PCSK9 inhibition and low-density lipoprotein cholesterol (LDL-C) lowering. The effects on PCSK9 inhibition and consequent LDL-C reduction are sustained for more than 6 months following a single subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only for up to 48 hours. A kinetic-pharmacodynamic (K-PD) model was developed to characterize inclisiran's dose-related LDL-C lowering effects and to evaluate the impact of intrinsic and extrinsic factors on LDL-C lowering. To accommodate the long duration of action, the K-PD model incorporated an effect compartment which represents the liver. Inclisiran concentration in the liver leads to decreased production of the PCSK9 protein and allow recycling of more LDL-C receptors on the hepatocyte cell surface, which results in a reduction of circulating LDL-C. The analysis of covariates identified PCSK9 and LDL-C baseline levels as important factors for the effects of LDL-C lowering. Observations and modeling and simulation results demonstrated that PCSK9 and LDL-C reductions are achieved rapidly after dosing and sustained when patients are treated with a 300 mg s.c. dose once every 6 months.

Abstract 10851: A Randomized Study to Compare LDL-C-Lowering Effects of Inclisiran With Usual Care vs Usual Care Alone in Patients With Recent Hospitalization for an Acute Coronary Syndrome: Rationale and Design of the VICTORION-INCEPTION Trial

Introduction: Patients are at high risk for a recurrent cardiovascular (CV) event in the first year following acute coronary syndrome (ACS). Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for recurrent CV events. Despite the availability of lipid-lowering therapies (LLT), many patients fail to achieve guideline recommended LDL-C &lt;70 mg/dL in the year post-ACS. Early LDL-C evaluation and LLT intensification after recent ACS may reduce recurrent CV event risk. In prior phase III trials, inclisiran plus maximally tolerated statin therapy effectively reduced LDL-C in patients with established ASCVD. As patients with an ACS within 3 months of screening were excluded from these trials, the efficacy of inclisiran in these patients is unknown. Objective: To assess the LDL-C-lowering effect of inclisiran with usual care vs usual care alone in patients with recent ACS and LDL-C ≥70 mg/dL, despite statin therapy. Methods: VICTORION-INCEPTION (NCT04873934) is a phase IIIb, randomized, parallel-group, open-label, multicenter, US-based trial enrolling eligible patients to receive inclisiran plus usual care or usual care ( Figure ). Concomitant LLT and routine LDL-C assessment is at the discretion of the managing physician to mimic real-world clinical practice. The primary endpoints are percent change from baseline in LDL-C and proportion of patients achieving LDL-C &lt;70 mg/dL. Key secondary endpoints include absolute change from baseline in LDL-C by visit, proportion of patients reaching pre-specified LDL-C targets, other plasma lipids, adherence to background LLT, and safety and tolerability of inclisiran. Exploratory endpoints include patient-reported outcomes and healthcare resource utilization. Conclusions: VICTORION-INCEPTION, an ongoing trial planned to complete in early 2024, will assess the effectiveness of inclisiran plus usual care for the management of patients with elevated LDL-C post-ACS despite receiving statin therapy.

Efficacy and Tolerability of Ezetimibe/Atorvastatin Fixed-dose Combination Versus Atorvastatin Monotherapy in Hypercholesterolemia: A Phase III, Randomized, Active-controlled Study in Chinese Patients

PurposeThe 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (“statins”) and the cholesterol-lowering medication ezetimibe are widely used in the treatment of patients with high- and very high–risk atherosclerotic cardiovascular disease. This study compared the efficacy and tolerability of a fixed-dose combination (FDC) of ezetimibe/atorvastatin (EZ/AS) with those of escalating doses of atorvastatin monotherapy in Chinese patients with hypercholesterolemia uncontrolled with statin monotherapy. MethodsThis Phase III, 12-week, randomized, double-blind study included patients aged 18 to 80 years with hypercholesterolemia uncontrolled on atorvastatin 10 or 20 mg/d monotherapy. After a 5-week run-in period of treatment with atorvastatin 10 or 20 mg/d (cohorts A and B, respectively), or a bioequivalent dosage of another statin, patients were randomized in a 1:1 ratio within each cohort to receive EZ/AS 10/10 mg FDC (EZ10/AS10) or atorvastatin 20 mg (AS20), once daily (cohort A); or EZ/AS 10/20 mg FDC (EZ10/AS20) or atorvastatin 40 mg (AS40), once daily (cohort B). The primary end point was the percentage change from baseline in low-density lipoprotein cholesterol (LDL-C). Tolerability was also evaluated. FindingsOf the 454 patients enrolled, 412 (90.7%) completed the study. The percentage change from baseline in LDL-C was statistically greater with EZ10/AS10 treatment (n = 88) compared with AS20 monotherapy (n = 89) (treatment difference, −19.5%; 95% CI, −26.7% to −12.3%; P < 0.001). The percentage change from baseline in LDL-C was statistically greater with EZ10/AS20 treatment (n = 137) compared with AS40 monotherapy (n = 140) (treatment difference, −15.9%; 95% CI, −21.0% to −10.7%; P < 0.001). The safety profile was comparable between the EZ/AS and atorvastatin groups in the two cohorts. ImplicationsThe LDL-C level at week 12 was significantly improved with both FDCs compared with escalated doses of atorvastatin (20 or 40 mg/d) in these Chinese patients with hypercholesterolemia uncontrolled on atorvastatin 10 or 20 mg/d. Both FDCs were well tolerated, with no new tolerability-related findings. Chinadrugtrials.org.cn identifier: CTR20190172; ClinicalTrials.gov identifier: NCT03768427

A Randomized Study to Evaluate the Effect of an Inclisiran First Implementation Strategy vs Usual Care in Patients with ASCVD and Elevated Low-density Lipoprotein Cholesterol: Rationale and Design of the VICTORION-INITIATE Trial

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Novartis Pharmaceuticals Corporation, East Hanover, NJ. Background/Synopsis Most patients with atherosclerotic cardiovascular disease (ASCVD) have elevated low-density lipoprotein cholesterol (LDL-C). Compared to placebo, inclisiran has been shown to be safe, tolerable, and effective at reducing LDL-C in patients with ASCVD. It is unknown whether an inclisiran first strategy compared to usual care (allowing for changes in lipid-lowering therapy to mimic routine clinical decision-making) can improve LDL-C control in patients with ASCVD when inclisiran is added to statin therapy. Objective/Purpose Describe the rationale and design of the ongoing VICTORION-INITIATE (NCT04929249) trial. Methods VICTORION-INITIATE is a phase 3, randomized, 2-arm, parallel-group, open-label, U.S.-based trial assessing the efficacy of an inclisiran first strategy vs usual care to treat ASCVD. Patients in the inclisiran arm will receive both inclisiran and maximally tolerated statin therapy immediately upon failure to reach LDL-C less than 70 mg/dL with statins alone. Patients in the usual care arm will continue to receive maximally tolerated statin therapy and may receive other non-statin therapies per usual care. Sites were selected based on geography, population, and lipid management practices. The trial will enroll ∼444 patients (aged greater than or equal to 18 years) with established ASCVD and elevated LDL-C (greater than or equal to 70 mg/dL) or non-high-density lipoprotein cholesterol (greater than or equal to 100 mg/dL) despite receiving maximally tolerated statin therapy, fasting triglycerides less than 500 mg/dL, and an estimated glomerular filtration rate greater than 30 mL/min. The study has 6 planned visits over 330 days from screening to completion. Results Primary outcomes are percent change from baseline in LDL-C and proportion of patients discontinuing statins during the 330-day trial. Key secondary outcomes include the proportion of patients achieving prespecified LDL-C targets, proportion of patients achieving greater than or equal to 50% LDL-C reductions, absolute and time-averaged changes in LDL-C, changes in other lipids, changes in and adherence to ongoing lipid-lowering therapy, visit-to-visit variability in LDL-C, and inclisiran safety and tolerability. Conclusions VICTORION-INITIATE is ongoing and planned to complete in early 2023. This trial aims to determine the efficacy of adding inclisiran first when maximally tolerated statin therapy fails to achieve LDL-C less than 70 mg/dL in those with ASCVD. Nothing to disclose.

Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis

Objective Network meta-analysis was used to derive estimates of the relative efficacy of inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with hypercholesterolemia and/or at increased cardiovascular risk due to elevated low-density lipoprotein cholesterol taking maximum tolerated dose statins. Methods Clinical trials published through February 2021 comparing percent change from baseline in low-density lipoprotein cholesterol were identified via a systematic review. Bayesian network meta-analyses were performed for patients with atherosclerotic cardiovascular disease and/or high cardiovascular risk on maximally tolerated statins in the base case, which included 23 trials. Results Results from the base-case analyses demonstrated that inclisiran, evolocumab, and alirocumab provide superior efficacy over placebo, bempedoic acid, and ezetimibe in terms of reduction in low-density lipoprotein cholesterol. Inclisiran was also comparable to alirocumab (mean difference: 0.78% [95% CrI: −8.35, 9.88]) and evolocumab (8.16%, [95% CrI: −1.82, 18.49]). Findings of a scenario which also included trials conducted in patients with heterozygous familial hypercholesterolemia were consistent with the base case. There was evidence of statistical heterogeneity across the included trials, roughly equivalent to variation of 5–10% change in low-density lipoprotein cholesterol, suggesting that any differences between treatments that were greater than 5–10% are generalizable. Conclusions This study provides insight regarding the comparative efficacy of drugs for which no head-to-head trials exist and suggests that inclisiran, alirocumab, and evolocumab are expected to provide similar clinically meaningful improvements in low-density lipoprotein cholesterol in patients with hypercholesterolemia on maximally tolerated statins who are at increased cardiovascular risk.

Evolocumab in patients with homozygous familial hypercholesterolemia in India

Evolocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 approved in India for treatment of homozygous familial hypercholesterolemia (HoFH) in patients aged ≥12 years. RAMAN (NCT03403374) was a single-country, open-label, phase 4 study evaluating the safety and tolerability of evolocumab in patients with HoFH in India. Patients ≥12 to ≤80 years of age on stable lipid-lowering therapy with fasting low-density lipoprotein cholesterol (LDL-C) >3.4mmol/L (>130mg/dL) received evolocumab 420mg subcutaneously monthly (every 2 weeks if on apheresis). The primary endpoint was patient incidence of treatment-emergent adverse events. Secondary endpoints included percent changes at week 12 in LDL-C and other lipids. Of 30 enrolled patients, 13 were <18 years of age. Mean±SD baseline levels of LDL-C, apolipoprotein B, and lipoprotein(a) were 12.3±3.5mmol/L (473.5±135.2mg/dL), 2.8±0.7g/L (275.3±69.1mg/dL), and 201.3±177.6nmol/L, respectively. Ten patients (33%) reported treatment-emergent adverse events, with 2 (7%) serious adverse events and none leading to discontinuation; no deaths occurred during evolocumab treatment. At week 12, mean (SE) percent changes from baseline in LDL-C, apolipoprotein B, and lipoprotein(a) were -6.4% (4.2), -6.0% (3.7), and -0.2% (4.9), respectively. Reductions in LDL-C among individual patients were variable and greatest in patients ≥18 years of age and with baseline LDL-C <13mmol/L (<500mg/dL). Evolocumab was safe and well tolerated in patients with HoFH in India with smaller reductions in LDL-C and other lipids than those observed in previous studies with HoFH and different populations.

Combination of bempedoic acid, ezetimibe, and atorvastatin in patients with hypercholesterolemia: A randomized clinical trial

Background and aimsMany patients with hypercholesterolemia fail to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering despite use of guideline-recommended lipid-lowering therapies. This study evaluated LDL-C lowering with the combination of bempedoic acid, ezetimibe, and atorvastatin. MethodsThis was a phase 2, randomized, double-blind, placebo-controlled study (NCT03051100). After washout of lipid-lowering drugs, patients were randomized 2:1 to triple therapy (bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg; n = 43) or placebo (n = 20) once daily for 6 weeks. The primary endpoint was percent change from baseline in LDL-C at week 6. ResultsMean age for the 63 randomized patients was 61.2 years; baseline LDL-C was 154.8 mg/dL. At week 6, mean LDL-C lowering with triple therapy (−63.6%) was significantly greater than with placebo [–3.1%; difference, −60.5% [(95% CI, −68.0% to −53.0%); p < 0.001]. Significant reductions with triple therapy vs. placebo were also observed for non–high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein (p < 0.001 for all). With triple-therapy, 90% of patients achieved LDL-C <70 mg/dL and 95% of patients had ≥50% lower LDL-C from baseline to week 6; no patients in the placebo group met either goal. The majority of treatment-emergent adverse events were mild to moderate in severity. No patients experienced clinically relevant elevations in aminotransferase or creatine kinase levels. ConclusionsAmong patients with hypercholesterolemia, the combination of bempedoic acid, ezetimibe, and atorvastatin significantly lowered LDL-C, allowing more than 90% of patients in this study to reach guideline-recommended LDL-C goals.

Efficacy and safety of co-administered telmisartan/amlodipine and rosuvastatin in subjects with hypertension and dyslipidemia.

Single risk factors, such as hypertension and dyslipidemia, can combine to exacerbate the development and severity of cardiovascular disease. Treatment goals may be more effectively achieved if multiple disease factors are targeted with combination treatment. We enrolled 202 patients who were randomly divided into the following three groups: telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg, telmisartan 80 mg + rosuvastatin 20 mg, and telmisartan/amlodipine 80/5 mg. The primary efficacy variables were changes from baseline in mean sitting systolic blood pressure (MSSBP) between telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan 80 mg + rosuvastatin 20 mg at 8 weeks, and the percent changes from baseline in low‐density lipoprotein (LDL) cholesterol between telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan/amlodipine 80/5 mg at 8 weeks. The secondary efficacy variables were changes in MSSBP, mean sitting diastolic blood pressure (MSDBP), LDL cholesterol and other lipid levels at 4 weeks and 8 weeks, as well as observed adverse events during follow‐up. There were no significant differences between the three groups in demographic characteristics and no significant difference among the three groups in terms of baseline characteristics for the validity evaluation variables. The mean overall treatment compliance in the three groups was, respectively, 98.42%, 96.68%, and 98.12%, indicating strong compliance for all patients. The Least‐Square (LS) mean (SE) for changes in MSSBP in the two (telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan 80 mg + rosuvastatin 20 mg) groups were −19.3 (2.68) mm Hg and −6.69 (2.76) mm Hg. The difference between the two groups was significant (−12.60 (2.77) mm Hg, 95% CI −18.06 to −7.14, P < .0001). The LS Mean for the percent changes from baseline in LDL cholesterol in the two (telmisartan/amlodipine 80/5 mg + rosuvastatin 20 mg and telmisartan/amlodipine 80/5 mg) groups were −52.45 (3.23) % and 2.68 (3.15) %. The difference between the two groups was significant (−55.13 (3.20) %, 95% CI −61.45 to −48.81, P < .0001). There were no adverse events leading to discontinuation or death. Combined administration of telmisartan/amlodipine 80/5 mg and rosuvastatin 20 mg for the treatment of hypertensive patients with dyslipidemia significantly reduces blood pressure and improves lipid control. ClinicalTrials.gov identifier: NCT03067688.

Long-term safety and efficacy of lomitapide in patients with homozygous familial hypercholesterolemia: Five-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER)

Lomitapide is a lipid-lowering agent indicated as adjunct therapy for homozygous familial hypercholesterolemia (HoFH) in adults. The Lomitapide Observational Worldwide Evaluation Registry is an international, observational registry assessing long-term safety, tolerability, and effectiveness of lomitapide. This analysis examines 5-year data from the registry up to February 28,2019. At lomitapide initiation, enrolled patients (N=187) were a mean±SD age of 52.2±15.3years with a mean±SD low-density lipoprotein cholesterol (LDL-C) measurement of 232.0±94.9mg/dL. Exposure duration was up to 5.9years (median, 1.98years), and median dose was 10mg (range, 5mg QOD to 40mg QD). After treatment, there was a mean 33% reduction in LDL-C (45% in patients remaining on lomitapide), 65.4% achieved LDL-C <100mg/dL, and 41.1% achieved LDL-C <70mg/dL. At year 4, the absolute mean change from baseline in LDL-C was -70.6±76.21mg/dL. Adverse events (AEs) occurred in 75.7% of patients, treatment-related AEs in 54.6%, and serious AEs in 22.2%; 23.2% of patients discontinued because of an AE. Events of special interest included gastrointestinal (13.5%), hepatic (15.1%), major adverse cardiovascular events (10.8%, resulting in 5 deaths), tumors (2.2%), and 4 pregnancies in 3 of 32 women of childbearing potential. The efficacy and safety of lomitapide are consistent with phase III trial data despite using a much lower median dose of 10mg vs 40mg in phase III. No new safety signals were identified. The incidence of AEs, serious AEs, and aminotransferase alanine transaminase elevations was lower than that seen in the phase III trial, potentially related to the lower median dose.

Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial

BackgroundHomozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein–cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. ObjectivesThis study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. MethodsThis randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. ResultsPatients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was −35.6% (alirocumab [−26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, −29.8%; non–high-density lipoprotein cholesterol, −32.9%; total cholesterol, −26.5%; and lipoprotein(a), −28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period. ConclusionsIn the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.)

Usefulness of Gemcabene in Homozygous Familial Hypercholesterolemia (from COBALT-1)

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C), and premature atherosclerotic cardiovascular disease. Depending on residual LDL receptor (LDLR) function, most HoFH patients respond modestly to statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. However, LDL-C typically remains markedly elevated necessitating additional therapies, including apheresis. Gemcabene is a novel lipid-lowering agent with a mechanism of action independent of the LDLR, which has previously demonstrated the ability to reduce levels of LDL-C on top of maximally tolerated statins. The present study (COBALT-1) assessed efficacy, tolerability, and safety of gemcabene as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients. Eight patients with either a clinical or genetic diagnosis of HoFH on stable standard of care, including statins, ezetimibe, and PCSK9 inhibitors, were treated with gemcabene in an open-label study for 12 weeks. DNA analysis for mutations in the LDLR, apolipoprotein B, and PCSK9 genes was performed. Patients received 300 mg gemcabene for the first 4 weeks, 600 mg for the next 4 weeks, and 900 mg for the final 4 weeks. All patients completed the 12-week study. Mean change from baseline in LDL-C was -26% (p = 0.004) at Week 4 (300 mg), -30% (p = 0.001) at Week 8 (600 mg), and -29% (p = 0.001) at Week 12 (900 mg). In conclusion, the COBALT-1 study demonstrates gemcabene has potential to significantly reduce LDL-C levels when used as an adjunctive therapy to current lipid-lowering treatment for familial hypercholesterolemia patients.

12-Week Effectiveness and Safety of Low-Density Lipoprotein Cholesterol-Lowering Therapy by Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition in Patients With Familial Hypercholesterolemia and Hypercholesterolemia - Data From a Real-World Observational Study of Evolocumab in Japan.

Background: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) approved in Japan for the treatment of patients with familial hypercholesterolemia (FH) and hypercholesterolemia (HC). This study assessed the 12-week effectiveness and safety of low-density lipoprotein cholesterol (LDL-C)-lowering therapy by PCSK9 inhibition in patients with FH (homozygous [HoFH] or heterozygous [HeFH]) and HC by analyzing evolocumab data collected in the real-world setting in Japan.Methods and Results: Overall, 427 patients (mean±SD age, 61.6±13.8 years; female, 38.4%; 28 HoFH, 320 HeFH, 79 HC), enrolled from 299 clinical sites, were included in the safety analysis set. The major cardiovascular risk factors were coronary artery disease (77.3%), diabetes mellitus/impaired glucose tolerance (38.6%), and hypertension (65.1%). Median follow-up duration was 85.0 days. After 12 weeks of evolocumab treatment, the mean±SD percent change from baseline in LDL-C was −45.5%±27.0% (n=23) in HoFH (P<0.001 vs. baseline; t-test), −54.2%±29.0% (n=280) in HeFH (P<0.001), and −64.6%±22.4% (n=72) in HC (P<0.001) patients. The incidence of adverse drug reactions was 5.4% (23/427).Conclusions: Results suggest that patients receiving evolocumab treatment in the real-world setting were predominantly those with FH and HC in the secondary prevention group. LDL-C-lowering effectiveness with evolocumab was observed in FH (both HoFH and HeFH) and HC patients.

Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy

While statins are used as first-line treatments for high-risk patients with hypercholesterolemia, statin monotherapy is often insufficient to achieve target low-density lipoprotein cholesterol (LDL-C) levels. Second-line treatment options include up-titration of statin dose, switching to a more potent statin, or combination therapy, e.g., with ezetimibe. The aim of this study was to evaluate the efficacy of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin monotherapy versus doubling the dosage or switching to a higher-potency statin in a population of patients with hypocholesterolemia at high risk of cardiovascular disease (CVD) and who had been previously treated with a statin. A systematic literature search was performed and evidence bases were established for populations of atorvastatin-, simvastatin-, and rosuvastatin-experienced patients using eligible randomized controlled trials (RCTs). Based on the available data, we constructed networks of evidence and conducted a Bayesian network meta-analysis (NMA) within each statin population. The primary outcome of interest was percent change from baseline in LDL-C. Changes in total cholesterol were explored as a secondary outcome. Across all patient populations, 35 RCTs were identified and included in the evidence base. Among patients on simvastatin therapy, the addition of ezetimibe resulted in a mean difference (MD) in LDL-C of - 13.62% (95% CrI - 19.99, - 6.91; see table below) compared to doubling the starting dose of simvastatin. In the population of patients on atorvastatin therapy, the addition of ezetimibe resulted in an MD in LDL-C of - 14.71% (95% CrI - 16.46, - 12.95) compared to doubling the starting dose of atorvastatin. The addition of ezetimibe to rosuvastatin resulted in an MD in LDL-C of - 14.96% (95% CrI - 17.79, - 12.11), compared to doubling the starting rosuvastatin dose. Similar trends were observed for changes in total cholesterol. Given the available data, the addition of ezetimibe to ongoing simvastatin, atorvastatin, or rosuvastatin monotherapy offers greater reduction in LDL-C among patients at high risk of CVD compared to doubling the initial statin dose.