Cardiovascular disease is a significant cause of morbidity and mortality in patients with diabetes mellitus (DM). DM is now recognized as a risk equivalent for coronary heart disease. The lipid profile in patients with type 2 DM is characterized by elevated triglycerides, low levels of high-density lipoprotein cholesterol, and small dense low-density lipoprotein cholesterol (LDLC) particles and is believed to be a key factor promoting atherosclerosis in these patients. Both primary and secondary prevention studies have provided ample evidence that aggressive statin therapy reduces cardiovascular end points in patients with DM. In all persons with DM, current treatment guidelines recommend reduction of LDLC to less than 100 mg/dL, regardless of baseline lipid levels. Lowering LDLC to less than 70 mg/dL may provide even greater benefits, particularly in very high risk patients with DM and coronary heart disease.

Objective-The study of PPAR-␣ activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-␣ agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-␣ 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 g) once daily (nϭ13) or placebo (nϭ15) 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 (Ϫ38%, Pϭ0.002) and triglyceride (Ϫ23%, Pϭ0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (Ϫ12%, Pϭ0.01) 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% (PϽ0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (Pϭ0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (PϽ0.0001) accompanied by a 25% increase in the FCR (PϽ0.0001), resulting in a significant increase in plasma apoA-II. Conclusions-Activation of PPAR-␣ with LY518674 (100 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.

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Background Postprandial triglyceridemia predicts cardiovascular events. Niacin might lower postprandial triglycerides (TG) by restricting free fatty acid (FFA). Immediate-release niacin reduced postprandial TGs, but extended-release niacin failed to do so when dosed the night before a fat challenge. Aims 1) Determine whether extended-release niacin dosed before a fat challenge suppresses postprandial TG. 2) Determine whether postprandial TG is related to FFA restriction. Methods Double-blinded, placebo-controlled, random-order crossover experiment, where healthy volunteers took 2 g extended-release niacin or placebo 1 hour before heavy cream. We sampled blood over 12 hours, and report TG and FFA as means±SD for incremental area under the curve (iAUC) and nadir. Results Combining 43 fat challenges from 22 subjects, postprandial TG iAUC was +312±200 on placebo vs +199±200 mg/dL*h on extended-release niacin (33% drop, p= 0.02). The incremental nadir for FFA was −0.07±0.15 on placebo vs −0.27±0.13 mmol/L on extended-release niacin (p<0.0001), and FFA iAUC fell from +2.9±1.5 to +1.5±1.5 mmol/L*h on extended-release niacin (20% drop, p=0.0015). The TG iAUC was strongly related to the post-dose drop in FFA (r=+0.58, p=0.0007). Conclusions Given right before a fat meal, even a single dose of extended-release niacin suppresses postprandial triglyceridemia. This establishes that postprandial TG suppression is an acute pharmacodynamic effect of extended-release niacin, probably the result of marked FFA restriction. Further study is warranted to determine whether mealtime dosing would augment the clinical efficacy of extended-release niacin therapy.

Elevated low-density lipoprotein cholesterol (LDL-C) levels are associated with an increased risk for cardiovascular disease (CVD). Statins have been the cornerstone of lipid therapy to lower LDL-C for the past two decades, but despite significant clinical efficacy in a majority of patients, a large residual risk remains for the development of initial or recurrent atherosclerotic CVD. In addition, owing to the side-effects, a significant percentage of patients cannot tolerate any statin dose or a high enough statin dose. Thus, novel therapeutic agents are currently being developed to lower LDL-C levels further. This review will highlight these novel therapeutic agents including antisense oligonucleotides focused on apolipoprotein B, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and microsomal triglyceride transfer protein inhibitors. For each therapeutic class, an overview of mechanism of action, pharmacokinetic data, and efficacy/safety evidence will be discussed.

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