Danielle Duffy

Update on strategies to increase HDL quantity and function

Low levels of HDL cholesterol are a significant predictor of atherosclerotic cardiovascular events. HDL is believed to protect against atherosclerosis by promoting reverse cholesterol transport, and potentially through anti-inflammatory, antioxidative, antithrombotic and nitric oxide effects. The multiple mechanisms of action, as well as a limited ability to measure these properties, make HDL a complex therapeutic target, albeit one with immense potential for the treatment of patients with atherosclerosis. Here, we discuss new therapeutic strategies currently being developed, which have the potential to increase plasma levels of HDL cholesterol and/or improve HDL function.

Effects of Pioglitazone on Lipoproteins, Inflammatory Markers, and Adipokines in Nondiabetic Patients with Metabolic Syndrome

Objective—The purpose of this research was to evaluate the short-term effects of pioglitazone (PIO) on high-density lipoprotein cholesterol (HDL-C) and other metabolic parameters in nondiabetic patients with metabolic syndrome (MetSyn). Methods and Results—Sixty nondiabetic adults with low HDL-C and MetSyn were randomized to PIO or matching placebo for 12 weeks. PIO increased HDL-C by 15% and 14% at 6 and 12 weeks, respectively, compared with placebo (P<0.001). Changes in HDL-C were correlated to changes in adiponectin (r=0.34; P=0.01) but not to changes in insulin resistance. PIO did not affect serum triglycerides or low-density lipoprotein (LDL) cholesterol concentrations but reduced the number of small LDL particles by 18% (P<0.001). PIO reduced median C-reactive protein levels by 31% (P<0.001) and mean resistin levels by 10% (P=0.02) while increasing mean serum levels of adiponectin by 111% (P<0.001) compared with placebo. PIO did not affect weight and modestly decreased insulin resistance. Conclusions—In nondiabetic patients with low HDL-C and MetSyn, PIO significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, LDL-C, or weight. These results suggest that PIO has direct effects on HDL, which may contribute to its antiatherogenic effects.

Emerging Therapies Targeting High-Density Lipoprotein Metabolism and Reverse Cholesterol Transport

Numerous prospective epidemiological studies have shown a strong inverse relationship between HDL cholesterol (HDL-C) levels and coronary heart disease (CHD).1 Many controlled clinical trials also demonstrate that treating patients who have low HDL-C with various lipid-modifying therapies, including statins, fibrates, niacin, or combination therapy, can reduce major coronary events.2–12 The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines recognize low HDL-C (<40 mg/dL) as an independent major risk factor for CHD, as a component of the metabolic syndrome, and as a potential target for therapeutic intervention.13 However, the primary target of the NCEP ATP III guidelines is to lower LDL cholesterol (LDL-C), given the strong and abundant clinical trial data for both primary and secondary prevention of adverse coronary events by lowering LDL-C. The recent update to the ATP III guidelines recommends even more aggressive treatment of LDL-C given new clinical trial data.14 However, even in patients treated to aggressive LDL-C goals, coronary events still occur,15,16 and low HDL-C is a major risk factor in this group. Therefore, a natural next step in the search for therapies to further reduce cardiovascular morbidity and mortality leads to raising HDL-C levels and/or improving HDL function. An important concept with regard to HDL-based therapies is that the plasma HDL-C level per se may not reflect the functionality of HDL or the impact of a specific HDL-targeted therapy on atherosclerosis or cardiovascular risk. In this review we focus on the concepts underlying the therapeutic targeting of HDL metabolism and the specific areas and compounds in clinical and preclinical development. Therapeutic lifestyle changes are currently recommended as first-line therapy in patients with low HDL-C levels. Smoking depresses HDL-C levels, and cessation is associated with modest increases in HDL-C.17,18 Aerobic exercise can raise HDL-C levels, but in …

Treatment Gaps in Adults with Heterozygous Familial Hypercholesterolemia in the United States: Data from the CASCADE-FH Registry

Background— Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results— We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08–2.82) and hypertension (2.48; 1.92–3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86–28.86) and use of >1 LDL-lowering medication (1.80; 1.34–2.41). Conclusions— FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

Potent and Selective PPAR-α Agonist LY518674 Upregulates Both ApoA-I Production and Catabolism in Human Subjects With the Metabolic Syndrome

Objective—The study of PPAR-α activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-α agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-α agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C). Methods and Results—Subjects were randomized to receive LY518674 (100 &mgr;g) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (−38%, P=0.002) and triglyceride (−23%, P=0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (−12%, P=0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P<0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (P=0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (P<0.0001) accompanied by a 25% increase in the FCR (P<0.0001), resulting in a significant increase in plasma apoA-II. Conclusions—Activation of PPAR-α with LY518674 (100 &mgr;g) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined.

Drugs in development: targeting high-density lipoprotein metabolism and reverse cholesterol transport.

Purpose of review This review summarizes currently available therapies for raising high-density lipoprotein cholesterol (HDL-C) and expands on therapies currently in development that target high-density lipoprotein cholesterol. Recent findings In the realm of new high-density lipoprotein-raising therapies, there is a strong focus on high-density lipoprotein metabolism and the reverse cholesterol transport pathway. Several infusions of recombinant apoA-I Milano/phospholipid complexes appeared to reduce atheroma volume as measured by intravascular ultrasound. Both intravenous and oral apoA-I mimetic peptides are in early clinical trials. Next generation PPAR-α agonists are more potent at high-density lipoprotein-raising than currently available fibrates, and dual PPAR-α/PPAR-γ agonists are under investigation to help correct atherogenic dyslipidemia seen in many diabetics. Two small molecule inhibitors of the cholesteryl ester transfer protein have shown promise in clinical trials at substantially raising high-density lipoprotein cholesterol. Summary Larger scale clinical trials, including those with additional surrogate outcome measures as well as cardiovascular event outcomes are needed to further assess the benefit of newer high-density lipoprotein-raising therapies. Additional therapeutics are currently in development that target other parts of the reverse cholesterol transport pathway and, in addition to providing new potential pharmaceuticals, will help to further elucidate the atheroprotective mechanisms of high-density lipoprotein cholesterol.

Pharmacokinetic Interactions of the Microsomal Triglyceride Transfer Protein Inhibitor, Lomitapide, with Drugs Commonly Used in the Management of Hypercholesterolemia

To characterize the effects of two doses (10 and 60 mg) of lomitapide—a microsomal triglyceride transfer protein inhibitor approved as adjunct treatment to lower low‐density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia—on the pharmacokinetics of several lipid‐lowering therapies: atorvastatin, simvastatin, rosuvastatin, fenofibrate, ezetimibe, and niacin.

The impact of high-density lipoprotein cholesterol levels on long-term outcomes after non-ST-elevation myocardial infarction

BACKGROUND Low serum high-density lipoprotein cholesterol (HDL-C) level is a potent risk factor for developing atherosclerosis, yet it is uncertain if HDL-C level at the time of non-ST-segment elevation myocardial infarction (NSTEMI) has downstream prognostic importance. METHODS We evaluated 24,805 patients with NSTEMI aged ≥ 65 years enrolled at 434 Can Rapid Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) participating hospitals between February 15, 2003, and December 30, 2006, who had clinical data linked to Medicare files through December 31, 2008. Unadjusted and adjusted hazard ratios (HRs) were calculated to determine the association between HDL-C level at initial hospitalization and all-cause mortality, as well as a combined outcome of all-cause mortality or recurrent myocardial infarction (MI). RESULTS Overall, 50% of patients had low HDL-C (≤ 40 mg/dL) and 18% had very low HDL-C (≤ 30 mg/dL). The rate of all-cause mortality was 39.5% during a median follow-up of 2.9 years; death or recurrent MI occurred in 43% in this older population with NSTEMI. Compared with patients who had normal HDL-C, those with very low HDL-C had a modest but significantly higher long-term mortality risk (adjusted HR 1.12, 95% CI 1.06-1.19, P = .0001). The adjusted HR for mortality or recurrent MI was the same. When modeled as a continuous variable, every 5-mg/dL decrement in HDL-C below 40 mg/dL was associated with a 5% increased risk of long-term mortality, as well as the combined end point. CONCLUSIONS Older patients with NSTEMI with low levels of HDL-C are at increased risk for downstream mortality or recurrent MI. Future studies are needed to evaluate strategies to reduce this residual risk.

2013 ACC/AHA cholesterol treatment guideline: Paradigm shifts in managing atherosclerotic cardiovascular disease risk

The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults represents a major shift from prior cholesterol management guidelines. The new guidelines include data from individual randomized trials as well as the most comprehensive meta-analyses, and introduce several major paradigm shifts, which include: aiming for ASCVD risk reduction as opposed to targeting LDL-C levels, advocating for the use of evidence-based doses of statins as first line therapy, and utilizing a new risk calculator and risk cut point to guide initiation of statin therapy. These major changes have created controversy and confusion among the medical community, with some clinicians hesitant to embrace the shift. We review the evidence that forms the basis for these major changes, compare them to other major lipid guidelines, and recommend an integrated approach to managing dyslipidemia to decrease atherosclerotic cardiovascular disease risk.

Aspirin for Cardioprotection and Strategies to Improve Patient Adherence

Abstract Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in North America. Aspirin therapy has proven clinical effectiveness in the prevention and treatment of CVD and is one of the most widely used drugs nationwide. However, despite the medications popularity and utility, adherence to a proper aspirin regimen is suboptimal, resulting in adverse health outcomes and increased health care costs. Our review outlines current knowledge on aspirin therapy adherence, causes of nonadherence, and strategies available to increase adherence to aspirin and medications in general. We demonstrate that, indeed, aspirin adherence rates are suboptimal, ranging from 72% to 92%, and that a combination of patient– and medication–related factors contribute to nonadherence. A multidimensional approach involving patient education and medication innovations to reduce aspirin side effects is imperative to improving rates of aspirin therapy adherence.