Reduction In Serum Low-density Lipoprotein Cholesterol Research Articles

First Report of Inclisiran Utilization for Hypercholesterolemia Treatment in Real-world Clinical Settings in a Middle East Population

Inclisiran is the first small interfering RNA-based treatment approved for reducing pro-atherogenic lipoproteins in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of low-density lipoprotein cholesterol (LDL-C). We report the first evaluation of the effects of inclisiran in a Middle East population. We conducted a retrospective review of patients initiating inclisiran treatment at an outpatient diabetology, endocrinology, and cardiology center between May 2021 and December 2022. All patients followed up for 90 days or more, or with at least 1 lipid determination post initiation were included. Participants were categorized into primary prevention (n = 57) and secondary prevention (n = 89) groups according to previous atherosclerotic cardiovascular disease. Inclisiran was initiated in 146 patients; mean (SD) age was 54.8 (12.12) years, 82 patients (56.2%) were male, 28 patients (19.2%) had received a diagnosis of familial hypercholesterolemia, 89 patients (61%) had received a diagnosis of diabetes mellitus, and 35 patients (23.9%) had a statin intolerance. Median (interquartile range) follow-up was 137 (90 to 193) days. At 90 days, median (interquartile range) reductions in serum LDL-C and triglycerides were -37.9% (-9.5% to -51.2%) and -12.0% (-9.8% to -40.5%), respectively, in primary prevention and -54.1% (-17.1% to -71.4%) and -15.3% (-14% to -38.8%), respectively, in secondary prevention (all, P < 0.001). LDL-C goals were attained in 110 patients (75.3%). Nonattainment of LDL-C goal was attributed to system effect in 26 patients (72.2%), biological effect in 5 patients (13.9%), and discontinuation of treatment in 5 patients (13.9%). Therapy was well tolerated. This study is the first from the Middle East and North Africa region that reported the real-world efficacy and safety profile of inclisiran in a mixed-risk population of patients with heterozygous familial hypercholesterolemia and other non-familial hypercholesterolemia indications. Clinically meaningful and sustained reductions in pro-atherogenic lipids with good tolerability were observed after inclisiran initiation. Fewer AEs were reported in this predominantly Arabic population, consistent with previous safety reports for inclisiran. It is important to note that no patient stopped inclisiran treatment due to AEs. Strengths of our study included an optimal cohort, patient heterogeneity, and high retention. In addition, we were able to report mean robust effects of inclisiran and good medication tolerability, quite like randomized studies and open-label extension periods. Despite this, our study had some limitations, including selection bias due to the retrospective design and the absence of a comparative group.

Effectiveness and Safety of Lipid-Lowering Drug Treatments in Japanese Patients with Familial Hypercholesterolemia: Familial Hypercholesterolemia Expert Forum (FAME) Study.

Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein (LDL)-cholesterol (LDL-C), tendon and skin xanthomas, and premature coronary artery disease (CAD). In Japan, detailed information on the current status of drug therapies for patients with FH has not been reported so far, and their efficacy and safety have not been clarified. After the introduction of ezetimibe, which can further reduce serum LDL-C levels on top of statins, the changes of management for FH patients with these drugs are of particular interest. The current study aimed to evaluate the clinical status of FH heterozygotes and homozygotes, especially focusing on the real-world lipid-lowering drug therapy, attained serum LDL-C levels, and cardiovascular events at registration and during the follow-up. Methods: The FAME Study enrolled 762 heterozygous (including 17 newly diagnosed cases) and 7 homozygous FH patients from hospitals and clinics nationwide. Diagnosis of FH was based upon the criteria defined in the Study Report in 2008 of the Research Committee on Primary Hyperlipidemia supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare. Data analysis was primarily carried on heterozygous FH patients. Results: Xanthoma or thickening of the Achilles tendon was observed in more than 80% of the patients. CAD was recorded in 23% of patients. Patients with parental and sibling CAD accounted for 47% and 24%, respectively. At baseline, patients without CAD who had LDL-C ＜100 mg/dL accounted for 12.3% and those with CAD who had attained the target (LDL-C ＜70 mg/dL) in the secondary prevention accounted for only 1.8%. In the multiple logistic analysis, male sex, age ＞40, heterozygous FH score ＞20, hypertension, and sibling CAD were significantly and positively associated with prevalent CAD, whereas serum HDL-cholesterol levels showed a significant inverse association with CAD. Patients treated with statin alone, statin＋ezetimibe, statin＋resin, or statin＋probucol accounted for 31.1%, 26.3%, 4.0%, and 3.7%, respectively. Patients treated with three-drug combination (statin＋ezetimibe＋resin or statin＋ezetimibe＋probucol) accounted for 7.5%. Statins and ezetimibe were used in 88.0% and 48.0% at the baseline, respectively. Although high-intensity statins were mainly prescribed, statin doses were much lower than those reported in Western countries. The addition of ezetimibe resulted in ~20% reduction in serum LDL-C. CAD was diagnosed in 17 patients with 21 episodes during follow-up. The Cox hazard model analysis demonstrated that male sex, CAD at the baseline, and parental CAD were related to the development of atherosclerotic cardiovascular disease (ASCVD) events. Furthermore, an increase in serum HDL-C was associated with a significant reduction of ASCVD events, while serum LDL-C and triglyceride levels were not related to ASCVD events. Conclusion: The prevalence of CAD in Japanese patients with heterozygous FH is still very high. In most of the cases, the target level of serum LDL-C was not achieved for primary and secondary prevention of CAD, suggesting that a more aggressive LDL-C lowering and appropriate management of residual risks are necessary.

A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9

PurposeAT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations.MethodsThis phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77–196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks.ResultsThe most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was −7.2% (95% CI [−10.4 to −3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%.ConclusionsAlthough both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development.Trial registrationEudraCT: 2015-001719-11. ClinicalTrials.govIdentifier: NCT02508896.

Hypocholesterolaemic action of Lactobacillus plantarum VJC38 in rats fed a cholesterol-enriched diet

This study was conducted to evaluate hypocholesterolaemic activity of probiotic strains Lactobacillus plantarum VJC38 and VJI21 in Wistar albino rats fed a cholesterol-enriched diet. The experimental animals were divided into five groups (n = 6) viz., normal diet control group (NDC), hypercholesterolaemic diet (HD) control group (HDC), HD supplemented with 3 × 108 CFU/ml of L. plantarum VJC38 group (HD-C38), HD supplemented with 3 × 108 CFU/ml of L. plantarum VJI21 group (HD-I21), and HD supplemented with 3 × 108 CFU/ml of L. rhamnosus GG group (HD-GG) as positive control. Animals were administered bacterial culture by oral gavage once daily for 45 days. After trial, animals were sacrificed and blood samples were collected. Serum total cholesterol (T-CHO), triglyceride (TG), high-density lipoprotein (HDL) cholesterol, glucose, glutamyl pyruvate transaminase (GPT), and glutamyl oxaloacetate transaminase (GOT) levels were determined. Serum low-density lipoprotein (LDL) cholesterol levels were estimated using the Friedewald’s equation. Liver and fecal lipid contents and fecal cholic acids were measured. Serum T-CHO levels were significantly decreased by 15.6 and 17.4% in the HD-GG and HD-C38 groups, respectively, but not in the HD-I21 group compared with HDC group (P < 0.05). HD-GG and HD-C38 groups showed 26.3 and 27.2% reduction in serum LDL cholesterol, respectively when compared with HDC group (P < 0.05). Serum LDL cholesterol levels in HD-I21 group were not significantly different from HDC group. Serum TG levels in the HD-GG and HD-C38 were decreased by 14.2 and 22.8%, respectively compared with HDC group (P < 0.05). Liver T-CHO and TG levels in the HD-GG, HD-C38, and HD-I21 were reduced significantly compared with the HDC group (P < 0.05). Atherogenic coefficient values of HD-GG, HD-C38, and HD-21 were significantly decreased compared with HDC group (P < 0.05). Serum GPT levels in the HD-GG, HD-C38, and HD-I21 were decreased by 20.6, 10.9, and 20.6%, respectively, vs. the HDC group. Serum GOT levels were not significantly different among the groups. Serum glucose levels were significantly low in HD-GG, HD-C38, and HD-I21 compared with HDC group (P < 0.05). Fecal cholesterol and cholic acid levels were significantly higher in the HD-C38 and HD-GG groups than other groups (P < 0.05). This study suggests that L. plantarum VJC38 exhibits hypocholesterolaemic effect through hydrolysis of conjugated bile acids in the small intestine and excretion of cholesterol in feces. Lactobacillus plantarum VJC38 could be used as a potential cholesterol-lowering probiotic after validation of the hypocholesterolaemic activity in placebo-controlled human clinical trials.

Proprotein convertase subtilisin/kexin type 9 inhibitors for reduction of cardiovascular events.

The efficacy, safety, and place in therapy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for lipid lowering are reviewed. PCSK9 inhibitors are injectable monoclonal antibodies that increase the availability of low-density lipoprotein (LDL) receptors, resulting in a reduction in serum LDL cholesterol (LDL-C). The currently available PCSK9 inhibitors alirocumab and evolocumab were shown to reduce LDL-C concentrations by approximately 55-60% relative to placebo use when used as monotherapy or added to other lipid-lowering therapies. A large randomized controlled trial of evolocumab demonstrated a reduction in cardiovascular events that translated to a 16% relative risk reduction per 1-mmol/L (39-mg/dL) reduction in LDL-C over 2 years, nearly identical to risk reductions reported with use of statins for LDL-C lowering. Another large outcome trial with alirocumab is ongoing. PCSK9 inhibitors are well tolerated, and minor injection-site reaction is the only known adverse effect. Routine use of these agents in all patients with cardiovascular disease is not cost-effective at the current annual cost of therapy of approximately $14,000 in the United States and $7,000 in other Western countries. Careful patient selection may increase the benefit-to-cost ratio of these agents. The PCSK9 inhibitors alirocumab and evolocumab, as adjuncts to oral lipid-lowering agents or as monotherapy, lower serum LDL-C concentrations and reduce the risk of cardiovascular events. These agents are safe and well tolerated, but high cost and lack of cost-effectiveness limit their routine use.

Influence of Chitosan Treatment on Surrogate Serum Markers of Cholesterol Metabolism in Obese Subjects.

Chitosan treatment results in significantly lower serum low density lipoprotein (LDL) cholesterol concentrations. To assess the working mechanisms of chitosan, we measured serum surrogate markers of cholesterol absorption (campesterol, sitosterol, cholestanol), synthesis (lathosterol, lanosterol, desmosterol), and degradation to bile acids (7α-hydroxy-cholesterol, 27-hydroxy-cholesterol), corrected for cholesterol concentration (R_sterols). Over 12 weeks, 116 obese subjects (Body Mass Index, BMI 31.7, range 28.1–38.9 kg/m2) were studied under chitosan (n = 61) and placebo treatments (n = 55). The participants were briefly educated regarding improvement of nutrition quality and energy expenditure. Daily chitosan intake was 3200 mg. Serum LDL cholesterol concentration decreased significantly more (p = 0.0252) under chitosan (−8.67 ± 18.18 mg/dL, 5.6%) than under placebo treatment (−1.00 ± 24.22 mg/dL, 0.9%). This reduction was not associated with the expected greater decreases in markers of cholesterol absorption under chitosan treatment. Also, increases in markers of cholesterol synthesis and bile acid synthesis under chitosan treatment were not any greater than under placebo treatment. In conclusion, a significant selective reduction of serum LDL cholesterol under chitosan treatment is neither associated with a reduction of serum surrogate markers of cholesterol absorption, nor with increases of markers for cholesterol and bile acid synthesis.

Low-density lipoprotein cholesterol lowering by adding ezetimibe to statin is associated with improvement of postprandial hyperlipidemia in diabetic patients with coronary artery disease

Objective and methodsWe investigated the hypothesis that serum low-density lipoprotein cholesterol (LDL-C) reduction by ezetimibe is associated with the improvement in postprandial hyperlipidemia by performing an oral fat loading test before and 24weeks after ezetimibe treatment in diabetic (n=29) and non-diabetic (n=30) male patients with coronary artery disease (CAD). ResultsSerum LDL-C levels were significantly reduced by ezetimibe in both groups (diabetic, from 120.3±39.4 to 79.5±23.2mg/dL, p<0.001; non-diabetic, from 98.2±41.7 to 76.7±29.2mg/dL, p<0.001), and the mean reduction in serum LDL-C was greater in diabetic than non-diabetic patients (−32.0 vs. −19.0%, p=0.004). The area under the curve (AUC) for triglyceride (TG) and remnant-like particle cholesterol (RLP-C) decreased significantly in both groups. When compared with the reduction before and after treatment in AUC of TG (∆AUC0–6h TG) and RLP-C (∆AUC0–6h RLP-C), they were significantly greater in diabetic than non-diabetic patients (∆AUC0–6h TG, −28.9 vs. −12.2%, p=0.028; ∆AUC0–6h RLP-C, −27.8 vs. −12.3%, p=0.007). In diabetic patients, ∆AUC0–6h TG and ∆AUC0–6h RLP-C in the highest tertile of serum LDL-C reduction were significantly greater than those in the lowest tertile (∆AUC0-6h TG, −34.1 vs. −20.9%, p=0.012; ∆AUC0-6h RLP-C, −34.5 vs. −15.1%, p=0.024). ConclusionsThese findings suggest that serum LDL-C reduction by ezetimibe might be associated with the improvement of postprandial hyperlipidemia in diabetic patients with CAD.

Potential protective effects of Nigella sativa and Allium sativum against fructose-induced metabolic syndrome in rats.

Among famous medicinal plants with known antioxidant activity; black seed (Nigella sativa, NS) and garlic (Allium sativum) which have been used in traditional medicine. In recent years, rates of metabolic syndrome (MS) have been increasing globally. The present work was designed to study the potential protective effects of black seed and raw garlic homogenate against fructose-induced MS in rats and to assess the benefits gained from their combination. Fifty male albino Wistar rats were divided into 5 groups. A control group was allowed to feed on normal chow and drink tap water. MS group was fed the same diet plus 10% fructose in drinking water. Treated groups received NS or garlic either alone or in combination as oral supplements along with high fructose diet for 8 weeks. Results revealed that body weight, liver weight, fasting blood glucose, serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were significantly increased while high density lipoprotein cholesterol (HDL-C) and the activities of Lactate dehydrogenase (LDH), glucose -6-phosphate dehydrogenase (G-6-PHD) and catalase in liver tissues were significantly decreased in MS group compared to the control group. Administration of NS or garlic either alone or in combination significantly ameliorated all the above-mentioned altered parameters. Treatment with both NS and garlic showed the utmost reduction in serum LDL-C and TG levels and could restore the activities of the studied enzymes in liver nearly to normal values. It was concluded that both NS and garlic were effective in attenuating multiple abnormalities of MS. Combination of these medicinal plants may have additional effectiveness in reducing serum TC, LDL-C and increasing HDL-C levels which could be a step in the prevention and management of MS.

Harnessing a Physiologic Mechanism for siRNA Delivery With Mimetic Lipoprotein Particles

Therapeutics based on RNA interference (RNAi) have emerged as a potential new class of drugs for treating human disease by silencing the target messenger RNA (mRNA), thereby reducing levels of the corresponding pathogenic protein. The major challenge for RNAi therapeutics is the development of safe delivery vehicles for small interfering RNAs (siRNAs). We previously showed that cholesterol-conjugated siRNAs (chol-siRNA) associate with plasma lipoprotein particles and distribute primarily to the liver after systemic administration to mice. We further demonstrated enhancement of silencing by administration of chol-siRNA pre-associated with isolated high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In this study, we investigated mimetic lipoprotein particle prepared from recombinant apolipoprotein A1 (apoA) and apolipoprotein E3 (apoE) as a delivery vehicle for chol-siRNAs. We show that apoE-containing particle (E-lip) is highly effective in functional delivery of chol-siRNA to mouse liver. E-lip delivery was found to be considerably more potent than apoA-containing particle (A-lip). Furthermore, E-lip–mediated delivery was not significantly affected by high endogenous levels of plasma LDL. These results demonstrate that E-lip has substantial potential as delivery vehicles for lipophilic conjugates of siRNAs.

Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia

ABSTRACT Statins effectively reduce levels of serum cholesterol and lower the risk of cardiovascular disease, but have limited effectiveness if stringent goals for serum low-density lipoprotein (LDL) cholesterol levels are not met or adverse effects develop, requiring a dose reduction or drug discontinuation. Previous studies have shown that thyroid hormone and some of its metabolites reduce levels of serum LDL cholesterol and have potentially favorable actions on other lipoproteins. The studies were discontinued because of reports of adverse effects on heart and bone, and possible deaths. In a recent report, eprotirome, a thyromimetic compound with minimal uptake in nonhepatic-tissues, was shown to reduce levels of serum total and LDL cholesterol and apolipoprotein B without apparent side effects in patients not receiving statin therapy. This randomized, placebo-controlled, double-blind, multicenter trial investigated the safety and efficacy of eprotirome in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who already were receiving simvastatin or atorvastatin. The aim of the study was to determine whether adding eprotirome to statin therapy would provide additional lipid-lowering actions without producing adverse extrahepatic thyromimetic effects. Patients were randomly assigned to receive daily oral doses of 25, 50, or 100 mcg of eprotirome or a placebo for 12 weeks. The primary study outcome was changes in serum LDL cholesterol. The potential adverse thyromimetic effects on the heart, bone, and pituitary were examined. Treatment of patients for 12 weeks already receiving statins with either placebo or eprotirome at a dose of 25, 50, or 100 μg reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) at baseline to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively; this represented a mean reduction from baseline of 7%, 22%, 28%, and 32%, respectively. Similar reductions were found in the secondary study outcomes, which included serum levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. No evidence of adverse effects of eprotirome on the heart, bone, or pituitary was noted. Although reductions in serum levels of thyroxine occurred in some patients who received eprotirome, there were no changes in levels of thyrotropin or triiodothyronine. These findings demonstrate that the addition of eprotirome to statin therapy produces substantial further reductions in serum LDL cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B. The drug appears to have an excellent safety profile.

Effect of Raloxifene on Serum Lipids for Type 2 Diabetic Menopausal Women with or without Statin Treatment

Objective: Our aim was to investigate the effect of 1-year treatment with raloxifene, a selective estrogen receptor modulator, on plasma lipid profiles in Japanese postmenopausal type 2 diabetic patients. Subjects and Methods: A total of 43 Japanese women with postmenopausal osteoporosis and type 2 diabetes with serum low-density lipoprotein cholesterol (LDL-C) <3.59 mmol/l, serum triglyceride <1.68 mmol/l and serum high-density lipoprotein cholesterol (HDL-C) >1.03 mmol/l, who took 60 mg/day of raloxifene for 12 months, were enrolled. For analysis, they were divided into 2 groups: nonhyperlipidemia (n = 23) and hyperlipidemia treated with statin (n = 20). Results: Raloxifene treatment significantly induced a mean reduction in serum LDL-C from 2.90 to 2.36 and 2.67 mmol/l in the nonhyperlipidemia and statin-treated group, respectively. However, the reduction ratio of serum LDL-C showed a significant difference in the nonhyperlipidemia group (17%) compared to the statin-treated group (7%; p = 0.03). Although serum HDL-C showed an increase in both groups (from 1.45 to 1.58 vs. from 1.40 to 1.47 mmol/l), the increase ratio of serum HDL-C was not significant between the two groups. Raloxifene administration showed 15% reduction in the nonhyperlipidemia group (p = 0.02) and 13% reduction in the statin-treated group (p = 0.02) of urinary N-telopeptide of type I collagen. No significant change in blood HbA_1c was observed in either group. Conclusion: The administration of raloxifene to type 2 diabetic women showed favorable efficacy on serum lipid profiles, particularly in patients without statin treatment.

Early Improvements in insulin sensitivity and inflammatory markers are induced by pravastatin in nondiabetic subjects with hypercholesterolemia

Background Statins may improve lipid profiles and inflammation-associated biomarkers, but the effect on insulin sensitivity is controversial. We investigated the effects of 2 doses of pravastatin (40 and 10 mg/day) on insulin sensitivity and serum inflammatory markers in nondiabetic hypercholesterolemic patients. Methods This was a randomized, parallel, comparative design study. A total of 40 nondiabetic subjects with elevated low-density lipoprotein (LDL) cholesterol were randomized to either the 40 mg pravastatin/day group ( n = 21) or the 10 mg pravastatin/day group ( n = 19) for 8 weeks. The fasting serum lipid profile, homeostasis model assessment (HOMA), glucose and insulin response of the two-hour glucose tolerance test (2 h-OGTT), and several inflammatory markers were determined. Results Eight weeks of pravastatin treatment in both dose groups led to a significant reduction in serum LDL cholesterol, total cholesterol, triglycerides, and total cholesterol/ high-density lipoprotein (HDL) cholesterol ratios (all p < 0.01 in 40 mg group and all p < 0.05 in 10 mg group), though the 40 mg group had greater effects. Although the fasting HOMA insulin resistance did not change significantly in either group, glucose and insulin areas under the curve of 2 h-OGTT were significantly decreased, suggesting improvement in insulin sensitivity post glucose challenge. Serum CD-40 ligand concentration was significantly reduced in the 40 mg pravastatin/day group and soluble P-selectin significantly reduced in both groups. Conclusions Pravastatin treatment, at 10 mg or 40 mg daily for 8 weeks, reduced serum lipids and some inflammatory markers in nondiabetic hypercholesterolemic subjects. Furthermore, insulin resistance was improved even in short-term treatment by pravastatin.

Effectiveness and Safety of Ezetimibe Added to Statin Therapy in??Patients with Primary Dyslipidaemia not Achieving the LDL-C??Treatment Goal??on Statin Monotherapy

Elevated serum low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor. This study aimed to determine the efficacy and safety of co-administration of the cholesterol absorption inhibitor ezetimibe with an HMG-CoA reductase inhibitor (statin) in the treatment of Mexican patients with dyslipidaemia who had not attained the LDL-C treatment goal with statin monotherapy. We studied 256 patients with elevated serum LDL-C (as defined by the US National Cholesterol Education Program Adult Treatment Panel III guidelines) despite statin therapy. All patients had lipid profiles performed at baseline and after 6-8 weeks of treatment with statin therapy plus ezetimibe 10 mg/day for 6-8 weeks. Addition of ezetimibe to statin treatment reduced mean serum LDL-C levels significantly (from 160 +/- 42.8 to 100 +/- 36 mg/dL; p<0.001) after 6-8 weeks of treatment, with 61.7% of patients achieving LDL-C values below the goal established according to their coronary risk group. Serum LDL-C goals were achieved at the end of the study in 88.2% of the low-risk coronary group, 75.7% of the moderate-risk group and 47.8% of the high-risk group. Ezetimibe was well tolerated; no hepatic or muscle-related adverse events were observed. Addition of ezetimibe to statin treatment was both efficacious and safe when used for further reduction of serum LDL-C in dyslipidaemic patients who had not reached their LDL-C treatment goal while taking statin monotherapy.

Effect of statins on mortality and cardiovascular events in elderly high-risk persons.

Review of: MRC/BHF Heart Protection Study of Cholesterol Lowering with Simvastatin in 20,536 High-Risk Individuals: a Randomized Placebo-Controlled Trial. Lancet 2002;360:7–22. PURPOSE: To determine the effect of simvastatin 40 mg daily versus placebo on all-cause mortality and cardiovascular events in high-risk persons with serum total cholesterol levels of 135 mg/dL or greater. BACKGROUND: Pooled data from three secondary prevention trials of patients with coronary artery disease (CAD) and two primary prevention studies showed that treatment of hypercholesterolemia with statins caused a 31% reduction in major coronary events (95% confidence interval (CI) = 26–36%) and a 21% reduction in all-cause mortality (95% CI = 14–28%).1 The secondary prevention trials included 4,444 persons (23% aged 65–70) treated with simvastatin in the Scandinavian Simvastatin Survival Study,2,3 4,159 persons (31% aged 65–75) treated with pravastatin in the Cholesterol and Recurrent Events Trial,4–6 and 9,014 persons (39% aged 65–75) treated with pravastatin in the long-term Intervention with Pravastatin in Ischaemic Disease Trial.7 The two primary prevention studies included 6,595 middle-aged men up to 64 years of age treated with pravastatin in the West of Scotland Coronary Prevention Study8 and 6,605 persons (22% aged 65–73) treated with lovastatin in the Air Force/Texas Coronary Atherosclerosis Prevention Study.9 The absolute risk reduction in major coronary events per 1,000 persons treated in these five studies was 33 (13–52) for women versus 37 (29–44) for men and 44 (30–58) for persons aged 65 and older versus 32 (24–40) for younger persons.1 METHODS: The Heart Protection Study included 20,536 persons (15,454 men and 5,082 women) aged 40 to 80 (5,806 aged 70–80) with serum total cholesterol of 135 mg/dL or greater and prior myocardial infarction (MI) (8,510 persons), other CAD (4,876 persons), or no CAD (7,150 persons). Of the 7,150 participants without CAD, 1,820 had cerebrovascular disease, 2,701 had peripheral arterial disease (PAD), and 3,982 had diabetes mellitus. Although treated hypertension was present in 8,457 persons, only 237 persons were included on the basis of hypertension alone. Patients were randomized to simvastatin 40 mg daily or double-blind placebo. Mean follow-up was 5 years. Average compliance was 85% for the simvastatin-treated group, and 17% of the placebo group took a statin during the 5-year study. RESULTS: During the 5-year study, simvastatin reduced serum total cholesterol 46 mg/dL, serum low-density lipoprotein (LDL) cholesterol 39 mg/dL, and serum triglycerides 12 mg/dL and increased serum high-density lipoprotein (HDL) cholesterol 1 mg/dL Simvastatin caused a 13% reduction in all-cause mortality (95% CI = 6–19%), a 17% reduction in any vascular death (95% CI = 9–25%), a 27% reduction in major coronary events (95% CI = 21–33%), a 25% reduction in any stroke (95% CI = 15–34%), a 24% reduction in coronary or noncoronary revascularization (95% CI = 17–30%), and a 24% reduction in any major vascular event (95% CI = 19–28%). Simvastatin significantly reduced the first major vascular event in patients with MI, other CAD, or no CAD; in patients with cerebrovascular disease, PAD, diabetes mellitus, treated hypertension, or no hypertension; in men and in women; in patients aged 40 to 64, 65 to 69, and 70 to 80; in patients with low or high serum total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides; in smokers and nonsmokers; and in patients treated with and without aspirin, beta blockers, and angiotensin-converting enzyme inhibitors. In the 3,500 persons with an initial serum LDL cholesterol of less than 100 mg/dL, reduction of serum LDL cholesterol from 97 mg/dL to 65 mg/dL by simvastatin caused a similar reduction in risk, as did treating patients with higher serum LDL cholesterol levels. Five years of simvastatin therapy prevented MI, stroke, and revascularization in 70 to 100 per 1,000 treated patients. CONCLUSION: In patients with serum total cholesterol of 135 mg/dL or higher at high risk for vascular events, simvastatin 40 mg daily significantly reduced all-cause mortality, vascular death, major coronary events, coronary or noncoronary revascularization, and any major vascular event regardless of initial levels of serum lipids, age, or gender.

Effects of D-003 on the Lipid Profile???of Patients with Type???II Hypercholesterolaemia

D-003 is a cholesterol-lowering agent that is isolated and purified from sugarcane wax and has concomitant antiplatelet effects. To evaluate lipid profile responses to different doses of D-003 in patients with type II hypercholesterolaemia. An 8-week, double-blind, placebo-controlled, parallel-group clinical study. After concluding a 5-week diet-only baseline period, 55 patients were randomly allocated to receive either placebo or D-003 at 5, 10, 20 or 40mg once daily with their evening meal for 8 weeks. An interim check-up was performed at week 4. The primary efficacy variable was the reduction of serum low-density lipoprotein-cholesterol (LDL-C) from baseline compared with placebo. Drug safety and tolerability were assessed on the basis of changes in physical, haematological and blood biochemical indicators and on questioning about adverse experiences (AEs). After 8 weeks of therapy, D-003 significantly lowered (p < 0.0001 vs baseline and placebo) serum LDL-C in a dose-related manner, with reductions of 20.5-26.1% from the lowest to the highest dose investigated. At study completion, 43 of 44 (97.7%) randomised patients treated with D-003 reached LDL-C reductions >15% compared with baseline, while 30 of 44 patients (68.2%) reached LDL-C targets according to their individual global coronary risk status. Decreases in total cholesterol (TC) and the ratios of TC/high-density lipoprotein-cholesterol (HDL-C) and LDL-C/HDL-C were also significant (p < 0.0001) and dose related. Changes in LDL-C, TC and both ratios were significant from the interim check-up. D-003 significantly increased HDL-C values (11.7-16.7%), but the increase was not dose related. No significant changes in lipid profile variables were observed with placebo. D-003 was well tolerated. The treatment did not affect any physical, haematological or blood safety indicators. All included patients completed the study. Four patients reported mild AEs during the study: headache (one patient treated with placebo and one treated with D-003 20 mg/day), insomnia (one patient treated with D-003 5 mg/day) and polyuria (one patient treated with D-003 40 mg/day). D-003 was effective in dose dependently reducing LDL-C in patients with type II hypercholesterolaemia, as documented by average percentage reductions and the percentage of patients achieving decreases >15% from baseline and LDL-C goals. The treatment was well tolerated by patients and did not affect any safety indicator. Further studies corroborating these results and exploring the effect of lower doses of D-003 and a longer treatment duration must be carried out, however, before definitive conclusions can be reached. These results encourage continuing clinical investigation on this drug.

The magnitude of the hypercholesterolemia of hypothyroidism is associated with variation in the low density lipoprotein receptor gene.

To assess whether the variable extent to which patients with hypothyroidism become hypercholesterolemic was associated with variation in the genes for the low density lipoprotein (LDL) receptor or apolipoprotein-B, we investigated prospectively 52 patients with primary hypothyroidism treated with L-T4. There was significant reduction in cholesterol, high density lipoprotein cholesterol, LDL cholesterol, and apolipoprotein-A1 and -B after thyroid hormone replacement. The reduction in cholesterol was associated significantly with the magnitude in the reduction of serum TSH levels (P < 0.001) and the variable AvaII restriction site in exon 13 of the LDL receptor gene. For a given reduction in TSH, patients of genotype -/- (no restriction site) demonstrated a reduction in serum LDL cholesterol that was 4-fold greater than that of patients homozygous for the AvaII restriction site (genotype +/+), with heterozygous (+/-) patients showing an intermediate response. The hypocholesterolemic response was significantly greater in patients of the -/- genotype than in patients carrying the +allele (genotypes +/- and +/+; for LDL cholesterol, P < 0.01; for cholesterol, P < 0.05). No such relationship was observed with a variation at any other polymorphic site studied (four in the LDL receptor gene and two in the apolipoprotein-B gene). The magnitude of the decrease in high density lipoprotein cholesterol and apolipoprotein-A1 and -B was independent of the AvaII genotype, the effect of which was specific to LDL cholesterol. Variation within the LDL receptor gene appears to influence the magnitude of both the hypercholesterolemia of hypothyroidism and, consequently, the reduction of serum LDL cholesterol in response to L-T4. Thus, it may be possible to predict which hypothyroid patients are at greatest risk for coronary artery disease.