Oral Lipid-lowering Therapy Research Articles

Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION-9, ORION-10 and ORION-11 Phase 3 randomized trials.

To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3-month doses up to 18 months, with background oral lipid-lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co-primary endpoints were percentage and time-adjusted percentage change in low-density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo-corrected) with inclisiran from baseline to Day 510 ranged from -47.6% to -51.9% and from -48.8% to -54.4% across glycaemic/BMI strata, respectively. Similarly, time-adjusted percentage changes after Day 90 and up to Day 540 ranged from -46.8% to -52.0% and from -48.6% to -53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment-emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%-7.7%) versus placebo (0.2%-2.1%). Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild-to-moderate TEAEs at the injection site.

A retrospective nationwide analysis of evolocumab use in Sweden and its effect on low-density lipoprotein cholesterol levels.

Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduces low-density lipoprotein cholesterol (LDL-C) levels and decreases the incidence of major ischaemic events in clinical trials. However, less is known about the efficacy of PCSK9 inhibition in clinical practice. This study aimed to describe the change in LDL-C levels over time and LDL-C goal achievement in patients with/without atherosclerotic cardiovascular disease (ASCVD), who were prescribed evolocumab in clinical practice, and to describe adherence to and persistence with treatment. Patients in Sweden with at least one evolocumab prescription filled between July 2015 and May 2020 were included. Medical history and lipid-lowering therapy (LLT) were sourced from national registries. LDL-C levels before and after treatment initiation were assessed using medical records. Persistence with and adherence to evolocumab and oral LLT were assessed up to 12 months after treatment initiation using the refill-gap method and proportion of days covered, respectively. Of the 2,360 patients with at least one prescription for evolocumab, 2,341 were included; 1,858 had ASCVD. Persistence with (76%) and adherence to (86%) evolocumab were high throughout the 12 months following initiation. Mean LDL-C levels decreased by 53% (95% confidence interval [CI]: 51-55%) in patients adherent to evolocumab (n = 567) and 59% (95% CI: 55-63%) in patients adherent to evolocumab and oral LLT (n = 186). Similar reductions in LDL-C were observed in patients with/without ASCVD. Reduced LDL-C levels remained stable during follow-up. Amongst patients adherent to evolocumab and those adherent to evolocumab and oral LLT, 23 and 55% achieved the LDL-C goal of <1.4 mmol/L, respectively. The evolocumab LDL-C-lowering effect observed in clinical trials was confirmed in clinical practice in Sweden, particularly in patients also treated with oral LLT. During follow-up, adherence to and persistence with evolocumab were high, with stable reduced levels of LDL-C during observation.

PCSK9 inhibition with orally administered NNC0385-0434 in hypercholesterolaemia: a randomised, double-blind, placebo-controlled and active-controlled phase 2 trial

Currently available injectable drugs that target proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce serum LDL cholesterol and improve cardiovascular outcomes. This phase 2 study assessed NNC0385-0434, an oral PCSK9 inhibitor, in individuals receiving oral lipid-lowering therapy. In this randomised, double-blind, placebo-controlled and active-controlled trial, 42 research sites across seven countries (Belgium, Germany, Greece, Japan, the Netherlands, Poland, and the USA) recruited individuals with established atherosclerotic cardiovascular disease (aged ≥40 years) or at high risk of atherosclerotic cardiovascular disease (aged >50 years), who had LDL cholesterol concentration of at least 1·8 mmol/L and were receiving maximum tolerated statins and stable lipid-lowering therapy. The study randomly allocated participants (3:1) with an interactive web response system to receive either NNC0385-0434 (15 mg, 40 mg, or 100 mg) once a day co-formulated with the oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (500 mg); placebo; or open-label evolocumab (140 mg) every 2 weeks administered subcutaneously. Blinding was performed within each dose level. The primary endpoint was percentage change from baseline in LDL cholesterol measured by β quantification at week 12. All randomly assigned participants received at least one dose of treatment and were included in both safety and efficacy analyses. The trial was registered on ClinicalTrials.gov, NCT04992065, and is completed. Between Aug 16, 2021, and Jan 28, 2022, we randomly assigned 267 patients to one of the three NNC0385-0434 dose cohorts (n=53 per cohort), matching placebo (n=54), or open-label evolocumab (n=54). The study population comprised 82 (31%) women and 185 (69%) men; mean age was 64·3 years (SD 9·0). Baseline mean LDL cholesterol concentration was 2·7 mmol/L (SD 0·8). Treatment with NNC0385-0434 resulted in reductions in LDL cholesterol from baseline to week 12, of 32·0 percentage points (95% CI 20·9 to 43·0) in the 15 mg cohort, 44·9 percentage points (33·8 to 56·0) in the 40 mg cohort, and 61·8 percentage points (50·7 to 72·9) in the 100 mg cohort, compared with the placebo group (p<0·0001 for each). Patients treated with evolocumab had similar LDL cholesterol reductions (59·6% [SE 4·1] decrease from baseline) to patients receiving NNC0385-0434 100 mg (56·2% [4·0]). The estimated treatment difference between NNC0385-0434 100 mg and evolocumab 140 mg was 3·4 percentage points [95% CI -7·8 to 14·7]. The most frequently reported adverse event was COVID-19, which affected 31 (12%) of 267 patients, with similar numbers across treatment groups. Investigative sites reported gastrointestinal disorders as the most frequent treatment-related adverse event (26 patients and 35 events total in the three NNC0385 cohorts and one patient and one event each in the placebo and evolocumab cohorts). No deaths or treatment-related serious adverse events occurred. This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations. Novo Nordisk.

Unrealized opportunities for cardiovascular risk reduction with optimized statin and ezetimibe in veterans with coronary artery disease

Abstract Background Many patients with coronary artery disease (CAD) do not achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals (1,2). Purpose To quantify unrealized opportunities to improve clinical outcomes of Veterans with CAD through optimized oral lipid-lowering therapy (LLT) with statins and ezetimibe within the United States Veterans Affairs healthcare system. Methods Veterans with CAD by coronary angiography between 2015 and 2020 were identified, the observed LLT and LDL-C were described, and the observed rates of death, myocardial infarction, stroke, and coronary revascularization were determined. Potential reductions in these events with optimized statin alone or with ezetimibe were modelled based on expected further LDL-C reductions (3). Results The analysis cohort comprised 111,954 Veterans (59.7% statin-treated at baseline angiography) observed for median 3.4 (IQR 2.1-4.0) years. At 6 months, statin prescription increased to 68.7%, but high-intensity statin regimens were prescribed in only 52.9%, ezetimibe use was low (1.1%), and LDL-C remained ≥70 mg/dL in 52.1% of patients. At 4 years, observed incidences (95% CI) of death, myocardial infarction, stroke, and coronary revascularization were 21.6% (21.3-21.8), 5.0% (4.9-5.2), 2.2% (2.1-2.3), and 15.4% (15.2-15.7), respectively (Figure 1). With optimized statin, projected absolute reductions in these incidences were 1.3% (0.9-1.7), 0.8% (0.7-1.0), 0.2% (0.1-0.3), and 2.3% (2.0-2.7). With optimized statin and ezetimibe, projected absolute reductions were 1.8% (1.2-2.4), 1.1% (0.9-1.3), 0.3% (0.2-0.4) and 3.1% (2.6-3.6). Conclusions Suboptimal LLT was prevalent among Veterans with CAD. Meaningful improvements in their cardiovascular outcomes could be achieved with optimized statin alone. Despite lesser lipid-lowering efficacy of ezetimibe, its widespread use on a population level could contribute substantially to cardiovascular risk reduction from intensified oral LLT.Figure 1Figure 2

Rationale and design of a randomized controlled trial: The effect of intensive lipid-lowering therapy with PCSK9 inhibitor on endothelial-coverage of stent strut after percutaneous coronary intervention (PCI) for patients with acute coronary syndrome (ACS): Optical coherence tomography (OCT) study (PIECES-OCT study)

BackgroundFor the patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) for at least 1 year is recommended in the guidelines to minimize the risk of stent thrombosis. Persistently uncovered stent strut means delayed neointima formation and extend the window of time in which the stent is prone to thrombosis. Previous studies showed that statins could improve post-stenting strut endothelial coverage for patients undergoing PCI. However, there are lack of evidences on whether early initiation of proprotein convertase subtilisin/Kexin type 9 monoclonal antibody (PCSK9mAb) after PCI in ACS patients can further improve the rate of stent strut coverage on the background of oral lipid-lowering therapy (LLT). MethodsThis is a single-center, randomized trial to enroll 36 patients undergoing PCI with a clinical diagnosis of non-ST-segment elevation ACS. The baseline level of low-density lipoprotein cholesterol (LDL-C) of these patients are between 1.4 mmol/L and 3.4 mmol/L. Patients will be assigned to intensive lipid-lowering therapy (LLT) with PCSK9mAb group and conventional LLT without PCSK9mAb group for 12 weeks in a clinical follow-up setting according to 1: 1 randomization. the rate of stent strut endothelial coverage by optical coherence tomography (OCT) examination at 12 weeks after enrollment between the groups will be compared. ConclusionThis will be the first study to investigate changes in the rate of stent strut endothelial coverage under intensive LLT with PCSK9mAb by OCT examination in ACS patients undergoing PCI. The finding of this study will provide clinical evidence for future research about the hypothesis of a novel strategy of “intensive LLT (PCSK9mAb + statin ± ezetimibe) combined with shortened DAPT duration” for ACS patients undergoing PCI.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: ChiCTR2200063395.

The role of bempedoic acid in the management of dyslipidaemia

Bempedoic acid is a new oral lipid-lowering therapy which has been licenced for use in the United Kingdom. It can be used alone, with a statin, or with other lipid-lowering therapies where the target level for low density lipoprotein has not been achieved with these therapies alone. Bempedoic acid with ezetimibe can be prescribed for people who are unable to tolerate statins. This combination has received NICE approval following a technology appraisal. This paper discusses the place for of bempedoic acid as a lipid lowering drug and consider the mode of action, licensed indications, adverse drug reactions and the NICE technology appraisal recommendations.

A real-world analysis of characteristics and lipid-lowering therapy use in patients initiating treatment with evolocumab in Sweden

Abstract Background/Introduction Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein cholesterol (LDL-C) levels and the risk of cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) in clinical trials. In January 2019, evolocumab reimbursement recommendation in Sweden was broadened to include patients on maximally tolerated oral lipid-lowering therapy (LLT) and either ASCVD and LDL-C ≥2.5 mmol/L, or familial hypercholesterolemia (FH) with no ASCVD and LDL-C ≥3.0 mmol/L. Purpose Describe characteristics and LLT use in patients initiating treatment with evolocumab in the context of the 2019 reimbursement recommendation in Sweden. Methods Cross-sectional, population-based, retrospective, observational study of patients initiating treatment with evolocumab between January 2019 and June 2020. Data were obtained from national healthcare registers and electronic medical records, covering more than half of the Swedish population. Results Out of 1560 patients included, 41% had LDL-C available ≤3 months prior to treatment initiation with evolocumab. Among those with LDL-C available, 79% had ASCVD and 19% had definite, probable or possible FH with no ASCVD. Mean pre-treatment LDL-C levels were 3.7 and 5.0 mmol/L for patients with ASCVD, and FH with no ASCVD, respectively. Most of the patients, 84.6% and 80.0%, respectively, had been ever treated with both statins and ezetimibe. However, 28.0% and 38.3% of them, respectively, were not on oral LLT at the time of treatment initiation with evolocumab. Patient characteristics and LLT use are presented in Table 1. Conclusions Patients initiating treatment with evolocumab in Sweden had pre-treatment LDL-C levels far from treatment targets, despite being at very high risk for cardiovascular events. Most of the patients had been treated with both statins and ezetimibe in the past. However, almost a third of them were not using oral LLT at the time of treatment initiation with evolocumab. The conditions in the 2019 evolocumab reimbursement recommendation in Sweden were generally met. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen

Treatment of high- and very high-risk patients for the prevention of cardiovascular events in Europe: baseline demographics from the multinational observational SANTORINI study

Abstract Background The ESC/EAS 2019 guidelines recommend ambitious lower goals for low-density lipoprotein cholesterol (LDL-C), especially for patients with high and very high cardiovascular (CV) risk which could necessitate more intensive lipid-lowering therapy (LLT) regimens. Multiple real-world studies in Europe have demonstrated suboptimal achievement of older 2016 LDL-C goals, with combination therapy with ezetimibe or proprotein convertase subtilisin kexin 9 inhibitors (PCSK9i) used in 9% and 1% of patients, respectively. SANTORINI is the first European observational study since the 2019 guidelines to assess whether management of high- and very high-risk patients has improved. Purpose To describe patient characteristics and treatment patterns of LLT in real-world practice for the management of LDL-C levels in high- and very high-risk patients. Methods Baseline data were assessed from SANTORINI, which recruited patients aged ≥18 years with high and very high CV risk requiring LLT. Risk was defined as per a commonly available assessment system, e.g. the Systematic Coronary Risk Estimation (SCORE) system, for which ESC/EAS guidelines classify high-risk and very high-risk as a calculated 10-year risk of fatal CV disease of ≥5–&amp;lt;10% and ≥10%, respectively. Patients were recruited from 14 European countries across primary and secondary care settings, with patient characteristics, medical history, current LLT and other co-medications documented at baseline. Results Of 9606 patients recruited from March 2020 to February 2021 (55.0% from secondary care), cleaned data on 4308 were available through to February 2021. In this interim report, mean (standard deviation [SD]) age was 64.8 (10.8) years and 27.8% were female. Mean (SD) LDL-C was 2.45 (1.21) mmol/L. The majority of patients were classified as very high risk (69.3%), with 30.6% high risk. ESC/EAS guidelines were the most common basis for risk classification (51.3%), then clinical experience (33.5%) and national guidelines (10.4%). Concomitant CV risk factors included being a current or former smoker (16.5% and 41.8%, respectively), hypertension (70.9%), diabetes (35.4%) and familial hypercholesterolemia (10.1%). At baseline, 18.6% of patients were not receiving any LLT. 54.1% of patients were receiving LLT monotherapy, including 51.1% on statins, 1.4% ezetimibe, 1.2% a PCSK9i, and 0.5% other oral LLT. Combination therapy was used in 27.3% of patients, including 17.1% receiving statin plus ezetimibe, 4.1% PCSK9i plus oral LLT, and 6.1% any other oral combination therapy. Conclusions This large study in patients at high and very high CV risk from 14 European countries suggests that, although the ESC/EAS guidelines are the most frequently used basis for risk classification, LDL-C levels remain substantially higher than recommended goals, with combination therapies underutilised. An expanded data cut from SANTORINI will be reported in 2021. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH, Munich, Germany

Clinical evaluation of bempedoic acid for the treatment of hyperlipidaemia

Bempedoic acid (BA) is a novel first-in-class oral lipid-lowering therapy. BA has been approved by the European Medicinal Agency and Food and Drug Administration and has been commercialised throughout Europe since the end of 2020 as an add-on therapy in patients at high/very-high cardiovascular risk that are not at LDL-C goals with current lipid-lowering treatments. Recently, Italian lipid management experts gathered to discuss several open questions on BA characteristics and BArelated practical clinical issues. The panel permitted collection of its opinions in a ten Q&A format. AimThe aim of this viewpoint is to discuss and answer several open questions on BA characteristics and BA-related practical clinical issues. Data synthesisThe data includes main phase III studies, subanalysis and meta-analysis on BA. ConclusionsThe panel permitted collection of its opinions in a ten Q&A format.

Intensive lipid-lowering therapy in the 12 months after an acute coronary syndrome in Australia: an observational analysis.

To determine the prevalence and identify predictors of people hospitalised with acute coronary syndrome (ACS) receiving intensive lipid-lowering therapy during the 12 months after their discharge from hospital. Retrospective observational analysis. Data were extracted from CONCORDANCE, a prospective, Australian investigator-initiated ACS registry. Patients enrolled in CONCORDANCE during January 2015 - May 2016 who survived to hospital discharge, for whom information on lipid-lowering therapy 6 or 12 months after discharge from hospital were available. Not receiving intensive lipid-lowering therapy (with or without ezetimibe) at the most recent follow-up (6 or 12 months); predictors of not receiving intensive lipid-lowering therapy. 1876 of 3441 patients (55%) were receiving intensive lipid-lowering therapy 6 or 12 months after their hospitalisation with an ACS. Predictors of not receiving intensive lipid-lowering therapy included not been prescribed this treatment prior to their hospital admission (odds ratio [OR], 1.53; 95% CI, 1.26-1.85) or at hospital discharge (aOR, 7.24; 95% CI, 4.37-12.0), being a woman (aOR, 1.20; 95% CI, 1.02-1.41), and not being referred for cardiac rehabilitation (aOR 1.39; 95% CI, 1.09-1.78). Patients who were managed medically in hospital (not revascularised; aOR, 1.54; 95% CI, 1.25-1.91) or underwent coronary artery bypass grafting (aOR 1.55; 95% CI, 1.26-1.92) were less likely to be receiving intensive lipid-lowering therapy at follow-up than those with a percutaneous coronary intervention. Unmeasured hospital factors accounted for 17% of the variation in the likelihood of intensive lipid-lowering therapy. 45% of patients in Australia are not receiving intensive lipid-lowering therapy in the 12 months after their ACS. Optimising oral lipid-lowering therapy would reduce the recurrence of coronary events in this high risk group.

Simulation of Lipid-Lowering Therapy Intensification in a Population With Atherosclerotic Cardiovascular Disease

In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend optimizing statin treatment, and consensus pathways suggest use of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with persistently elevated low-density lipoprotein cholesterol (LDL-C) levels despite use of statins. Recent trials have provided evidence of benefit in reduction of cardiovascular events with these agents. To estimate the percentage of patients with ASCVD who would require a PCSK9 inhibitor when oral lipid-lowering therapy (LLT) is intensified first. This simulation model study used a large administrative database of US medical and pharmacy claims to identify a cohort of 105 269 patients with ASCVD enrolled from January 1, 2012, through December 31, 2013, who met the inclusion criteria (database cohort). Patients were sampled with replacement (bootstrapping) to match the US epidemiologic distribution and entered into a Monte Carlo simulation (simulation cohort) that applied stepwise treatment intensification algorithms in those with LDL-C levels of at least 70 mg/dL. All patients not initially receiving a statin were given atorvastatin, 20 mg, and the following LLT intensification steps were applied: uptitration to atorvastatin, 80 mg; add-on ezetimibe therapy; add-on alirocumab therapy, 75 mg (a PCSK9 inhibitor); and uptitration to alirocumab, 150 mg. Sensitivity analyses included evolocumab as a PCSK9 inhibitor. Efficacy was estimated from published studies and incorporated patient-level variation. Data were analyzed from December 2015 to May 2017. Treatment intensification strategies with LLT. Use of LLT among the population with ASCVD and distributions of LDL-C levels under various treatment intensification scenarios. Inclusion criteria were met by 105 269 individuals in the database cohort (57.2% male and 42.8% female; mean [SD] age, 65.1 [12.1] years). In the simulation cohort (1 million patients; 54.8% male and 45.2% female; mean [SD] age, 66.4 [12.2] years), before treatment intensification, 51.5% used statin monotherapy and 1.7% used statins plus ezetimibe. Only 25.2% achieved an LDL-C level of less than 70 mg/dL. After treatment intensification, 99.3% could achieve an LDL-C level of less than 70 mg/dL, including 67.3% with statin monotherapy, 18.7% with statins plus ezetimibe, and 14% with add-on PCSK9 inhibitor. Large gaps exist between recommendations and current practice regarding LLT in the population with ASCVD. In our model that assumes no LLT intolerance and full adherence, intensification of oral LLT could achieve an LDL-C level of less than 70 mg/dL in most patients, with only a modest percentage requiring a PCSK9 inhibitor.

Evaluating bempedoic acid for the treatment of hyperlipidaemia

ABSTRACTIntroduction: Despite the effectiveness of statins in the treatment of lipid disorders, residual risk still exists, and hitherto studies where additional drugs were added to statin therapy have been mainly negative or the outcomes were very modest. Therefore there is still a need for new and effective oral agents in the combination therapy of lipid disorders.Areas covered: The review covers the current state of knowledge on the mechanism of action of bempedoic acid (ETC-1002) and results from recent clinical studies.Expert opinion: ETC-1002 is a novel oral lipid-lowering therapy. The reduction of both low-density lipoprotein cholesterol (LDL-C) and high sensitivity C-reactive protein (hsCRP) demonstrated by ETC-1002 in clinical trials suggests that agent may have the potential for CV risk reduction. Adverse effects of current lipid-lowering agents can be dose-limiting, and combination approaches to lipid-lowering may often be utilized for optimal CV risk reduction. Because of this, new lipid-modulating drugs are urgently required. ETC-1002 has a unique mechanism of action (adenosine triphosphate-citrate lyase inhibition). It has been shown to be safe in combination with statins as well as ezetimibe, and appears to effectively lower LDL-C and has the potential to reduce the risk of muscle-related adverse events, which can limit the utilization and effectiveness of statin therapy.

Challenges in Oral Lipid-lowering Therapy: Position Document of the Spanish Society of Cardiology

Lipid-lowering therapy is one of the cornerstones of cardiovascular prevention and is one of the most effective strategies in the secondary prevention of ischemic heart disease. Nevertheless, the current treatment of lipid disorders, together with lifestyle changes, fails to achieve the targets recommended in clinical guidelines in a substantial proportion of patients. PCSK9 inhibitors have demonstrated safety and efficacy in the treatment of dyslipidemia. Due to their ability to reduce low-density lipoprotein cholesterol levels, these drugs have recently been approved for clinical use by Spanish regulatory agencies, with the aim of reducing cardiovascular risk in selected patient groups.

PCSK9 inhibitors : Recommendations for patient selection

The 2 or 4‑week subcutaneous therapy with the recently approved antibodies alirocumab and evolocumab for inhibition of proprotein convertase subtilisin-kexin type 9 (PCSK9) reduces low-density lipoprotein cholesterol (LDL-C) in addition to statins and ezetimibe by 50-60 %. The therapy is well-tolerated. The safety profile in the published studies is comparable to placebo. Outcome data and information on long-term safety and the influence on cardiovascular events are not yet available but the results of several large trials are expected in 2016-2018. At present (spring 2016) PCSK9 inhibitors represent an option for selected patients with a high cardiovascular risk and high LDL-C despite treatment with the maximum tolerated oral lipid-lowering therapy. This group includes selected patients with familial hypercholesterolemia and high-risk individuals with statin-associated muscle symptoms (SAMS).

Gender Difference in the Level of Highdensity Lipoprotein Cholesterol in Elderly Japanese Patients with Coronary Artery Disease

High-density lipoprotein cholesterol (HDLC) levels are known to be reduced in the metabolic syndrome, but the HDLC profile of elderly patients with coronary artery disease (CAD) has not been well characterized. This study investigated the gender difference of HDLC levels in elderly Japanese patients with CAD. Serum lipid data were analyzed retrospectively to assess sex-related differences of the lipid profile, and to evaluate the effects of pharmacotherapy or physical exercise on hyperlipidemia. A total of 163 elderly (> or = 65 years) outpatients with CAD (128 men aged 70.6+/-5.2 years and 35 women aged 74.1+/-6.0 years [mean+/-SD]) were investigated. The mean total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and triglyceride (TG) levels were similar in men and women, while the mean HDLC level was significantly higher in women than men (58.3+/-18.1 vs. 50.3+/-13.5 mg/dL; p=0.0064). The HDLC level was not significantly influenced by oral lipid-lowering therapy or regular exercise in either sex. However, women without lipid-lowering therapy had significantly higher HDLC levels than men with (p=0.0312) or without (p=0.0338) lipid-lowering therapy, while women performing regular exercise had significantly higher HDLC levels than men with (p=0.0047) or without (p<0.001) regular exercise. Elderly women with CAD have higher HDLC levels relative to their postmenopausal state than those of men with CAD. Low HDLC levels, unlike in men, may not be a major risk factor for CAD in elderly women.

Short-term effect of atorvastatin on ischaemic threshold in hypercholesterolaemic patients with stable ischaemic heart disease

Objective — Hypercholesterolaemia is associated with a loss of endothelium-dependent vasodilation, which may facilitate the occurrence of myocardial ischaemia in patients with coronary artery disease (CAD). The improvement of endothelial dilator function after 4 to 6 weeks of oral lipidlowering therapy has been documented. Whether this early restoration of endothelial function by statins translates into anti-ischaemic effects is unknown.This study was designed to determine the effect of 4 weeks’ treatment with 80 mg atorvastatin daily on exercise-induced ischaemia in patients with stable ischaemic heart disease (IHD) receiving standard anti-anginal drug therapy.Methods and results — A total of 41 patients with documented CAD, exercise-induced ischaemia and LDL-cholesterol > 130 mg/dl underwent exercise ECG, angina score and lipid level assessment at baseline, after 4 weeks of placebo treatment, and after 4 weeks of therapy with atorvastatin 80 mg. Primary endpoint was the change in time to 1 mm ST-segment depression (= ischaemic threshold) between placebo and treatment period.Atorvastatin treatment resulted in a 55% reduction of low-density lipoprotein (LDL) cholesterol (from mean of 162 (SD 32) to 72 (20) mg/dl). For a comparable rate-pressure product, the average time to 1 mm ST-segment depression was 295 (112) s at baseline, 314 (149) s after placebo and 301 (131) s after atorvastatin, indicating that the ischaemic threshold was not significantly modulated after 4 weeks of atorvastatin treatment.There was also no significant change in global angina score or in time to maximal ST-segment depression.Conclusions — High-dose atorvastatin treatment for 4 weeks drastically reduced LDLcholesterol. However, the present study did not demonstrate a significant effect on the ischaemic threshold in patients with stable IHD already under treatment with anti-ischaemic agents.