mk-0524 and Atherosclerosis

The absolute level of HDL cholesterol (HDL-C) may not be the only criterion contributing to their antiatherothrombotic effects. This review focuses on evidence in support of the concept that HDL-bound sphingosine-1-phosphate (S1P) plays a role in different HDL atheroprotective properties and may represent a potential target for therapeutic interventions.. Recent large randomized clinical trials testing the hypothesis of raising HDL-C with niacin and dalcetrapib in statin-treated patients failed to improve cardiovascular outcomes. Emerging evidence suggests that many of the cardioprotective functions of HDL, such as vasodilation, angiogenesis and endothelial barrier function, protection against ischemia/reperfusion injury, and inhibition of atherosclerosis, may be attributable to its S1P cargo. HDL-associated S1P may represent a future therapeutic target.. HDL functionality is affected by its composition and there is evidence to suggest S1P plays a role in some of HDL's functions and atheroprotective properties.

Topics: Animals; Atherosclerosis; Cardiotonic Agents; Cholesterol, HDL; Coronary Artery Disease; Drug Therapy, Combination; Humans; Indoles; Lysophospholipids; Niacin; Randomized Controlled Trials as Topic; Sphingosine; Treatment Outcome

Atherosclerosis is a chronic inflammatory disease affecting medium and large arteries resulting from a complex interaction between genetic and environmental risk factors that include dyslipidemia, hypertension, diabetes mellitus, and smoking. The most serious manifestations of atherosclerotic vascular disease, such as unstable angina, myocardial infarction, ischemic stroke, and sudden death, largely result from thrombosis superimposed on a disrupted (ruptured or eroded) atherosclerotic plaque. Adoption and maintenance of a healthy lifestyle coupled with management of modifiable risk factors significantly reduce the adverse clinical consequences of athero-thrombosis. Reducing low-density lipoprotein cholesterol levels using statins and other agents serves as the primary pharmacologic approach to stabilize atherosclerotic vascular disease. However, a large residual risk remains, prompting the search for additional therapies for atherosclerosis management, such as raising atheroprotective high-density lipoprotein (HDL) and/or improving HDL function. This review focuses on new and emerging HDL-based therapeutic strategies targeting atherosclerosis.

Topics: Animals; Apolipoproteins; Atherosclerosis; Dyslipidemias; Endothelium, Vascular; Fibric Acids; Fibrinolysis; Gene Transfer Techniques; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins, HDL; Lipoproteins, LDL; Niacin; Oxidation-Reduction; Risk Factors; Thrombosis

Prevention of cardiovascular disease has been only partially successful with the use of cholesterol-lowering drugs like statins. There is a residual risk remaining, which may be addressed by increasing protective high-density lipoprotein (HDL) cholesterol and apolipoprotein A1. The best drug available for that purpose is niacin. In addition to increasing HDL cholesterol and apolipoprotein A1, niacin decreases triglycerides, low-density lipoprotein (LDL)-cholesterol and lipoprotein(a) and has been named the broad-spectrum lipid drug.. This review summarizes to what extent a new formulation of niacin may meet this request. The effects of niacin on lipoproteins, atherosclerosis and cardiovascular disease are described, from its first publication in 1955, and also its mechanism of action on lipoproteins and on flushing. The flushing inhibitor laropiprant is described as well as the antiflushing effect of this compound when added to extended-release niacin.. The reader will gain knowledge of the development of niacin as an antiatherosclerosis treatment and of the added value that laropiprant may offer this treatment principle; and also the present place of niacin/laropiprant in the armamentarium of cardiovascular preventive drugs.. Niacin/laropiprant is a welcome means to address the residual risk in high-risk patients on statin therapy. However, the drug combination cannot completely eliminate niacin-induced side effects. Prescribing this treatment, therefore, will require careful provision of information and instruction to the patient.

Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Drug Therapy, Combination; Dyslipidemias; Flushing; Humans; Indoles; Lipid Metabolism; Niacin

Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain.. After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).. During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001).. Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.).

Topics: Aged; Atherosclerosis; Cholesterol, LDL; Delayed-Action Preparations; Diabetes Mellitus; Double-Blind Method; Drug Combinations; Female; Follow-Up Studies; Hemorrhage; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Infections; Male; Middle Aged; Musculoskeletal Diseases; Niacin; Risk Factors; Treatment Failure

The effects of different hypolipidemic treatment strategies on emerging atherosclerosis risk factors remain unknown.. This is a prespecified analysis of a prospective, randomized, open-label, blinded end point (PROBE) study (ClinicalTrials.gov identifier: NCT01010516). Patients (n = 100) with mixed dyslipidaemia on a standard statin dose who had not achieved lipid targets were randomized to switch to the highest dose of rosuvastatin (40 mg/day) or to add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) or to add-on-statin micronized fenofibrate for a total of 3 months.. Following 3 months of treatment, low-density lipoprotein (LDL) particle size increased equally in all groups. Similarly, all treatments were associated with comparable small dense LDL cholesterol reduction. Apolipoprotein B levels decreased by 15%, 7% and 4% in the rosuvastatin, add-on ER-NA/LRPT and add-on fenofibrate group, respectively (P < 0.01 for all compared with baseline, P < 0.01 for all comparisons between groups). Only add-on ER-NA/LRPT was associated with lipoprotein (a) reduction (26%, P < 0.01 compared with baseline). Rosuvastatin monotherapy and add-on ER-NA/LRPT groups were associated with 56% and 24% reduction in high-sensitivity C-reactive protein levels (hsCRP), respectively (P < 0.01 compared with baseline), while add-on fenofibrate was not associated with changes in hsCRP concentration. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity decreased similarly in both rosuvastatin and add-on fenofibrate groups, while add-on ER-NA/LRPT was associated with a more pronounced Lp-PLA2 activity reduction. ER-NA/LRPT was associated with more side effects compared with rosuvastatin and add-on fenofibrate.. Add-on ER-NA/LRPT followed by switch to the highest dose rosuvastatin were associated with more pronounced beneficial modifications in emerging cardiovascular risk factors compared with add-on fenofibrate in patients with mixed dyslipidaemia.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; Aged; Apolipoproteins B; Atherosclerosis; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Drug Therapy, Combination; Dyslipidemias; Female; Fenofibrate; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Male; Middle Aged; Niacin; Pilot Projects; Prospective Studies; Pyrimidines; Risk Factors; Rosuvastatin Calcium; Sulfonamides; Time Factors

A potentially atherogenic lipid profile often found in patients with type 2 diabetes mellitus (T2DM) includes increased concentrations of small, low-density lipoprotein (LDL) and intermediate-density lipoprotein (IDL) and decreased concentration of medium/large high-density lipoprotein (HDL) particles. Extended-release niacin/laropiprant (ERN/LRPT) lowers LDL-cholesterol (LDL-C) and triglycerides (TG), and raises HDL cholesterol (HDL-C) levels with attenuation of niacin-induced flushing.. Plasma HDL, LDL, IDL, very-low-density lipoprotein (VLDL), and chylomicron particle concentration and size at were evaluated at baseline and week 12 using nuclear magnetic resonance (NMR). The data were acquired from a randomized, multicenter, double-blind, placebo-controlled study including 796 patients with T2DM treated with either 1 tablet of ERN 1 gram/LRPT 20 mg or matching placebo daily, increased after 4 weeks to 2 tablets daily.. ERN/LRPT significantly (P≤0.001 for all) reduced LDL-C 17.9% and TG 23.1%, and increased HDL-C levels 23.2%. Compared to placebo, ERN/LRPT decreased LDL, IDL, VLDL, and chylomicron particle concentrations [median concentration of smallest LDL particles decreased 16.6%, 95% confidence interval (CI) -22.3, -10.9, whereas the largest LDL particles decreased 11.0%, 95% CI -18.7, -3.2, and total VLDL/chylomicron mean plasma particle concentration decreased 34.7%, 95% CI -41.3, -28.1]. Compared to placebo, ERN/LRPT shifted the distribution of HDL particle diameter from smaller to larger (median concentration of the largest HDL particles increased 32.7% (95% CI 25.30, 40.58), whereas concentration of the smallest HDL particles decreased 8.2% (95% CI -11.29, -5.06).. Compared with placebo in patients with T2DM, ERN/LRPT shifted the lipoprotein profile toward a potentially less atherogenic pattern with reduced atherogenic LDL and IDL particle concentrations, and increased large HDL plasma particle concentrations. (ClinicalTrials.gov: NCT00485758).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atherosclerosis; Cholesterol, HDL; Cholesterol, LDL; Chylomicrons; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypolipidemic Agents; Indoles; Lipids; Lipoproteins; Magnetic Resonance Spectroscopy; Male; Middle Aged; Niacin; Placebos; Triglycerides

Topics: Atherosclerosis; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Infections; Male; Niacin