Jennifer Moon

Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease.

The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.

Management of Cardiovascular Risk: The Importance of Meeting Lipid Targets

Strategies to reduce cardiovascular risk in primary and secondary prevention focus on optimization of low-density lipoprotein (LDL) cholesterol levels. Since the 2004 update of the Adult Treatment Panel (ATP) III guidelines, developments in the field of preventive cardiology have included new guidelines for women and for familial hypercholesterolemia; a risk assessment algorithm incorporating the inflammatory marker high-sensitivity C-reactive protein (hsCRP); and clinical trial data confirming the efficacy of aggressive lipid management. Within secondary prevention in particular, there is a need for more widespread use of intensive statin therapy to achieve low LDL cholesterol levels to reduce cardiovascular morbidity and mortality in patients at high risk for recurrent events. Within primary prevention, individuals with diabetes mellitus, mixed dyslipidemia, or elevated hsCRP also are at increased risk and may warrant treatment with aggressive lipid-modifying therapy. In this article, we provide an update on recent guidelines, risk algorithms, and trials related to the prevention and treatment of coronary artery disease.

Recent clinical studies of the effects of lipid-modifying therapies.

Results from multiple clinical trials, primarily with the class of lipid-lowering agents known as statins, have shown that reductions in low-density lipoprotein (LDL) cholesterol are associated with reduced risk of coronary artery disease. Although LDL cholesterol is the primary target of cholesterol management strategies, increasing attention has focused on the role of inflammation, high-density lipoprotein cholesterol, and triglycerides in atherosclerosis and cardiovascular disease. We review major trials with lipid-modifying therapies published since the 2004 update of the Adult Treatment Panel (ATP) III guidelines. A pivotal trial was the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which demonstrated significant reductions in cardiovascular morbidity and mortality in healthy individuals without elevated LDL cholesterol but with high levels of the inflammatory marker high-sensitivity C-reactive protein. Additional trials demonstrated the efficacy of intensive statin therapy in secondary prevention, whereas other agents, including fibrates, omega-3 fatty acids, niacin, ezetimibe, and experimental cholesteryl ester transfer protein inhibitors, have been evaluated for their ability to reduce residual cardiovascular risk.

Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with Anacetrapib in the DEFINE study

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.

Pharmacotherapies for lipid modification: beyond the statins

The widespread clinical use of statins has contributed to significant reductions in the rate of cardiovascular morbidity and mortality over the past 3 decades, and statins are considered first-line therapy for the prevention and treatment of atherosclerotic vascular disease. Nevertheless, various other lipid-lowering agents can provide clinical benefit by supplementing or augmenting statin therapy in patients with severe hypercholesterolaemia or mixed dyslipidaemia, or by providing an alternative for patients who are intolerant to statins. Bile acid resins and niacin were prescribed for lipid modification for years before the introduction of the statins, and new data continue to emerge regarding their use in different patient groups and for specific conditions. Ezetimibe can be appropriate for patients whose primary lipid abnormality is an elevated LDL-cholesterol level, whereas the fibrates seem to be most beneficial in patients with low levels of HDL cholesterol and elevated triglycerides. At the end of 2012 and the beginning of 2013, the first microsomal triglyceride transfer protein inhibitor, lomitapide, and the first antisense therapy to target apolipoprotein B, mipomersen, were approved for the treatment of individuals with extremely elevated LDL-cholesterol levels caused by homozygous familial hypercholesterolaemia. Although two agents in the experimental class of cholesteryl ester transfer protein inhibitors have failed to show a benefit in clinical trials, newer drugs in this class could provide an additional strategy to address residual cardiovascular risk in patients treated with statins.

Safety of inhibition of cholesteryl ester transfer protein with anacetrapib: the DEFINE study.

Inhibition of cholesteryl ester transfer protein is a strategy under investigation for raising HDL cholesterol levels and addressing residual cardiovascular risk after effective reduction of LDL cholesterol. In the Phase III DEFINE trial conducted in patients with or at high risk for coronary heart disease, anacetrapib reduced LDL cholesterol levels by 39.8% after 24 weeks compared with placebo and demonstrated an acceptable safety profile through 76 weeks of treatment (the primary end points). Anacetrapib caused a placebo-adjusted 138.1% increase in HDL cholesterol levels, with no alterations in blood pressure, aldosterone or electrolytes. The trial also provided reassurance that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with a previous cholesteryl ester transfer protein inhibitor. Sustained effects on lipids were observed 12 weeks following cessation of anacetrapib treatment. Anacetrapib is being evaluated in an ongoing cardiovascular outcomes trial.

Pitavastatin for the treatment of primary hyperlipidemia and mixed dyslipidemia

Pitavastatin is a new, synthetic member of the statin class of lipid-lowering drugs. Compared with other available statins, it has a unique cyclopropyl group on its base structure that is believed to increase 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition by a factor of five and to significantly increase the transcription and activity of LDL receptors. Pitavastatin is primarily metabolized via glucuronidation and is not a substrate for the cytochrome P450 3A4 enzyme, thus avoiding the potential for cytochrome P450-mediated drug–drug interactions. Clinical trials have shown that pitavastatin is comparable to atorvastatin and simvastatin in improving lipid measures, and more potent than pravastatin. Pitavastatin is effective in reducing triglycerides and increasing HDL-cholesterol, so it will be particularly beneficial in treating patients with mixed dyslipidemia. Its safety and adverse event profile is similar to that of other available statins, and it has an established history of use in Asia indicating tolerability and safety for treatment lasting up to 7 years.

Diversity Efforts, Admissions, and National Rankings: Can We Align Priorities?

Background: Increasing student body diversity is a priority for national health education and professional organizations and for many medical schools. However, national rankings of medical schools, such as those published by U.S. News & World Report, place a heavy emphasis on grade point average (GPA) and Medical College Admissions Test (MCAT) scores, without considering student body diversity. These rankings affect organizational reputation and admissions outcomes, even though there is considerable controversy surrounding the predictive value of GPA and MCAT scores. Summary: Our aim in this article was to explore the relationship between standard admissions practices, which typically aim to attract students with the highest academic scores, and student body diversity. We examined how changes in GPA and MCAT scores over 5 years correlated with the percentage of enrolled students who are underrepresented in medicine. In a majority of medical schools in the United States from 2005 to 2009, average GPA and MCAT scores of applicants increased, whereas the percentage of enrolled students who are underrepresented in medicine decreased. Conclusions: Our findings suggest that efforts to increase the diversity of medical school student bodies may be complicated by a desire to maintain high average GPA and MCAT scores. We propose that U.S. News revise its ranking methodology by incorporating a new diversity score into its student selectivity score and by reducing the weight placed on GPA and MCAT scores.

Twenty-five years of statins: where do we go from here?

Abstract More than 25 years of clinical trial data have established statins as first-line therapy for the prevention and treatment of atherosclerotic cardiovascular disease. With regard to low-density lipoprotein cholesterol, a wealth of evidence indicates that ‘lower is better,’ although recent guidelines from the American College of Cardiology and the American Heart Association take a different approach. A variety of approved and experimental lipid-lowering agents may be used as supplements or alternatives to statin therapy in patient subgroups, including those with familial hypercholesterolemia, mixed dyslipidemia or statin intolerance. Strategies to achieve further reductions in low-density lipoprotein cholesterol, target high-density lipoprotein cholesterol and triglycerides or reduce inflammation may help address residual cardiovascular risk, although early lifestyle interventions are crucial to prevention strategies.

Statins: Risk-Benefits and Role in Treating Dyslipidemias

Statins are the mainstay of therapy for the management of dyslipidemia, and particularly elevations in low-density lipoprotein cholesterol (LDL-C). Currently available statins include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. The advent of statin therapy has contributed to a substantial decrease in cardiovascular mortality over the past several decades. Results from multiple clinical trials have shown conclusively that lowering LDL-C levels leads to clinical event reduction in primary and secondary prevention, for both men and women, and across various other patient subgroups. Extensive clinical experience indicates that statin therapy may be initiated and maintained over the long term with a high degree of safety, and adverse effects associated with statin use are outweighed by their proven benefits in clinical event reduction.