Effect of raloxifene on the incidence of elevated low density lipoprotein (LDL) and achievement of LDL target goals in postmenopausal women

OBJECTIVE: To determine the extent to which raloxifene can maintain low density lipoprotein cholesterol (LDL-C) levels below 160 mg/dL or reduce elevated LDL-C levels to below lipid-lowering goals in postmenopausal women. PATIENTS AND METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial randomized 7705 postmenopausal women to placebo or raloxifene (60 mg or 120 mg) daily for a core treatment phase of 3 years. Changes in LDL-C and other serum lipids in a subset of women was a predefined secondary objective. This post-hoc analysis included the 2413 women who did not take lipid-lowering medications at any time during the trial and for whom LDL-C measurements were available. The threshold for high LDL-C (> or = 160 mg/dL) and LDL-C lipid-lowering goals were defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines. RESULTS: The percent of women with LDL-C < 160 mg/dL was comparable between treatment groups at baseline (placebo, 57.5%; raloxifene 60 mg, 56.4%; raloxifene 120 mg, 56.8%). At 3 years, the percent of these women whose LDL-C had increased to above 160 mg/dL was significantly less in the raloxifene 60 mg and 120 mg groups compared with placebo by 65% (95% CI, 44%-78%) and 64% (95% CI, 43%-77%), respectively. Among women with elevated (defined for these analyses as > or = 160 mg/dL) LDL-C at baseline, the proportion having elevated LDL-C at 3 years was significantly less in the raloxifene 60 mg and 120 mg groups compared with placebo by 32% (95% CI, 24%-40%) and 40% (95% CI, 32%-48%), respectively. Fifty percent and 13% of these women achieved LDL-C goals of < 160 mg/dL and < 130 mg/dL, respectively (P < 0.001 vs. placebo for both) in the raloxifene 60 mg group, with similar results for the raloxifene 120 mg group. CONCLUSIONS: In postmenopausal women with osteoporosis not taking concurrent lipid-lowering therapy, raloxifene significantly reduced the incidence of LDL-C > or = 160 mg/dL and significantly increased the proportion achieving LDL-C goals for lipid-lowering compared with placebo. Whether these and other effects of raloxifene on cardiovascular risk markers will improve cardiovascular outcomes requires further study.     

Lipid-modifying effects of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy*

SUMMARY

Objective: To evaluate the efficacy and safety of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy (HRT) in a randomized, double-blind, placebo-controlled trial.

Methods: After a 6-week dietary lead-in period, 135 postmenopausal women who had been taking a stable HRT regimen for at least 3 months were randomized to receive rosuvastatin 5?mg, 10?mg or placebo for 12 weeks. Fasting levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) were assessed at weeks 0, 2, 6, 10, and 12; apolipoprotein (Apo) B and Apo A-I were measured at weeks 0 and 12.

Results: Rosuvastatin 5?mg and 10?mg significantly reduced LDL-C by 38% (SE = 2.1) and 49% (SE = 2.1), respectively, compared with placebo (1% [SE = 2.1]; p < 0.001). TC, TG, Apo B, and all lipid ratios examined (LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, and Apo B/Apo A-I) were also reduced significantly by both rosuvastatin doses (?p < 0.001). HDL-C levels increased significantly in the rosuvastatin groups (11% and 8% for 5?mg and 10?mg, respectively, vs. –0.5% for placebo; p < 0.001), as did Apo A-I levels (?p < 0.05). The combination of rosuvastatin plus HRT was well tolerated with no apparent differences among treatments in the numbers or types of adverse events reported.

Conclusions: Rosuvastatin 5?mg or 10?mg once daily is a well-tolerated and highly efficacious lipid-lowering therapy in postmenopausal women receiving HRT.     

Effectiveness of simvastatin therapy in raising HDL-C in patients with type 2 diabetes and low HDL-C

SUMMARY

Objective: To evaluate the efficacy of high and moderate doses of simvastatin (80 and 40?mg), for raising high density lipoprotein-cholesterol (HDL-C), improving HDL sub-fractions, and affecting other parameters, including high sensitivity C-reactive protein (hs-CRP), in patients with type 2 diabetes mellitus (DM) and low HDL-C.

Research design and methods: This double-blind, placebo-controlled, randomized, 3-period, complete block, 6-week crossover study examined the efficacy of simvastatin in adult men and women (N = 151) with stable type 2 DM (HbA_1C < 9%), low density lipoprotein-cholesterol (LDL-C) > 100?mg/dL (2.6?mmol/L), HDL-C < 40?mg/dL (< 1?mmol/L), and fasting triglyceride level > 150 (> 1.7?mmol/L) and < 700?mg/dL (< 7.9?mmol/L). This study included adult men (71%) and women (29%) of various races (89% white, 6% black, 1% Asian, 3% other) enrolled from 29 practice-based sites in the United States.

Main outcome measures: Percentage change in HDL-C from baseline at the end of each 6-week treatment interval.

Results: Both simvastatin 80 and 40?mg significantly increased total HDL-C from baseline (mean increases of 8% ± 1 [SE] and 5% ± 1, respectively; p < 0.001) compared with placebo, and significantly reduced plasma concentrations of LDL-C (?p < 0.001), triglycerides (?p < 0.001), apolipoprotein B (?p < 0.001), and hs-CRP (?p ≤ 0.012). Compared with simvastatin 40?mg, the 80?mg dose provided additional efficacy. Simvastatin 80?mg also significantly (?p < 0.001) increased HDL₂ from baseline (14% ± 3[SE]) and placebo phases (10 ± 3). An exploratory analysis showed 87% (simvastatin 80?mg) and 82% (simvastatin 40?mg) of patients reached the NCEP ATP III treatment goals for LDL-C compared with 14% on placebo.

Conclusions: Both simvastatin 80 and 40?mg raise HDL-C and improve other measures associated with elevated coronary risk in patients with type 2 DM and low HDL-C.     

Current status of cholesterol goal attainment after statin therapy among patients with hypercholesterolemia in Asian countries and region: the Return on Expenditure Achieved for Lipid Therapy in Asia (REALITY-Asia) study

ABSTRACT

Background: Data on achieving National Cholesterol Education Program Adult Treatment Panel III (ATP III) goals in Asia are limited.

Objective: To examine treatment patterns, goal attainment, and factors influencing treatment among patients in 6 Asian countries who were taking statins.

Methods: A retrospective cohort study was conducted in China, Korea, Malaysia, Singapore, Taiwan, and Thailand, where 437 physicians (41% cardiologists) recruited adults with hypercholesterolemia newly initiated on statin monotherapy.

Results: Of 2622 patients meeting inclusion and exclusion criteria, approximately 66% had coronary heart disease (CHD)/diabetes mellitus, 24% had no CHD but ≥2 risk factors, and 10% had no CHD and <2 risk factors. Most patients (～90%) received statins at medium or lower equipotency doses. Across all cardiovascular risk categories, 48% of patients attained ATP III targets for low-density lipoprotein cholesterol (LDL-C), including 38% of those with CHD/diabetes (goal: <100 mg/dL), 62% of those without CHD but with ≥2 risk factors (goal: <130 mg/dL), and 81% of those without CHD and <2 risk factors (goal: <160 mg/dL). Most patients who achieved goals did so within the first 3 months. Increasing age (odds ratio (OR) = 1.015 per 1-year increment; 95% confidence interval (CI) = 1.005–1.206; p = 0.0038) and initial statin potency (OR = 2.253; 95% CI = 1.364–3.722; p = 0.0015) were directly associated with goal attainment, whereas increased cardiovascular risk (OR=0.085; 95% CI = 0.053–0.134; p < 0.0001 for CHD/diabetes mellitus at baseline compared with <2 risk factors,) and baseline LDL-C (OR = 0.990; 95% CI = 0.987–0.993); p < 0.0001 per 1-mg/dL increment) were inversely associated with LDL-C goal achievement. Limitations of this study include potential differences in treatment settings and cardiovascular risk factors between different countries and centers. In addition, the effects on cholesterol goal achievement of concomitant changes in lifestyle were not assessed.

Conclusion: LDL-C goal attainment is low in Asians, particularly those with CHD/diabetes. More effective patient monitoring, treatments, including combining regimens and dose titration, and adherence to these treatments along with therapeutic lifestyle counseling may facilitate goal attainment.     

Year-by-year analysis of cardiovascular events in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial

ABSTRACT

Objective: To assess the effect of raloxifene 60?mg/day (RLX) on year-by-year cardiovascular (CV) events in postmenopausal women participating in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a double-blind, placebo-controlled osteoporosis treatment trial.

Research design and methods: Post hoc analysis, using data from participants receiving placebo (N = 2576) or RLX 60?mg/day (N = 2557) in MORE, was performed to determine the relative risk (RR, 95% CI) of CV events in each individual trial year. Analyses were performed for the overall cohort and for women in high and low risk subsets. Women were retrospectively assessed as high CV risk using established criteria and the remaining women were considered low CV risk.

Results: The incidence of CV events did not differ between the RLX and placebo groups in the overall cohort (RR 0.86, 95% CI 0.64–1.15), or the low CV risk subset (RR 1.01, 95% CI 0.70–1.46). In the high-risk subset, the incidence of CV events was less in the RLX group (RR 0.60, 95% CI 0.38–0.95). There was no significant increase in CV risk during any single year in the RLX group for either the overall cohort or the low or high CV risk subsets.

Conclusion: In this post hoc analysis, the risk of CV events was not increased in any single year of MORE in women taking RLX, either in the overall cohort or in the low and high CV risk subsets.     

Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with diabetes mellitus or metabolic syndrome

SUMMARY

Objective: To conduct a post-hoc assessment of the lipid-modifying effects of adding the cholesterol absorption inhibitor, ezetimibe, to on-going statin therapy in patients with diabetes mellitus (DM) or metabolic syndrome (MetS).

Research design and methods: This was a post-hoc analysis of data from a randomized, double-blind, placebo-controlled trial designed to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy and safety of adding ezetimibe 10?mg/day versus placebo to ongoing, open-label statin treatment for 8 weeks in hypercholesterolemic patients. Qualifying LDL-C levels and target LDL-C goals were based on National Cholesterol Education Program risk categories. The DM subgroup were patients who entered the study with a prior diagnosis of DM. Patients were classified as having MetS if they met 3 or more of the following criteria at baseline: triglycerides (TG) ≥ 150?mg/dL (1.69 mmol/L); high-density lipoprotein cholesterol (HDL-C) < 40?mg/dL (1.04 mmol/L) for men or < 50?mg/dL (1.29 mmol/L) for women; fasting serum glucose (FSG) ≥ 110?mg/dL (≥ 6.1 mmol/L); a diagnosis of hypertension or taking hypertension medication or blood pressure ≥ 130/ ≥ 85 mmHg; waist circumference > 88?cm (women) or > 102?cm (men). DM patients were excluded from the MetS subgroup analysis.

Main outcome measures: The objectives were to assess the effects of treatment on plasma concentrations of LDL-C and other lipid variables, and on the percentage of patients achieving LDL-C target levels at the end of the study.

Results: Of 769 patients enrolled in the original study, there were 191 (24.8%) with DM and 195 (25.4%) with MetS. Regardless of subgroup, ezetimibe + statin was significantly more effective than statin alone at lowering plasma levels of LDL-C, non-HDL-C, total cholesterol, apolipoprotein B, and triglycerides (between-group p < 0.001 for all). For all lipid parameters, the relative treatment effects were generally consistent regardless of DM or MetS status. Significantly more ezetimibe than placebo patients in all subgroups achieved prespecified LDL-C goals (?p < 0.001 for all), and although more patients in the DM and MetS groups, respectively, achieved the goal compared with their non-DM and non-MetS counterparts [83.6% (DM) versus 67.2 (non-DM) and 71.8% (MetS) versus 65.6% (non-MetS)], these differences were not significant after adjusting for differences in baseline LDL-C levels. Ezetimibe was well-tolerated and had a favorable safety profile in all subgroups.

Conclusions: The co-administration of ezetimibe with statins, a therapeutic regimen that inhibits both the absorption and synthesis of cholesterol, offers a well-tolerated and efficacious treatment to lower LDL-C in patients with DM and MetS.     

The effect of raloxifene therapy on the risk of new clinical vertebral fractures at three and six months: a secondary analysis of the MORE trial

ABSTRACT

Objective: Raloxifene treatment (60?mg/day) significantly decreases the risk of new clinical vertebral fractures by 68% at 1 year compared with placebo. The objective of the present analysis is to evaluate the effects of raloxifene on the incidence of new clinical vertebral fractures at 3 and 6 months after initiation of treatment.

Research design and methods: A double-blind, randomized, placebo-controlled, 4‐year Multiple Outcomes of Raloxifene Evaluation (MORE) trial was conducted in 180 study centers. Postmenopausal women with osteoporosis (N = 7705) were randomized to placebo, or raloxifene at 60 or 120?mg/day.

Main outcome measures: Vertebral radiographs were obtained when patients reported symptoms suggestive of vertebral fracture at or between clinic visits, which were held at 3 and 6 months, and every 6 months thereafter. If a new adjudicated fracture was found, this was considered as a clinical vertebral fracture. The analyses included all randomized patients with a baseline and at least one follow-up radiograph (n = 6828).

Results: One woman treated with raloxifene 60?mg/day (n = 2259) and 10 in the placebo group (n = 2292) had a clinical vertebral fracture in the first 6 months, resulting in a 90% relative risk (RR) reduction [RR 0.10 (95% CI 0.01, 0.63)] and a 0.39% absolute risk reduction (ARR). Similar results were observed with raloxifene 120?mg/day at 6 months. When the raloxifene groups were pooled, a significant (?p = 0.034) decrease in clinical vertebral fracture risk [RR 0.20 (95% CI 0.03, 0.90), ARR 0.17%] was seen as early as 3 months.

Conclusion: The risk of new clinical vertebral fractures was reduced after 3 or 6 months of raloxifene.     

Adherence to lipid-lowering therapy and reaching treatment goals in youth seen in a preventive cardiology clinic

IntroductionThe efficacy of lipid-lowering therapy in reducing cardiovascular disease in adults is well-established. Unfortunately, it is also well-established that adults have inadequate adherence to lipid-lowering therapy, which is associated with increased costs and mortality. However, the adherence patterns of youth prescribed lipid-lowering therapy is not well-described.MethodsWe analyzed data that was prospectively collected from patients <27 years-old who were referred to a large regional preventive cardiology clinic from 2010 to 2017. Adherence to lipid-lowering therapy was self-reported at the patient's most recent clinic visit and categorized as either adequate adherence (≥80%) or inadequate adherence (<80%). We compared adherence rates by demographic factors, class of lipid-lowering therapy, length of time on lipid-lowering therapy, family history, lipid parameters, and laboratory measures of adverse effects.ResultsIn our cohort, we had 318 patients prescribed a lipid-lowering medication over a seven-year period. Of those, 235 (75%) had adequate adherence. Those with adequate adherence had an improved LDL-C (123 mg/dL [standard deviation (SD) 32.3] vs. 167 mg/dL [SD 50.4], p < 0.05), total cholesterol (198 mg/dL [49.5] vs. 239 mg/dL [SD 53.2]), and non-HDL-C (148 mg/dL [SD 38.7] vs. 193 mg/dL [SD 43.9]). In addition, patients with adequate adherence were more likely to reach goal LDL-C of <130 mg/dL than those with inadequate adherence (130 vs. 25, p < 0.01). The relationship between LDL-C and adherence remained statistically significant after controlling for age, gender, and the length of time on therapy (β = ?0.66, p < 0.01). Adherence level did not differ by gender, class of lipid-lowering therapy, length of time on lipid-lowering therapy, or presence of a family history of an atherosclerotic event. The findings were similar when we only analyzed those prescribed a statin.ConclusionsSelf-reported adherence to lipid-lowering therapy in youth is excellent and was associated with achieving goal LDL-C goals. Obtaining adherence data from patients may help more patients reach LDL-C goals.     

Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies

SUMMARY

Background: Asians are thought to be more responsive to the lipid-lowering effects of statins than non-Asians although there are no head-to-head trials that examine this perception.

Objective: To compare the results of the GOALLS and STATT studies that used similar titrate-to-goal protocols with 20?mg up to 80?mg simvastatin in Asian and non-Asian coronary heart disease (CHD) patients.

Methods: GOALLS (N = 198; included non-Asians and Asians) and STATT (N = 133; included Asians only) were both multi-center, open-label 14-week studies in CHD patients with serum low density lipoprotein cholesterol (LDL-C) levels 115?mg/dL–180?mg/dL and triglycerides (TG) levels ≤ 400?mg/dL. Simvastatin was titrated from 20?mg/day up to 80?mg/day in order to achieve the National Cholesterol Education Program (NCEP) LDL-C target ≤ 100?mg/dL. The primary efficacy variable was the percentage of patients attaining the NCEP LDL-C target at Week 14. Secondary endpoints included proportion of patients achieving the European Society of Cardiology/European Atherosclerosis Society/European Society of Hypertension (European) LDL-C target ≤ 115?mg/dL at Week 14 and percentage change in lipid parameters. Safety and tolerability were assessed by monitoring adverse experiences and safety laboratory tests. Fifteen Asian patients were part of the GOALLS cohort and their data were compared separately with results of non-Asians from GOALLS and Asians from the STATT study.

Results: After 14?weeks of simvastatin treatment, 87.1% of GOALLS non-Asians, 85.7% of GOALLS Asians, and 78.2% of STATT patients attained the NCEP LDL-C target. At Week 14, 94.4%, 92.9%, and 91.7% of the GOALLS non-Asians, GOALLS Asians, and STATT patients achieved the European LDL-C target, respectively. The average treatment doses to attain NCEP and European targets were comparable among groups. The percentage reductions in lipid parameters from baseline to week 14 were similar among groups except, changes in high density lipoprotein cholesterol and apolipoprotein A-I favored Asian subjects. There was also a greater reduction in TG in the STATT study, but this was not consistent with TG reductions experienced by Asians in the GOALLS study. In both studies, simvastatin was generally well tolerated by all patients across the dosage range of 20?mg–80?mg. No cases of rhabdomyolysis or myopathy were reported in either study.

Conclusions: A great majority of CHD patients is able to achieve LDL-C treatment goals (up to 90%) on simvastatin regardless of racial background. Simvastatin treatment at doses of 20?mg–80?mg is well-tolerated in Asian and non-Asian CHD patients. This side-by-side comparison provides evidence that Asian and non-Asian CHD populations respond similarly to comparable doses of simvastatin.     

Attainment of optional low-density lipoprotein cholesterol goal of less than 70 mg/dl and impact on prognosis of very high risk stable coronary patients: a 3-year follow-up

Objectives: We aimed to investigate the proportion of very high-risk patients with coronary heart disease (CHD) who achieve the optional low-density lipoprotein cholesterol (LDL-C) target of < 70 mg/dl (1.8 mmol/liter), the factors that influence the success rate and the impact on their prognosis.

Research design and methods: We enrolled 1337 consecutive patients with stable CHD. Fasting lipids were determined and all cardiovascular events were recorded during a median follow-up of 33 months.

Results: The majority (86.5%) of patients were taking lipid-lowering medication (95.5% statins), but only 50.6% had LDL-C levels of < 100 mg/dl (2.6 mmol/liter). In total, 941 (70.4%) patients were considered very high risk and only 15.1% of them had LDL-C levels of < 70 mg/dl. Τhe use of intensive lipid-lowering medication was associated with 12-fold (95% CI 6.98 – 20.76; p < 0.001) higher possibility in achieving LDL-C levels of < 70 mg/dl. Attainment of LDL-C levels of < 70 mg/dl by patients at very high risk were independent predictors of all cardiovascular events (HR = 0.34, 95% CI 0.17 – 0.70; p = 0.003).

Conclusions: The vast majority of very high-risk patients do not achieve the optional LDL-C goal; this is mainly due to the suboptimal uptitration of statin dose and is translated into loss of clinical benefits.     

Raloxifene: a review of its use in postmenopausal osteoporosis

Raloxifene is a selective estrogen receptor modulator that partially mimics the effects of estrogens in bone and the cardiovascular system, while functioning as an antiestrogen in endometrial and breast tissue. In randomised placebo-controlled studies involving postmenopausal women or patients with osteoporosis, raloxifene 60 to 150 mg/day was effective in increasing bone mineral density (BMD) over 12- to 36-month periods. At the 60 mg/day recommended dosage, increases of 1.6 to 3.4%, 0.9 to 2.3% and 1.0 to 1.6% were reported in lumbar spine, femoral neck and total hip, respectively, versus < or =0.5% with placebo. Raloxifene 60 or 120 mg/day decreased the risk of vertebral fractures over a 36-month period in postmenopausal patients with osteoporosis. Significant reductions in radiographic fracture risk versus placebo (30 and 50%) occurred regardless of whether patients had existing fractures at baseline. Although raloxifene did not affect the overall incidence of nonvertebral fractures, a reduction in the incidence of ankle fracture was reported in comparison with placebo. In postmenopausal women, raloxifene 60 mg/day significantly reduced serum levels of total and low density lipoprotein cholesterol from baseline, compared with placebo. High density lipoprotein cholesterol and triglyceride levels were unaffected. Raloxifene 60 or 120 mg/day reduced the risk of invasive breast cancer by 76% during a median of 40 months' follow-up in postmenopausal patients with osteoporosis and no history of breast cancer. A relative risk reduction of 90% was reported for estrogen-receptor positive invasive breast cancers; estrogen-receptor negative cancer risk was unaffected by raloxifene. Raloxifene was generally well tolerated in clinical trials at dosages up to 150 mg/day. Adverse events thought to be related to raloxifene treatment were hot flushes and leg cramps. Venous thromboembolism was the only serious adverse event thought to be related to raloxifene treatment and a relative risk of 3.1 compared with placebo treatment was reported in patients with osteoporosis. Vaginal bleeding occurred in < or =6.4% of raloxifene-treated women but was reported by 50 to 88% of those receiving estrogens or hormone replacement therapy (HRT). Raloxifene treatment was not associated with stimulatory effects on the endometrium. CONCLUSIONS: Raloxifene significantly increases BMD in postmenopausal women and reduces vertebral fracture risk in patients with osteoporosis. In clinical trials, raloxifene was generally well tolerated compared with placebo and HRT, although its propensity to cause hot flushes precludes use in women with vasomotor symptoms. In particular, the lack of stimulatory effects on the endometrium and the reduction in invasive breast cancer incidence indicate raloxifene as an attractive alternative to HRT for the management of postmenopausal osteonorosis.     

Abaloparatide in patients with mild or moderate renal impairment: results from the ACTIVE phase 3 trial

Abstract

Objective: To evaluate, post hoc, the efficacy and safety of abaloparatide by degree of renal impairment.

Methods: ACTIVE was a phase 3, 18-month, randomized, double-blind, active-comparator, placebo-controlled study of postmenopausal women with osteoporosis who received subcutaneous abaloparatide 80?µg, placebo, or open-label teriparatide 20?µg daily. Patients with serum creatinine >2.0?mg/dL or 1.5–2.0?mg/dL with an estimated glomerular filtration rate (eGFR) <37?mL/min, calculated by Cockcroft-Gault formula, were excluded.

Results: At baseline, 660 patients had eGFR ≥90?mL/min, 1276 had 60 to ?90?mL/min, and 527 had <60?mL/min. Older age and lower T-scores were associated with greater renal impairment. Among renal-function subgroups, there were no meaningful changes in bone mineral density, fracture risk reduction, or overall incidence of treatment-emergent adverse events in the active-treatment arms. Anemia, nausea, hypercalcemia, and upper-respiratory-tract infection tended to be more frequent with increasing renal impairment. Hypercalcemia measured by albumin-adjusted serum calcium occurred significantly less frequently with abaloparatide than teriparatide in patients with eGFR <60?mL/min (3.6% versus 10.9%; p?=?.008) and in the overall ACTIVE safety population (3.4% versus 6.4%; p?=?.006). Computed tomography scans in 376 patients revealed no evidence of increased renal calcification.

Conclusion: Increased exposure to abaloparatide and teriparatide in patients with renal impairment led to no meaningful differences in efficacy or safety. These results support the use of abaloparatide without dosage adjustment in patients with renal impairment, provided those with severe renal impairments are monitored for adverse events.     

Comparison of self-reported survey (SHIELD) versus NHANES data in estimating prevalence of dyslipidemia

ABSTRACT

Objectives: The study purpose was to compare the prevalence of dyslipidemia between a self-reported survey, Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD), and survey and laboratory data from National Health and Nutrition Examination Survey (NHANES 1999–2002).

Methods: A SHIELD questionnaire was mailed to 200?000 households representative of US adult population (64% response, n = 211?097 individuals) and included if ever diagnosed with diabetes, high blood pressure or cholesterol problems, high total cholesterol (TC), high bad cholesterol (LDL-C), low good cholesterol (HDL-C), or high triglycerides (TG). In NHANES using a combination of interviewer-administered survey and clinical and laboratory data, dyslipidemia was defined as any one of: TC ≥?240?mg/dL or diagnosis of high cholesterol; TG >?200?mg/dL;LDL-C ≥?160?mg/dL; or HDL-C <?40?mg/dL. NHANES diabetes mellitus definition was doctor diagnosis or fasting glucose >?125?mg/dL and hypertension was elevated blood pressure or taking anti-hypertensive medication. Prevalence of dyslipidemia was determined for SHIELD in 2004 and compared to NHANES 1999–2002. Prevalence of diabetes and hypertension was estimated for broader contextual comparison within cardiometabolic diseases.

Results: In contrast to the prevalence of diabetes (8% in SHIELD and 9% in NHANES, p < 0.01) and hypertension (23% in SHIELD and 29% in NHANES, p < 0.01), dyslipidemia was reported only half as frequently in SHIELD (26%) as in NHANES (53%), p < 0.01. Com­ponents of dyslipidemia were uniformly less in SHIELD than NHANES: high TC = 17 vs. 35%, high LDL-C = 10 vs. 14%, high TG = 7 vs. 17% and low HDL-C = 5 vs. 24%; all comparisons p < 0.01.

Limitations: Differences in survey methodology, non-response and timing may have impacted the comparison of SHIELD to NHANES.

Conclusions: Dyslipidemia prevalence was lower in self-reported SHIELD than the objectively assessed NHANES, with especially low self-report of high TG and low HDL-C. Self-reported prevalence of dyslipidemia may under-report the prevalence based on laboratory data.     

Pharmacodynamic interaction between ezetimibe and rosuvastatin

SUMMARY

Background: Ezetimibe is a lipid-lowering drug indicated for the treatment of hypercholesterolemia as co-administration with HMG-CoA reductase inhibitors (statins) or as monotherapy. The primary objectives of this study were to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and the new statin rosuvastatin. A secondary objective was to examine the potential for a pharmacokinetic interaction between ezetimibe and rosuvastatin.

Methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study in healthy hypercholesterolemic subjects (untreated low-density lipoprotein cholesterol [LDL-C] ≥ 130?mg/dL [3.37?mmol/L]). After the outpatient screening and NCEP Step I diet stabilization periods, 40 subjects were randomized to one of the 4 following treatments: rosuvastatin 10?mg plus ezetimibe 10?mg (n = 12); rosuvastatin 10?mg plus placebo (matching ezetimibe 10?mg) (n = 12); ezetimibe 10?mg plus placebo (matching ezetimibe 10?mg) (n = 8); or placebo (2 tablets, matching ezetimibe 10?mg) (n = 8). All study treatments were administered once daily in the morning for 14 days as part of a 16-day inpatient confinement period. Fasting serum lipids were assessed pre-dose on days 1 (baseline), 7, and 14 by direct quantitative assay methods. Safety was evaluated by monitoring laboratory tests and recording adverse events. Blood samples were collected for ezetimibe and rosuvastatin pharmacokinetic evaluation prior to the first and last dose and at frequent intervals after the last dose (day 14) of study treatment. Plasma ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and rosuvastatin concentrations were determined by validated liquid chromatography with tandem mass spectrometric detection (LC–MS/MS) assay methods.

Results: All active treatments caused statistically significant (?p ≤ 0.02) decreases in LDL-C concentration versus placebo from baseline to day 14. The co-administration of ezetimibe and rosuvastatin caused a significantly (?p < 0.01) greater reduction in LDL-C and total cholesterol than either drug alone. In this 2-week inpatient study with restricted physical activity there was no apparent effect of any treatment on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The co-administration of ezetimibe and rosuvastatin caused a significantly (?p < 0.01) greater percentage reduction in mean LDL-C (–61.4%) than rosuvastatin alone (–44.9%), with a mean incremental reduction of –16.4% (95%CI –26.3 to –6.53). Reported side effects were generally mild, nonspecific, and similar among treatment groups. There were no significant increases or changes in clinical laboratory tests, particularly those assessing muscle and liver function. There was no significant pharmacokinetic drug interaction between ezetimibe and rosuvastatin.

Conclusions: Co-administration of ezetimibe 10?mg with rosuvastatin 10?mg daily caused a significant incremental reduction in LDL-C compared with rosuvastatin alone. Moreover, co-administering ezetimibe and rosuvastatin was well tolerated in patients with hypercholesterolemia.     

Efficacy and Safety of Cerivastatin, 0.2 mg and 0.4 mg,in Patients with Primary Hypercholesterolemia: a Multinational,Randomised, Double-blind Study

Summary

Elevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4?mg.

This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin OAmglday with that of cerivastatin 0.2?mg/day in patients with primary hypercholesterolemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive cerivastatin 0.4mg (n = 332) or 0.2mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 ± 0.7% from baseline in the 0.4?mg group, compared with a decrease of 31.5 ± 0.9% in the 0.2mg group (p < 0.0001). There was a significant gender difference in the 0.4?mg group: LDL-C decreased by 44.4 ± 8.9% in women, compared with a decrease of 37.0 ± 0.9% in men (p < 0.046). In the PP group as a whole, total cholesterol decreased by 26.0 ± 0.5% from baseline in the 0.4mg group, compared with a decrease of 21.6 ± 0.7% in the 0.2mg group (p < 0.0001). Both doses were well tolerated; only eight (2.4 %) patients in the 0.4?mg group and five (3.1 %) patients in the 0.2?mg group withdrew owing to adverse events.

Cerivastatin 0.2?mg/day and 0.4?mg/day was found to lower low-density lipoprotein cholesterol and total cholesterol levels in a dose-dependent manner, with both doses exhibiting a good safety profile.     

The analgesic effect of etoricoxib relative to that of two opioid-acetaminophen analgesics: a randomized,controlled single-dose study in acute dental impaction pain

ABSTRACT

Background: To compare the analgesic effect of single doses of etoricoxib 120?mg, oxycodone/acetaminophen 10?mg/650?mg and codeine/acetaminophen 60?mg/600?mg in acute pain using the dental impaction model.

Methods: In this randomized, double-blind, placebo-controlled, parallel-group study, patients reported pain intensity and pain relief (16 times) and global scores (twice) during a 24-h period. The primary endpoint was the overall analgesic effect, total pain relief over 6?h (TOPAR6). Other endpoints were patient global evaluation, time to onset (2-stopwatch method), duration of analgesic effect (median time to and amount of rescue medication use). Tolerability was evaluated by overall and opioid-related (nausea and vomiting) adverse experiences.

Results: 302 patients (mean age 23; 63% women; 63 % White) were randomized to etoricoxib 120?mg, oxycodone/acetaminophen 10?mg/650?mg, codeine/acetaminophen 60?mg/600?mg, and placebo (2:2:1:1). Etoricoxib demonstrated significantly greater overall analgesic efficacy (TOPAR6) (13.2?units) versus oxycodone/acetaminophen (10.2?units); and codeine/acetaminophen (6.0?units); p < 0.001 for all. All active treatments were superior to placebo. Median time to onset was significantly (?p < 0.001) shorter for oxycodone/acetaminophen (20?min) and numerically but not significantly shorter (?p = 0.259) for codeine/acetaminophen (26?min) compared with etoricoxib (40?min). Etoricoxib (24?h) had a significantly longer lasting analgesic effect than oxycodone/acetaminophen (5.3?h), codeine/acetaminophen (2.7?h), and placebo (1.7?h) (?p < 0.001 for all). Etoricoxib patients experienced fewer clinical adverse experiences than patients on oxycodone/acetaminophen and codeine/acetaminophen, specifically, significantly (?p < 0.05) fewer episodes of nausea.

Conclusion: Etoricoxib 120?mg provided superior overall analgesic effect with a smaller percentage of patients experiencing nausea versus both oxycodone/acetaminophen 10?mg/650?mg and codeine/acetaminophen 60?mg/600?mg.     

The effect of orlistat and ezetimibe,alone or in combination,on serum LDL and small dense LDL cholesterol levels in overweight and obese patients with hypercholesterolaemia

ABSTRACT

Background: Increased concentrations of low density lipoprotein cholesterol (LDL-C), as well as of small dense LDL-C (sdLDL-C), are considered as cardiovascular risk factors.

Objective: An assessment of the effects of ezetimibe and orlistat administration, alone or in combination, on LDL-C and sdLDL-C levels (primary endpoint), as well as on anthropometric variables and metabolic parameters (secondary endpoints) in overweight and obese patients [body mass index (BMI) > 28 kg/m²] with hypercholesterolaemia [total cholesterol > 200 mg/dL (5.2 mmol/L)].

Methods: Eighty six subjects were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg, 3 times daily (O group), ezetimibe 10 mg/day (E group) or both (OE group) for 6 months.

Results: Significant reductions in LDL-C (?19%, ?21%, ?32% in groups O, E and OE, respectively, all p < 0.01 vs. baseline) and sdLDL-C levels (?45%, ?48%, ?76% in groups O, E, OE, respectively, all p < 0.01 vs. baseline) were observed. Group OE experienced a significantly greater reduction in LDL-C and sdLDL-C levels compared with groups O and E (p < 0.05). Furthermore, significant reductions of BMI, homeostasis model assessment (HOMA) index, serum uric acid, transaminase activities and plasma lipoprotein-associated phospholipase A₂ (Lp-PLA₂) activity were observed in the O and OE groups. Gamma-glutamyl transpeptidase activity and Lp-PLA₂ activity improved significantly more with the combination treatment compared with either orlistat or ezetimibe monotherapy.

Conclusions: Orlistat and ezetimibe combination had a more favourable effect on LDL-C and sdLDL-C levels in overweight and obese hypercholesterolaemic patients than either drug alone. Furthermore, orlistat, alone or in combination with ezetimibe, additionally improved several anthropometric and metabolic variables.     

Safety assessment of raloxifene over eight years in a clinical trial setting

ABSTRACT

Objective: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting.

Methods: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4‐year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4‐year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test.

Results: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups (?p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively (?p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93–3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups (?p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo (?p = 0.028, p < 0.001, and p = 0.008, respectively).

Conclusion: These 8‐year data support the known clinical safety profile of raloxifene, established in the MORE trial.     

Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin

SUMMARY

Background: Ezetimibe is a cholesterol absorption inhibitor which decreases low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. This study investigated the potential for pharmacodynamic and/or pharmacokinetic interactions between ezetimibe and lovastatin.

Methods: In a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study, 48 healthy men with hypercholesterolemia (screening LDL-C ≥ 130?mg/dL) who were stabilized and maintained on a National Cholesterol Education Program (NCEP) Step I diet were randomized to one of the following six oral treatments once daily for 14?days: lovastatin 20?mg; lovastatin 20?mg plus ezetimibe 5, 10, or 20?mg; lovastatin 40?mg plus ezetimibe 10?mg; or placebo.

Results: Reported adverse events were generally mild, nonspecific, and similar among treatments. There were no significant changes in safety laboratory test results, including those for enzymes indicative of muscle or liver injury. Co-administration of ezetimibe and lovastatin did not increase the plasma concentrations of lovastatin or β-hydroxylovastatin. In this parallel comparison study there was an apparent decrease in lovastatin exposure, however, the reduction in lovastatin or β-hydroxylovastatin concentrations was not related to the ezetimibe dose and is not considered to be clinically important. Ezetimibe 5, 10, or 20?mg combined with lovastatin 20?mg caused a significantly (?p < 0.01) greater reduction in LDL-C than lovastatin 20?mg alone, with no apparent effect on HDL-C or triglycerides. LDL-C was reduced by 51.0% with ezetimibe 10?mg plus lovastatin 20?mg, 56.0% with ezetimibe 10?mg plus lovastatin 40?mg, 33.2% with lovastatin alone, and 17.3% with placebo.

Conclusions: The co-administration of ezetimibe and lovastatin was well tolerated and resulted in a significantly greater percentage reduction in serum LDL-C concentrations than with lovastatin alone, with an average incremental reduction of 16–18%. Ezetimibe 10?mg appears to be the optimal dose when co-administered with lovastatin 20?mg once daily. Further incremental reductions in LDL-C from the co-administration of ezetimibe and lovastatin are expected only when the dose of lovastatin is increased. The co-administration of ezetimibe and lovastatin has the potential to produce clinically significant reductions in LDL-C compared to either drug alone, with favorable safety and tolerability.     

Evolocumab: A Review in Hyperlipidemia

Evolocumab (Repatha^®) is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously at a dosage of 140 mg every 2 weeks or 420 mg once monthly. Across 12-week phase III trials in patients with primary hypercholesterolemia or mixed dyslipidemia, evolocumab was more effective than placebo (treatment difference ?54.8 to ?76.3 %) and/or ezetimibe (treatment difference ?36.9 to ?47.2 %) at reducing low-density lipoprotein cholesterol (LDL-C) levels, including when added to statin therapy, when administered to statin-intolerant patients, when administered as monotherapy, and in patients with heterozygous familial hypercholesterolemia who were receiving statins with or without other lipid-lowering drugs. Evolocumab also significantly lowered LDL-C levels (treatment difference of ≈30 % vs. placebo) in patients with homozygous familial hypercholesterolemia when added to statins with or without ezetimibe in a 12-week phase III trial. The efficacy of evolocumab was maintained in the longer term, and it was well tolerated. In conclusion, subcutaneous evolocumab is a valuable new treatment for use in primary hypercholesterolemia or mixed dyslipidemia and homozygous familial hypercholesterolemia, particularly in patients unable to reach LDL-C goals despite treatment with statins with or without other lipid-lowering therapies and in patients who do not tolerate or are not able to receive statins.