Current Atherosclerosis Reports

Sampson, Uchechukwu; Fazio, Sergio; Linton, MacRae

doi: 10.1007/s11883-011-0219-7pmid: 22102062

This review captures the existence, cause, and treatment challenges of residual cardiovascular risk (CVR) after aggressive low-density lipoprotein cholesterol (LDL-C) reduction. Scientific evidence implicates low high-density lipoprotein cholesterol (HDL-C) and high triglycerides (TG) in the CVR observed after LDL-C lowering. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial with fenofibrate, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) study with torcetrapib, and the recently terminated Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study with niacin, do not clearly attribute risk reduction value to HDL-C/TG modulation. The optimum approach to long-term lipid-modifying therapies for CVR reduction remains uncertain. Consequently, absolute risk modulation via lifestyle changes remains the centerpiece of a strategy addressing the physiologic drivers of CVR associated with HDL-C/TG, especially in the context of diabetes/metabolic syndrome.

Raper, Anna; Kolansky, Daniel; Cuchel, Marina

doi: 10.1007/s11883-011-0215-ypmid: 22135161

Familial hypercholesterolemia (FH) is a genetic lipid disorder that is characterized by severely elevated cholesterol levels and premature cardiovascular disease. Both the heterozygous and homozygous forms of FH require aggressive cholesterol-lowering therapy. Statins alone frequently do not lower these patients’ cholesterol to therapeutic levels, and some patients are intolerant to statins. Combination or monotherapy with other current pharmacotherapies are options, but even with these some FH patients do not meet their low-density lipoprotein (LDL) cholesterol goals. In the cases of statin intolerance, LDL apheresis may be another treatment option. There are currently several novel therapies in development for LDL lowering that target either production or catabolism of LDL, plaque regression, and potentially gene transfer. We conclude that there is a need beyond statins for patients with FH, especially in cases of statin intolerance, and when even the highest doses of statin do not get patients to goal cholesterol levels.

Desai, Dipan; Zakaria, Sammy; Ouyang, Pamela

doi: 10.1007/s11883-011-0220-1pmid: 22086344

Cardiovascular disease (CVD) is the leading cause of death, with a higher prevalence in older adults who form an increasing proportion of the population of the United States. Statin treatment reduces cardiovascular morbidity and mortality in middle-aged adults. However, few studies have included older individuals, particularly ages 80 years or older. We review recent publications regarding primary and secondary prevention of CVD with statin therapy in older adults. Risk scores and their limitations in this population are discussed. The association of adverse effects with intensive doses of statin and their interactions with other drugs may be more problematic in older adults. Statin therapy appears cost-effective for individuals with higher CVD risk but this is dependent on the assumptions used. Evidence remains limited regarding the overall benefit of starting statin therapy in adults ages 80 years and older; thus, clinical judgment remains necessary in making this decision.

Kinlay, Scott

doi: 10.1007/s11883-011-0218-8pmid: 22125118

The clinical value of measuring C-reactive protein (CRP) to guide statin therapy is uncertain. It has no value in patients at high risk who would be treated regardless of CRP (eg, patients with coronary disease or of equivalent risk), in patients at low risk who do not warrant treatment, and those with other acute or chronic inflammatory conditions that amplify CRP. Drawbacks to the widespread clinical use of CRP include its small impact on risk prediction beyond other risk factors, and evidence from JUPITER and other trials that baseline CRP is unable to identify patients who obtain greater absolute benefits from statin therapy. Furthermore, the within-person variability of CRP is about the same as the reduction in CRP from intensive statin therapy, and this leads to many patients registering an increase in CRP with treatment. For these reasons, CRP has no clear role in determining who should receive statin therapy or for monitoring the success of treatment.

Shanes, Jeffrey

doi: 10.1007/s11883-011-0222-zpmid: 22109348

Statins alone are not always adequate therapy to achieve low-density lipoprotein (LDL) goals in many patients. Many options are available either alone or in combination with statins that makes it possible to reach recommended goals in a safe and tolerable fashion for most patients. Ezetimibe and bile acid sequestrants reduce cholesterol transport to the liver and can be used in combination. Niacin is very effective at lowering LDL, beyond its ability to raise high-density lipoprotein and shift LDL particle size to a less atherogenic type. When statins cannot be tolerated at all, red yeast rice can be used if proper formulations of the product are obtained. Nutrients can also be added to the diet, including plant stanols and sterols, soy protein, almonds, and fiber, either individually or all together as a portfolio diet. A clear understanding of how each of these strategies works is essential for effective results.

Schwartz, Gregory

doi: 10.1007/s11883-011-0217-9pmid: 22083134

High-density lipoprotein (HDL) cholesterol levels bear an inverse relationship to cardiovascular risk. To date, however, no intervention specifically targeting HDL has been demonstrated to reduce cardiovascular risk. Cholesterol ester transfer protein (CETP) mediates transfer of cholesterol ester from HDL to apolipoprotein B–containing particles. Most, but not all observational cohort studies indicate that genetic polymorphisms of CETP associated with reduced activity and higher HDL cholesterol levels are also associated with reduced cardiovascular risk. Some, but not all studies indicate that CETP inhibition in rabbits retards atherosclerosis, whereas transgenic CETP expression in mice promotes atherosclerosis. Torcetrapib, the first CETP inhibitor to reach phase III clinical development, was abandoned due to excess mortality associated with increases in aldosterone and blood pressure. Two other CETP inhibitors have entered phase III clinical development. Anacetrapib is a potent inhibitor of CETP that produces very large increases in HDL cholesterol and large reductions in low-density lipoprotein (LDL) cholesterol, beyond those achieved with statins. Dalcetrapib is a less potent CETP inhibitor that produces smaller increases in HDL cholesterol with minimal effect on LDL cholesterol. Both agents appear to allow efflux of cholesterol from macrophages to HDL in vitro, and neither agent affects blood pressure or aldosterone in vivo. Two large cardiovascular outcomes trials, one with anacetrapib and one with dalcetrapib, should provide a conclusive test of the hypothesis that inhibition of CETP decreases cardiovascular risk.

Villines, Todd; Kim, Andrew; Gore, Rosco; Taylor, Allen

doi: 10.1007/s11883-011-0212-1pmid: 22037771

The use of FDA-approved niacin (nicotinic acid or vitamin B3) formulations at therapeutic doses, alone or in combination with statins or other lipid therapies, is safe, improves multiple lipid parameters, and reduces atherosclerosis progression. Niacin is unique as the most potent available lipid therapy to increase high-density lipoprotein (HDL) cholesterol and it significantly reduces lipoprotein(a). Through its action on the GPR109A receptor, niacin may also exert beneficial pleiotropic effects independent of changes in lipid levels, such as improving endothelial function and attenuating vascular inflammation. Studies evaluating the impact of niacin in statin-naïve patients on cardiovascular outcomes, or alone and in combination with statins or other lipid therapies on atherosclerosis progression, have been universally favorable. However, the widespread use of niacin to treat residual lipid abnormalities such as low HDL cholesterol, when used in combination with statins among patients achieving very low (<75 mg/dL) low-density lipoprotein cholesterol levels, is currently not supported by clinical outcome trials.

Igel, Leon; Powell, Amanda; Apovian, Caroline; Aronne, Louis

doi: 10.1007/s11883-011-0221-0pmid: 22113707

Overweight and obesity are now recognized as leading causes of diseases such as type 2 diabetes, hypertension, hyperlipidemia, and ultimately, cardiovascular disease. Despite the serious consequences, roughly two thirds of Americans are presently classified as overweight, and about one third are classified as obese. Weight loss via lifestyle modification and pharmacotherapy can promote improvement in many of these obesity-related conditions. This review addresses recent advances in pharmacotherapy for the management of obesity and obesity-related co-morbidities, with a focus on the management of obesity specifically in individuals with type 2 diabetes. Emphasis is also placed on a proposed paradigm shift from the glucose-centric to the weight-centric management of type 2 diabetes mellitus.

Deano, Roderick; Sorrentino, Matthew

doi: 10.1007/s11883-011-0214-zpmid: 22037772

Thiazide diuretics and beta-blockers are first-line therapies for hypertension unless there are compelling indications for other drug classes. Diuretics and beta-blockers, however, may worsen dyslipidemia and glucose tolerance whereas antihypertensive agents in other drug classes may have neutral or beneficial effects. Initial clinical trials of antihypertensive regimens suggested that blood pressure lowering was the most important aspect of therapy and that the adverse effects on lipids and glucose tolerance did not impact clinical outcomes. Newer trials, however, question this finding and implicate these pleotropic effects as contributing to the results of the trials. Patients with cardiometabolic risk factors may have compelling indications for agents that inhibit the renin-angiotensin-aldosterone system, relegating diuretics and beta-blockers to third-line therapy.

Kim, Luke; Charitakis, Konstantinos; Swaminathan, Rajesh; Feldman, Dmitriy

doi: 10.1007/s11883-011-0216-xpmid: 22102061

Advances in antiplatelet therapy have significantly improved outcomes in patients with ischemic heart disease. Thienopyridines remain a cornerstone of therapy along with aspirin. Recently, concerns have been raised about the use of clopidogrel due to its pharmacokinetic and pharmacogenetic interpatient variability. A third-generation thienopyridine, prasugrel, overcomes some of these problems by improving inhibition of platelet aggregation, but increasing the risk of peri-procedural bleeding. Other novel antiplatelet agents, such as ticagrelor, have shown improved efficacy in recent trials and require further investigations. The field of pharmacotherapy continues to rapidly evolve as newer agents, such as thrombin receptor antagonists, along with older agents, such as cilostazol and glycoprotein IIb/IIIa inhibitors, are being explored.