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Background: Dimethandrolone (DMA) and 11β-methyl-19-nortestosterone (11β-MNT) are two novel compounds with both androgenic and progestational activity that are under investigation as potential male hormonal contraceptives. Their metabolic effects have never been compared in men., Objective: Assess for changes in insulin sensitivity and adiponectin and compare the metabolic effects of these two novel androgens., Materials/methods: In two clinical trials of DMA undecanoate (DMAU) and 11β-MNT dodecylcarbonate (11β-MNTDC), oral prodrugs of DMA and 11β-MNT, healthy men received drug, or placebo for 28 days. Insulin and adiponectin assays were performed on stored samples. Mixed model analyses were performed to compare the effects of the two drugs. Student's t test, or the non-parametric Kruskal-Wallis test as appropriate, was used to evaluate for an effect of active drug versus placebo., Results: Class effects were seen, with decrease in HDL-C and SHBG, and increase in weight and hematocrit, with no statistically significant differences between the two compounds. No changes in fasting glucose, fasting insulin, or HOMA-IR were seen with either compound. There was a slight decrease in adiponectin with DMAU that was not seen with 11β-MNTDC. An increase in LDL-C was seen with 11β-MNTDC but not with DMAU., Discussion: There were no significant changes in insulin resistance after 28 days of oral administration of these novel androgens despite a mild increase in weight. There may be subtle differences in their metabolic impacts that should be explored in future studies., Conclusion: Changes in metabolic parameters should be carefully monitored when investigating androgenic compounds., (© 2021 American Society of Andrology and European Academy of Andrology.)

Background It is unclear if statin therapy in midlife can restore low cardiovascular risk in hypercholesterolemic individuals. Methods and Results At baseline, we grouped 5687 MESA (Multi-Ethnic Study of Atherosclerosis) participants aged ≥50 years without clinical cardiovascular disease (CVD) by Adult Treatment Panel III statin treatment recommendation and statin treatment status. We used Cox regression to compare the risks for coronary heart disease and CVD between the untreated group with low-density lipoprotein cholesterol (LDL-C) <100 mg/dL (reference) and other groups, adjusting for CVD risk factors. We also grouped participants by LDL-C level (< or ≥100 mg/dL), coronary artery calcium score (0 or >0 Agatston units), and statin status (untreated or treated) with the untreated LDL-C <100 mg/dL and coronary artery calcium=0 Agatston units as the reference. There were 567 coronary heart disease and 848 CVD events over 15 years of follow-up. The hazard ratios (HRs) for coronary heart disease and CVD in the group with statin-treated LDL-C <100 mg/dL were 1.16 (95% CI, 0.85-1.58) and 1.02 (95% CI, 0.78-1.32), respectively. However, participants with coronary artery calcium >0 Agatston units, treated to LDL-C <100 mg/dL had HRs of 2.6 (95% CI, 1.7-4.2) for coronary heart disease and 1.8 (95% CI, 1.2-2.6) for CVD. Conclusions Individuals treated with statins to LDL-C <100 mg/dL had similar levels of risk for atherosclerotic CVD as individuals with untreated LDL-C <100 mg/dL. However, individuals with coronary artery calcium >0 Agatston units have substantially higher risks despite lipid-lowering therapy, suggesting that statin treatment in midlife may not restore a low-risk state in primary prevention patients with established coronary atherosclerosis.

Background Few adults at high risk for atherosclerotic cardiovascular disease events use a PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitor). Methods and Results Using data from the US Veterans Health Administration, we identified veterans who initiated a PCSK9i between January 2018 and December 2019, matched 1:4 to veterans who did not initiate this medication over this time period (case-cohort study). Two cohorts of veterans were analyzed: (1) atherosclerotic cardiovascular disease, with a most recent low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL; and (2) severe hypercholesterolemia (ie, familial hypercholesterolemia or any prior LDL-C ≥190 mg/dL, with most recent LDL-C ≥100 mg/dL). Conditional logistic regression was used to analyze factors associated with PCSK9i initiation, adjusting for all factors, simultaneously. There were 2394 initiators and 9576 noninitiators in the atherosclerotic cardiovascular disease cohort (median LDL-C, 141 and 96 mg/dL, respectively; P <0.001). Factors associated with a higher likelihood of PCSK9i initiation included age 65 to <75 versus <65 years, highest versus lowest quartile of median area-level income, familial hypercholesterolemia, former statin use, and current ezetimibe use. PCSK9i initiation was lower among veterans of a race/ethnicity other than non-Hispanic White. There were 245 initiators and 980 noninitiators in the severe hypercholesterolemia cohort (median LDL-C, 183 and 151 mg/dL, respectively; P <0.001). Age ≥75 versus <65 years, history of chronic kidney disease, former statin use, and current ezetimibe use were associated with a higher likelihood of PCSK9i initiation. Conclusions Several patient-level factors, including age, sex, and race/ethnicity, were significantly associated with PCSK9i initiation, suggesting an unmet treatment need in several patient groups.

Background The relationship between lowering LDL (low-density lipoprotein) cholesterol with contemporary lipid-lowering therapies and incident diabetes mellitus ( DM ) remains uncertain. Methods and Results Thirty-three randomized controlled trials (21 of statins, 12 of PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, and 0 of ezetimibe) were selected using Medline , Embase, and the Cochrane Central Register of Controlled Trials (inception through November 15, 2018). A total of 163 688 nondiabetic patients were randomly assigned to more intensive (83 123 patients) or less intensive (80 565 patients) lipid-lowering therapy. More intensive lipid-lowering therapy was defined as the more potent pharmacological strategy ( PCSK 9 inhibitors, higher intensity statins, or statins), whereas less intensive therapy corresponded to active control group or placebo/usual care of the trial. Metaregression and meta-analyses were conducted using a random-effects model. No significant association was noted between 1-mmol/L reduction in LDL cholesterol and incident DM for more intensive lipid-lowering therapy (risk ratio: 0.95; 95% CI , 0.87-1.04; P=0.30; R 2 =14%) or for statins or PCSK 9 inhibitors. More intensive lipid-lowering therapy was associated with a higher risk of incident DM compared with less intensive therapy (risk ratio: 1.07; 95% CI , 1.03-1.11; P<0.001; I 2 =0%). These results were driven by higher risk of incident DM with statins (risk ratio: 1.10; 95% CI , 1.05-1.15; P<0.001; I 2 =0%), whereas PCSK 9 inhibitors were not associated with incident DM (risk ratio: 1.00; 95% CI , 0.93-1.07; P=0.96; I 2 =0%; P=0.02 for interaction). Conclusions Among intensive lipid-lowering therapies, there was no independent association between reduction in LDL cholesterol and incident DM . The risk of incident DM was higher with statins, whereas PCSK 9 inhibitors had no association with risk of incident DM .

There is now significant evidence for the benefits of lowering low-density lipoprotein cholesterol (LDL-c) to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Although statins are the most widely prescribed lipid-lowering therapy that effectively lower LDL-c, especially in combination with ezetimibe, some patients require adjunctive therapy to further lower LDL-c and mitigate attendant risk of ASCVD. The gap can be filled by proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies whose use is currently supported by two recent cardiovascular outcome studies and new treatment guidelines. We provide an overview of extant studies investigating PCSK9 monoclonal antibodies in various patient populations, an update of the guidelines regarding their use and a case-based discussion., (© 2019 John Wiley & Sons Ltd.)

Aim: To determine whether high triglycerides (TG) in the presence of statin-controlled LDL-C influence the risk of cardiovascular disease (CVD) among patients with diabetes in real-world clinical practice., Materials and Methods: We identified adults with diabetes from the Southern California and Pacific Northwest regions of Kaiser Permanente. We included patients undergoing statin therapy with LDL-C from 40-100 mg/dL who were not undergoing other lipid-lowering therapies and had a prior diagnosis of atherosclerotic CVD or at least one other CVD risk factor. We grouped patients into high TG (200-499 mg/dL; n = 5542) or normal TG (<150 mg/dL, n = 22 411) from January 2010 through December 2016 to compare incidence rates and rate ratios of first non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina and coronary revascularization. We adjusted multivariable analyses for age, sex, race/ethnicity, smoking status, blood pressure, HbA1c, serum creatinine, presence of ischaemic heart disease and study site., Results: Adjusted rate ratios for the four outcomes were all statistically significantly different. The incidence rate for non-fatal MI was 30% higher in the high TG group (rate ratio, 1.30; 95% CI, 1.08-1.58; P = 0.006). The rate was 23% higher for non-fatal stroke (1.23, 1.01-1.49, P = 0.037), 21% higher for coronary revascularization (rate ratio, 1.21; 95% CI, 1.02-1.43; P = 0.027) and was, non-significantly, 33% higher for unstable angina (rate ratio, 1.33; 95% CI, 0.87-2.03; P = 0.185)., Conclusions: Despite statin-controlled LDL-C levels, CV events were greater among patients with diabetes and high TG levels. Because we controlled for cardiometabolic risk factors, it is likely that the difference in TG levels contributed to the excess risk observed in patients with high TGs., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background Whether use of high-intensity statins is more important than achieving low-density lipoprotein cholesterol ( LDL -C) target remains controversial in patients with coronary artery disease. We sought to investigate the association between statin intensity and long-term clinical outcomes in patients achieving treatment target for LDL -C after percutaneous coronary intervention. Methods and Results Between February 2003 and December 2014, 1746 patients who underwent percutaneous coronary intervention and achieved treatment target for LDL -C (<70 mg/dL or >50% reduction from baseline level) were studied. We classified patients into 2 groups according to an intensity of statin prescribed after index percutaneous coronary intervention: high-intensity statin group (atorvastatin 40 or 80 mg, and rosuvastatin 20 mg, 372 patients) and non-high-intensity statin group (the other statin treatment, 1374 patients). The primary outcome was a composite of cardiac death, myocardial infarction, or stroke. Difference in time-averaged LDL -C during follow-up was significant, but small, between the high-intensity statin group and non-high-intensity statin group (59±13 versus 61±12 mg/dL; P=0.04). At 5 years, patients receiving high-intensity statins had a significantly lower incidence of the primary outcome than those treated with non-high-intensity statins (4.1% versus 9.9%; hazard ratio, 0.42; 95% confidence interval, 0.23-0.79; P<0.01). Results were consistent after propensity-score matching (4.2% versus 11.2%; hazard ratio, 0.36; 95% confidence interval, 0.19-0.69; P<0.01) and across various subgroups. Conclusions Among patients achieving treatment target for LDL -C after percutaneous coronary intervention, high-intensity statins were associated with a lower risk of major adverse cardiovascular events than non-high-intensity statins despite a small difference in achieved LDL -C level.

Background In statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/ dL low-density lipoprotein cholesterol ( LDL -C) reduction. We explored whether lower LDL -C levels and greater LDL -C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event ( MACE ) rates in women as well as men. Methods and Results Data pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on-treatment LDL -C and percentage LDL -C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL -C was 135 mg/dL (women) and 121 mg/dL (men). Average on-treatment LDL -C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on-treatment LDL -C <50 mg/dL. Each 39 mg/dL lower LDL -C was associated with a 33% and 22% lower risk of MACE in women ( P=0.0209) and men ( P=0.0307), respectively, with no significant between-sex difference ( P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL -C reduction, 24% ( P=0.1094) and 29% ( P=0.0125) lower MACE risk in women and men, respectively ( P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes. Conclusions The present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL -C lowering. Although women had slightly higher on-treatment LDL -C than men, both sexes showed a similar lower MACE risk with lower LDL -C.

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub-fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis., (© 2016 John Wiley & Sons Ltd.)

Background: Healthy People 2020 aim to reduce fatal atherosclerotic cardiovascular disease (ASCVD) by 20%, which translates into 310 000 fewer events annually assuming proportional reduction in fatal and nonfatal ASCVD. We estimated preventable ASCVD events by implementing the American College of Cardiology/American Heart Association (ACC/AHA) 2013 Cholesterol Guideline in all statin-eligible adults. Absolute risk reduction (ARR) and number needed-to-treat (NNT) were calculated., Methods and Results: National Health and Nutrition Examination Survey data for 2007-2012 were analyzed for adults aged 21 to 79 years and extrapolated to the US population. Literature-guided assumptions were used including (1) low-density lipoprotein cholesterol falls 33% with moderate-intensity statins and 51% with high-intensity statins; (2) for each 39 mg/dL decline in low-density lipoprotein cholesterol, 10-year ASCVD10 risk would fall 21% when ASCVD10 risk was ≥20% and 33% when ASCVD10 risk was <20%; and (3) either all statin-eligible untreated adults or all with ASCVD10 risk ≥7.5% would receive statins. Of 175.9 million adults aged 21 to 79 years not taking statins, 44.8 million (25.5%) were statin eligible. Treating all statin-eligible adults would prevent an estimated 243 589 ASCVD events annually (ARR 5.4%, 10-year NNT 18). Treating all statin-eligible adults with ASCVD10 risk ≥7.5% reduces the number treated to 32.2 million (28.2% fewer), whereas ASCVD events prevented annually fall only 10.5% to 217 974 (6.8% ARR, NNT 15)., Conclusions: Implementing the ACC/AHA 2013 Cholesterol Guideline in all untreated, statin-eligible adults could achieve ≈78% of the Healthy People 2020 ASCVD prevention goal. Most of the benefit is attained by individuals with 10-year ASCVD risk ≥7.5%., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Aims: To investigate the impact of intensive lipid-lowering with high-dose atorvastatin on the cardiovascular risk associated with individual metabolic syndrome components [high body mass index (BMI), elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, hypertension and elevated fasting glucose] in patients with coronary heart disease (CHD)., Methods: Patients with clinically evident, stable CHD and low-density lipoprotein (LDL) cholesterol <3.4 mmol/l (130 mg/dl) were randomized to double-blind therapy with atorvastatin 10 mg/day (n = 5006) or 80 mg/day (n = 4995) after an 8-week open-label run-in with atorvastatin 10 mg. The median follow-up was 4.9 years. The impact of individual metabolic syndrome risk factors was tested on the primary endpoint, which was the occurrence of a first major cardiovascular event., Results: On-treatment LDL cholesterol was 2.6 mmol/l (101 mg/dl) with atorvastatin 10 mg and 2.0 mmol/l (77 mg/dl) with atorvastatin 80 mg. Among patients receiving atorvastatin 10 mg, the presence of each individual metabolic syndrome component significantly increased the risk of major cardiovascular events compared with the absence of each (BMI, p = 0.014; triglycerides, p = 0.006; HDL cholesterol, p = 0.0006; hypertension, p < 0.0001; and fasting glucose p < 0.0001). In patients receiving atorvastatin 80 mg, elevated triglycerides and fasting glucose were no longer significant predictors of major cardiovascular events. The predictive power of hypertension on the risk of major cardiovascular events was reduced in patients treated with atorvastatin 80 mg, although it remained a significant predictor., Conclusions: Treatment with high-dose atorvastatin to a mean LDL cholesterol level of 2.0 mmol/l (77 mg/dl) considerably attenuated the predictive power associated with three metabolic syndrome components., (© 2015 John Wiley & Sons Ltd.)

Aims: The long-term efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, was evaluated over 104 weeks in patients aged 55-80 years with type 2 diabetes mellitus (T2DM) inadequately controlled on a stable antihyperglycaemic agent regimen., Methods: In this randomized, double-blind, phase III study, patients received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period (N = 714) and a 78-week extension period (n = 624). Efficacy endpoints at week 104 included change from baseline in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and systolic blood pressure, and percent change from baseline in body weight and fasting plasma lipids. Safety was assessed by adverse event (AE) reports., Results: At week 104, canagliflozin 100 and 300 mg were associated with reductions in HbA1c versus placebo (-0.32 and -0.43% vs 0.17%, respectively; overall mean baseline, 7.7%) and more patients achieved HbA1c <7.0% with canagliflozin 100 and 300 mg than with placebo (35.8 and 41.9% vs 20.3%, respectively). Reductions in FPG, body weight and systolic blood pressure, and increases in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were seen with canagliflozin compared with placebo. The overall incidence rates of AEs over 104 weeks were 88.0, 89.8 and 86.1% with canagliflozin 100 and 300 mg and placebo, respectively; serious AE rates were low across treatment groups. The incidence rates of urinary tract infections, genital mycotic infections and osmotic diuresis- and volume depletion-related AEs were higher with canagliflozin than with placebo., Conclusion: Canagliflozin improved glycaemic control, reduced body weight and systolic blood pressure, and was generally well tolerated in patients aged 55-80 years with T2DM over 104 weeks., (© 2014 John Wiley & Sons Ltd.)

Sevelamer is a calcium-free and metal-free phosphate-binding oral drug used in the management of hyperphosphataemia in chronic kidney disease. Preclinical and clinical trials have shown glucose and lipid-lowering effects of sevelamer, thereby giving rise to a potential role of the drug in the treatment of patients with type 2 diabetes. These 'novel' effects are most probably derived from the bile acid-binding properties of sevelamer. The proposed potential is supported by the approval of the bile acid sequestrant colesevelam in the United States for the treatment of type 2 diabetes and hypercholesterolaemia. This article offers a brief review on the effects of sevelamer and a perspective on the potential mechanisms behind the glucose-lowering effect of the drug., (© 2014 John Wiley & Sons Ltd.)

Rationale, Aims and Objectives: Measuring self-reported adherence may contribute to minimizing the risk of therapy failure. Hence, the main aim of the study was to assess the psychometric properties of the Czech version of Medication Adherence Report Scale (MARS-CZ) and its appropriateness for use in long-term statin therapy where goal levels of low-density lipoprotein cholesterol (LDL-c) should be achieved., Methods: Anonymous structured interview was performed to determine self-reported adherence by MARS-CZ in outpatients chronically treated with statins. At the same time, medication records were reviewed for inclusion of patients into groups of those who achieved and do not achieved LDL-c goal according to cardiovascular risk level. Reliability and validity of MARS-CZ were tested as well as the relationship between adherence and LDL-c goal achievement was examined., Results: A total of 136 (86.6%) patients completed the interview; mean age was 66.1 years; 49.3% were male. The mean score of MARS-CZ was 24.4 and showed positive skewing. Satisfactory internal consistency (Cronbach's α=0.54), strong test-retest reliability (r=0.83, P<0.001; intra-class correlation=0.63, 95% confidence interval: 0.35-0.81) and positive correlation with eight-item Morisky Medication Adherence Scale (r=0.62, P<0.001) were indicated. Low validity values were found between MARS-CZ and 12-item Short Form Health Survey mental and physical subscales. MARS-CZ score significantly correlated with LDL-c goal achievement (P<0.05) when all patients who achieved LDL-c goal (35%) reported high adherence to statin. MARS-CZ score also correlated with cardiovascular risk level and doctor's judgments on adjusting treatment targets for each patient., Conclusion: This study proved MARS-CZ as an acceptable self-reported adherence measure. In routine clinical practice, MARS-CZ could be helpful to reveal medication non-adherence before the alteration of drug regimen and thereby contributing to enhancement of statin therapy management., (© 2014 John Wiley & Sons, Ltd.)

Aims: The objective was to assess the consistency of effect of switching to ezetimibe/simvastatin 10/20 mg versus doubling the baseline statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg across subgroups of subjects with (n = 617) and without (n = 191) metabolic syndrome (MetS)., Methods: This was a post hoc analysis of a randomized, double-blind, 6-week study of adults 18-79 years with cardiovascular disease and diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. The percent change in LDL-C and other lipids was estimated within each subgroup separately. Safety and tolerability were assessed., Results: In subjects with MetS, percent changes in LDL-C and other lipids were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin, except high-density lipoprotein cholesterol and apolipoprotein (Apo) AI (mean percent changes in LDL-C were: -22.49% ezetimibe/simvastatin, -9.64% doubled baseline statin and -19.20% rosuvastatin). In subjects without MetS, percent changes in LDL-C, total cholesterol and Apo B were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin (mean percent changes in LDL-C were: -25.14% ezetimibe/simvastatin, -4.75% doubled baseline statin and -19.75% rosuvastatin). Safety profiles were generally similar., Conclusion: These results showed that switching to ezetimibe/simvastatin 10/20 mg was more effective at reducing LDL-C, total cholesterol and Apo B versus doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg regardless of MetS status. These results were generally similar to those of the full cohort., (© 2012 Blackwell Publishing Ltd.)

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme that impairs low-density lipoprotein cholesterol (LDL-C) clearance from the plasma by promoting LDL receptor degradation. Patients with familial hypercholesterolemia (FH) have reduced or absent LDL receptors and should therefore have elevated PCSK9 levels., Methods and Results: Fasting lipograms and PCSK9 levels were measured 51 homozygous FH (HoFH), 20 heterozygous FH (HeFH), and 20 normocholesterolemic control subjects. Levels were repeated following high-dose statin therapy. LDL-C levels were significantly higher in untreated HoFH (13.4±0.7 mmol/L) and HeFH patients (7.0±0.2 mmol/L) compared with controls (2.6±0.1 mmol/L) (P<0.01). Statin therapy decreased LDL-C levels from 13.4±0.7 to 11.1±0.7 mmol/L in HoFH and from 7.0±0.2 to 3.6±0.2 mmol/L in HeFH patients (P<0.01). PCSK9 levels were higher in untreated HoFH (279±27 ng/mL) and HeFH (202±14 ng/mL) than in controls (132±10 ng/mL) (both P<0.01). High-dose statin therapy increased PCSK9 levels from 279±27 to 338±50 ng/mL in HoFH, and significantly so in the HeFH patients from 202±14 to 278±20 ng/mL (P<0.01). Linear regression analysis showed a correlation between PCSK9 and LDL-C (r=0.6769; P<0.0001); however, this was eliminated following statin therapy (r=0.2972; P=0.0625)., Conclusions: PCSK9 levels are elevated in untreated FH patients, particularly in those with HoFH. High-dose statin therapy further increases PCSK9 levels. PCSK9 inhibitors might be a beneficial therapy for FH patients, even in those with HoFH.

Aim: Colesevelam lowers glucose and low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. This study examined the mechanisms by which colesevelam might affect glucose control., Methods: In this 12-week, randomized, double-blind, placebo-controlled study, subjects with type 2 diabetes and haemoglobin A(1c) (HbA(1c)) ≥7.5% on either stable diet and exercise or sulphonylurea therapy were randomized to colesevelam 3.75 g/day (n = 16) or placebo (n = 14). Hepatic/peripheral insulin sensitivity was evaluated at baseline and at week 12 by infusion of (3) H-labelled glucose followed by a 2-step hyperinsulinemic-euglycemic clamp. Two 75-g oral glucose tolerance tests (OGTTs) were conducted at baseline, one with and one without co-administration of colesevelam. A final OGTT was conducted at week 12. HbA(1c) and fasting plasma glucose (FPG) levels were evaluated pre- and post-treatment., Results: Treatment with colesevelam, compared to placebo, had no significant effects on basal endogenous glucose output, response to insulin or on maximal steady-state glucose disposal rate. At baseline, co-administration of colesevelam with oral glucose reduced total area under the glucose curve (AUC(g)) but not incremental AUC(g). At week 12, neither total AUC(g) nor incremental AUC(g) were changed from pre-treatment values in either group. Post-load insulin levels increased with colesevelam at 30 and 120 min, but these changes in total area under the insulin curve (AUC(i)) and incremental AUC(i) did not differ between groups. Both HbA(1c) and FPG improved with colesevelam, but treatment differences were not significant., Conclusions: Colesevelam does not affect hepatic or peripheral insulin sensitivity and does not directly affect glucose absorption., (Published 2011. This article is a U.S. Government work and is in the public domain in the USA.)

Aims: Mixed dyslipidaemia, characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides, is common in patients with type 2 diabetes mellitus (T2DM) and/or metabolic syndrome. Dalcetrapib effectively increases HDL-C levels by modulating cholesteryl ester transfer protein (CETP) activity. The aim of this analysis was to investigate the lipid modifying efficacy and safety of dalcetrapib in patients with T2DM and/or metabolic syndrome., Methods: Post hoc analysis of dalcetrapib therapy in five placebo-controlled, Phase II trials (4-48 weeks of duration) involving T2DM and/or metabolic syndrome, in dyslipidaemic patients with coronary heart disease (CHD) or CHD risk equivalent., Results: Both in patients with and without T2DM and/or metabolic syndrome, dalcetrapib decreased CETP activity by 26-58% and increased HDL-C levels by 23-34%, depending on dose and duration of treatment. Dalcetrapib did not significantly affect low-density lipoprotein cholesterol (LDL-C) or apolipoprotein B levels. Treatment with dalcetrapib was generally well tolerated with a similar number of adverse events reported between patient groups and between those receiving dalcetrapib compared with placebo., Conclusions: Dalcetrapib similarly decreased CETP activity and increased HDL-C levels in patients with and without T2DM or metabolic syndrome; the ongoing Phase III dal-OUTCOMES study will help to determine if dalcetrapib's improvement in lipid levels also reduces cardiovascular morbidity and mortality., (© 2011 Blackwell Publishing Ltd.)

Aim: To compare the long-term efficacy and safety of pitavastatin with atorvastatin in patients with type 2 diabetes and combined (mixed) dyslipidaemia., Methods: Randomised, double-blind, active-controlled, multinational non-inferiority study. Patients were randomised 2 : 1 to pitavastatin 4 mg (n = 279) or atorvastatin 20 mg (n = 139) daily for 12 weeks. Patients completing the core study could continue on pitavastatin 4 mg (n = 141) or atorvastatin 20 mg (n = 64) [40 mg (n = 7) if lipid targets not reached by week 8] for a further 44 weeks (extension study). The primary efficacy variable was the change in low-density lipoprotein cholesterol (LDL-C)., Results: Reductions in LDL-C were not significantly different at week 12 between the pitavastatin (-41%) and atorvastatin (-43%) groups. Attainment of National Cholesterol Education Program and European Atherosclerosis Society targets for LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) was similarly high for both treatment groups. Changes in secondary lipid variables (e.g. HDL-C, apolipoprotein B and triglycerides) were similar between treatments. Post hoc analysis showed that adjusted mean treatment differences for pitavastatin vs. atorvastatin were within the non-inferiority margin at weeks 16 (+0.11%; 95% confidence interval (CI), -5.23 to 5.44) and 44 (-0.02%; 95% CI, -5.46 to 5.41) of the extension study. Both treatments were well tolerated; atorvastatin increased fasting blood glucose from baseline (+7.2%; p < 0.05), whereas pitavastatin had no significant effect (+2.1%)., Conclusions: Reductions in LDL-C and changes in other lipids were not significantly different in patients treated with pitavastatin 4 mg or atorvastatin 20 or 40 mg. Pitavastatin may, however, have a more favourable effect on the glycaemic status., (© 2011 Blackwell Publishing Ltd.)

Aim: colesevelam is indicated to lower low density lipoprotein cholesterol (LDL-C) in hyperlipidaemia and improve glycaemic control in adults with type 2 diabetes. This short-term pilot study evaluates its effects in type 1 diabetes., Methods: this double-blind, randomized, investigator-initiated, single-centred, 12-week pilot study evaluated 40 adults (age = 36.4 ± 9.4 years) with type 1 diabetes (duration = 20.4 ± 8.5 years) and hyperlipidaemia. It was powered to show a treatment difference of >10% LDL-C reduction. Subjects received 3.75 g/day colesevelam (n = 20) or placebo (n = 20) for 12 weeks. LDL-C and haemoglobin A1c (A1c) levels were assessed at screening (week 2), baseline (week 0) and every 4 weeks throughout the treatment duration. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels were measured during 4-h meal (Boost Plus, Nestle HealthCare Nutrition Inc., Florham Park, New Jersey, USA) challenge tests (MCT) at baseline and 12 weeks., Results: colesevelam treatment resulted in a significant reduction in LDL-C values at 4 weeks [-12.1% (95% CI: -20.1 to -4.1), p = 0.004] which was sustained for the study duration (p = 0.005 at 12 weeks). The treatment group also showed a significant change in A1c from baseline at week 4; however, this was not significant for the study duration. There was a significant median increase in GLP-1 levels during the first 2 h of the baseline MCT in the treated group but no difference at 12 weeks., Conclusions: during this short-term pilot study, colesevelam treatment effectively lowered LDL-C in patients with type 1 diabetes. Improvements in A1c seen at week 4 were not sustained. Effects on glycaemic control in subjects with type 1 diabetes may be related to a postprandial rise in GLP-1 levels and require further clinical study.

Aims: To assess the efficacy and safety of ezetimibe/simvastatin (E/S) plus extended-release niacin (N) in hyperlipidaemic patients with diabetes mellitus (DM), metabolic syndrome (MetS) without DM (MetS/non-DM) or neither (non-DM/non-MetS)., Methods: A subgroup analysis of a double-blind, 64-week trial of 1220 randomized patients who received E/S (10/20 mg) + N (to 2 g) or E/S (10/20 mg) for 64 weeks, or N (to 2 g) for 24 weeks then E/S (10/20 mg) + N (2 g) or E/S (10/20 mg) for 40 additional weeks. The evaluable populations of this analysis included n = 765 patients at 24 weeks and n = 574 at 64 weeks. Among those receiving N, only those who attained the 2-g dose were included in the analysis., Results: E/S+N improved levels of low-density lipoprotein cholesterol, other lipids and lipoprotein ratios compared with N and E/S at 24 weeks and E/S at 64 weeks. The combination increased high-density lipoprotein cholesterol and apolipoprotein AI comparably to N and more than E/S. E/S+N reduced high-sensitivity C-reactive protein (hsCRP) levels more effectively than N and similarly to E/S. E/S+N was generally well tolerated. Discontinuations due to flushing with N and E/S+N were comparable and greater than E/S in all subgroups. Fasting glucose trended higher for N vs. E/S. Glucose elevations from baseline to 12 weeks were highest for patients with DM (24.9 mg/dl for N, 21.2 mg/dl for E/S+N, 17.5 mg/dl for E/S); fasting glucose then declined to pretreatment levels at 64 weeks in all subgroups. New-onset DM was more frequent among MetS patients than those without MetS during the first 24 weeks and trended higher among those assigned to N-containing regimens [n = 5(5.1%) for N, n = 2(1.7%) for E/S, n = 21(8.8%) for E/S+N]; during the 24-64 week extension study, diabetes was diagnosed in five additional patients in the E/S(cumulative incidence of 5.9%) and one in the E/S+N (cumulative incidence of 9.2%). Treatment-incident elevations in uric acid levels were increased among subjects assigned to N-containing regimens, but there were no effects on symptomatic gout., Conclusion: Combination E/S+N is a safe treatment option for hyperlipidaemic patients including those with DM and MetS, but requires monitoring of glucose and potentially uric acid levels., (© 2010 Blackwell Publishing Ltd.)

Ezetimibe is a relatively new drug that inhibits the absorption of dietary cholesterol in the small intestine. It is a low density lipoprotein-cholesterol (LDL-C) lowering medication that acts directly on the intestine by inhibiting Niemann-Pick C1 Like1 (NPC1L1). Recently, results of the ARBITER 6-HALTS trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) and the ENHANCE trial (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) showed that ezetimibe had no effect on atherosclerosis despite producing a marked decrease in LDL-C. Recent studies show a potential benefit of ezetimibe in treating insulin resistance, non-alcoholic fatty liver disease (NAFLD), gallstones and dyslipidaemia associated with chronic renal failure and organ transplantation. All of these conditions are known to be associated with an increase in risk of cardiovascular disease (CVD) and further studies are needed to assess the potential benefits of ezetimibe in these therapeutics areas., (© 2010 Blackwell Publishing Ltd.)

Aim: The benefit of direct, as opposed to calculated, low density lipoprotein -cholesterol (LDL-C) measurement remains unclear. This study compared the biological variability of direct LDL in patients with type 2 diabetes (T2DM) on equivalent doses of the short half-life statin, simvastatin or the longer half-life statin, atorvastatin., Methods: A cross-over study of biological variation of lipids in 26 patients with T2DM taking either simvastatin 40 mg (n = 10) or atorvastatin 10 mg. After 3 months on one statin, fasting lipids were measured on 10 occasions over a 5-week period. The same procedure was then followed on the other statin. The variability of LDL-C was established using a Beckman direct assay., Results: As a group, mean LDL was no different between statins (mean +/- s.d.) (1.69 +/- 0.60 mmol/l simvastatin vs. 1.67 +/- 0.60 mmol/l atorvastatin, p = 0.19). However, in all patients, the intraindividual biological variability of LDL while taking simvastatin was markedly higher than with atorvastatin (average s.d. = 0.17 mmol /l simvastatin vs. 0.01 mmol/l, p < 0.0001). Friedewald calculated LDL variability was no different between statins (average s.d. = 0.34 mmol /l simvastatin vs. 0.21 mmol/l atorvastatin, p = 0.19)., Conclusions: In contrast to calculated values, direct measurement revealed LDL to be much more stable (the s.d. being an order of magnitude) in T2DM patients taking atorvastatin rather than simvastatin. This means LDL targets can be consistently met with less lipid monitoring using atorvastatin rather than simvastatin. Direct LDL measurement may therefore have a particular role in monitoring patients on statin treatment.

Hydroxymethylglutaryl-coenzyme A reductase inhibitors or statins are the most effective medications for reducing elevated concentrations of low-density lipoprotein cholesterol (LDL-C). Statins reduce cardiac events in patients with coronary artery disease and previously healthy persons. Current recommendations for LDL-C treatment goals indicate that more patients will be treated with higher doses of these medications. Statins have been extremely well-tolerated in controlled clinical trials but are increasingly recognized to produce skeletal muscle myalgia, cramps, and weakness. The reported frequency of such mild symptoms is not clear, and muscle performance has not been examined with these medications. Accordingly, the present investigation, the Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study, will recruit approximately 440 healthy persons. Participants will be randomly assigned to treatment with atorvastatin 80 mg/d or placebo. Handgrip, elbow and knee isometric and isokinetic strength, knee extensor endurance, and maximal aerobic exercise performance will be determined at baseline. Participants will undergo repeat testing after 6 months of treatment or after meeting the study definition of statin myalgia. This study will determine the effect of statins on skeletal muscle strength, endurance, and aerobic exercise performance and may ultimately help clinicians better evaluate statin-related muscle and exercise complaints., ((c) 2009 Wiley Periodicals, Inc.)

Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil, extended-release niacin, colesevelam hydrochloride, and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin. The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol., ((c) 2009 Wiley Periodicals, Inc.)

Multiple-drug therapy of dyslipidemia is frequently used to achieve treatment goals in high-risk patients with coronary artery disease. The authors report a case of a patient treated with a statin, fibrate, ezetimibe, and niacin in whom a calculated low-density lipoprotein cholesterol level of 5 mg/dL was achieved.

The authors examined the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) reduction and the magnitude of cardiovascular risk reduction. From the Veterans Integrated Service Network 1 databases, the authors selected 54,611 patients with prevalent ischemic heart disease, peripheral vascular disease or diabetes mellitus, and >or=2 documented LDL-C levels who were followed between 1997 and 2006. The outcome was defined as acute myocardial infarction or revascularization. Preoutcome LDL-C reduction was categorized as follows: <10 mg/dL, reference; >or=10 but <40 mg/dL, small reduction; >or=40 but <70 mg/dL, moderate reduction; >or=70 mg/dL, large reduction. Proportional hazards were used to determine the hazard ratio for the outcome for each LDL-C reduction category compared with the reference. Results revealed a graded relationship between the magnitude of reduction in LDL-C and cardiovascular risk reduction. Stratified analyses demonstrated these findings to be robust regardless of initial LDL-C levels or whether patients achieved "target" final LDL-C values of <100 mg/dL., ((c) 2009 Wiley Periodicals, Inc.)

Among individuals with diabetes mellitus, cardiovascular disease remains the leading cause of death, despite the many treatment modalities that have been developed over time. The PPAR family, including PPAR-alpha, play important roles in glucose and lipid metabolism and atherosclerosis and thus are potential therapeutic targets. Fibrates act upon PPAR-alpha and appear to target the typical dyslipidaemia of diabetes. Several large prospective clinical trials have shown both primary prevention and secondary prevention benefit with fibrates, although they only had small subgroups of patients with diabetes. The first large outcome study to exclusively study those with diabetes was the FIELD study, which showed no reduction in the primary cardiovascular end-point and only some benefit in the secondary end-point. There are many potential explanations for these results; however, it would appear that at present, there is no role for fibrates as monotherapy for the reduction of cardiovascular risk among those with diabetes. However, their potential role in combination with statin therapy remains to be further elucidated with ongoing studies.

Aims: To evaluate the effect of a lower dose (20 mg) of atorvastatin on hs-CRP concentrations in patients with ACS., Methods: Group A (n = 50) patients received atorvastatin 20 mg day(-1) for 4 weeks in addition to standard anti-anginal treatment. Group B (n = 50) patients received standard anti-anginal treatment without atorvastatin., Results: hs-CRP concentrations decreased in both groups, but the decrease was greater in group A. The decrease in hs-CRP was also significantly greater in the subgroups of smoking, hypertension and past history of cardiovascular disease with atorvastatin., Conclusions: The use of a lower dose (20 mg) of atorvastatin can offer an attractive approach for early treatment of patients with ACS.

What Is Already Known About This Subject: * Statins reduce cholesterol concentrations and cardiovascular events in randomized clinical trials. * Much less is known about their impact in the setting of normal care., What This Study Adds: * This is the first study to assess the effectiveness of lipid-lowering treatment in the general population. * We have also estimated the resultant impact on major vascular events. * We have examined the actual and potential impact of lipid-lowering treatment., Aims: To evaluate the impact of lipid-lowering treatment on cholesterol concentrations in the setting of normal care., Methods: This was a retrospective review of all cholesterol measurements made in Tayside, Scotland, between 1993 and 2002, linked to dispensed prescribing data for lipid-lowering drugs. It was conducted in the setting of normal care and included all patients who underwent cholesterol measurement. The main outcome measure was cholesterol concentration., Results: A total of 401,489 cholesterol measurements were made on 128,240 patients over the study period. Measurements were categorized as treated and untreated according to whether patients were exposed to lipid-lowering treatment at the time the total cholesterol concentration was measured. Those categorized as untreated fell by 0.86 mmol l(-1) (13.9%) and those categorized as treated by 1.45 mmol l(-1) (23.5%). The difference between baseline and follow-up cholesterol concentrations in intention-to-treat patients was 1.53 mmol l(-1) (24%) in 2002. In the same year, mean cholesterol concentration was 4.71 mmol l(-1) (a fall of 1.65 mmol l(-1) or 25.9%) in patients judged to be taking their lipid-lowering medication, compared with 5.20 mmol l(-1) (a fall of 1.16 mmol l(-1) or 18.2%) in those judged not to be taking treatment. Cholesterol fell by 0.38 mmol l(-1) (6.3%) in a cohort of never treated patients (n = 33,679) between 1993 and 2002., Conclusions: The impact of lipid-lowering drugs on population cholesterol concentrations in the setting of normal care was significant and comparable with the cholesterol reductions seen in the setting of major statin trials, despite a significant proportion of the population receiving low dose treatment. In those subjects judged to be taking their medication, the benefits achieved were substantial. The impact of nondrug factors is indicated by the fall in population cholesterol seen in the absence of lipid-lowering treatment.

Study Objective: To evaluate the effectiveness and hepatotoxicity of statins in patients who are seropositive for hepatitis C virus (HCV)., Design: Retrospective review of a registry of patients with HCV., Setting: Veterans Affairs Medical Center., Patients: One hundred forty-six male patients who were seropositive for HCV and had received statin therapy between January 1, 1995, and September 9, 2003., Measurements and Main Results: Demographic and clinical data were collected for each patient; lipid and alanine aminotransferase (ALT) levels at baseline (within 6 mo of starting a statin), at 3 and 6 months after starting a statin, and at long-term follow-up (mean 22 mo) were also recorded. The primary efficacy end point was a significant decrease from baseline to long-term follow-up low-density lipoprotein cholesterol (LDL) level; the primary safety end point was a significant increase from baseline in ALT level. The mean change in LDL level was a reduction of 22% (p<0.01). No significant increases in ALT levels were observed; only one patient discontinued therapy due to ALT level elevations greater than 3 times the upper limit of normal., Conclusion: In men seropositive for HCV, statins were effective in reducing LDL levels and did not result in significant increases in ALT levels from baseline. Thus, statin therapy should be considered for patients with HCV who are at risk for coronary heart disease and do not have significantly elevated serum transaminase levels at baseline.

Study Objectives: To determine the baseline arachidonic acid:eicosapentaenoic acid (AA:EPA) ratio in patients with coronary artery disease and healthy subjects, and whether supplementation of omega-3 fatty acids, administered as fish oil capsules, affects this ratio., Design: Prospective, open-label trial., Setting: University-affiliated cardiology clinic., Subjects: Thirty patients with stable coronary artery disease (CAD) and 30 healthy subjects., Intervention: All participants received omega-3 fatty acids 1.5 g/day for 4 weeks, followed by 3 g/day for an additional 4 weeks., Measurements and Main Results: For each participant, a lipid profile was determined at baseline and after 4 weeks of treatment with each dose. Other laboratory results analyzed were serum AA:EPA ratios, high-sensitivity C-reactive protein (hs-CRP) levels, and blood glucose levels. Mean +/- SD baseline AA:EPA ratios were 39.6 +/- 19.0 in healthy subjects and 23.7 +/- 12.5 in patients with CAD. These ratios decreased significantly in both groups after treatment with 1.5 g/day of omega-3 fatty acids: 9.0 +/- 4.2 in healthy subjects and 10.3 +/- 8.8 in patients with CAD. After treatment with 3 g/day, the ratios were further reduced: 5.1 +/- 3.2 in healthy subjects and 4.9 +/- 2.6 in patients with CAD. Supplementation with omega-3 fatty acids did not significantly affect hs-CRP, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or blood glucose levels. Triglyceride levels were not reduced in patients with CAD but were significantly decreased in healthy subjects (by 20% decrease with omega-3 fatty acids 1.5 g/day and by 32% decrease with 3 g/day)., Conclusion: Treatment with omega-3 fatty acids significantly reduced AA:EPA ratios in both healthy subjects and in patients with stable CAD. The treatment had no effect on hs-CRP levels in either group, and it reduced triglyceride levels in healthy subjects but not in patients with CAD.

This report describes a patient with coronary artery disease who was instructed to take extended-release niacin to treat low high-density lipoprotein cholesterol and instead purchased "flush-free niacin" available at the pharmacy. There was no significant change in his lipids. Once the patient switched to extended-release niacin, the anticipated beneficial effects were seen. The article reviews the composition of flush-free niacin, its purported and real lipid effects, and warns against the effects of misleading marketing.

The authors measured coronary artery calcification as a means of examining the impact of anabolic steroids on the development of atherosclerotic disease in body builders using anabolic steroids over an extended period of time. Fourteen male professional body builders with no history of cardiovascular disease were evaluated for coronary artery calcium, serum lipids, left ventricular function, and exercise-induced myocardial ischemia. Seven subjects had coronary artery calcium, with a much higher than expected mean score of 98. Six of the 7 calcium scores were >90th percentile. Mean total cholesterol was 192 mg/dL, while mean high-density lipoprotein was 23 mg/dL and the mean ratio of total cholesterol to high-density lipoprotein was 8.3. Left ventricular ejection fraction ranged between 49% and 68%, with a mean of 59%. No subject had evidence of myocardial ischemia. This small group of professional body builders with a long history of steroid abuse had high levels of coronary artery calcium for age. The authors conclude that in this small pilot study there is an association between early coronary artery calcium and long-term steroid abuse. Large-scale studies are warranted to further explore this association.

Study Objective: To compare, in a usual care setting, the effects of rosuvastatin and other 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) on lipid levels and on goal attainment of low-density lipoprotein cholesterol (LDL) levels from the National Cholesterol Education Program (NCEP) third report of the Adult Treatment Panel (ATP III)., Design: Retrospective, longitudinal, cohort study., Data Source: Managed care medical and pharmacy claims and laboratory database., Patients: A total of 8251 patients starting treatment with rosuvastatin, atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin from August 1, 2003-September 30, 2004, excluding those who received dyslipidemic therapy in the previous 12 months., Measurements and Main Results: Patients with at least one pretreatment and posttreatment lipid level were followed until their initial statin was changed or they reached the end of benefit eligibility or the study period. Percent changes in lipid levels were calculated, and adjusted changes in LDL and goal attainment were evaluated by regression techniques. Absolute and percent reductions in LDL, triglyceride, and total cholesterol levels were significantly greater with rosuvastatin than with other statins (all p<0.05 except for triglyceride reduction vs atorvastatin). After adjustment for age, sex, and baseline LDL, percent LDL reductions still were significantly greater with rosuvastatin than with other statins (p<0.05). Changes in high-density lipoprotein cholesterol were not significant. Goal attainment was higher with rosuvastatin than with other statins after adjustment for age, sex, baseline LDL, risk status, dose, and duration of therapy (p<0.05). Dose-stratified analysis showed that LDL goal attainment was significantly higher with rosuvastatin 10 mg than with atorvastatin 10 or 20 mg., Conclusion: Rosuvastatin was more effective than other statins in reducing LDL, triglyceride (except vs atorvastatin), and total cholesterol levels. Significantly more patients taking rosuvastatin than patients taking other statins attained their LDL goals.

Intensive lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is now an established regimen for patients at high risk for cardiovascular events, regardless of baseline low-density lipoprotein cholesterol levels. Treatment with statins to reduce low-density lipoprotein cholesterol levels significantly below 100 mg/dL has been shown to further reduce the risk of cardiovascular morbidity and mortality in high-risk patients and has provided the necessary data for an update to the National Cholesterol Education Program's Third Adult Treatment Panel (ATP III) guidelines. Intensive statin therapy is also well tolerated, with no increased risk of noncardiovascular adverse events and a low incidence of clinically significant liver or muscle enzyme abnormalities. Results of recent clinical and surrogate end point trials confirm that intensive lowering of low-density lipoprotein cholesterol is beneficial and safe in a majority of high-risk patients.

Recent comparative trials of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) suggest that lower is better and that reducing low-density lipoprotein cholesterol (LDL-C) levels to below 100 mg/dL can provide additional clinical benefit. Non-high-density lipoprotein cholesterol (non-HDL-C) contains more atherogenic cholesterol than LDL-C and is considered a more accurate measurement of the total amount of atherogenic particles in the circulation. Therefore, the principle that "lower is better" may also apply to lowering levels of non-HDL-C. In persons with high triglycerides (200-499 mg/dL), LDL-C remains the primary target of therapy, but non-HDL-C is an important secondary therapeutic target. Non-HDL-C is strongly correlated with small dense LDL as well as apolipoprotein B, an established predictor of cardiovascular disease risk. Current evidence indicates that statins not only rapidly and dramatically reduce LDL-C, but also have a similar effect on non-HDL-C, and that the greater the reduction in LDL-C, the greater will be the reduction in non-HDL-C.

Considerable data on the pathophysiology, epidemiology, and treatment of dyslipidemia-induced coronary heart disease (CHD) have accumulated in recent years. These data have been assessed and incorporated into the guidelines of the National Cholesterol Education Program Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] III). A major focus of the new guidelines is the assessment of the near-term (i.e., 10-yr) risk of experiencing a CHD event and matching the intensity of treatment to this risk. Patients with diabetes and those with a greater than 20% 10-year risk of experiencing a CHD event have been elevated to the risk level of CHD equivalent. The ATP III guidelines also modify several lipid and lipoprotein classifications. A low-density lipoprotein cholesterol (LDL) level below 100 mg/dl is now considered optimum for all individuals. In addition, high-density lipoprotein cholesterol (HDL) and triglyceride cutoff points have been modified to reflect more accurately the risk associated with abnormalities in these lipoproteins. As with the previous guidelines, the primary target of therapy remains LDL. Therapeutic lifestyle changes consisting of diet, weight reduction, and increased physical activity should be included in all treatment regimens. Based on their potent LDL-lowering properties and their proven ability to decrease mortality in a variety of patient populations, statins are generally the first choice for pharmacologic therapy. A secondary target of therapy includes non-HDL goals for patients with high triglyceride levels and the metabolic syndrome, which is characterized by abdominal obesity, elevated triglyceride levels, low HDL levels, and insulin resistance. Management of these secondary targets includes weight reduction and increased physical activity, and treatment of the lipid and nonlipid risk factors. Overall, ATP III represents an aggressive approach to treating dyslipidemia, greatly extending the number of individuals who qualify for treatment.

Emerging data implicate inflammation as integral to atherosclerosis and its complications. From a clinical perspective, the inflammatory biomarker C-reactive protein has demonstrated consistent predictive value in the detection of individuals at high risk for cardiovascular disease. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduces C-reactive protein as well as low-density lipoprotein cholesterol, thus providing a potential additional mechanism for the reduction in cardiovascular events associated with the use of these agents. Evidence from the Air Force/Texas Coronary Atherosclerosis Prevention Study suggests that statin therapy may be effective in reducing incident coronary events among those with elevated levels of C-reactive protein but normal levels of low-density lipoprotein cholesterol. These data, along with accumulating laboratory data, support a potential anti-inflammatory benefit of statins. Large-scale, randomized trials in the primary prevention of acute coronary events among individuals without overt hyperlipidemia but with evidence of elevated C-reactive protein are now needed to directly test this hypothesis.

Aims: The aim of this study was to investigate the effect of policosanol on the susceptibility of LDL-C to in vitro lipid peroxidation in human healthy volunteers., Methods: The effect of policosanol (5 and 10 mg day(-1) on LDL-C oxidation was studied in a double-blind, randomized, placebo-controlled trial conducted in 69 subjects. LDL-C samples isolated at baseline and after 8 weeks were subjected to in vitro tests of LDL-C oxidation. We tested the susceptibility of LDL-C to lipid peroxidation in a cell-free system by the addition of copper ions as well as in a more physiological system, macrophage-mediated oxidation., Results: At baseline all groups were well matched regarding all variables. After 8 weeks of therapy policosanol administered at 5 and 10 mg, significantly and in a dose-dependent manner increased the lag phase of conjugated diene generation (mean +/- s.d.) from 83.79+/-29.16 min to 94.90+/-25.50 min (5 mg day(-1)) and from 82.74+/-17.16 min to 129.89+/-35.71 min (10 mg day(-1)), while in the placebo group LDL-C oxidation did not change significantly. Policosanol (10 mg day(-1)), but not placebo, significantly decreased the rate of conjugated diene generation. Comparison with placebo after therapy also showed significant differences. Macrophage mediated-oxidation was also inhibited by policosanol as evident by measuring thiobarbituric acid reactive substances (TBARS). Policosanol (10 mg day(-1)) significantly lowered malondialdehyde (MDA) generation from 8.50+/-0.91 to 5.76+/- 1.01 nmol mg(-1) protein. Comparison with placebo after 5 and 10 mg day(-1) showed significant differences. Policosanol significantly lowered total cholesterol by 10.5% (5 mg day(-1)) and 12.4% (10 mg day(-1)) and LDL-C by 16.7% and 20.2%, respectively. Also, policosanol (10 mg day(-1)) increased HDL-C by 15.2%. Five subjects withdrew from the study, none because of adverse experiences. No clinical or blood biochemical drug-related disturbances were found., Conclusions: The present study demonstrated that policosanol administered within its therapeutic dosage for lowering cholesterol (5 and 10 mg day(-1)), decreased the susceptibility of LDL-C to lipid peroxidation in vitro.

Aims: The objective of this study was to examine the effects of continuous transdermal oestradiol with or without sequential oral medroxyprogesterone acetate on serum lipids and lipoproteins in menopausal women., Methods: Sixty-two healthy menopausal women, attending at two menopause clinics in Western India, were recruited for this study over a period of 1 year. Group 1 included 38 hysterectomised women being treated with continuous transdermal oestradiol only (50 microg daily). Group 2 included 24 menopausal women with an intact uterus being treated with transdermal oestradiol (50 microg daily) and medroxyprogesterone acetate (10 mg daily for the first 12 days of each calendar month). Women maintained on 50 microg oestradiol throughout 6 months (group 1: n = 22; group 2: n = 16) were reviewed for changes in serum lipids and lipoproteins at the end of 6 months (group 1), and between days 8 and 12 of the seventh month (combined phase of treatment) (group 2)., Results: In group 1, there was a small reduction in the concentrations of total cholesterol (-5.5%, P = 0.04) and a small but not significant reduction in LDL-cholesterol (-5.7%, P = 0.16). In group 2, there were no significant changes in total cholesterol (-4.2%, P = 0.43) and LDL-cholesterol (-3.9%, P = 0.57). HDL-cholesterol levels did not change significantly with unopposed transdermal oestradiol (+3.0%, P = 0.53), or with additional sequential medroxyprogesterone acetate (-3.8%, P = 0.32). Serum triglyceride concentrations decreased significantly in both the groups (-13.9%, P = 0.01, and -13.4%, P = 0.008, respectively). Serum lipid changes did not differ between the groups., Conclusions: Transdermal oestrogen therapy appears to be of particular benefit for women with hypertriglyceridaemia. There were no significant adverse effects of medroxyprogesterone acetate on serum lipids and lipoproteins.