mk-0524 and Hypercholesterolemia

Hypercholesterolemia is one of the main factors in the development of atherosclerotic cardiovascular disease. The advent of statins led to huge progress in the treatment of hypercholesterolemia, yet the proportion of patients with prohibitive lipid values and the high incidence of cardiovascular events despite treatment are still very high. Niacin, one of the older drugs used to treat hyperlipidemia, was shown to reduce low-density lipoprotein-cholesterol (LDL-C) and triglycerides and to markedly increase high-density lipoprotein-cholesterol (HDL-C) levels. This drug came into disuse owing to frequent side effects, mainly flushing, but in recent years a reemergence of its application has occurred, and multiple clinical trials have shown its effectiveness in the treatment of hyperlipidemia and in the reduction of cardiovascular events. New formulations such as extended-release niacin (ERN) have been developed with the purpose of reducing side effects. Lately, a new compound, laropiprant, which selectively antagonizes the prostaglandin 2 (PGD2) receptor responsible for flushing, has been developed. Laropiprant, when combined with ERN, significantly reduces the incidence of flushing. New and ongoing trials will definitively prove in the long term whether this drug combination significantly reduces the severity of flushing and the incidence of cardiovascular events.

Topics: Cholesterol; Dose-Response Relationship, Drug; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Niacin; Nicotinic Acids; Treatment Outcome; Vitamin B Complex

Although statins reduce cardiovascular morbidity and mortality further risk reduction is needed. In this respect low HDL-cholesterol concentrations and/or elevated triglyceride concentrations may be potential treatment targets. Niacin (nicotinic acid) is an effective drug which increases the plasma concentration of high-density lipoprotein (HDL)-cholesterol and decreases the concentration of low-density lipoprotein (LDL)-cholesterol, triglycerides and lipoprotein(a). Clinical studies indicate that niacin can significantly reduce the risk for cardiovascular events. However, niacin is not very commonly used because of significant side effects (especially flushing). Laropiprant is a potent selective antagonist of PGD2-receptor subtype-1 and can thus reduce niacin-induced flushing. Although the addition of laropiprant will reduce the frequency of flushing, it will not completely eliminate this side effect. Laropiprant does not change the effect of niacin on lipids or other side effects of niacin (ie, gastro-intestinal problems, glucose elevation). The combination of niacin with laropiprant may therefore enable use of niacin at higher doses and therefore exploit the full potential of the drug. Endpoint studies that will be published over the next few years will show whether this treatment modality also translates into clinical effect in patients treated with statins. Until publication of these studies niacin/laropiprant should be used only in high-risk patients not achieving lipid goals on statins.

Topics: Biomarkers; Cholesterol, HDL; Cholesterol, LDL; Drug Combinations; Dyslipidemias; Flushing; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Lipids; Lipoprotein(a); Niacin; Receptors, Immunologic; Receptors, Prostaglandin; Treatment Outcome; Triglycerides

Laropiprant is an antagonist of the prostaglandin PGD2 receptor DP1. Laropiprant has a weak affinity for the thromboxane A2 receptor TP. Two double-blinded, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose laropiprant at steady state on the antiplatelet effects of multiple-dose aspirin and clopidogrel. Study 1 had two treatment periods, in which each healthy subject received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 80 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 80 mg (Treatment B) once daily for 7 days. Study 2 consisted of three treatment periods. In the first two, each patient with hypercholesterolemia or mixed dyslipidemia received laropiprant 40 mg, clopidogrel 75 mg, and aspirin 81 mg (Treatment A), or placebo, clopidogrel 75 mg, and aspirin 81 mg (Treatment B) once daily for 7 days. In period 3, patients received a single dose of two tablets of extended release nicotinic acid 1 g/laropiprant 20 mg (Treatment C). In both studies, pharmacodynamic endpoints included bleeding time at 24 (primary) and 4 hours (secondary) post-dose following 7 days of once-daily laropiprant in combination with clopidogrel and aspirin, and platelet aggregation in platelet-rich plasma at 4 and 24 hours post-dose on day 7 (secondary). After 7 days, increased bleeding time of 27% (Study 1) and 23% (Study 2) at 24 hours post-dose was observed with laropiprant compared to placebo (both combined with clopidogrel and aspirin), with corresponding upper bounds of the 90% CI marginally exceeding the prespecified upper comparability bound of 1.50 in both studies. The GMR and 90% CI for bleeding time of laropiprant compared to placebo (both combined with clopidogrel and aspirin) at 4 hours post-dose on day 7 was 0.92 (0.70, 1.21) in Study 1, and 1.46 (1.20, 1.78) in Study 2. Compared with placebo, laropiprant (both combined with clopidogrel and aspirin) increased the inhibition of collagen- and ADP-induced platelet aggregation, respectively, by ∼2.4% and ∼8.1% in Study 1 and by ∼4% and ∼5.4% in Study 2, at 24 hours post-dose on day 7. The inhibition of collagen- and ADP-induced platelet aggregation, respectively, was increased by ∼0.1% and ∼5.0% in Study 1, and by ∼5% and ∼12% in Study 2, at 4 hours post-dose on day 7. In conclusion, co-administration of multiple doses of laropiprant with aspirin and clopidogrel induced a prolongation of bleeding time and an inhibitory effect on platelet aggregation ex vivo in healthy s

Topics: Adult; Aged; Aspirin; Clopidogrel; Cross-Over Studies; Double-Blind Method; Drug Interactions; Dyslipidemias; Female; Humans; Hypercholesterolemia; Indoles; Male; Middle Aged; Platelet Aggregation Inhibitors; Ticlopidine; Young Adult

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

To establish determinants of lipid goal attainment in primary care patients, with particular focus on participation in a disease management programme (DMP) on diabetes mellitus (DM) and/or coronary heart disease (CHD), with real-world practical relevance.. The present analysis was based on an observational study in 2359 patients with dyslipidaemia or hypercholesterolaemia that were treated with nicotinic acid 1000 mg/laropiprant 20 mg (Tredaptive) one or two tablets daily. Subgroups were formed by DMP participation (DMP vs. no DMP). A stepwise logistic regression model with backward selection of variables was applied to investigate factors influencing the probability of reaching lipid goals. Follow-up was 23 ± 7 weeks.. Low density lipoprotein cholesterol (LDL-C) <100 mg/dl was achieved by 30.8% in DMP versus 26.8% (no DMP), high density lipoprotein (HDL-C) >40/50 mg/dl in 61.3% versus 66.1%, and triglycerides (TG) <150 mg/dl in 28.9% versus 31.7%. On multivariate analysis, age, sex, concomitant high-risk cardiovascular disease, or participation in a DMP appeared to have inconsistent effects on reaching LDL-C, HDL-C and TG goals. Likelihood to reach the LDL-C goal tended to be higher in males, in patients outside DMP, and in patients with DM or CHD, and those treated with 1 tablet (versus 2 tablets) extended release nicotinic acid 1000 mg/laropiprant 20 mg. The likelihood of reaching the HDL-C goal was higher in males and in patients without DM or DM+CHD (no effect of DMP). The likelihood of reaching the TG goals was higher in females, in patients outside DMP, and in patients with DM and/or CHD. Limitations include potential bias due to study design, physician and patient selection, and missing values at follow-up.. DMP participation was not associated with overall improved lipid goal attainment. Physicians cannot predict the magnitude of effects of newly initiated lipid modifying therapy based on baseline characteristics of their patients.

Topics: Age Factors; Aged; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Diabetes Mellitus; Disease Management; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Male; Middle Aged; Niacin; Sex Factors

Co-administration of niacin with statin offers the potential for additional lipid management and cardiovascular risk reduction. However, niacin is underutilised because of the side effects of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). A combination tablet containing extended-release niacin and laropiprant (ERN/LRPT), a PGD(2) receptor (DP1) antagonist, offers improved tolerability. This study assessed the efficacy and safety of ERN/LRPT added to statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia who were not at their National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal based on their coronary heart disease risk category (high, moderate or low).. After a 2- to 6-week run-in statin (simvastatin 10 or 20 mg or atorvastatin 10 mg) period, 1216 patients were randomised equally to one of two treatment groups in a double-blind fashion: group 1 received ERN/LRPT (1 g) plus the run-in statin dose and advanced to ERN/LRPT (2 g) after 4 weeks for an additional 8 weeks, with no adjustments to the run-in statin dose; group 2 received simvastatin or atorvastatin at twice their run-in statin dose and remained on this stable dose for 12 weeks.. ERN/LRPT added to statin (pooled across statin and statin dose) significantly improved key lipid parameters vs. the doubled statin dose (pooled): the between-treatment group difference in least squares mean per cent change [95% confidence interval (CI)] from baseline to week 12 in LDL-C (primary end-point) was -4.5% (-7.7, -1.3) and in high-density lipoprotein cholesterol (HDL-C) was 15.6% (13.4, 17.9) and in median per cent change for triglyceride (TG) was -15.4% (-19.2, -11.7). Treatment-related adverse experiences (AEs) related to flushing, pruritis, rash, gastrointestinal upset and elevations in liver transaminases and fasting serum glucose occurred more frequently with ERN/LRPT added to statin vs. statin dose doubled.. The addition of ERN/LRPT to ongoing statin treatment produced significantly improved lipid-modifying benefits on LDL-C, HDL-C and TG and all other lipid parameters compared with doubling the statin dose in patients with primary hypercholesterolaemia or mixed dyslipidaemia. The types of AEs that occurred at a greater frequency in the ERN/LRPT group were those typically associated with niacin.

Topics: Adult; Aged; Aged, 80 and over; Cholesterol, HDL; Cholesterol, LDL; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Dyslipidemias; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Male; Middle Aged; Niacin; Prostaglandin D2; Treatment Outcome; Young Adult

Laropiprant, an antagonist of the PGD(2) receptor, DP1, is effective in reducing the flushing symptoms associated with extended-release (ER) niacin and thereby improves the tolerability of niacin therapy for dyslipidemia. Because PGD(2) has been reported to inhibit platelet aggregation in vitro, it has been speculated that antagonism of DP1 may enhance platelet reactivity. Three clinical studies evaluated the potential effect of laropiprant, with or without coadministration of ER niacin, on in vivo platelet function in healthy subjects and hypercholesterolemic or diabetic subjects by measuring urinary levels of 11-dehydrothromboxane B(2) (11-dTxB(2)), a marker of in vivo platelet activation. Following 7 days of multiple-dose administration, coadministration of laropiprant with ER niacin did not increase urinary 11-dTxB(2) levels compared to ER niacin alone in healthy, hypercholesterolemic, or diabetic subjects. In hypercholesterolemic and diabetic subjects, laropiprant did not increase urinary 11-dTxB(2) levels compared to placebo. These results demonstrate that laropiprant does not enhance in vivo platelet reactivity, either alone or in combination with niacin.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Platelets; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus; Double-Blind Method; Epoprostenol; Female; Humans; Hypercholesterolemia; Indoles; Male; Middle Aged; Niacin; Platelet Activation; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Thromboxane B2; Young Adult

Improving lipids beyond low-density lipoprotein cholesterol (LDL-C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid-modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin (ERN) into a fixed-dose tablet.. Dyslipidaemic patients were randomised to ERN/LRPT 1 g (n = 800), ERN 1 g (n = 543) or placebo (n = 270) for 4 weeks. Doses were doubled (2 tablets/day; i.e. 2 g for active treatments) for 20 weeks. ERN/LRPT 2 g produced significant changes vs. placebo in LDL-C (-18.4%), high-density lipoprotein cholesterol (HDL-C; 20.0%), LDL-C:HDL-C (-31.2%), non-HDL-C (-19.8%), triglycerides (TG; -25.8%), apolipoprotein (Apo) B (-18.8%), Apo A-I (6.9%), total cholesterol (TC; -8.5%), TC:HDL-C (-23.1%) and lipoprotein(a) (-20.8%) across weeks 12-24. ERN/LRPT produced significantly less flushing than ERN during initiation (week 1) and maintenance (weeks 2-24) for all prespecified flushing end-points (incidence, intensity and discontinuation because of flushing). Except for flushing, ERN/LRPT had a safety/tolerability profile comparable with ERN.. Extended-release niacin/LRPT 2 g produced significant, durable improvements in multiple lipid/lipoprotein parameters. The improved tolerability of ERN/LRPT supports a simplified 1 g-->2 g dosing regimen of niacin, a therapy proven to reduce cardiovascular risk.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Dyslipidemias; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Male; Middle Aged; Niacin; Treatment Outcome; Young Adult

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

When cholesterol levels remain high despite appropriate lifestyle measures, the choice of lipid-lowering drug should focus on products that have been shown to prevent fatal and nonfatal cardiovascular events. On this basis, simvastatin and pravastatin, unlike sustained-release nicotinic acid, are first-line options. A fixed-dose combination of nicotinic acid and laropiprant is authorised in the European Union for the treatment of lipid disorders, either alone or together with a statin. The role of laropiprant, a type 1 prostaglandin D2 receptor antagonist, is to prevent the flushing caused by nicotinic acid. The nicotinic acid + laropiprant combination, used alone or simultaneously with a statin, has only been tested for its effect on surrogate lipid endpoints, not for its ability to prevent cardiovascular events. Three comparative trials in a total of about 4000 patients showed that laropiprant partly prevented the flushing due to sustained-release nicotinic acid. However, about one in three patients still had at least moderately intense flushing at the outset of treatment, while about half the patients subsequently had flushing on up to 3 days a week. Compared with sustained-release nicotinic acid alone, laropiprant + nicotinic acid combination therapy provokes more gastrointestinal disorders, more hypersensitivity reactions, and more transaminase and creatine phosphokinase elevations. Through its effect on prostaglandin D2 and thromboxane A2, laropiprant also has effects on blood coagulation, with uncertain clinical consequences. Animal and human data argue against the use of the nicotinic acid + laropiprant combination during pregnancy and breast-feeding. In practice, patients with hypercholesterolaemia need drugs with well-documented clinical efficacy, and this excludes the nicotinic acid + laropiprant combination.

Topics: Drug Combinations; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Niacin; Pregnancy; Randomized Controlled Trials as Topic

Topics: Animals; Cholesterol, HDL; Cholesterol, LDL; Dyslipidemias; Humans; Hypercholesterolemia; Indoles; Niacin; Triglycerides