Percent Change In Low-density Lipoprotein Cholesterol Research Articles

Abstract P125: Change In Low-density Lipoprotein Cholesterol And Risk Of Subsequent Cardiovascular Events Among Patients With Myocardial Infarction

Background: Among patients who experience a myocardial infarction (MI), elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for experiencing a subsequent cardiovascular (CV) event; however, real-world evidence is lacking in regard to how changes in LDL-C levels after a MI hospitalization are related to subsequent CV events. Methods: Adults with a hospitalized MI and an available baseline LDL-C (closest LDL-C within 2 years prior to hospital discharge) between 2012 and 2018 within a 27-county region across MN and WI were included for study. For each LDL-C measurement during follow-up (starting with the first LDL-C >30 days after baseline and ≤1-year post-discharge), percent change from baseline LDL-C was calculated. Patients were followed for subsequent CV events (composite endpoint 1: MI, ischemic stroke [IS], coronary artery bypass grafting [CABG], percutaneous coronary intervention [PCI]; composite endpoint 2: MI, IS, CABG, PCI, CV death). Cox models were used to evaluate the association between time-dependent LDL-C percent change and CV events, stratified by baseline LDL-C (<70, 70-99, ≥100 mg/dL). Results: Among 3,034 MI patients identified, 740 (24%), 940 (31%) and 1354 (45%) had a baseline LDL-C <70, 70-99 and ≥100 mg/dL, respectively. After a mean follow-up of 3.4 years, 471 and 667 patients experienced the composite endpoint 1 and 2, respectively. After covariate adjustment, a trend towards a lower risk of CV events with decreasing LDL-C from baseline, compared to those with no change or an increase in LDL-C, was observed among those with a LDL-C <70 and > 100 mg/dl but not in those with a LDL-C 70-99 mg/dL (Table). Conclusions: In a population-based cohort of MI patients, there is evidence that patients with a decrease in LDL-C after MI may have a reduced risk of subsequent CV events. These results underscore the importance of lowering LDL-C after a MI and may help to identify subgroups at highest risk for additional CV events and those who may benefit from targeted LDL-C treatment recommendations.

Rationale and design of two trials assessing the efficacy, safety, and tolerability of inclisiran in adolescents with homozygous and heterozygous familial hypercholesterolaemia.

Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option. The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16). ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to <18 years diagnosed with familial hypercholesterolaemia. ORION-13 will include ∼12 participants diagnosed with homozygous familial hypercholesterolaemia and ORION-16 will include ∼150 participants diagnosed with heterozygous familial hypercholesteroleamia. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. Secondary efficacy and safety endpoints include changes in other lipid parameters and treatment-emergent adverse events as well as laboratory parameters and vital signs. Exploratory endpoints include individual responsiveness of the participants and change in LDL-C according to the type of underlying causal mutation. https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16).

Effects of Evolocumab Added to Moderate-Intensity Statin Therapy in Chinese Patients With Acute Coronary Syndrome: The EMSIACS Trial Study Protocol

Background: Several studies have demonstrated that using a higher dose of statin can easily induce liver injury and myopathy. Low-density lipoprotein cholesterol (LDL-C) is a well-established modifiable risk factor for cardiovascular disease; however, the large majority of Chinese patients cannot meet the target level of LDL-C recommended by the Chinese expert consensus. Evolocumab has been demonstrated to reduce LDL-C by approximately 60% in many studies. Nevertheless, whether combined evolocumab and moderate-intensity statin is as effective in lowering LDL-C and decreasing incidence of MACE in Chinese patients presenting with the acute phase of acute coronary syndrome (ACS) remains unknown. Therefore, the “Evolocumab added to Moderate-Intensity Statin therapy on LDL-C lowering and cardiovascular adverse events in patients with Acute Coronary Syndrome” (EMSIACS) is conducted.Methods: The EMSIACS is a prospective, randomized, open-label, parallel-group, multicenter study involving analyzing the feasibility and efficacy of evolocumab added to moderate-intensity statin therapy on lowering LDL-C levels in adult Chinese patients hospitalized for acute phase ACS. The sample size calculation is based on the primary outcome, and 500 patients will be planned to recruit. Patients are randomized in evolocumab arm (evolocumab 140mg every 2weeks plus rosuvastatin 10mg/day or atorvastatin 20mg/day) and statin-only arm (rosuvastatin 10mg/day or atorvastatin 20mg/day). The primary outcome is the percentage change in LDL-C in weeks 4 and week 12 after treatment. The secondary outcome is the occurrence of MACE after 12weeks and 1year of treatment.Discussion: If the EMSIACS trial endpoints prove statistically significant, the evolocumab added to moderate-intensity statin therapy will have the potential to effectively lower subjects’ LDL-C levels, especially for the Chinese patients with acute phase ACS. However, if the risk of MACE is not significantly different between the two groups, we may extend follow-up time for secondary outcome when the clinical trial is over.Clinical trial registration: The study is registered to ClinicalTrials.gov (NCT04100434), which retrospectively registered on November 24, 2020.

Abstract 12027: Low-Density Lipoprotein Cholesterol in Patients With Homozygous Familial Hypercholesterolemia Who Participated in Sequential Studies of Alirocumab and Evinacumab

Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. This analysis evaluated LDL-C changes in patients with HoFH who sequentially participated in interventional trials with alirocumab (NCT03156621) and evinacumab (NCT03399786). Methods: A total of 25 patients completed the alirocumab trial and entered the evinacumab trial and were randomized to intravenous evinacumab 15 mg/kg (n=16) or placebo (n=9) every 4 weeks. The primary outcome for the evinacumab trial was percent change in LDL-C from baseline to week 24. Results: Baseline characteristics were generally well balanced. Among patients who participated in the alirocumab trial, a reduction in LDL-C of –44.6% and –1.1% was observed at week 24 in patients treated with evinacumab versus placebo, respectively. Overall, mean total reductions in LDL-C (Figure) and apolipoprotein B of -62.9% and -54.9%, respectively, were observed in patients treated with the combination of alirocumab and evinacumab; and triglycerides were lowered by -54.5%. The absolute LDL-C reduction from their baseline in patients treated with the combination of alirocumab and evinacumab was -216.3 mg/dL. No new safety signals were observed when treated with alirocumab and evinacumab, and were consistent with the respective trial results. Conclusions: Combination therapy with alirocumab and evinacumab reduced LDL-C by more than 60% in patients with HoFH and was well tolerated.

Statin treatment and LDL-cholesterol treatment goal attainment among individuals with familial hypercholesterolaemia in primary care

ObjectivesGuidance recommends statin treatment in familial hypercholesterolaemia (FH) to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). We assessed statin prescribing rates and LDL-C treatment goal attainment...

LDL-cholesterol change and goal attainment following statin intensity titration among Asians in primary care: a retrospective cohort study

BackgroundClinical trials have demonstrated that either initiating or up-titrating a statin dose substantially reduce Low-Density Lipoprotein-Cholesterol (LDL-C) levels. However, statin adherence in actual practice tends to be suboptimal, leading to diminished effectiveness. This study aims to use real-world data to determine the effect on LDL-C levels and LDL-C goal attainment rates, when selected statins are titrated in Asian patients.MethodsA retrospective cohort study over a 5-year period, from April 2014 to March 2019 was conducted on a cohort of multi-ethnic adult Asian patients with clinical diagnosis of Dyslipidaemia in a primary care clinic in Singapore. The statins were classified into low-intensity (LI), moderate-intensity (MI) and high-intensity (HI) groups according to the 2018 American College of Cardiology and American Heart Association (ACC/AHA) Blood Cholesterol Guidelines. Patients were grouped into “No statin”, “Non-titrators” and “Titrators” cohorts based on prescribing patterns. For the “Titrators” cohort, the mean percentage change in LDL-C and absolute change in LDL-C goal attainment rates were computed for each permutation of statin intensity titration.ResultsAmong the cohort of 11,499 patients, with a total of 266,762 visits, there were 1962 pairs of LDL-C values associated with a statin titration. Initiation of LI, MI and HI statin resulted in a lowering of LDL-C by 21.6% (95%CI = 18.9–24.3%), 28.9% (95%CI = 25.0–32.7%) and 25.2% (95%CI = 12.8–37.7%) respectively. These were comparatively lower than results from clinical trials (30 to 63%). The change of LDL-C levels due to up-titration, down-titration, and discontinuation were − 12.4% to − 28.9%, + 13.2% to + 24.6%, and + 18.1% to + 32.1% respectively. The improvement in LDL-C goal attainment ranged from 26.5% to 47.1% when statin intensity was up-titrated.ConclusionIn this study based on real-world data of Asian patients in primary care, it was shown that although statin titration substantially affected LDL-C levels and LDL-C goal attainment rates, the magnitude was lower than results reported from clinical trials. These results should be taken into consideration and provide further insight to clinicians when making statin adjustment recommendations in order to achieve LDL-C targets in clinical practice, particularly for Asian populations.

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.)

A Meta-Analysis Assessing Additional LDL-C Reduction from Addition of a Bile Acid Sequestrant to Statin Therapy

BackgroundStatins are the first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C). However, there are secondary prevention patients who are either intolerant to maximal statin therapy or do not get adequate effects from a high-intensity statin. While data exist for the additional LDL-C-lowering effects of ezetimibe, there are no data on additional LDL-C lowering of bile acid sequestrants when combined with statin therapy. The purpose of this study was to quantify the LDL-C-lowering effects of bile acid sequestrants when added to statin therapy. MethodsDatabases (Medline via PubMed, Embase, and the Cochrane Library) were searched for randomized controlled trials comparing statin therapy to statin therapy with the addition of bile acid sequestrants. Nine studies were included in the meta-analysis. A meta-regression was performed to estimate the mean difference in LDL-C between the 2 groups. ResultsWithout controlling for other variables, data suggest that combining statin with bile acid sequestrant increases the percentage change in LDL-C by 16.2 points, on average, compared with statin use alone. ConclusionIn patients unable to tolerate an adequate statin dosage, bile acid sequestrants offer a viable alternative with additional LDL-C-lowering benefit.

Lipid-Lowering Efficacy and Safety of a New Generic Rosuvastatin in Koreans: an 8-Week Randomized Comparative Study with a Proprietary Rosuvastatin.

ObjectiveThe aim of this study was to investigate whether a new generic rosuvastatin is non-inferior to a proprietary one in terms of lipid-lowering efficacy. We also evaluated its non-lipid effects including adverse events.MethodsOne-hundred and fifty-eight patients with cardiovascular risks requiring pharmacological lipid-lowering therapy were screened. After a 4-week run-in period, 126 individuals who met the lipid criteria for drug therapy were randomly assigned to receive the new generic or proprietary rosuvastatin 10 mg daily for 8 weeks. The primary outcome variables were low-density lipoprotein-cholesterol (LDL-C) reduction and LDL-C target achievement. Hematological and biochemical parameters and adverse events were assessed.ResultsAfter 8 weeks of drug treatment, the mean percentage change in LDL-C was not different between the groups (−45.5%±19.9% and −45.1%±19.0% for generic and proprietary rosuvastatin, respectively; p=0.38). The LDL-C target achievement rate was similar between the groups (75.0% and 77.1% for generic and proprietary rosuvastatin, respectively; p=0.79). The percentage change in the other lipid profiles was not significantly different. Although generic- and proprietary rosuvastatins modestly affected creatine kinase and blood pressure, respectively, the changes were all within normal ranges. Incidence of adverse events did not differ between the receivers of the 2 formulations.ConclusionThe new generic rosuvastatin was non-inferior to the proprietary rosuvastatin in terms of lipid-lowering efficacy. The rosuvastatin formulations did not exhibit clinically significant non-lipid effects with good safety profiles. Our study provides comprehensive data regarding 2 rosuvastatin formulations in East Asian subjects.Trial RegistrationClinicalTrials.gov Identifier: NCT03949374

P6192Effects of evolocumab on LDL-C by race and ethnicity: an analysis of double-blind and open-label extension studies

Abstract Background/Introduction Cardiovascular risk factors and clinical outcomes of atherosclerotic cardiovascular disease (ASCVD) vary amongst racial and ethnic groups. Purpose To examine the effects of evolocumab on low-density lipoprotein cholesterol (LDL-C) levels and achievement of LDL-C target goals by race or ethnicity. Methods Data from global phase 2 and 3 studies with at least 12 weeks of treatment with approved evolocumab doses vs. placebo or ezetimibe were included in this analysis (n=4375). Results were analysed by patient characteristics (statin intolerance, type 2 diabetes, heterozygous familial hypercholesterolaemia, and hypercholesterolaemia/mixed dyslipidaemia), self-identified race (White, Black/African American, and Asian), and self-identified ethnicity (Hispanic/Latino). Key outcomes included percent change in LDL-C, achievement of LDL-C &lt;1.8 mmol/L (&lt;70 mg/dL), and LDL-C achievement of at least 50% reduction. Results After 12-week evolocumab treatment, mean percent change in LDL-C from baseline ranged from approximately −52% to −59% for white patients to −49% to −67% for non-white patients, across all groups with adequate sample size (n&gt;20) (Table). LDL-C &lt;1.8 mmol/L was achieved in 43–84% of white patients and 62–94% of non-white patients receiving evolocumab (n&gt;20). Similarly, 63–78% of white patients and 58–86% of non-white patients achieved at least a 50% reduction in LDL-C. The magnitude of treatment effect on mean percent change in LDL-C differed significantly only between white and non-white patients with diabetes (interaction p-values of treatment by race for evolocumab every 2 weeks p&lt;0.001; once monthly p=0.007). This was driven by a greater reduction in Asian patients. Mean (standard deviation) percent change in LDL-C levels from baseline, % Achievement of LDL-C &lt;1.8 mmol/L (70 mg/dL)/LDL-C achievement of at least 50% reduction, % Population White Non-White Non-Hispanic Black or African American Asian Hispanic/Latino* White Non-White Non-Hispanic Black or African American Asian Hispanic/Latino* Statin-Intolerant† −55.4 (14.8) −46.3 (20.9) −46.0 (13.4) −49.0 (29.3) −54.6 (12.3) 42.9 / 68.6 26.7 / 60.0 14.3 / 42.9 50.0 / 83.3 0 / 66.7 n=210 n=15 n=7 n=6 n=3 Diabetes‡ −51.5 (25.6) −66.5 (21.2) −50.4 (22.2) −69.6 (20.2) −59.7 (20.5) 82.3 / 63.0 93.9 / 82.0 90.0 / 62.5 95.1 / 86.6 89.2 / 75.3 n=440 n=395 n=40 n=305 n=158 HeFH§ −57.3 (19.7) −64.1 (12.0) −73.8 (4.1) −60.5 (12.8) −35.8§§ 66.1 / 73.7 61.5 / 84.6 100 / 100 53.3 / 80.0 0 / 0 n=236 n=26 n=3 n=15 n=1 Hyper-cholesterolaemia/ −58.8 (19.2) −65.5 (17.0) −51.2 (19.4) −69.4 (13.9) −54.6 (20.3) 83.3 / 77.6 89.7 / 86.0 74.4 / 60.5 94.7 / 93.5 79.1 / 69.2 Mixed Dyslipidaemia¶ n=1399 n=437 n=86 n=339 n=91 Hyper-cholesterolaemia/ −59.4 (17.1) −58.4 (16.9) −52.8 (19.4) −65.8 (10.3) −56.7 (22.1) 80.2 / 78.5 85.7 / 75.7 82.4 / 67.6 96.7 / 93.3 77.3 / 68.2 Mixed Dyslipidaemia†† n=605 n=70 n=34 n=30 n=44 1-Year Study‡‡ −52.1 (27.7) −48.6 (29.2) −50.8 (22.0) −49.5 (29.4) −43.0 (43.1) 84.4 / 67.4 73.6 / 57.5 74.5 / 59.6 76.5 / 58.8 82.1 / 60.7 n=436 n=106 n=47 n=34 n=28 †GAUSS-1, -2 studies; ‡BANTING and BERSON studies; §RUTHERFORD-1, -2 studies; ¶Placebo comparator: MENDEL-1, -2, LAPLACE-TIMI-57, LAPLACE-2 and YUKAWA-1, -2 studies; ††Ezetimibe comparator: MENDEL-2 and LAPLACE-2 atorvastatin cohorts; ‡‡DESCARTES; §§Standard deviation could not be calculated due to insufficient sample size. *A total of 22 patients receiving evolocumab self-identified as Hispanic Black. Conclusion Reduction in LDL-C levels with evolocumab treatment was similar across race and ethnicity, apart from the diabetes population where Asian patients had a greater reduction in LDL-C. Acknowledgement/Funding Amgen Inc.

Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease

BackgroundRemnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. MethodsA total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6–9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. ResultsTreatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = −0.18, p = 0.03), RLP-C (r = −0.39, p < 0.001), RLP-C/TG (r = −0.34, p < 0.001), and CRP (r = −0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. ConclusionImprovement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.

A subanalysis of Taiwanese patients from ODYSSEY South Korea and Taiwan study evaluating the efficacy and safety of alirocumab.

Alirocumab can provide significant reductions in low-density lipoprotein cholesterol (LDL-C). However, data regarding its efficacy and safety in Asians are limited. A subgroup analysis of Taiwanese patients (n = 116) in a randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT, clinicaltrials.gov Identifier: NCT02289963) was performed. Patients with hypercholesterolemia at high cardiovascular risk on maximally tolerated statin were randomized to alirocumab (75 mg every 2 weeks; with dose increased to 150 mg at Week 12 if LDL-C ≥ 70 mg/dL at Week 8) or placebo for 24 weeks. The primary efficacy endpoint was the percent change in LDL-C from baseline to Week 24. Safety was assessed for a total of 32 weeks. At Week 24, the percent change in calculated LDL-C in the alirocumab group (n = 57) was -51%, whereas that in the placebo group (n = 59) was 2.5%. Alirocumab significantly improved other lipid parameters, including non-high-density lipoprotein cholesterol, apolipoprotein B and A1, lipoprotein (a), high-density lipoprotein cholesterol, and total cholesterol. A significantly higher proportion of patients in the alirocumab group reached an LDL-C target below 70 mg/dL than those in the placebo group (81.3% vs 15.4%). The incidence of treatment-emergent adverse events was comparable between both groups. Alirocumab treatment provided a favorable effect on LDL-C levels and other lipid parameters, and was generally well-tolerated in patients from Taiwan. The results of current analysis were consistent with the overall ODYSSEY phase 3 program.

Efficacy and safety of alirocumab 150 mg every 4 weeks in hypercholesterolemic patients on non-statin lipid-lowering therapy or lowest strength dose of statin: ODYSSEY NIPPON

BackgroundAlirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, given every 2 weeks (Q2W), significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in Japanese hypercholesterolemic patients on background statin. We evaluated alirocumab 150mg every 4 weeks (Q4W) in patients on lowest-dose statin or non-statin lipid-lowering therapy (LLT). MethodsODYSSEY NIPPON was a double-blind study conducted in Japanese patients with LDL-C ≥100mg/dL (heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia with coronary heart disease) or ≥120mg/dL (non-familial hypercholesterolemia, Japan Atherosclerosis Society category III) on atorvastatin 5mg/day or non-statin LLT. Patients were randomized (1:1:1) to subcutaneous alirocumab 150mg Q4W, alirocumab 150mg Q2W, or placebo for the 12-week double-blind treatment period (DBTP), followed by a 52-week open-label treatment period (OLTP). At entry into the OLTP, patients received alirocumab 150mg Q4W, with possible up-titration to 150mg Q2W at Week 24. ResultsLeast-square mean percent change in LDL-C from baseline at Week 12 (primary efficacy endpoint) was −43.8% for alirocumab Q4W, −70.1% for Q2W, and −4.3% for placebo. During the OLTP, mean LDL-C change from baseline was −45.1% at Week 20, with a further reduction at Week 36, with achieved levels maintained to Week 64. Percent of patients with ≥1 adverse event (DBTP) was 51.9% with alirocumab Q4W, 47.2% with Q2W, and 46.4% with placebo. Most common adverse events were infections and infestations (25.9%, 22.6%, 17.9%, respectively), gastrointestinal disorders (13.0%, 9.4%, 12.5%), nervous system disorders (5.6%, 7.5%, 10.7%), and general disorders and administration-site conditions (3.7%, 11.3%, 5.4%). ConclusionsHypercholesterolemic Japanese patients who tolerate only lowest-strength dose statin or non-statin LLT can achieve robust LDL-C reduction with alirocumab 150mg Q4W, in addition to their current LLT. Alirocumab 150mg Q4W dosing was efficacious and generally well tolerated without new safety concerns.(ClinicalTrials.gov number: NCT02584504)

Efficacy and safety of alirocumab in Korean patients with hypercholesterolemia and high cardiovascular risk: subanalysis of the ODYSSEY-KT study.

Background/AimsEfficacy and safety data of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), is not yet well established in the Korean population. We assessed them in ODYSSEY-KT through the pre-specified Korean subanalysis.MethodsIn the ODYSSEY-KT study, South Korean and Taiwanese patients with hypercholesterolemia and high cardiovascular risks were randomized (1:1) to alirocumab or placebo. Alirocumab was self-administered subcutaneously at 75 mg every 2 weeks with a maximally tolerated statin dose with or without other lipid-modifying therapies. Alirocumab dose was increased to 150 mg every 2 weeks at week 12 if low density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL at week 8. Primary endpoint was percent change in LDL-C from baseline to week 24. Results from Korean cohort (n = 83: 40 for alirocumab and 43 for placebo, respectively) analyses are reported here.ResultsIn alirocumab group, the least square of mean change percent in LDL-C levels was –65.7% (placebo: 11.1%; p < 0.0001) and 92.0% of them achieved LDL-C < 70 mg/dL (placebo: 12.7%; p < 0.0001) at week 24. Alirocumab also showed significantly greater improvements in high density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol, lipoprotein(a), and apolipoprotein B than placebo (p < 0.05). Two consecutive calculated LDL-C values < 25 mg/dL were observed in 37.5% of alirocumab-treated patients. Overall, 45.0% alirocumab-treated and 51.2% placebo-treated patients experienced treatment-emergent adverse events (TEAEs) without discontinuation of treatment due to TEAEs.ConclusionsAlirocumab has demonstrated to be effective in improvement of LDL-C and related lipid profiles in Korean cohort. Alirocumab was generally well tolerated with no significant safety signals.

Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies.

IntroductionDiabetes mellitus (DM) carries an elevated risk for cardiovascular disease. Here, we assessed alirocumab efficacy and safety in people with/without DM from five placebo-controlled phase 3 studies.MethodsData from up to 78 weeks were analyzed in individuals on maximally tolerated background statin. In three studies, alirocumab 75 mg every 2 weeks (Q2W) was increased to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dL; two studies used alirocumab 150 mg Q2W throughout. The primary endpoint was percentage change in LDL-C from baseline to week 24.ResultsIn the alirocumab 150 mg pool (n = 2416), baseline LDL-C levels were 117.4 mg/dL (DM) and 130.6 mg/dL (without DM), and in the 75/150 mg pool (n = 1043) 112.8 mg/dL (DM) and 133.0 mg/dL (without DM). In the 150 mg Q2W group, week 24 LDL-C reductions from baseline were observed in persons with DM (− 59.9%; placebo, − 1.4%) and without DM (− 60.6%; placebo, + 1.5%); 77.7% (DM) and 76.8% (without DM) of subjects achieved LDL-C < 70 mg/dL. In the alirocumab 75/150 mg group, 26% (DM) and 36% (without DM) of subjects received dose increase. In this group, week 24 LDL-C levels changed from baseline by − 43.8% (DM; placebo, + 0.3%) and − 49.7% (without DM; placebo, + 5.1%); LDL-C < 70 mg/dL was achieved by 68.3% and 65.8% of individuals, respectively. At week 24, alirocumab was also associated with improved levels of other lipids. Adverse event rates were generally comparable in all groups (79.8–82.0%).ConclusionsRegardless of DM status, alirocumab significantly reduced LDL-C levels; safety was generally similar.FundingSanofi and Regeneron Pharmaceuticals, Inc.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0439-8) contains supplementary material, which is available to authorized users.

Glucagon-like peptide-1 receptor agonists reduced the low-density lipoprotein cholesterol in Japanese patients with type 2 diabetes mellitus treated with statins

Patients with type 2 diabetes mellitus (T2DM) often have hypercholesterolemia, and their serum low-density lipoprotein cholesterol (LDL-C) levels are not always well-controlled even by statin treatment. The glucose-lowering glucagon-like peptide-1 receptor agonists (GLP-1RAs) are reported to change the lipid profiles in T2DM patients, but their effects have been unclear. We examined whether GLP-1RAs affect serum cholesterol levels in T2DM patients with/without statin treatment. We retrospectively assessed the baseline and follow-up (median 119days) levels of serum lipids, HbA1c, and body mass index (BMI) in 103 and 214 Japanese patients with T2DM in whom GLP-1RAs were initiated (GLP-1RA group) and not initiated (control group), stratified by the use of statins. In the GLP-1RA group, the LDL-C, HbA1c, and BMI significantly decreased; high-density lipoprotein cholesterol and triglycerides did not decrease during follow-up. In the control group, these did not decrease. Among the statin users, the percentage change in LDL-C during follow-up was significantly greater in the GLP-1RA group than that in the control group (-6.5% vs -1.0%, P=.040). In the GLP-1RA group, the percentage reduction in LDL-C was not associated with that in BMI but was associated with that in HbA1c only among the statin users. Our findings demonstrated that GLP-1RAs reduced the serum LDL-C in Japanese patients with T2DM treated with statins. The percentage reduction in LDL-C by GLP-1RAs was associated with that in HbA1c, but not associated with that in BMI. The combination of GLP-1RAs and statins may be a reasonable therapeutic option in T2DM with dyslipidemia.

A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT)

Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, has been shown to provide significant reductions in low-density lipoprotein cholesterol (LDL-C). Data about its efficacy and safety in patients from South Korea and Taiwan are limited. ODYSSEY KT assessed the efficacy and safety of alirocumab in patients from South Korea and Taiwan. Patients with hypercholesterolemia at high cardiovascular risk who were on maximally tolerated statin were randomized (1:1) to alirocumab (75mg every 2weeks, with dose increase to 150mg every 2weeks at week 12 if LDL-C ≥70mg/dL at week 8) or placebo for 24weeks. The primary efficacy endpoint was percentage change in LDL-C from baseline to week 24. Safety was assessed throughout. At week 24, alirocumab changed LDL-C levels by -57.1% (placebo:+6.3%). In the alirocumab group, 9 patients (9.5%) received dose increase at week 12. At week 24, 85.8% of patients in the alirocumab group reached LDL-C <70mg/dL (placebo: 14.2%; P≤.0001 vs placebo). Alirocumab significantly improved non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total cholesterol, lipoprotein (a), and HDL-C vs placebo (P≤.05). Two consecutive calculated LDL-C values <25mg/dL were recorded in 27.8% of alirocumab-treated patients. Overall, 58.8% (alirocumab) and 61.8% (placebo) of patients experienced treatment-emergent adverse events; 2.1% and 1.0% discontinued treatment due to treatment-emergent adverse events, respectively. Alirocumab significantly improved LDL-C, apolipoprotein B, non-HDL-C, lipoprotein (a), HDL-C, and total cholesterol in Asian patients. Alirocumab was generally well tolerated. These findings are consistent with ODYSSEY findings to date.

Efficacy and safety of a generic rosuvastatin in a real-world setting: prospective, observational clinical study in Lebanese patients.

BACKGROUNDNo published studies have assessed the efficacy and safety of rosuvastatin generics.OBJECTIVESPrimary objective to assess the safety and efficacy of a generic rosuvastatin in reducing plasma low-density-lipoprotein cholesterol (LDL-C) in Lebanese dyslipidemic patients. Changes in high-density lipoprotein cholesterol, triglycerides and adverse effects were secondary objectives.DESIGNProspective, observational, non-comparative.SETTINGMultiple outpatient clinics in Lebanon.PATIENTS AND METHODSDyslipidemic patients requiring statin therapy were followed for 2 months after prescription of a generic rosuvastatin at the physician’s discretion. Efficacy and safety measurements were collected from medical records.MAIN OUTCOME MEASURE(S)Efficacy was assessed based on the evaluation of mean and percent change in LDL-C between baseline and week 8 as well as the proportion of patients reaching target LDL-C levels. Safety was assessed based on the evaluation of the incidence of adverse events (AEs) during the study period.RESULTSTwo months after initiation of generic rosuvastatin, LDL-C levels in the 313 eligible patients who completed the study significantly decreased from 4.3 (0.8) mmol/L (168.2 [31.3] mg/dL) at baseline to 2.7 (0.7) mmol/L (105.9 [25.5] mg/dL) (P<.001). The mean percent change in LDL-C level was highest in subjects receiving generic rosuvastatin at a dose of 40 mg/day (−47.4%), followed by 20 mg/day (−36.8%), and 10 mg/day (−31.4%); 82.5% of patients reached the target LDL-C level as set by their physician at baseline. Thirteen patients (4%) reported six AEs during treatment: abdominal pain, headache, stomach ache, insomnia, musculoskeletal pain/myalgia and nausea. No clinically significant changes in serum creatinine, serum creatine kinase, or liver function tests were reported. One patient withdrew because of an adverse event.CONCLUSIONSGeneric rosuvastatin was efficacious and safe in reducing LDL-C levels and helping the majority of patients achieve LDL-C targets after a short treatment period.LIMITATIONSThe observational nature, and a control group, and the relatively short duration of follow-up limit the generalizability of results. The authors received fees for study activities at patient visits from an independent clinical research organization subcontracted by the sponsor.

TLC vs Simvastatin vs Simvastatin and TLC in hypercholesterolemia

Purpose National Health and Morbidity Survey of Malaysia 2011 revealed that hypercholesterolemia (35.1 per cent, 6.2 million) was the primary leading causes of cardiovascular disease in Malaysia. Currently, three established recommended approaches such as therapeutic lifestyle change (TLC) diet, pharmacotherapy (simvastatin) and TLC + simvastatin are available to the public but, to our knowledge, have never been compared in Malaysia Primary Health Care setting. Hence, this paper aims to compare the lipid lowering effects of these three approaches in a primary health care clinic. Design/methodology/approach This randomized trial enrolled 180 patients with hypercholesterolemia who met adult treatment panel III (ATP III) criteria. All participants were randomized to TLC diet, simvastatin (10-20 mg/d) or TLC + simvastatin diets. The TLC group was enrolled in a 12-week multidisciplinary lifestyle program that involved monthly 45 minutes to hour meetings. The simvastatin group received medication, and traditional counseling was conducted by registered medical officer. Another group was enrolled into TLC + simvastain treatment. The primary outcome measure was the percentage change in low-density lipoprotein-cholesterol. Secondary measures were changes in weight loss, blood pressure and dietary changes. Assessments were repeated at three-month interval. Findings Lifestyle changes combined with simvastatin had a better lipid lowering effect compared to the other two treatments. However, TLC had a better weight and blood pressure reduction compared to the other two treatments. Nevertheless, TLC group showed reduction proportions similar to standard therapy with simvastatin or TLC + simvastatin. TLC has proven as an alternative approach to hyperlipidemia for a subset of patients unwilling or unable to take statins especially in a community-based, primary health care setting. Research limitations/implications Weight loss was not recorded for simvastatin participants, and this was the major drawback of this study, and there was no comparable weight loss reduction with other groups. Originality/value In Malaysia, the efficacy of hypocholesterolemic therapies among patients who are receiving the most common lipid-lowering drug, simvastatin, in primary health care setting has not been clearly defined. There is also a lack of research on the efficacy of TLC conducted by registered dietitian in a primary health care setting in Malaysia.

Efficacy and safety of fixed dose combination of atorvastatin and hydroxychloroquine: a randomized, double-blind comparison with atorvastatin alone among Indian patients with dyslipidemia

Objective:To evaluate the efficacy and safety of atorvastatin + hydroxychloroquine fixed-dose combination tablets in comparison with atorvastatin alone in treatment of dyslipidemia.Methods:This double-blind, randomized, out-patient study was conducted in 328 patients with primary dyslipidemia having low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL (3.37 mmol/L) to ≤250 mg/dL (6.48 mmol/L) and triglycerides ≤400 mg/dL (4.52 mmol/L). Eligible patients were randomized to receive either atorvastatin 10 mg (n = 167) or atorvastatin 10 mg + hydroxychloroquine 200 mg (n = 161) for 24 weeks.Clinical trial registration:CTRI/2010/091/006138.Main outcome measures:To compare percentage change in LDL-C, total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to Week 12 and Week 24 between groups. To compare mean change in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), high-sensitivity C-reactive protein (Hs-CRP), and percentage of patients achieving lipid goals at Week 12 and Week 24.Results:At Week 24, percentage reduction in LDL-C (−32.52 [−36.13 to −28.91] vs −39.54 [−43.25 to −35.83]; p = 0.008), TC (−24.41 [−27.10 to −21.72] vs −29.30 [−32.07 to −26.54]; p = 0.013), and non-HDL-C (−30.37 [−33.71 to −27.04] vs −36.76 [−40.18 to −33.33]; p = 0.009) was significantly greater in combination treated patients. Both the treatments showed a significant reduction in triglycerides at Week 24 from baseline, however, this reduction was not statistically significantly different between treatment groups. No significant change in HDL-C was observed in patients from both the treatment groups. At Week 24, change in HbA1c (0.22 [0.07 to 0.37] vs −0.13 [−0.28 to 0.03]; p = 0.002) and FBG was also statistically significant in favor of combination therapy (0.37 [0.07 to 0.67] vs −0.29 [−0.59 to 0.03]; p = 0.003), whereas no statistically significant difference was observed in change in Hs-CRP (p = 0.310). Significantly more patients from the combination group achieved LDL-C and TC goals. Exploratory analysis in patients with pre-diabetes showed development of diabetes in 8 patients (15.09%) from the monotherapy group and 1 patient (1.96%) from the combination group (p = 0.034). Study medications were generally safe and well tolerated.Conclusion:Based on study results and widely reported pleiotropic benefits, hydroxychloroquine could emerge as a potential drug for combination with statins for treatment of dyslipidemia. Long duration studies with larger sample sizes are required to further explore the role of hydroxychloroquine as adjunct to statins in reducing risk of cardiovascular events and prevention of statin-induced diabetes.