Mean Baseline Low-density Lipoprotein Cholesterol Research Articles

Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia

BackgroundEvolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over <3 years median treatment duration. ObjectivesThe OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of evolocumab during open-label hypercholesterolemia treatment for up to 5 years. MethodsPatients randomized to standard of care (SOC) or evolocumab 420 mg monthly (evolocumab + SOC) for year 1. After year 1, patients could enter the all-evolocumab period and receive evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation. ResultsA total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed. ConclusionsThe OSLER-1 trial demonstrated consistently excellent LDL-C–lowering efficacy, tolerance, and safety of evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880)

Real-World Outcomes with Lomitapide Use in Paediatric Patients with Homozygous Familial Hypercholesterolaemia.

IntroductionHomozygous familial hypercholesterolaemia (HoFH) is a rare, autosomal disease affecting the clearance of low-density lipoprotein cholesterol (LDL-C) from circulation, and leading to early-onset atherosclerotic cardiovascular disease (ASCVD). Treatment consists mainly of statins, lipoprotein apheresis (LA) and, more recently, the microsomal triglyceride transfer protein inhibitor lomitapide. Lomitapide is not licensed for use in children, but has been made available through an expanded access programme or on a named patient basis.MethodsThis case series includes 11 HoFH patients in 10 different centres in eight countries, less than 18 years of age (mean 11.6 ± 1.1 years, 64% male), with signs of ASCVD, and who have received treatment with lomitapide (mean dose 24.5 ± 4.3 mg/day; mean exposure 20.0 ± 2.9 months). Background lipid-lowering therapy was given according to local protocols. Lomitapide was commenced with a stepwise dose escalation from 2.5 mg or 5 mg/day; dietary advice and vitamin supplements were provided as per the product label for adults. Laboratory analysis was conducted as part of regular clinical care.ResultsIn the 11 cases, mean baseline LDL-C was 419 ± 74.6 mg/dL and was markedly reduced by lomitapide to a nadir of 176.7 ± 46.3 mg/dL (58.4 ± 6.8% decrease). Six patients achieved recommended target levels for children below 135 mg/dL, five of whom had LA frequency reduced. In one case, LDL-C levels were close to target when lomitapide was started but remained stable despite 75% reduction in LA frequency (from twice weekly to biweekly). Adverse events were mainly gastrointestinal in nature, occurred early in the treatment course and were well managed. Three patients with excursions in liver function tests were managed chiefly without intervention; two patients had decreases in lomitapide dose.ConclusionsLomitapide demonstrated promising effectiveness in paediatric HoFH patients. Adverse events were manageable, and the clinical profile of the drug is apparently similar to that in adult patients.FundingAmryt Pharma.

Long-term benefits of high-intensity atorvastatin therapy in Chinese acute coronary syndrome patients undergoing percutaneous coronary intervention: A retrospective study.

There is lack of long-term data on high-intensity statin therapy of Chinese acute coronary syndrome (ACS) patients scheduled to undergo percutaneous coronary intervention (PCI). In this retrospective study, we compared the long-term efficacy and safety of high-intensity and conventional atorvastatin therapy in reducing low-density lipoprotein cholesterol (LDL-C) and plaque size, and improving cardiac function of ACS patients who underwent PCI.We retrospectively analyzed the clinical records of 120 consecutive ACS patients who underwent PCI at our hospital. Group I received a loading dose of atorvastatin (80 mg/day) prior to PCI, followed by a maintenance dose of 40 mg/day for 3 months post-PCI. Group II received a regular dose of atorvastatin (20 mg/day) from the date of admission until 1 year post-PCI. The composite primary efficacy end point was the mean percent change in calculated LDL-C from baseline to week 48 in both groups and percentage of patients achieving the LDL-C target of ≤1.81 mmol/L.Group I had significantly higher mean baseline LDL-C than group II. Moreover, 8.3% of group I patients had an LDL-C ≤1.81 mmol/L versus 43.3% for group II. At week 24, 75.0% and 90.0% of group I and II patients, respectively, achieved the LDL-C target. At week 48, 85.0% and 96.7% of group I and II patients, respectively, achieved the LDL-C target. Additionally, the mean percent changes at week 4 from baseline in LDL-C were −33.6% ± 20.0% for group I versus −12.8% ± 19.6% for group II, and −47.0% ± 25.5% at week 48 for group I versus −36.4% ± 20.2% for group II. Meanwhile, significant reduction in plaque size and marked improvement in cardiac function were seen in patients receiving high-intensity atorvastatin therapy.Compared to conventional therapy, high-intensity statin therapy is more effective in reducing LDL-C and improving cardiac function of ACS patients, with a general benign safety profile over a period of 48 weeks. Our findings support the use of high-intensity statin therapy for Chinese ACS patients to improve the proportion of patients attaining the LDL-C target and reduction in plaque size and improvement cardiac function.

Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab

Familial hypercholesterolemia (FH) is a dominant genetic disorder associated with elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic events. Although therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are indicated for LDL-C reduction among adult patients with FH, placebo-controlled outcome data among FH patients are scant. Directly compare the efficacy of PCSK9 inhibition as compared to placebo on hard cardiovascular outcomes in FH patients enrolled in the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) program. We estimated the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular event rates among 1578 FH patients and 15,959 patients without FH who were selected for comparable lipid levels (on-statin levels of LDL-C >100mg/dL or non-high-density lipoprotein cholesterol>130mg/dL). All patients were randomized by computer generated codes to bococizumab 150mg subcutaneously every 2weeks or to matching placebo in the SPIRE clinical trials program and were followed over a median period of 11.2months for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). Analysis is by intention to treat. The SPIRE trials are closed and registered at ClinicalTrials.gov: NCT01968954, NCT01968967, NCT02100514, NCT01968980, NCT01975376, and NCT01975389. Compared to non-FH patients, FH patients enrolled in the SPIRE trials were on average younger (58 vs 63years), more likely to be women (42 vs 35%), more likely to be primary prevention patients (42 vs 23%), had higher mean baseline LDL-C levels (151 vs 127mg/dL), and lower rates of diabetes (25 vs 52%) and hypertension (59 vs 82%). FH and non-FH patients both had 55% reductions in LDL-C with bococizumab. Among FH patients, major adverse cardiovascular events occurred among 18 of 781 allocated to bococizumab and 22 of 797 allocated to placebo (hazard ratio 0.83; 95% confidence interval 0.44-1.54, P=.55). This best estimate of effect was similar in magnitude to that observed in the much larger group of patients without FH (hazard ratio 0.79, 95% confidence interval 0.64-0.97, P=.023) with no statistically significant evidence of heterogeneity between groups (P=.87). Incidence rate ratios comparing bococizumab to placebo for adverse events were similar among those with and without FH. The proportion of patients developing antidrug antibodies was higher among those with FH compared to those without FH (43% vs 36%, P<.001). In these randomized placebo-controlled data, the subgroup of statin-treated FH patients had a similar magnitude of risk reduction for hard cardiovascular events with the PCSK9 inhibitor bococizumab as did patients without FH, with no evidence of statistical heterogeneity between groups.

Dyslipidemia.

Dyslipidemia.

Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Of 1191 patients sequenced, 20 patients were double heterozygotes (n=7), compound heterozygotes (n=10), or homozygotes (n=3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n=11; 198mg/dL) vs placebo (n=9; 189mg/dL). All patients treated with alirocumab 75/150 or 150mg every 2weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39-114mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10-165mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Clinically meaningful LDL-C-lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH.

Abstract 203: Gender Differences in PCSK9 Inhibitor Prescribing

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) alirocumab (Sanofi and Regeneron) and evolocumab (Amgen) were approved by the FDA in the summer of 2015 for use in patients on maximally tolerated statins with clinical atherosclerotic cardiovascular disease (ASCVD) and heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of low-density lipoprotein cholesterol (LDL-C). Both clinical trial programs were skewed towards male participants so little is known about the characteristics of female patients treated with PCSK9i in real-world settings. Objective: To understand the demographic and clinical differences between male and female patients prescribed a PCSK9i in real-world settings. Methods: All patients 18 years of age and older with evidence of a PCSK9i prescription (Rx) between July 27, 2015 and November 1, 2016 were included from Accenture’s “Predictive Health Intelligence Environment”, a database consisting of electronic medical records (EMR) from 26 integrated delivery networks in the US. Patients were also required to have at least one encounter in the EMR in the 24-month period prior to the first PCSK9i Rx. Demographic and clinical characteristics of these patients were evaluated as well as the Rx history prior to the first PCSK9i Rx. Results: The inclusion criteria were met by 1,754 patients with 906 (51.7%) being female. Mean (SD) age was 65.9 (10.4) for females compared to 64.3 (10.3) for males; however, a higher proportion of females (59.6%) were over age 65 as compared to males (51.5%, difference not significant). Females were statistically less likely to have a prior event for ASCVD (54% vs. 73%, p&lt;0.0001). Additionally, females were significantly more likely to have a BMI &lt; 25 kg/m 2 compared to males (19.1% v. 11.0%, p&lt;0.001). No differences were observed in prescribing specialty, prior lipid modifying treatment or history of smoking. Finally, females had a significantly higher mean baseline LDL-C as compared to males (149.4 mg/dL [58.2] v. 123.9 mg/dL [56.6], p&lt;0.001). Conclusions: Despite the clinical trial programs of both PCSK9i’s being skewed toward male participants, this real-world data consisted of nearly equal numbers of males and females. In this study, females were more likely to be identified as FH, as indicated by their significantly higher levels of LDL-C, despite similarities in prior treatment regimens as compared to males. Further research is warranted to understand diagnosis and treatment patterns in women as compared to men as well as how their cardiovascular health can be improved.

Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis.

The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included. Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression. The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level. A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P < .001). In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.

Lipoprotein Apheresis for Lipoprotein(a)-Associated Cardiovascular Disease: Prospective 5 Years of Follow-Up and Apolipoprotein(a) Characterization.

Lipoprotein(a)-hyperlipoproteinemia (Lp(a)-HLP) along with progressive cardiovascular disease has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. We aimed to study the long-term preventive effect of LA and to assess hypothetical clinical correlations of apolipoprotein(a) (apo(a)) by analyzing genotypes and phenotypes. This prospective observational multicenter study included 170 patients with Lp(a)-HLP and progressive cardiovascular disease (48.9 years median age at diagnosis) despite other cardiovascular risk factors, including low-density lipoprotein cholesterol had maximally been treated (mean baseline low-density lipoprotein cholesterol: measured, 2.56 mmol/L [98.9 mg/dL] and corrected, 1.72 mmol/L [66.3 mg/dL]). Patients were prospectively investigated during a 5-year period about annual incidence rates of cardiovascular events. In addition, apo(a) isoforms and polymorphisms at the apo(a) gene (LPA) were characterized. One hundred fifty-four patients (90.6%) completed 5 years of follow-up. Mean Lp(a) concentration before commencing regular LA was 108.1 mg/dL. This was reduced by a single LA treatment by 68.1% on average. Significant decline of the mean annual cardiovascular event rate was observed from 0.58±0.53 2 years before regular LA to 0.11±0.15 thereafter (P<0.0001); 95.3% of patients expressed at least 1 small apo(a) isoform. Small apo(a) isoform (35.2%) carrying phenotypes were not tagged by single-nucleotide polymorphisms rs10455872 or rs3798220. Results of 5 years of prospective follow-up confirm that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP. Patients clinically selected by progressive cardiovascular disease were characterized by a highly frequent expression of small apo(a) isoforms. Only Lp(a) concentration seemed to comprehensively reflect Lp(a)-associated cardiovascular risk, however.

Angiographic progression of coronary atherosclerosis in patients with familial hypercholesterolaemia treated with non-statin therapy: Impact of a fat-modified diet and a resin

Background and aimsFamilial hypercholesterolaemia (FH) profoundly increases the risk of coronary artery disease (CAD). We investigated whether diet and a bile-acid sequestrant decrease coronary atherosclerosis in patients with FH. MethodsWe identified 26 men with FH and CAD, participating in the St Thomas' Atherosclerosis Regression Study, who had been randomized to receive a fat-modified diet plus cholestyramine (8 g twice daily) (DC, n = 12) or usual care (UC, n = 14), and investigated the relative effects of these treatments on the angiographic progression of coronary atherosclerosis over 39 months. FH was defined as probable/definite according to Dutch Lipid Clinic Network criteria; mean FH score was 8.7 (range 6–15) and mean baseline low-density lipoprotein cholesterol (LDL-Ch) concentration was 5.4 (SD 1.4) mmol/L. Coronary atherosclerosis was assessed by serial quantitative angiography as the global changes in mean and minimum absolute width of segments (MAWS and MinAWS, respectively). ResultsMean plasma LDL-Ch concentration fell by 35% with DC and remained significantly (p < 0.001) lower during the trial at 3.78 (SD 0.98) mmol/L compared with UC at 4.89 (1.04). MAWS decreased by 0.252 (SEM 0.072) mm in the UC group and by 0.001 (0.065) mm in the DC group (p = 0.007), with corresponding reductions in MinAWS of 0.290 (0.087) mm and 0.013 (0.058) mm (p = 0.009); these changes were significant after adjusting for baseline variables, including coronary luminal dimensions and lipoprotein(a). Progression was observed in 7 patients (50%) on UC and 3 (25%) on DC (p = 0.19), with regression in no patients (0%) and 3 patients (25%) (p < 0.05), respectively. ConclusionsThis investigation, carried out in the pre-statin era, demonstrates that a prudent diet and cholestyramine could improve the course of coronary atherosclerosis in men with phenotypic FH through sustained reductions in LDL-Ch.

Abstract 427: An Oral, Rising, Multiple-dose Tolerance, Pharmacokinetic, and Pharmacodynamic Study of Gemcabene in Healthy Volunteers

Background: Gemcabene is a novel lipid-regulating compound being developed as an adjunct to diet and statin therapy for the treatment of dyslipidemia. Gemcabene was administered in a randomized, double-blind, rising, multiple-dose safety, tolerance, pharmacokinetic, and pharmacodynamic study in healthy subjects. Methods: Fifty healthy subjects (34 men and 16 women), with a mean age of 39.7 years and mean baseline LDL-C of 116.7 mg/dL were randomized (6:1) to either gemcabene 50, 150, 300, 450, 600/750, or 900 mg or placebo once daily for 29 days in six rising-dose cohorts. Results: Forty-seven subjects completed the study. Gemcabene significantly lowered total cholesterol by 18-21%, low-density lipoprotein-cholesterol (LDL-C) by 26-32%, and apolipoprotein B (apoB) by 8-21% from both baseline and placebo at the 450, 750/600, and 900 mg doses ( Table below ). Gemcabene was rapidly absorbed with dose proportional increases in maximum plasma concentration (Cmax) and area under plasma concentration time curve from 0 to 24 hours (AUC (0-24) ) values. Elimination half-life values were independent of dose and averaged 32-41 hours. Multiple doses of gemcabene up to 900 mg for 29 days were generally well-tolerated. There were no treatment-related serious adverse events. Adverse events reported were generally mild to moderate in intensity. Conclusion: Gemcabene exposure increased proportional with dose, was well tolerated, and was observed to significantly lower total cholesterol, LDL-C, and apo B at once daily doses of 450 to 900 mg. Gemcabene is being developed as an oral, lipid-altering agent to be used as an adjunctive therapy for the treatment of dyslipidemia, including the rare indication of HoFH. Clinical Implications: Gemcabene is being developed as a potential treatment for dyslipidemia.

Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study.

AimsThe objective of this study was to evaluate the efficacy, safety, and tolerability of LY3015014 (LY), a neutralizing antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), administered every 4 or 8 weeks in patients with primary hypercholesterolaemia, when added to a background of standard-of-care lipid-lowering therapy, including statins.Methods and resultsDouble-blind, placebo-controlled trial randomized 527 patients with primary hypercholesterolaemia from June 2013 to January 2014 at 61 community and academic centres in North America, Europe, and Japan. Patients were randomized to subcutaneous injections of LY 20, 120, or 300 mg every 4 weeks (Q4W); 100 or 300 mg every 8 weeks (Q8W) alternating with placebo Q4W; or placebo Q4W. The primary endpoint was percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) by beta quantification at Week 16. The mean baseline LDL-C by beta quantification was 136.3 (SD, 45.0)mg/dL. LY3015014 dose-dependently decreased LDL-C, with a maximal reduction of 50.5% with 300 mg LY Q4W and 37.1% with 300 mg LY Q8W compared with a 7.6% increase with placebo maintained at the end of the dosing interval. There were no treatment-related serious adverse events (AEs). The most common AE terms (>10% of any treatment group) reported more frequently with LY compared with placebo were injection site (IS) pain and IS erythema. No liver or muscle safety issues emerged.ConclusionsLY3015014 dosed every 4 or 8 weeks, resulted in robust and durable reductions in LDL-C. No clinically relevant safety issues emerged with the administration of LY. The long-term effects on cardiovascular outcomes require further investigation.

Lower the Low-density Lipoprotein Cholesterol to the Level When You Born

Lower the Low-density Lipoprotein Cholesterol to the Level When You Born

Association Between Paradoxical HDL Cholesterol Decrease and Risk of Major Adverse Cardiovascular Events in Patients Initiated on Statin Treatment in a Primary Care Setting.

Background and ObjectivesStatin-induced changes in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are unrelated. Many patients initiated on statins experience a paradoxical decrease in HDL-C. The aim of this study was to evaluate the association between a decrease in HDL-C and risk of major adverse cardiovascular events (MACE).MethodsData from 15,357 primary care patients initiated on statins during 2004–2009 were linked with data from mandatory national hospital, drug-dispensing, and cause-of-death registers, and were grouped according to HDL-C change: decreased ≥0.1 mmol/L, unchanged ±0.1 or ≥0.1 mmol/L increased. To evaluate the association between decrease in HDL-C and risk of MACE, a sample of propensity score-matched patients from the decreased and unchanged groups was created, using the latter group as reference. MACE was defined as myocardial infarction, unstable angina pectoris, ischaemic stroke, or cardiovascular mortality. Cox proportional hazards models were used to estimate relative risks.ResultsHDL-C decreased in 20 %, was unchanged in 58%, and increased in 22 % of patients initiated on statin treatment (96 % treated with simvastatin). The propensity score-matched sample comprised 5950 patients with mean baseline HDL-C and LDL-C of 1.69 and 4.53 mmol/L, respectively. HDL-C decrease was associated with 56 % higher MACE risk (hazard ratio 1.56; 95 % confidence interval 1.12–2.16; p < 0.01) compared with the unchanged HDL-C group.ConclusionsParadoxical statin-induced reduction in HDL-C was relatively common and was associated with increased risk of MACE.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-015-0372-9) contains supplementary material, which is available to authorized users.

Abstract 15248: Comparison of the Effects of Two Low-Density Lipoprotein Cholesterol Goals on Secondary Prevention After Acute Myocardial Infarction: ≥50% Reduction From Baseline versus &lt;70 mg/dL

Background: There haven’t been well-designed studies conducted to know an optimal goal for low-density lipoprotein cholesterol (LDL-C) after acute myocardial infarction (AMI). Methods: Of 2,409 consecutive patients (62.7 ± 12.4 years, 74.1% men) with AMI who had baseline LDL-C levels ≥70mg/dL and received discharge statin prescriptions after successful percutaneous coronary intervention, 1,305 patients (61.0 ± 11.8 years, 77.0% men) who had LDL-C levels tested at 1 year (mean baseline LDL-C, 126.5 ± 33.5 mg/dL; mean LDL-C reduction at 1 year, 53.1 ± 29.3 mg/dL) were analyzed in this study. Patients were categorized into 2 groups according to the values of LDL-C at 1 year in two different ways using percent change from baseline (≥50% reduction, n=428 versus &lt;50% reduction, n=877) and fixed levels (&lt;70 mg/L, n=625 versus ≥70 mg/dL, n=680). The primary endpoint was the composite of major cardiac events (MCEs) including cardiac deaths, non-fatal myocardial infarctions and coronary revascularizations (angioplasty or bypass grafting) after hospital discharge. A median follow-up duration was 2.0 years (interquartile range, 1.9 to 2.1 years). Results: At 2 years, MCEs occurred in 139 patients (10.7%). Kaplan-Meier estimates of the MCEs rates at 2 years revealed that patients with ≥50% LDL-C reduction from baseline had fewer MCEs compared with &lt;50% LDL-C reduction (8.2% versus 11.9%; Log rank P =0.026), while those with LDL-C levels &lt;70 mg/dL at 1 year did not (&lt;70 mg/L, 10.7% versus ≥70 mg/dL, 10.6%; Log rank P =0.998). In a multivariable Cox proportional hazard model, patients with ≥50% LDL-C reduction from baseline had a 39% reduction in the risk of MCEs compared with &lt;50% LDL-C reduction (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.41 to 0.90; P =0.012). But, compared with LDL-C levels ≥70 mg/dL at 1 year, patients with LDL-C levels &lt;70 mg/dL didn’t have a significant reduction in the risk of MCEs (adjusted HR, 0.98; 95% CI, 0.69 to 1.37; P =0.975). Conclusions: Obtaining a ≥50% reduction in LDL-C was associated with a significant reduction in the risk of MCEs after AMI, whereas achieving a &lt;70 mg/dL was not. Our study suggests that obtaining a ≥50% reduction from baseline could be an optimal goal for LDL-C after AMI, not achieving a &lt;70 mg/dL.

Effects of Evolocumab (AMG 145), a Monoclonal Antibody to PCSK9, in Hypercholesterolemic, Statin-Treated Japanese Patients at High Cardiovascular Risk

YUKAWA is a 12-week, randomized, double-blind, placebo-controlled, phase 2 study evaluating the efficacy and safety of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. 310 eligible patients receiving stable statin (±ezetimibe) therapy were randomized to 1 of 6 treatments: placebo every 2 weeks (Q2W) or monthly (QM), evolocumab 70 mg or 140 mg Q2W, or evolocumab 280 mg or 420 mg QM. The primary endpoint was the percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) measured by preparative ultracentrifugation (UC). Secondary endpoints included percentage changes in other lipid parameters and the proportion of patients with LDL-C <1.8 mmol/L. Mean (SD) age was 62 (10) years; 37% were female; and the mean (SD) baseline LDL-C was 3.7 (0.5) mmol/L (by UC). Mean (SE) changes vs. placebo in LDL-C were greatest in the high-dose groups: -68.6 (3.0) % and -63.9 (3.2) % with 140 mg Q2W and 420 mg QM dosing, respectively. Up to 96% of evolocumab-treated patients achieved LDL-C <1.8 mmol/L. Adverse events (AEs) were more frequent in evolocumab (51%) vs. placebo (38%) patients; 4 patients taking evolocumab discontinued treatment because of an AE. There were no significant differences in AE rates based on dose or dose frequency. In Japanese patients at high cardiovascular risk with hypercholesterolemia on stable statin therapy, evolocumab significantly reduced LDL-C and was well tolerated during this 12-week study.

Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients With Severe Hypercholesterolemia at High Cardiovascular Risk: A Randomized, Double-Blind, Placebo-Controlled Trial

This study sought to examine the efficacy and safety of mipomersen for reducing atherogenic lipids and lipoproteins in patients with hypercholesterolemia. Many patients on lipid-lowering therapies remain unable to achieve target low-density lipoprotein (LDL) cholesterol levels. Mipomersen, an antisense oligonucleotide inhibitor of apolipoprotein B, reduces LDL cholesterol and atherogenic lipoproteins. This randomized, double-blind, multicenter study enrolled 158 patients with baseline LDL cholesterol levels ≥100 mg/dl with, or at high risk for, coronary heart disease who were receiving maximally tolerated lipid-lowering therapy. Patients received weekly subcutaneous mipomersen 200 mg (n = 105) or placebo (n = 52) for 26 weeks, with a 24-week follow-up period. Randomization was stratified by type 2 diabetes status. Sixty mipomersen and 44 placebo patients completed treatment. Mean baseline LDL cholesterol levels were 122.7 and 122.6 mg/dl in the placebo and mipomersen patients, respectively. Mipomersen reduced LDL cholesterol by -36.9% compared with placebo at -4.5% (p < 0.001). Target LDL cholesterol <100 mg/dl was attained in 76% of mipomersen and 38% of placebo patients. Mipomersen also significantly reduced apolipoprotein B (-38%) and lipoprotein(a) (-24%) (p < 0.001). Common adverse events included injection site reactions (78% with mipomersen, 31% with placebo) and flu-like symptoms (34% with mipomersen, 21% with placebo). Elevations in transaminases and liver fat also occurred in some patients, and these levels returned toward baseline after treatment cessation. Mipomersen significantly reduced LDL cholesterol, apolipoprotein B, and lipoprotein(a) in patients with hypercholesterolemia with, or at risk for, coronary heart disease not controlled by existing therapies. (Safety and Efficacy of Mipomersen [ISIS 301012] as Add-On Therapy in High Risk Hypercholesterolemic Patients; NCT00770146).

The Cholesterol, Hypertension, And Glucose Education (CHANGE) study: Results from a randomized controlled trial in African Americans with diabetes

Cardiovascular disease (CVD) and diabetes account for one-third of the mortality difference between African American and white patients. We evaluated the effect of a CVD risk reduction intervention in African Americans with diabetes. We randomized 359 African Americans with type 2 diabetes to receive usual care or a nurse telephone intervention. The 12-month intervention provided monthly self-management support and quarterly medication management facilitation. Coprimary outcomes were changes in systolic blood pressure (SBP), hemoglobin A1c (HbA1c), and low-density lipoprotein cholesterol (LDL-C) over 12 months. We estimated between-intervention group differences over time using linear mixed-effects models. The secondary outcome was self-reported medication adherence. The sample was 72% female; 49% had low health literacy, and 37% had annual income <$10,000. Model-based estimates for mean baseline SBP, HbA1c, and LDL-C were 136.8 mm Hg (95% CI 135.0-138.6), 8.0% (95% CI 7.8-8.2), and 99.1 mg/dL (95% CI 94.7-103.5), respectively. Intervention patients received 9.9 (SD 3.0) intervention calls on average. Primary providers replied to 76% of nurse medication management facilitation contacts, 18% of these resulted in medication changes. There were no between-group differences over time for SBP (P = .11), HbA1c (P = .66), or LDL-C (P = .79). Intervention patients were more likely than those receiving usual care to report improved medication adherence (odds ratio 4.4, 95% CI 1.8-10.6, P = .0008), but adherent patients did not exhibit relative improvement in primary outcomes. This intervention improved self-reported medication adherence but not CVD risk factor control among African Americans with diabetes. Further research is needed to determine how to maximally impact CVD risk factors in African American patients.

Emerging low-density lipoprotein therapies: Microsomal triglyceride transfer protein inhibitors

Microsomal triglyceride transfer protein, which is localized in the endoplasmic reticulum of enterocytes and hepatocytes, is necessary for the formation of chylomicron and very low-density lipoprotein particles. Lomitapide is a small molecule microsomal triglyceride transfer protein inhibitor that was recently approved by the Food and Drug Administration as an adjunct to a low-fat diet and other lipid-lowering therapies for reducing low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (FH). Results from clinical trials of lomitapide have demonstrated its ability to reduce atherogenic lipoprotein concentrations in this population. Most recently, in a phase 3 clinical trial of 29 men and women with homozygous FH (mean baseline LDL-C, 336 mg/dL) who were on stable doses of concomitant lipid therapies and a low-fat diet, lomitapide was gradually titrated over 26 weeks (from 5 to 60 mg/d), followed by 52 weeks at the maximum tolerated dose. LDL-C decreased from baseline by 50% at 26 weeks, and reductions were maintained through the end of the study. Gastrointestinal disorders were the most frequent side effects and the most common reason for failure to tolerate lomitapide dose escalation. Few patients had elevated aspartate or alanine aminotransferases; bilirubin and alkaline phosphatase levels were unaffected; and hepatic fat increased by ≈ 10 g/100 g. In conclusion, recent data support the LDL-C-lowering efficacy of low-dose titrated lomitapide in patients with homozygous FH; however, concerns regarding increased hepatic fat will need to be addressed in long-term safety studies.

Effect of a Monoclonal Antibody to PCSK9 on Low-Density Lipoprotein Cholesterol Levels in Statin-Intolerant Patients

An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, promoting their degradation and increasing LDL cholesterol levels. In phase 1 studies, a human monoclonal antibody to PCSK9, AMG145, was well tolerated and reduced LDL cholesterol levels. To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects. A 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites. Patients were randomized equally to 1 of 5 groups: AMG145 alone at doses of 280 mg, 350 mg, or 420 mg; AMG145 at 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks. The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol. Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe. Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline LDL cholesterol, 193 mg/dL); all patients had intolerance to 1 or more statins because of muscle-related events. At week 12, mean changes in LDL cholesterol levels were -67 mg/dL (-41%; 95% CI, -49% to -33%) for the AMG145, 280-mg, group; -70 mg/dL (-43%; 95% CI, -51% to -35%) for the 350-mg group; -91 mg/dL (-51%; 95% CI, -59% to -43%) for the 420-mg group; and -110 mg/dL (-63%; 95% CI, -71% to -55%) for the 420-mg/ezetimibe group compared with -14 mg/dL (-15%; 95% CI, -23% to -7.0%) for the placebo/ezetimibe group (P < .001). Four serious adverse events were reported with AMG145 (coronary artery disease, acute pancreatitis, hip fracture, syncope). Myalgia was the most common treatment-emergent adverse event during the study, occurring in 5 patients (15.6%) in the 280-mg group (n = 32); 1 patient (3.2%) in the 350-mg group (n = 31), 1 patient (3.1%) in the 420-mg group (n = 32), 6 patients (20.0%) receiving 420-mg AMG145/ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe. In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01375764.