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

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.

Safety and tolerability of extended-release niacin-laropiprant: Pooled analyses for 11,310 patients in 12 controlled clinical trials.

BACKGROUND: The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) showed that adding extended-release niacin-laropiprant (ERN-LRPT) to statin provided no incremental cardiovascular benefit vs placebo (PBO). ERN-LRPT was also associated with an excess of serious adverse experiences (AEs), some of which were unexpected (infections and bleeding). These findings led to the withdrawal of ERN-LRPT from all markets. OBJECTIVE: We examined the safety profile of ERN-LRPT vs the comparators ERN alone and statins in the ERN-LRPT development program to assess whether similar safety signals were observed to those seen in HPS-THRIVE and whether these might be attributed to ERN or LRPT. METHODS: Postrandomization safety data from 12 clinical studies, 12 to 52 weeks in duration and involving 11,310 patients, were analyzed across 3 treatments: (1) ERN-LRPT; (2) ERN-NSP (ERN, Merck & Co, Inc or Niaspan [NSP], Abbott Laboratories); and (3) statin-PBO (statin or PBO). RESULTS: The safety profiles of ERN-LRPT and ERN-NSP were similar, except for less flushing with ERN-LRPT. Nonflushing AEs reported more frequently with ERN-LRPT or ERN-NSP than with statin-PBO were mostly nonserious and typical of niacin (nausea, diarrhea, and increased blood glucose). There was no evidence for an increased risk of serious AEs related to diabetes, muscle, infection, or bleeding. CONCLUSIONS: Pooled data from 11,310 patients revealed that, except for reduced flushing, the safety profile of ERN-LRPT was similar to that of ERN-NSP; LRPT did not appear to adversely affect the side-effect profile of ERN. The inability to replicate the unexpected AE findings in HPS2-THRIVE could be because of the smaller sample size and substantially shorter duration of these studies.

Extended-release niacin/laropiprant significantly improves lipid levels in type 2 diabetes mellitus irrespective of baseline glycemic control.

BACKGROUND: The degree of glycemic control in patients with type 2 diabetes mellitus (T2DM) may alter lipid levels and may alter the efficacy of lipid-modifying agents. OBJECTIVE: Evaluate the lipid-modifying efficacy of extended-release niacin/laropiprant (ERN/LRPT) in subgroups of patients with T2DM with better or poorer glycemic control. METHODS: Post hoc analysis of clinical trial data from patients with T2DM who were randomized 4:3 to double-blind ERN/LRPT or placebo (n=796), examining the lipid-modifying effects of ERN/LRPT in patients with glycosylated hemoglobin or fasting plasma glucose levels above and below median baseline levels. RESULTS: At Week 12 of treatment, ERN/LRPT significantly improved low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol, triglycerides, and lipoprotein (a), compared with placebo, with equal efficacy in patients above or below median baseline glycemic control. Compared with placebo, over 36 weeks of treatment more patients treated with ERN/LRPT had worsening of their diabetes and required intensification of antihyperglycemic medication, irrespective of baseline glycemic control. Incidences of other adverse experiences were generally low in all treatment groups. CONCLUSION: The lipid-modifying effects of ERN/LRPT are independent of the degree of baseline glycemic control in patients with T2DM (NCT00485758).

Lipid-altering efficacy and safety profile of co-administered extended release niacin/laropiprant and simvastatin versus atorvastatin in patients with mixed hyperlipidemia.

BACKGROUND: Extended-release niacin/laropiprant (ERN/LRPT) reduces flushing and preserves the lipid-modifying effects of ERN. This study compared the efficacy and safety of ERN/LRPT plus simvastatin (ERN/LRPT+SIMVA) with atorvastatin (ATORVA) in patients with mixed hyperlipidemia. METHODS: After a 4-week placebo run-in, 2340 patients (LDL-C ≥ 130 and ≤ 190 mg/dL, TG ≥ 150 and ≤ 500 mg/dL and above NCEP ATP III risk-based LDL-C goal) were randomized to 1 of 6 treatment arms: ERN/LRPT 1g/20mg+SIMVA (10 or 20mg), or ATORVA (10, 20, 40, or 80 mg) once daily. RESULTS: At Week 12, ERN/LRPT+SIMVA was superior to ATORVA in decreasing LDL-C/HDL-C (primary endpoint) at each pre-specified dose comparison: ERN/LRPT+SIMVA 20mg vs. ATORVA 10mg (-13.2%; p<0.001); ERN/LRPT+SIMVA 40 mg vs. ATORVA 20mg (-10.8%; p<0.001); ATORVA 40 mg (-5.1%; p<0.001); and ATORVA 80 mg (-4.2%; p=0.007). At Week 12, ERN/LRPT+SIMVA was superior to ATORVA in increasing HDL-C and reducing TG for all pre-specified treatment comparisons, and reducing non-HDL-C and LDL-C for the ERN/LRPT+SIMVA 20mg versus ATORVA 10mg and ERN/LRPT+SIMVA 40 mg versus ATORVA 20-mg dose comparisons, but not the ERN/LRPT+SIMVA 40 mg versus ATORVA 40- and 80-mg dose comparisons. Adverse experiences (AEs) typically associated with niacin (flushing, pruritus, increased glucose, increased uric acid) were more common with ERN/LRPT+SIMVA, and hepatic-related laboratory AEs were more common with ATORVA. CONCLUSION: ERN/LRPT+SIMVA was generally superior to ATORVA in improving lipid parameters after 12 weeks and was generally well tolerated in patients with mixed hyperlipidemia.

Effectiveness and safety of laropiprant on niacin-induced flushing.

Extended-release niacin (ERN) improves multiple lipid parameters but is underused owing to niacin-induced flushing (NIF). Laropiprant (LRPT) reduces NIF; however, its effects on chronic flushing (>6 months) have not been studied. We examined whether after 20 weeks of treatment with ERN/LRPT, patients who continued ERN/LRPT would experience less NIF than patients who stopped LRPT and continued ERN alone. A total of 1,152 dyslipidemic patients were randomized 2:2:1 to group 1, ERN/LRPT 1 g/20 mg/day from 0 to 4 weeks and then ERN/LRPT 2 g/40 mg/day from 5 to 32 weeks; group 2, ERN/LRPT 1 g/20 mg/day from 0 to 4 weeks, ERN/LRPT 2 g/40 mg/day from 5 to 20 weeks, and then ERN 2 g/day without LRPT from 21 to 32 weeks; or group 3, placebo for the entire study. The end points included the number of days each week with a moderate or greater Global Flushing Severity Score (GFSS) ≥4 (primary end point) and the percentage of patients with a maximum GFSS of ≥4 (secondary end point) during the postwithdrawal period (weeks 21 to 32). ERN/LRPT produced significantly less NIF than ERN alone during the postwithdrawal period, as measured by the number of days each week with a GFSS of ≥4 (p <0.001) and the percentage of patients with a maximum GFSS of ≥4 (p <0.001; ERN/LRPT 19.6%; ERN 48.9%; placebo 9.2%). Compared with ERN alone, ERN/LRPT produced fewer drug-related adverse experiences during the postwithdrawal period. After 20 weeks of stable maintenance therapy, dyslipidemic patients treated continuously with ERN/LRPT experienced less NIF than did patients who had had LRPT withdrawn and had continued with ERN alone. In conclusion, the results of our study support the long-term efficacy of ERN/LRPT in reducing NIF symptoms.

Consistency of extended-release niacin/laropiprant effects on Lp(a), ApoB, non-HDL-C, Apo A1, and ApoB/ApoA1 ratio across patient subgroups.

BACKGROUND: According to prior analyses, extended-release niacin/laropiprant (ERN/LRPT) consistently reduces low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) levels across a wide range of dyslipidemic patient subgroups. OBJECTIVES: This analysis examined ERN/LRPT's consistency across four phase III, randomized, double-blind trials in improving other lipid/lipoprotein parameters associated with cardiovascular risk, across several key dyslipidemic patient subgroups. METHODS: In three of the studies, the randomized population included patients with primary hypercholesterolemia or mixed hyperlipidemia; in the remaining study, the population included patients with type 2 diabetes mellitus. The lipid-altering consistency of ERN/LRPT's efficacy was evaluated versus the pre-defined comparator (placebo or active control) among key subgroups of sex, race (White, non-White), region (US, ex-US), baseline age (<65 years, ≥65 years), use of statin therapy (yes, no), coronary heart disease (yes, no), risk status (low, multiple, high), and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline LDL-C, HDL-C, and TG levels. The consistency of the treatment effects on lipoprotein(a).[Lp(a)], apolipoprotein B (ApoB), non-HDL-C, ApoA1, and ApoB/ApoA1 ratio was evaluated by examining treatment difference estimates of the percentage change from baseline with 95% confidence intervals. RESULTS: Treatment with ERN/LRPT produced significantly greater improvements in Lp(a), ApoB, non-HDL-C, ApoA1, and ApoB/ApoA1 ratio compared with placebo/active comparator in each study. These effects were generally consistent across key subgroups within each study. CONCLUSION: ERN/LRPT produced lipid-altering efficacy on the parameters evaluated in four controlled studies; these effects were generally consistent across all examined subgroups. ERN/LRPT represents an effective and reliable therapeutic option for the treatment of dyslipidemia in a wide range of patient types. CLINICAL TRIAL REGISTRATION: Registered as Clinicaltrials.gov NCT00269204, NCT00269217, NCT00479388, and NCT00485758.

Extended-release niacin/laropiprant lowers serum phosphorus concentrations in patients with type 2 diabetes.

BACKGROUND: Niacin compounds lower serum phosphorus concentrations in patients with end-stage renal disease. METHODOLOGY: We evaluated the impact of extended release niacin, given in fixed-dose combination with laropiprant, a specific inhibitor of prostaglandin-mediated, niacin-induced flushing, versus placebo, on serum phosphorus concentrations measured serially (at weeks 0, 4, 8, 12, 18, 24, 30, and 36) during a 36-week randomized, controlled trial. All subjects had a confirmed diagnosis of type 2 diabetes (n = 446 niacin/laropiprant; n = 339 placebo). Estimated glomerular filtration rate ranged from 36 to 184 mL/min/1.73 m(2), with n = 111 (14.1%) having a value <60 mL/min/1.73 m(2). Subjects received one tablet daily of extended-release niacin/laropiprant (1g niacin/ 20 mg laropiprant) for the first 4 weeks, and 2 tablets once daily, thereafter, or matched placebo. Niacin lowered serum phosphorus concentrations by 0.36 mg/dL (95% CI: -0.40, -0.31; P < .001), relative to placebo, from baseline values of 3.57 and 3.56 mg/dL in the niacin and placebo groups, respectively. Subgroup analyses revealed no evidence for phosphorus-lowering effect modification by these baseline variables: glomerular filtration rate <60 (n = 111;14.1%) vs ≥60 mL/min/m(2) (n = 674; 85.9%); phosphorus ≤3.5 mg/dL (n = 392; 49.9%) vs >3.5 mg/dL (n = 393; 50.1%); or prior statin use (n = 618; 78.7%) vs nonuse (n = 167; 21.3%). CONCLUSIONS AND IMPLICATIONS: These data confirm that niacin's phosphorus-lowering effects-which may have therapeutic implications for the management of hyperphosphatemia and possible prevention of cardiorenal outcomes in renal disease-extend across a broad spectrum of renal function in type 2 diabetics without stage 4 or 5 chronic kidney disease (a glomerular filtration rate ≥30 mL/min/1.73 m(2)).

Efficacy and tolerability of extended-release niacin/laropiprant in dyslipidemic patients with metabolic syndrome.

OBJECTIVE: Patients with metabolic syndrome (MetS) are at increased risk for cardiovascular disease. Niacin improves lipid abnormalities associated with MetS, but is underused, mainly because of flushing. Laropiprant (LRPT) reduces niacin-induced flushing and, in combination with extended-release niacin (ERN/LRPT), improves lipid levels. METHODS: In this post-hoc subgroup analysis of a phase 3 randomized, double-blind, placebo-controlled, 24-week study (n = 1613), we evaluated the efficacy and safety of ERN/LRPT in dyslipidemic patients with MetS. Dyslipidemic patients were randomized 3:2:1 to ERN/LRPT 1 g, ERN 1 g, or placebo. After 4 weeks, active treatment doses were doubled (2 tablets) for 20 weeks. RESULTS: Relative to placebo, ERN/LRPT significantly lowered low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol levels to a similar degree in MetS and non-MetS cohorts. ERN/LRPT significantly (P < .001) lowered triglyceride levels versus placebo in patients with MetS and without MetS (-30.2% vs -22.2%, respectively). The between subgroup difference in triglyceride lowering was not significant. For all lipid parameters, ERN/LRPT and ERN produced similar magnitude changes. ERN/LRPT and ERN produced similar increases in median fasting blood glucose levels versus placebo in patients with MetS (2.0 and 4.0 mg/dL, respectively) and without MetS (4.0 mg/dL for both groups), consistent with a known effect of niacin. CONCLUSION: In patients with MetS, ERN/LRPT improves multiple lipid parameters associated with increased cardiovascular disease risk. ERN/LRPT numerically improved triglyceride levels more in patients with versus without MetS, which is likely related to greater baseline triglycerides in MetS patients.

Safety of extended-release niacin/laropiprant in patients with dyslipidemia.

OBJECTIVE: To evaluate the safety profile of extended-release niacin/laropiprant (ERN/LRPT), pooling data from studies in the clinical development program. METHODS: Data were pooled from three active- or placebo-controlled phase 3 studies and three 1-year extensions of phase 2 studies that ranged from 12 to 52 weeks (N = 4747): ERN/LRPT = 2548; ERN or Niaspan® (ERN-NSP = 1268); or simvastatin or placebo (SIMVA-PBO = 931). RESULTS: The safety and tolerability profile for ERN/LRPT was similar to that of ERN-NSP, except for fewer flushing-related adverse experiences and discontinuations with ERN/LRPT than ERN-NSP. The incidence of consecutive ≥3× the upper limit of normal increases in alanine aminotransferase and/or aspartate aminotransferase was numerically (but not statistically) greater with ERN/LRPT (1.0%) than ERN-NSP (0.5%) and similar to SIMVA-PBO (0.9%). Elevations were reversible with therapy discontinuation and not associated with clinical hepatotoxicity. There was no evidence that ERN/LRPT administered alone or concurrently with a statin had adverse effects on muscle. ERN/LRPT and ERN-NSP produced small median increases in fasting blood glucose levels (∼4 mg/dL) after 24 weeks of treatment, consistent with known effects of niacin. CONCLUSION: The favorable safety and tolerability profile of ERN/LRPT for up to 1 year supports the use of LRPT to achieve improved therapeutic dosing of niacin, an agent with comprehensive lipid-modifying efficacy and shown to reduce cardiovascular risk.

Hypophosphatemic effect of niacin in patients without renal failure: a randomized trial.

BACKGROUND AND OBJECTIVES: Niacin administration lowers the marked hyperphosphatemia that is characteristic of renal failure. We examined whether niacin administration also reduces serum phosphorus concentrations in patients who have dyslipidemia and are free of advanced renal disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a post hoc data analysis of serum phosphorus concentrations that had been determined serially (at baseline and weeks 4, 8, 12, 18, and 24) among 1547 patients who had dyslipidemia and were randomly assigned in a 3:2:1 ratio to treatment with extended release niacin (ERN; 1 g/d for 4 weeks and dose advanced to 2 g/d for 20 weeks) combined with the selective prostaglandin D2 receptor subtype 1 inhibitor laropiprant (L; n = 761), ERN alone (n = 518), or placebo (n = 268). RESULTS: Repeated measures analysis revealed that ERN-L treatment resulted in a net mean (95% confidence interval) serum phosphorus change comparing ERN-L with placebo treatment of -0.13 mmol/L (-0.15 to -0.13 mmol/L; -0.41 mg/dl [-0.46 to -0.37 mg/dl]). These results were consistent across the subgroups defined by estimated GFR of <60 or > or =60 ml/min per 1.73 m(2), a serum phosphorus of >1.13 mmol/L (3.5 mg/dl) versus < or =1.13 mmol/L (3.5 mg/dl), the presence of clinical diabetes, or concomitant statin use. CONCLUSIONS: We have provided definitive evidence that once-daily ERN-L treatment causes a sustained 0.13-mmol/L (0.4-mg/dl) reduction in serum phosphorus concentrations, approximately 10% from baseline, which is unaffected by estimated GFR ranging from 30 to > or =90 ml/min per 1.73 m(2) (i.e., stages 1 through 3 chronic kidney disease).

Flushing profile of extended-release niacin/laropiprant at initiation of therapy in Asian lipid clinic patients.

OBJECTIVE: Niacin is underutilized due to flushing, which occurs in over 90% of niacin-treated patients. Laropiprant (LRPT) reduces flushing associated with niacin. This study compared flushing with a combination tablet of extended-release (ER) niacin (ERN)/LRPT to niacin ER (N-ER; without LRPT) during the first week of therapy among patients in Asia. METHODS: Following a 1-week placebo run-in, 332 patients with dyslipidemia from China, Korea and Singapore were randomized to ERN/LRPT 1 g/20 mg, N-ER 1 g (given as Niaspan(R)) or placebo in a 2:2:1 ratio for 1 week. Patient-reported flushing severity was assessed using the Global Flushing Severity Score (GFSS; none/mild = 0-3; moderate = 4-6; severe = 7-9; extreme = 10). RESULTS: Compared with N-ER, the ERN/LRPT group experienced significantly less flushing (p < 0.001), as measured by maximum GFSS categorized as none/mild, moderate, severe or extreme. Overall, 23.8% of patients in the ERN/LRPT group and 50.0% in the N-ER group (p < 0.001), versus 12.1% in the placebo group, had moderate or greater flushing (GFSS > or =4). Except for flushing, which occurred more frequently in the N-ER group, ERN/LRPT had a safety/tolerability profile similar to that of N-ER. CONCLUSION: ERN/LRPT produced significantly less flushing than N-ER during the initiation of therapy and was generally well tolerated in Asian patients with dyslipidemia.

Flushing profile of extended-release niacin/laropiprant versus gradually titrated niacin extended-release in patients with dyslipidemia with and without ischemic cardiovascular disease.

Niacin has beneficial effects on a patient's lipid and lipoprotein profiles and cardiovascular risk, particularly at doses >2 g/day, but is underused due to flushing. Laropiprant (LRPT), a selective prostaglandin D(2) receptor-1 antagonist, decreases flushing associated with extended-release niacin (ERN). We compared flushing with ERN/LRPT dosed by a simplified 1-g --> 2-g regimen versus gradually titrated niacin extended-release (N-ER; given as NIASPAN, trademark of Kos Life Sciences LLC). Patients with dyslipidemia (n = 1,455) were randomized 1:1 to ERN/LRPT (1 g for 4 weeks advanced to 2 g for 12 weeks) or N-ER (0.5 g for 4 weeks titrated in 0.5-g increments every 4 weeks to 2 g for the final 4 weeks). Aspirin/nonsteroidal anti-inflammatory drugs were allowed to mitigate flushing. Flushing severity was assessed using the validated Global Flushing Severity Score (GFSS; none 0, mild 1 to 3, moderate 4 to 6, severe 7 to 9, extreme 10). Patients on ERN/LRPT, despite more rapid niacin titration, had less flushing than those on N-ER, as measured by number of days per week with moderate or greater GFSS across the treatment period (p <0.001). More than 2 times as many patients had no episodes of moderate, severe, or extreme flushing (GFSS > or =4) with ERN/LRPT than with N-ER (47.0% vs 22.0%, respectively) across the treatment period. Fewer patients on ERN/LRPT discontinued due to flushing than those on N-ER (7.4% vs 12.4%, p = 0.002). Other than the decrease in flushing, the safety and tolerability profile of ERN/LRPT was similar to that of N-ER. In conclusion, improvement in flushing with ERN/LRPT versus gradually titrated N-ER supports a rapidly advanced 1-g --> 2-g dosing regimen, allowing patients to start at 1 g and quickly reach and tolerate the optimal 2 g dose of ERN.

Blood pressure-lowering effects of extended-release niacin alone and extended-release niacin/laropiprant combination: a post hoc analysis of a 24-week, placebo-controlled trial in dyslipidemic patients.

BACKGROUND: Dyslipidemia and high blood pressure are both major cardiovascular disease risk factors. Niacin is an effective lipid-altering agent that has been reported to reduce the risk of cardiovascular disease. However, the more widespread use of niacin is limited, mainly due to the occurrence of flushing. Laropiprant (LRPT) is a selective antagonist of prostaglandin D(2) receptor subtype 1 that reduces extended-release niacin (ERN)-induced flushing without affecting its beneficial lipid effects. While the lipid effects of ERN are well known, the blood pressure effects are unclear. OBJECTIVE: The aim of this analysis was to examine the blood pressure effects of ERN and ERN/LRPT. METHODS: This was a post hoc analysis of a 24-week, worldwide, multicenter, double-blind, randomized, placebo-controlled, parallel, Phase III, previously published study of dyslipidemic patients, which examined the effect of ERN and ERN/LRPT on systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: A total of 1613 men and women, aged 21 to 85 years, with primary hypercholesterolemia or mixed dyslipidemia (66% on statins), were included in the original analysis. ERN alone, or in combination with LRPT, was associated with significant reductions in SBP and DBP at 24 weeks from baseline. The placebo-adjusted mean changes from baseline at week 24 in SBP were -2.2 and -3.1 mm Hg for the ERN and ERN/LRPT groups, respectively (P < 0.05 and P < 0.001). Similar changes in DBP were observed; -2.7 and -2.5 mm Hg in the ERN and ERN/ LRPT groups, respectively (both, P < 0.001). CONCLUSION: This post hoc analysis of a 24-week trial found that ERN alone, or in combination with LRPT, was associated with significant placebo-adjusted reductions from baseline in blood pressure in these hyperlipidemic hypertensive or normotensive subjects.

Lipid-modifying efficacy of extended release niacin/laropiprant in Asian patients with primary hypercholesterolemia or mixed hyperlipidemia.

BACKGROUND: Niacin has proven lipid-modifying efficacy and cardiovascular benefit; however, it is underused because of skin flushing, a process mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that mitigates niacin-induced flushing, has been combined with extended-release niacin (ERN) into a fixed-dose tablet containing 1g of ERN and 20mg of LRPT (ERN/LRPT 1g). In a large-scale (n=∼1600), multinational, 6-month study in dyslipidemic patients, ERN/LRPT 2g produced superior lipid-modifying efficacy vs placebo, whether administered alone or with concomitant statins. OBJECTIVE: This Phase III, randomized, double-blind study evaluated the lipid-modifying efficacy of ERN/LRPT alone or added to ongoing statins in Asian patients with primary hypercholesterolemia or mixed hyperlipidemia. METHODS: After a 4-week placebo run-in, patients were randomized to ERN/LRPT 1g (n=322) or placebo (PBO; n=324). After 4 weeks, the dose was advanced to 2 tablets/d (ERN/LRPT 2g or PBO) for 8 additional weeks. End points included effects of ERN/LRPT 2g vs PBO on low-density lipoprotein cholesterol (LDL-C; primary), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and other lipids/lipoproteins. RESULTS: Relative to PBO, ERN/LRPT 2g produced significant (P < .001) changes in LDL-C (-14.7%), HDL-C (15.9%), TG (-23.4%), LDL-C:HDL-C (-25.5%), non-HDL-C (-16.4%), apolipoprotein (Apo) B (-15.4%), and Apo A-I (5.3%) from baseline to week 12 in the total population. Similar results were observed in patients treated with ERN/LRPT alone or added to ongoing statin. CONCLUSION: ERN/LRPT 2g, administered alone or with a statin, produced significant improvements in multiple lipid/lipoprotein parameters in dyslipidemic Asian patients.

Extended-release niacin/laropiprant: reducing niacin-induced flushing to better realize the benefit of niacin in improving cardiovascular risk factors.

Treatment with niacin effectively improves multiple lipid parameters and cardiovascular outcomes. Widespread use of niacin, however, is limited by flushing, which is mediated primarily by prostaglandin D2 (PGD2). Laropiprant is a selective PGD2 receptor 1 (DP1) antagonist that reduces objective measures of niacin-induced flushing symptoms upon initiation of therapy and with more chronic use. Results from early dosing and formulation studies have culminated in the development of a combination extended-release (ER) niacin/laropiprant tablet aimed at providing the beneficial lipid-modifying effects of niacin, while reducing niacin-induced flushing. The improvement in the tolerability of niacin with ER niacin/laropiprant allows niacin dosing to initiate directly at 1 g and rapidly advance to a 2-g target dose. ER niacin/laropiprant generally is tolerated well and represents a new treatment option for dyslipidemia that offers the potential for more patients to receive the lipid-modifying and cardiovascular benefits of niacin.

Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels.

The lowering effects of ezetimibe/simvastatin combination therapy on low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) were compared with those of simvastatin or atorvastatin monotherapy in a large cohort of patients with primary hypercholesterolemia. To compare ezetimibe/simvastatin with simvastatin, data were combined from 3 identical, prospective 12-week trials in which patients were randomized to receive placebo; ezetimibe 10 mg; ezetimibe 10 mg added to simvastatin 10, 20, 40, or 80 mg; or simvastatin 10, 20, 40, or 80 mg. To compare ezetimibe/simvastatin with atorvastatin, data were analyzed from a phase III double-blind, active-controlled study in which patients were randomized equally to receive ezetimibe/simvastatin 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg for 6 weeks. When averaged across doses, ezetimibe/simvastatin produced significantly greater reductions compared with simvastatin alone in LDL cholesterol (52.5% vs 38.0%, respectively) and CRP levels (31.0% vs 14.3%, respectively). At each individual simvastatin dose, co-administration with ezetimibe produced significant further CRP reductions versus simvastatin alone. Ezetimibe/simvastatin was significantly more effective at lowering LDL cholesterol than atorvastatin when pooled across doses (53.4% vs 45.3%, respectively) and in each milligram-equivalent dose comparison. Reductions in CRP of similar magnitude were observed with ezetimibe/simvastatin and atorvastatin when averaged across doses and at each milligram-equivalent statin dose comparison. In conclusion, the lipid-modulating and anti-inflammatory effects of ezetimibe/simvastatin provide additional benefits not realized by statin monotherapy alone.

Efficacy and safety of ezetimibe/simvastatin versus simvastatin monotherapy in hypercholesterolemic patients with metabolic syndrome.

BACKGROUND: The combination of ezetimibe and simvastatin (EZE/SIMVA) inhibits intestinal absorption and hepatic synthesis of cholesterol, providing significantly greater LDL-C-lowering compared to either drug alone. We examined the efficacy and safety of EZE/SIMVAin hypercholesterolemic patients with metabolic syndrome (MetS). METHODS: We evaluated pooled data from three similarly designed, randomized, doubleblinded, placebo-controlled studies in patients with primary hypercholesterolemia. After a 6- to 8-week washout and a 4-week diet/placebo run-in, patients received one of the following treatments for 12 weeks: EZE/SIMVA (10/10, 10/20, 10/40 or 10/80 mg); SIMVA (10, 20, 40 or 80 mg); EZE 10 mg; or placebo. For this analysis, the efficacy of EZE/SIMVA versus SIMVA was evaluated in patients with and without MetS. The primary endpoint was mean percent change from baseline in LDL-C for EZE/SIMVA (pooled across doses) versus SIMVA (pooled across doses). RESULTS: Of 2394 patients who received SIMVA or EZE/SIMVA and for whom MetS status at baseline could be determined, 31% were identified as having MetS. In the entire cohort, treatment with EZE/SIMVA led to a significant incremental reduction in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, triglyceride (TG), and C-reactive protein compared to SIMVA and these effects were similar across the MetS and non-MetS subgroups. EZE/SIMVA was well tolerated in both the MetS and non-MetS subgroups. CONCLUSION: EZE/SIMVA significantly improved the lipid and inflammatory profiles of hypercholesterolemic patients with MetS and was well tolerated. Thus, EZE/SIMVA offers an efficacious and safe treatment option for these patients.

Comparison of the lipid-modifying efficacy and safety profiles of ezetimibe coadministered with simvastatin in older versus younger patients with primary hypercholesterolemia: a post Hoc analysis of subpopulations from three pooled clinical trials.

BACKGROUND: Despite the need for effective and well-tolerated lipid-lowering therapies for primary hypercholesterolemia in older patients, there is a relative paucity of published data on such treatments in this population. OBJECTIVE: We conducted a post hoc analysis to examine the lipid-modifying efficacy and safety profile of simvastatin (SIMVA) monotherapy, and the coadministration of ezetimibe (EZE) and SIMVA (EZE/SIMVA) in older (ie, aged>or=65 years) versus younger (ie, aged<65 years) patients with primary hypercholesterolemia. METHODS: We analyzed pooled data from 3 previously published, similarly designed, randomized, double-blind, placebo-controlled studies in patients with primary hypercholesterolemia. After a 6- to 8-week washout, a 4-week dietary stabilization period, and a 4-week placebo run-in period, patients with low-density lipoprotein cholesterol (LDL-C) of 145 to 250 mg/dL were randomized to EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo for 12 weeks. In this post hoc analysis, the percent change from baseline to week 12 in LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein B (apo B), triglycerides (TG), and high-sensitivity C-reactive protein (hs-CRP) for EZE/SIMVA (pooled across doses) versus SIMVA alone (pooled across doses) was compared between older and younger patients with primary hypercholesterolemia. Tolerability was assessed by adverse event reports and laboratory and vital signs assessments throughout the study. RESULTS: A total of 3083 patients aged 20 to 87 years were included in the 3 studies (2320 were aged<65 years and 763 were aged>or=65 years). Baseline lipid values and patient characteristics were similar among all treatment groups for patients aged<65 years versus those aged>or=65 years except that there was a higher percentage of females (62% vs 50%) and patients with hypertension (46% vs 29%) in the older versus younger subgroup (both, P<0.001). EZE/SIMVA was associated with greater improvements than SIMVA alone in LDL-C, non-HDL-C, apo B, TG, and hs-CRP (all, P<0.001); these effects did not appear to differ between the older and younger sub-groups (all, P=NS). Changes in HDL-C did not differ significantly between the EZE/SIMVA and SIMVA groups. More patients receiving EZE/SIMVA than SIMVA monotherapy achieved the target LDL-C level<100 mg/dL (P<0.001), regardless of age subgroup (77% vs 41% for patients aged<65 years and 85% vs 48% for patients aged>or=65 years). In the younger sub-group, the incidence of creatinine phosphokinase (CK) elevations>or=10x the upper limit of normal (ULN) was or=10x ULN were reported. In younger patients, the incidence of consecutive alanine amino-transferase or aspartate aminotransferase levels>or=3x ULN was 0% for placebo and EZE, <1% for SIMVA, and 2% for EZE/SIMVA; in older patients, it was 1% for placebo and EZE, <1% for SIMVA, and 0% for EZE/SIMVA. CONCLUSION: This post hoc analysis of pooled data from 3 previously published large clinical trials suggests that EZE/SIMVA was well tolerated and associated with improved lipid profiles in both older and younger patients with primary hypercholesterolemia.

Consistency of lipid-altering effects of ezetimibe/simvastatin across gender, race, age, baseline low density lipoprotein cholesterol levels, and coronary heart disease status: results of a pooled retrospective analysis.

BACKGROUND: The combination tablet containing ezetimibe and simvastatin (EZE/SIMVA), inhibits both the intestinal absorption and endogenous production of cholesterol, providing significantly greater low-density lipoprotein cholesterol (LDL-C) lowering than EZE or SIMVA alone. The purpose of this pooled analysis was to evaluate the consistency of efficacy (i.e., between-treatment difference) of EZE/SIMVA versus SIMVA within several selected subgroups of patients with primary hypercholesterolemia. METHODS: For the present analysis, data were pooled from three similarly designed, 12-week, randomized, double-blind, placebo-controlled factorial studies consisting of 3083 patients with primary hypercholesterolemia (n = 311 in placebo group; n = 302 in EZE group; n = 1234 in pooled SIMVA group; n = 1236 in pooled EZE/SIMVA group). In these clinical studies, primary hypercholesterolemia was defined as an LDL-C value between 145 and 250 mg/dL inclusive and a triglyceride (TG) level of less than 350 mg/dL. The results for the pooled SIMVA and pooled EZE/SIMVA groups were used for the present analyses. The pooled analyses focused on the consistency of the between-treatment differences (i.e., incremental effect) for EZE/SIMVA (pooled across doses) versus SIMVA (pooled across doses) on various lipid and non-lipid parameters within different patient subgroups defined according to gender, race (Caucasian, Non-Caucasian), baseline age (< 65, > or = 65 years), baseline LDL-C (< 160, > or = 160 mg/dL), and coronary heart disease (CHD) history. Tolerability was also examined for pooled EZE/SIMVA and pooled SIMVA within these selected subgroups. In a modified intention-to-treat analysis, an ANOVA model was used for testing the consistency of pooled treatment effects on lipid and non-lipid parameters within each selected subgroup. RESULTS: For the entire cohort, baseline lipid profiles were similar for the patients in the pooled EZE/SIMVA group compared with those in the pooled SIMVA group. Treatment with EZE/SIMVA led to significant (p < 0.001) incremental improvements in LDL-C, non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, TG and high sensitivity C-reactive protein compared to SIMVA, across the entire cohort. These changes were consistent within each of the selected subgroups. Moreover, more patients attained LDL-C goal levels < 100 mg/dL with EZE/SIMVA than with SIMVA in the entire cohort and this was consistent across all subgroups, except baseline LDL-C. In this pooled retrospective analysis, treatment with EZE/SIMVA was generally well tolerated across subgroups, with a safety profile similar to SIMVA monotherapy. Although this pooled analysis was performed on a large cohort of patients with primary hypercholesterolemia, the results of this analysis were specific for this select patient population and generalizations to other populations should be applied with caution. CONCLUSION: The enhanced lipid-altering effects of EZE/SIMVA versus those of SIMVA observed in the entire cohort were consistent within all subgroups examined. EZE/SIMVA represents an effective and well-tolerated therapeutic option for the treatment of a wide range of patient subgroups with primary hypercholesterolemia.

Striated muscle safety of ezetimibe/simvastatin (Vytorin).

Despite the excellent benefit/risk profile of statins, their use is limited by a dose-related risk of adverse events, particularly those related to muscle toxicity. Ezetimibe/simvastatin (Vytorin) is a cholesterol-lowering therapy that inhibits the intestinal absorption (ezetimibe) and synthesis (simvastatin) of cholesterol. This analysis compared the muscle safety profiles of ezetimibe/simvastatin and simvastatin monotherapy. We reviewed muscle-related adverse event (AE) data from 17 randomized, blinded clinical trials (13 base and 4 extension studies), in which ezetimibe and simvastatin were either co-administered as separate entities or given as a combination tablet to 4,558 patients. The following AE categories were summarized: incidence of musculoskeletal or connective-tissue AEs (all and drug related); discontinuations due to musculoskeletal or connective-tissue AEs (all and drug related); incidence of AEs reported under the term "myalgia" (all and drug related); discontinuation due to myalgia (all and drug related); incidence of "myopathy" (all and drug related); increases in creatine kinase to 3 to < 5, 5 to < 10, and > or = 10 times the upper limit of normal. For all AE categories examined, the incidence of muscle-related clinical and laboratory AEs or discontinuations due to muscle-related AEs was no more common in patients taking ezetimibe/simvastatin than in those taking simvastatin alone. Thus, the clinical trial experience with ezetimibe/simvastatin suggests that ezetimibe does not enhance or aggravate the muscle effects of simvastatin.