Laropiprant

Laropiprant(Cardaptive; MK 0524) is a potent, selective DP1 receptor antagonist with Ki values of 0.57 nM and 0.75 μM for the DP1 and DP2 receptors, respectively. Laropiprant(Cardaptive; MK 0524) inhibits PGD2-induced accumulation of cAMP in both washed platelets and platelet-rich plasma with IC50 values of 0.09 and 4.0 nM, respectively. In a sheep model of allergic rhinitis, 0.1 mg/kg MK 0524 completely blocked PGD2-induced nasal congestion. At a dose of 4 mg/kg, MK 0524 suppressed a nicotinic acid-induced vasodilatory response by 80% in a murine model of flushing, an undesirable side-effect of niacin treatment for dyslipidemia.

Detrimental effects of niacin/laropiprant on microvascular reactivity and red cell deformability in patients with elevated lipoprotein(a) levels.[Pubmed:26289089]

J Thromb Thrombolysis. 2016 Apr;41(3):433-5.

Several studies have found a beneficial effect of nicotinic acid on lipid profile, but there remains a limitation in the clinical use of nicotinic acid due to its side effects. In this study, 46 (F/M = 22/24, age = 58.74 +/- 10.02 years) patients with Lp(a) >/=500 mg/L and with a previous arterial thrombotic event were treated with nicotinic acid/Laropiprant (Tredaptive(R)). We found a significant reduction in the Lp(a) values at T1 (after 12 months), with a decrease of 32.3 % from baseline levels. At T1, 11 patients (23.9 %) showed Lp(a) levels to be <500 mg/L. PAT values were significantly decreased after treatment (2.13 +/- 0.81 vs 1.74 +/- 0.42, p = 0.001), showing a worsening of endothelial function in 27 (58.6 %) patients. A significantly higher number of patients had RHI <1.5 after the treatment [18 (39.1 %) vs 8 (17.4 %)]. Blood rheology worsened as ED was impaired (p < 0.0001) after 12 months, whereas WHV, plasma viscosity, and red cell aggregation did not show any significant differences in comparison to baseline. Patients with a worsening in microvascular reactivity in comparison to baseline showed a marked impairment in ED (0.3327 +/- 0.037 vs 0.3091 +/- 0.0351; p < 0.0001), while others showed only a mild, even though significant, reduction (0.3347 +/- 0.0299 vs 0.3272 +/- 0.0235; p = 0.044). In the light of the results of HPS2-THRIVE study, we may hypothesize that the addition of Laropiprant to niacin might be responsible for these negative effects. In turn, these effects might explain, at least in part, the lack of a clinical net benefit of niacin/Laropiprant in the trial.

Extended-Release Niacin/Laropiprant Improves Overall Efficacy of Postprandial Reverse Cholesterol Transport.[Pubmed:26681758]

Arterioscler Thromb Vasc Biol. 2016 Feb;36(2):285-94.

OBJECTIVES: Postprandial atherogenic lipoproteins, characterizing high-risk patients, correlate positively with cardiovascular events. Although the effect of niacin on fasting lipids is well established, its impact on atheroprotective reverse cholesterol transport (RCT) pathway and on functional features of circulating lipoproteins during the postprandial state remains indeterminate. APPROACH AND RESULTS: We evaluated RCT pathway during postprandial phase in dyslipidemic patients displaying a low high-density lipoprotein (HDL) cholesterol phenotype. Ten subjects on stable statin therapy received 1 g/20 mg extended-release niacin/Laropiprant (ERN/LRPT) for 4 weeks followed by 2 g/40 mg ERN/LRPT for additional 8 weeks. At each experimental period, postprandial hypertriglyceridemia and major steps of RCT, including cholesterol efflux from human macrophages, cholesteryl ester transfer protein-mediated cholesteryl ester transfer, and hepatic HDL-cholesteryl ester selective uptake were evaluated. Equally, the capacity of postprandial HDL particles isolated from patients before and after ERN/LRPT treatment to mediate RCT to feces was evaluated in vivo in human apolipoprotein B/cholesteryl ester transfer protein double transgenic mouse model. Compared with baseline, ERN/LRPT significantly reduced postprandial hypertriglyceridemia (incremental area under the curve-triglyceride: -53%; P=0.02). Postprandial increase in endogenous plasma cholesteryl ester transfer protein activity was completely abolished after ERN/LRPT treatment. Despite a slight reduction in plasma cholesterol efflux capacity from human THP-1 macrophages, evaluation of global RCT efficacy by combining both ex vivo and in vivo approaches indicate that postprandial HDL particles formed under ERN/LRPT therapy displayed a greater capacity for HDL-mediated RCT to feces. CONCLUSIONS: ERN/LRPT treatment efficiently attenuates atherogenic postprandial lipemia and stimulates HDL-mediated cholesterol return to the liver and elimination into feces during postprandial phase, thus maintaining an efficient removal of cholesterol from the body.

Effects of extended-release niacin/laropiprant on correlations between apolipoprotein B, LDL-cholesterol and non-HDL-cholesterol in patients with type 2 diabetes.[Pubmed:27405296]

Lipids Health Dis. 2016 Jul 12;15(1):116.

BACKGROUND: LDL-C, non-HDL-C and ApoB levels are inter-correlated and all predict risk of atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes mellitus (T2DM) and/or high TG. These levels are lowered by extended-release niacin (ERN), and changes in the ratios of these levels may affect ASCVD risk. This analysis examined the effects of extended-release niacin/Laropiprant (ERN/LRPT) on the relationships between apoB:LDL-C and apoB:non-HDL-C in patients with T2DM. METHODS: T2DM patients (n = 796) had LDL-C >/=1.55 and <2.97 mmol/L and TG <5.65 mmol/L following a 4-week, lipid-modifying run-in (~78 % taking statins). ApoB:LDL-C and apoB:non-HDL-C correlations were assessed after randomized (4:3), double-blind ERN/LRPT or placebo for 12 weeks. Pearson correlation coefficients between apoB:LDL-C and apoB:non-HDL-C were computed and simple linear regression models were fitted for apoB:LDL-C and apoB:non-HDL-C at baseline and Week 12, and the correlations between measured apoB and measured vs predicted values of LDL-C and non-HDL-C were studied. RESULTS: LDL-C and especially non-HDL-C were well correlated with apoB at baseline, and treatment with ERN/LRPT increased these correlations, especially between LDL-C and apoB. Despite the tighter correlations, many patients who achieved non-HDL-C goal, and especially LDL-C goal, remained above apoB goal. There was a trend towards greater increases in these correlations in the higher TG subgroup, non-significant possibly due to the small number of subjects. CONCLUSIONS: ERN/LRPT treatment increased association of apoB with LDL-C and non-HDL-C in patients with T2DM. Lowering LDL-C, non-HDL-C and apoB with niacin has the potential to reduce coronary risk in patients with T2DM.

Effects of Vascular and Nonvascular Adverse Events and of Extended-Release Niacin With Laropiprant on Health and Healthcare Costs.[Pubmed:27407053]

Circ Cardiovasc Qual Outcomes. 2016 Jul;9(4):348-54.

BACKGROUND: Extended-release niacin with Laropiprant did not significantly reduce the risk of major vascular events and increased the risk of serious adverse events in Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), but its net effects on health and healthcare costs are unknown. METHODS AND RESULTS: 25 673 participants aged 50 to 80 years with previous cardiovascular disease were randomized to 2 g of extended-release niacin with 40 mg of Laropiprant daily versus matching placebo, in addition to effective statin-based low-density lipoprotein cholesterol-lowering treatment. The net effects of niacin-Laropiprant on quality-adjusted life years and hospital care costs (2012 UK pound; converted into US $ using purchasing power parity index) during 4 years in HPS2-THRIVE were evaluated using estimates of the impact of serious adverse events on health-related quality of life and hospital care costs. During the study, participants assigned niacin-Laropiprant experienced marginally but not statistically significantly lower survival (0.012 fewer years [standard error (SE) 0.007]), fewer quality-adjusted life years (0.023 [SE 0.007] fewer using UK EQ-5D scores; 0.020 [SE 0.006] fewer using US EQ-5D scores) and accrued greater hospital costs (UK pound101 [SE pound37]; US $145 [SE $53]). Stroke, heart failure, musculoskeletal events, gastrointestinal events, and infections were associated with significant decreases in health-related quality of life in both the year of the event and in subsequent years. All serious vascular and nonvascular events were associated with substantial increases in hospital care costs. CONCLUSIONS: In HPS2-THRIVE, the addition of extended-release niacin-Laropiprant to statin-based therapy reduced quality of life-adjusted survival and increased hospital costs. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00461630.

Laropiprant is a potent, selective DP receptor antagonist with Ki values of 0.57 nM and 2.95 nM for DP receptor and TP Receptor, respectively.

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