Statins and mortality: the untold story.

Statins are first-line evidence-based drugs for the management of dyslipidaemias and to reduce the risk of cardiovascular events. However, statin clinical trials have shown marginally significant benefits on mortality, especially in the primary prevention setting. A major limitation of those trials is their relatively short follow-up. A reduced number of fatal events within a 5-year follow-up make mortality benefits unlikely to arise. This is particularly relevant for the primary prevention trials, where the risk of cardiovascular death is low. The short follow-up is a limitation for safety assessments too. However, extended major statin trials failed to detect any major safety concerns. Safety and efficacy assessments are even more complicated considering the differences of cardiovascular risk status in primary prevention individuals, and also given some potential ethnic and inter-individual genetic variations in response to statin treatment. Considerable evidence suggests a favourable risk-benefit balance for statin treatment. It can be assumed that statins reduce mortality in the long term by preventing cardiovascular events with complications that reduce lifespan. Unfortunately, this hypothesis cannot be proven as there is no current ethical basis on designing long-term placebo-controlled statin trials. Nevertheless, by effectively reducing disabilities related to cardiovascular events, statins have major benefits for public health. Therefore, clinicians should not withhold statin treatment awaiting proof of mortality benefits, as this may remain an 'untold story'.

Emerging drugs for hyperlipidaemia: an update.

INTRODUCTION: Hypercholesterolaemia is a significant risk factor for cardiovascular disease (CVD), a major cause of morbidity and mortality. Up to now, the appropriate management has been aggressive hypolipidaemic therapy, particularly with statins, aiming at certain low-density lipoprotein cholesterol (LDL-C) levels for each patient population. This strategy has reduced CVD-related morbidity and mortality. However, many cardiovascular events still occur, probably as a consequence of lipid disorders other than high LDL-C concentration or other risk factors. Because statins do not eliminate the residual CVD risk, there seems to be place for novel lipid modifying drugs with different mechanisms of action. AREAS COVERED: This review is an update since 2010 regarding lipid-modifying drugs in development and their potent role in clinical practice. It focuses on cholesterol ester transfer protein inhibitors, mainly anacetrapib and evacetrapib, microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides, pre-protein convertase subtilisin kexin-9 inhibitors and high-density lipoprotein mimetics. EXPERT OPINION: Several novel lipid-modifying drugs may be beneficial for certain patient populations. However, ongoing and future studies with clinical outcomes will clarify their actual role in clinical practice.

Fenofibrate and the kidney: an overview.

BACKGROUND: Fenofibrate has been used for the management of atherogenic dyslipidaemia for many years. Reports of fenofibrate-associated increases in serum creatinine (SCr) levels raised concerns regarding deleterious effects on renal function. DESIGN: In this narrative review, we discuss available literature on the effect of fenofibrate on the kidney. RESULTS: Most clinical studies showed a rapid (within weeks) raising effect of fenofibrate on SCr levels. This was often accompanied by declined estimated glomerular filtration rate. Risk predictors of this adverse effect might include increased age, impaired renal function and high-dose treatment. Also, the concomitant use of medications affecting renal hemodynamics (e.g. angiotensin-converting enzyme-inhibitors (ACEi) and angiotensin receptor blockers) may predispose to fenofibrate-associated increased SCr levels. Interestingly, SCr increases by fenofibrate were transient and reversible even without treatment discontinuation. Furthermore, fenofibrate was associated with a slower progression of renal function impairment and albuminuria in a long-term basis. Also, fenofibrate might be protective against pathological changes in diabetic nephropathy and hypertensive glomerulosclerosis. In this context, it is uncertain whether fenofibrate-associated increase in SCr levels mirrors true renal function deterioration. Several theories have been expressed. The most dominant one involved the inhibition of renal vasodilatory prostaglandins reducing renal plasma flow and glomerular pressure. Increased creatinine secretion or reduced creatinine clearance by fenofibrate was also suggested. These hypotheses should be settled by further studies. CONCLUSIONS: Fenofibrate may not be a nephrotoxic drug. However, a close monitoring of SCr levels is relevant especially in high-risk patients. Increases in SCr levels ≥30% can impose treatment discontinuation.

Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.

CONTEXT: Considerable controversy exists regarding the association of omega-3 polyunsaturated fatty acids (PUFAs) and major cardiovascular end points. OBJECTIVE: To assess the role of omega-3 supplementation on major cardiovascular outcomes. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through August 2012. STUDY SELECTION: Randomized clinical trials evaluating the effect of omega-3 on all-cause mortality, cardiac death, sudden death, myocardial infarction, and stroke. DATA EXTRACTION: Descriptive and quantitative information was extracted; absolute and relative risk (RR) estimates were synthesized under a random-effects model. Heterogeneity was assessed using the Q statistic and I2. Subgroup analyses were performed for the presence of blinding, the prevention settings, and patients with implantable cardioverter-defibrillators, and meta-regression analyses were performed for the omega-3 dose. A statistical significance threshold of .0063 was assumed after adjustment for multiple comparisons. DATA SYNTHESIS: Of the 3635 citations retrieved, 20 studies of 68,680 patients were included, reporting 7044 deaths, 3993 cardiac deaths, 1150 sudden deaths, 1837 myocardial infarctions, and 1490 strokes. No statistically significant association was observed with all-cause mortality (RR, 0.96; 95% CI, 0.91 to 1.02; risk reduction [RD] -0.004, 95% CI, -0.01 to 0.02), cardiac death (RR, 0.91; 95% CI, 0.85 to 0.98; RD, -0.01; 95% CI, -0.02 to 0.00), sudden death (RR, 0.87; 95% CI, 0.75 to 1.01; RD, -0.003; 95% CI, -0.012 to 0.006), myocardial infarction (RR, 0.89; 95% CI, 0.76 to 1.04; RD, -0.002; 95% CI, -0.007 to 0.002), and stroke (RR, 1.05; 95% CI, 0.93 to 1.18; RD, 0.001; 95% CI, -0.002 to 0.004) when all supplement studies were considered. CONCLUSION: Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.

Early Investigational and Experimental Therapeutics for the Treatment of Hypertriglyceridemia.

Hypertriglyceridemia has been identified as a risk factor for cardiovascular disease and acute pancreatitis. To date, there are only few drug classes targeting triglyceride levels such as fibrates and ω-3 fatty acids. These agents are at times insufficient to address very high triglycerides and the residual cardiovascular risk in patients with mixed dyslipidemia. To address this unmet clinical need, novel triglyceride-lowering agents have been in different phases of early clinical development. In this review, the latest and experimental therapies for the management of hypertriglyceridemia are presented. Specifically, ongoing trials evaluating novel apolipoprotein C-III inhibitors, ω-3 fatty acids, as well as fibroblast growth 21 analogues are discussed.

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.

Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment.

The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.

Lipoprotein (a) as a treatment target for cardiovascular disease prevention and related therapeutic strategies: a critical overview.

Advances in several fields of cardiovascular (CV) medicine have produced new treatments (e.g. to treat dyslipidaemia) that have proven efficacy in terms of reducing deaths and providing a better quality of life. However, the burden of CV disease (CVD) remains high. Thus, there is a need to search for new treatment targets. Lipoprotein (a) [Lp(a)] has emerged as a potential novel target since there is evidence that it contributes to CVD events. In this narrative review, we present the current evidence of the potential causal relationship between Lp(a) and CVD and discuss the likely magnitude of Lp(a) lowering required to produce a clinical benefit. We also consider current and investigational treatments targeting Lp(a), along with the potential cost of these interventions.

Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia.

HMG-CoA reductase inhibitors (statins) are the mainstay in the pharmacologic management of dyslipidemia. Since they are widely prescribed, their safety remains an issue of concern. Rosuvastatin has been proven to be efficacious in improving serum lipid profiles. Recently published data from the JUPITER study confirmed the efficacy of this statin in primary prevention for older patients with multiple risk factors and evidence of inflammation. Rosuvastatin exhibits high hydrophilicity and hepatoselectivity, as well as low systemic bioavailability, while undergoing minimal metabolism via the cytochrome P450 system. Therefore, rosuvastatin has an interesting pharmacokinetic profile that is different from that of other statins. However, it remains to be established whether this may translate into a better safety profile and fewer drug-drug interactions for this statin compared with others. Herein, we review evidence with regard to the safety of this statin as well as its interactions with agents commonly prescribed in the clinical setting. As with other statins, rosuvastatin treatment is associated with relatively low rates of severe myopathy, rhabdomyolysis, and renal failure. Asymptomatic liver enzyme elevations occur with rosuvastatin at a similarly low incidence as with other statins. Rosuvastatin treatment has also been associated with adverse effects related to the gastrointestinal tract and central nervous system, which are also commonly observed with many other drugs. Proteinuria induced by rosuvastatin is likely to be associated with a statin-provoked inhibition of low-molecular-weight protein reabsorption by the renal tubules. Higher doses of rosuvastatin have been associated with cases of renal failure. Also, the co-administration of rosuvastatin with drugs that increase rosuvastatin blood levels may be deleterious for the kidney. Furthermore, rhabdomyolysis, considered a class effect of statins, is known to involve renal damage. Concerns have been raised by findings from the JUPITER study suggesting that rosuvastatin may slightly increase the incidence of physician-reported diabetes mellitus, as well as the levels of glycated hemoglobin in older patients with multiple risk factors and low-grade inflammation. Clinical trials proposed no increase in the incidence of neoplasias with rosuvastatin treatment compared with placebo. Drugs that antagonize organic anion transporter protein 1B1-mediated hepatic uptake of rosuvastatin are more likely to interact with this statin. Clinicians should be cautious when rosuvastatin is co-administered with vitamin K antagonists, cyclosporine (ciclosporin), gemfibrozil, and antiretroviral agents since a potential pharmacokinetic interaction with those drugs may increase the risk of toxicity. On the other hand, rosuvastatin combination treatment with fenofibrate, ezetimibe, omega-3-fatty acids, antifungal azoles, rifampin (rifampicin), or clopidogrel seems to be safe, as there is no evidence to support any pharmacokinetic or pharmacodynamic interaction of rosuvastatin with any of these drugs. Rosuvastatin therefore appears to be relatively safe and well tolerated, sharing the adverse effects that are considered class effects of statins. Practitioners of all medical practices should be alert when rosuvastatin is prescribed concomitantly with agents that may increase the risk of rosuvastatin-associated toxicity.

Apolipoprotein B-to-A1 ratio as a predictor of acute ischemic nonembolic stroke in elderly subjects.

Among traditional cardiovascular risk factors, apolipoprotein (apo)B/apoA1 ratio is considered to have the strongest predictive value for ischemic stroke. Nevertheless, there are imsufficient data to support this ratio as an independent risk predictor of ischemic stroke in elderly individuals. In this case-control study, we evaluated apoB/apoA1 ratio as a predictor of ischemic stroke in a cohort of elderly subjects. A total of 163 patients aged>70 years (88 men) admitted due to a first-ever acute ischemic/nonembolic stroke and 166 volunteers (87 men) with no history of cardiovascular disease were included. The association between apoB/apoA1 ratio and stroke was determined by multivariate logistic regression modeling after adjusting for potential confounding factors, including lipid parameters. Stroke patients exhibited a higher apoB/apoA1 ratio than controls (1.04±0.33 vs 0.86±0.22; P<.001). In univariate analysis, crude odds ratio (OR) for apoB/apoA1 ratio was 1.27 per 0.1 increase (95% confidence interval [CI]=1.15-1.39; P<.001). Compared with subjects with an apoB/apoA1 ratio in the lowest quartile, those within the highest quartile had a 6.3-fold increase in the odds of suffering an ischemic stroke (95% CI=3.17-12.48; P<.001). This association remained significant after controlling for potential confounders, including sex, age, smoking status, body mass index, waist circumference, glucose and insulin levels, the presence of hypertension and diabetes mellitus, and lipid profile parameters (adjusted OR=3.02; 95% CI=1.16-7.83; P=.02). Our findings support elevated apoB/apoA1 ratio as an independent predictor of ischemic stroke in individuals over age 70.

Recent developments in pharmacotherapy for hypertriglyceridemia: what's the current state of the art?

Introduction: Hypertriglyceridemia is associated with both the development of cardiovascular disease (CVD) when mild-to-moderate and high risk of pancreatitis when more severe. The residual CVD risk after low-density lipoprotein cholesterol (LDL-C) lowering is, in part, attributed to high triglyceride (TG) levels. Therefore, there appears to be a need for effective TG-lowering agents.Areas covered: This review presents the most recent advances in hypertriglyceridemia treatment; specifically, it discusses the results of clinical trials and critically comments on apolipoprotein C-III inhibitors, angiopoietin-like 3 inhibitors, alipogene tiparvovec, pradigastat, pemafibrate and novel formulations of omega-3 fatty acids.Expert opinion: In the era of extreme lowering of LDL-C levels with several agents, there seems to be space for novel therapeutic options to combat parameters responsible for residual CVD risk, among which are elevated TGs. Furthermore, a significant number of individuals have very high TG levels and encounter the risk of acute pancreatitis. The most recently developed TG-lowering drugs appear to have a role in both conditions; the choice is mainly based on baseline TG levels. Dyslipidemia guidelines are likely to change in the near future to include some of these agents. Of course, long-term data regarding their safety and efficacy in terms of CVD outcomes and pancreatitis are warranted.

Dose-dependent effect of rosuvastatin treatment on HDL-subfraction phenotype in patients with primary hyperlipidemia.

Although the raising effect of rosuvastatin on high-density lipoprotein cholesterol is well-established, there is a paucity of data regarding the effect of this statin on the high-density lipoprotein subfraction phenotype. A total of 150 participants without evidence of cardiovascular disease were randomized to therapeutic lifestyle modification (nonstatin-treated group) or to therapeutic lifestyle modification plus rosuvastatin at 10 mg/d (RSV10 group) or 20 mg/d (RSV20 group). We assessed the effect of rosuvastatin on the cholesterol mass of high-density lipoprotein subfractions at baseline as well as after 12 weeks post-treatment. Rosuvastatin treatment dose-dependently increased the high-density lipoprotein cholesterol (3.4% vs 5.3% in the RSV10 and RSV20 groups, respectively, P = .02). A dose-related rosuvastatin-induced increase in the cholesterol concentration of large high-density lipoprotein particles was also noted (by 11.4% in RSV10 group vs 22.0% in the RSV20 group, P = .01). Rosuvastatin treatment increases the high-density lipoprotein cholesterol by increasing the cholesterol mass only of the larger high-density lipoprotein particles in a dose-dependent manner.

Investigating the lowest threshold of vascular benefits from LDL cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers - a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale.

Objective: Whether reducing low density lipoprotein cholesterol (LDL-C) is associated with cardiovascular benefits in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW [Investigating the lowest threshold of vascular benefits from LDL-cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers] study aims to assess whether lowering LDL-C by alirocumab monotherapy can improve endothelial-dependent vascular function compared with placebo (primary objective) in low-risk normocholesterolaemic healthy individuals. Changes in endothelial-dependent or endothelial-independent vascular function, arterial stiffness and biomarkers of systemic inflammation by alirocumab, atorvastatin or their combination are secondary objectives. Study design and methods: This is a single-center, randomized, two-period, single-blind, placebo-controlled clinical trial. The study was registered on clinicaltrials.gov (N03273972). It will include 30 healthy low-risk subjects with LDL-C < 4.1 mmol/l. After passing the screening visit (Visit 1), eligible participants will be randomized 1:1 to either subcutaneous alirocumab 150 mg or placebo. These will be administered as single doses in 2 visits 14 days apart (Visits 2 and 3). Atorvastatin 20 mg once nightly will be prescribed for 14 days at Visit 3 in both groups through to Visit 4. At baseline (Visit 2) and during all post-dose visits (Visits 3-4), endothelial function will be assessed using venous occlusion plethysmography. Specifically, changes in forearm blood flow responses to intra-arterial infusions of acetylcholine, sodium nitroprusside and L-NG-monomethyl-arginine acetate will be assessed as surrogates of endothelial-dependent and -independent vasodilatation. Additionally, arterial stiffness and carotid intima-media thickness will be evaluated at the same timepoints. The above-mentioned changes will be correlated with changes in lipid and systemic inflammation biomarkers.

Baseline triglyceride levels and insulin sensitivity are major determinants of the increase of LDL particle size and buoyancy induced by rosuvastatin treatment in patients with primary hyperlipidemia.

The influence of various statins on low-density-lipoprotein (LDL)-particle phenotype has been reportedly trivial or moderate. We assessed the effect of rosuvastatin (the newest statin available) on the LDL subfraction profile in patients with primary hyperlipidemia. One hundred and twenty patients with primary hyperlipidemia without evidence of cardiovascular disease were randomized to therapeutic lifestyle modification ('control' group, N=60) or therapeutic lifestyle modification plus rosuvastatin 20 mg/day (N=60). Laboratory evaluation was performed at baseline and 12 weeks post-treatment. LDL subfraction analysis was carried out electrophoretically using of high-resolution 3% polyacrylamide gel tubes and the Lipoprint LDL System. Rosuvastatin induced a redistribution of LDL-cholesterol from small-dense LDL particles to large-buoyant ones and increased the mean LDL particle size. This beneficial effect was observed only in patients with baseline triglyceride levels >or=150 mg/dl (mean LDL particle size 255+/-7 A vs 260+/-5 A, P<0.01), whereas the LDL subfraction profile was not altered in those with triglyceride levels <150 mg/dl. Stepwise multivariate linear regression analysis revealed that baseline triglyceride levels (R(2)=0.29, P=0.001) followed by baseline insulin resistance as assessed by the HOmeostasis Model Assessment (HOMA) (R(2)=0.25, P=0.001) were independently associated with the rosuvastatin-induced increase in the mean LDL particle size. In conclusion, rosuvastatin at 20 mg/day favorably modified the relative distribution of LDL-cholesterol distribution on LDL subfractions as well as on the mean LDL particle size in patients treated for primary dyslipidemia. Baseline triglyceride levels as well as baseline HOMA-index were found to be the major predictors of this beneficial action of rosuvastatin.

Effect of rosuvastatin treatment on plasma visfatin levels in patients with primary hyperlipidemia.

Visfatin is a novel adipokine involved in the process of atherosclerosis. We assessed the effect of rosuvastatin on plasma visfatin levels in patients with primary hyperlipidemia. Eighty hyperlipidemic patients without evidence of cardiovascular disease were randomized to receive either rosuvastatin 10 mg/day or therapeutic lifestyle changes intervention. Plasma visfatin levels were determined at baseline and after 12-weeks post-randomization. Rosuvastatin induced a significant decrease in plasma visfatin levels (17.1+/-2.1 versus 15.5+/-2.0 ng/ml, P=0.03). This effect correlated with baseline visfatin levels (r=0.51, P<0.01) and was independent of any lipid-lowering actions of rosuvastatin.

An overview of the extra-lipid effects of rosuvastatin.

Statins, in addition to their beneficial lipid modulation effects, exert a variety of several so-called "pleiotropic" actions that may result in clinical benefits. Rosuvastatin, the last agent of the class to be introduced, has proved remarkably potent in reducing low-density lipoprotein cholesterol levels. At present, no large-scale primary or secondary prevention clinical trials document either its long-term safety or its effectiveness in preventing cardiovascular events. A substantial number of experimental and clinical studies have indicate favorable effects of rosuvastatin on endothelial function, oxidized low-density lipoprotein, inflammation, plaque stability, vascular remodeling, hemostasis, cardiac muscle, and components of the nervous system. Available data regarding the effects of rosuvastatin on renal function and urine protein excretion do not seem to raise any safety concerns. Whether the established "pleiotropy" and/or lipid-lowering efficacy of rosuvastatin may translate into reduced morbidity and mortality remains to be shown in ongoing clinical outcome trials.

Prevalence, Identification, and Scouting for Familial Hypercholesterolaemia Including Registries.

BACKGROUND: Familial Hypercholesterolaemia (FH) is the most common metabolic genetic disorder, with around 13 million people worldwide having the disease. However, FH is globally underdiagnosed and undertreated, while the vast majority of those treated do not achieve treatment goals. OBJECTIVE: This review aims to clarify how to identify patients with FH. METHODS: We performed a comprehensive search of the literature to identify available data. RESULTS: Patients with FH are at high risk for cardiovascular events and death at an early age. Therefore, prompt detection of individuals with FH is of pivotal importance in order to implement appropriate preventive measures at a young age. Patient registries are a powerful tool for recording and monitoring a disease and encouraging clinical practices, subsequently improving outcomes and reducing healthcare costs. National FH registries are successfully applied in several countries (e.g. Spain, Denmark, UK, USA and the Netherlands). Importantly, in the last few years, the European Atherosclerosis Society (EAS) launched a global FH network aiming to collect data from specialized FH centres from different countries and establish a worldwide, standardised registry of patients with FH. CONCLUSION: It appears that the establishment and proper function of such registries will improve FH diagnosis, as well as preventive measures and management of FH patients.

A 12-week, prospective, open-label analysis of the effect of rosuvastatin on triglyceride-rich lipoprotein metabolism in patients with primary dyslipidemia.

BACKGROUND: Although the effect of statins on lowering low-density lipoprotein cholesterol (LDL-C) has been extensively studied, their hypotriglyceridemic capacity is not fully understood. OBJECTIVE: The present study examined clinical and laboratory factors potentially associated with the triglyceride (TG)-lowering effect of rosuvastatin. METHODS: Eligible patients had primary dyslipidemia and a moderate risk of heart disease. Patients were prescribed rosuvastatin 10 mg/d in an open-label fashion and kept 3-day food diaries. Laboratory measurements, performed at baseline and 12 weeks, included serum lipid parameters (total cholesterol [TC], TGs, LDL-C, high-density lipoprotein cholesterol [HDL-C], and apolipoprotein [apo] levels), non-lipid metabolic variables (including carbohydrate metabolism parameters and renal, liver, and thyroid function tests), and LDL-subfraction profile (by high-resolution 3% polyacrylamide gel electrophoresis). Tolerability was assessed at each visit. RESULTS: Participants were 75 hyperlipidemic patients (39 men and 36 women; mean age, 51.7 years). At 12 weeks, TC levels were reduced by 35.1% (P < 0.001), TGs by 15.2% (P < 0.001), LDL-C by 48.5% (P < 0.001), apoE by 35.4% (P < 0.001), and apoE by 17.3% (P < 0.001) from baseline, whereas HDL-C and apoA1 levels were not significantly changed. Stepwise linear regression analysis showed that baseline TG levels were most significantly correlated (R(2) = 42.0%; P < 0.001) with the TG-lowering effect of rosuvastatin, followed by the reduction in apoCIII levels (R(2) = 13.6%; P < 0.01). Rosuvastatin use was associated with a reduction in cholesterol mass of both large LDL particles (mean [SD], from 150.5 [36.6] to 90.5 [24.3] mg/dL; P < 0.001) and small, dense LDL (sdLDL) particles (from 11.5 [8.4] to 6.6 [4.5] mg/dL; P < 0.001). Rosuvastatin had no effect on cholesterol distribution of the LDL subfractions (mean [SD], large particles, from 90.8% [7.0%] to 91.8% [5.1%]; sdLDL, from 7.1% [4.7%] to 7.5% [4.8%]) or the mean LDL particle size (from 26.5 [4.2] to 26.6 [4.0] rim). A significant increase in mean LDL particle size after rosuvastatin treatment (mean [SD], from 26.4 [0.4] to 26.9 [0.4] rim; P = 0.02) was observed only in patients with baseline TG levels > or =120 mg/dL. No serious adverse events requiring study treatment discontinuation were reported. One patient who presented with headache and 2 patients who presented with fatigue quickly recovered without discontinuing rosuvastatin treatment. A posttreatment elevation in aminotransferase levels <3-fold the upper limit of normal (ULN) was recorded in 5 (6.7%) patients, and 2 (2.7%) patients experienced elevated creatine kinase concentrations <5-fold ULN. CONCLUSION: Baseline TG levels were the most important independent variable associated with the TG-lowering effect of rosuvastatin.