The Journal of Clinical Endocrinology & Metabolism
Context In the ODYSSEY CHOICE I trial, alirocumab 300 mg every 4 weeks (Q4W) was assessed in pati... more Context In the ODYSSEY CHOICE I trial, alirocumab 300 mg every 4 weeks (Q4W) was assessed in patients with hypercholesterolemia. Alirocumab efficacy and safety were evaluated in a patient subgroup with type 2 diabetes mellitus (T2DM) and who were receiving maximally tolerated statins with or without other lipid-lowering therapies. Methods Participants received either alirocumab 300 mg Q4W (n = 458, including 96 with T2DM) or placebo (n = 230, including 50 with T2DM) for 48 weeks, with alirocumab dose adjustment to 150 mg every 2 weeks at Week (W) 12 if W8 low-density lipoprotein cholesterol (LDL-C) levels were ≥70 mg/dL or ≥ 100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline. Efficacy end points included percentage change from baseline to W24 for lipids, and time-averaged LDL-C over W21 to W24. Results In individuals with T2DM, LDL-C reductions from baseline to W24 and the average of W21 to W24 were significantly greater with alirocumab (−61...
Background: At least 4 grams of prescription omega-3 ethyl esters (EE) are required to lower non-... more Background: At least 4 grams of prescription omega-3 ethyl esters (EE) are required to lower non-high density lipoprotein cholesterol (non-HDL-c) in patients treated with a statin with triglycerides (TG) between 200-499 mg/dL. Omega-3 EE require hydrolysis to free-fatty acids (FFA) by pancreatic lipases for absorption. Epanova, a novel omega-3 FFA does not require hydrolysis and has been shown to have up to 5-fold greater bioavailability (BA) than the EE form. This improvement in BA may lead to a lower daily dosage compared to EE formulations. The ESPRIT trial evaluated a 2 g/d dosage as well as a 4 g/d of Epanova compared to olive oil (OO) in patients with persistent high TG (HTG) and high risk for cardiovascular disease.
Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited tre... more Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled phase 2 studies of 8 or 12 weeks duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, NCT01288443). Data were available for 102/108 patients who received alirocumab 150 mg Q2W and 74/77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (-30.3% versus -0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that less than 5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C). In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of LDL-C lowering.
ABSTRACT Alirocumab is a fully human monoclonal antibody to PCSK9. The ODYSSEY MONO study was th... more ABSTRACT Alirocumab is a fully human monoclonal antibody to PCSK9. The ODYSSEY MONO study was the first alirocumab Phase III study to test a previously unused dose of 75 mg subcutaneously every 2 weeks in a population on no lipid-lowering therapy. A total of 103 patients were randomly assigned to alirocumab starting at 75 mg subcutaneously every 2 weeks or ezetimibe 10 mg per os every day with alirocumab dose uptitration at 12 weeks based on achieved LDL-cholesterol level at week 8 and followed to week 24. At the week-24 primary end point, the alirocumab intent-to-treat group showed a 47.2% (least square [LS] mean) reduction in LDL-cholesterol compared with a 15.6% (LS mean) reduction with ezetimibe (LS mean difference of 31.6%; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Safety parameters and adverse events were similar between the two groups.
Background: Xuezhikang (XZK) is an extract of fermented red yeast rice that has lipidlowering pro... more Background: Xuezhikang (XZK) is an extract of fermented red yeast rice that has lipidlowering properties.
Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PC... more Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).
Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) rec... more Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation. REGN727/SAR236553 (designated here as SAR236553), a fully human PCSK9 monoclonal antibody, increases the recycling of LDL receptors and reduces LDL cholesterol levels.
increases in FG levels that appeared to decline over time in non-diabetic, hypercholesterolemic p... more increases in FG levels that appeared to decline over time in non-diabetic, hypercholesterolemic patients, whereas Eze monotherapy had no significant effects. These data suggest that coadministration of Eze with statin therapy does not further increase FG levels beyond those observed with statin monotherapy. Additional analyses are in progress to assess the relationships between various baseline factors and FG changes in these patients.
Introduction: Retapamulin is a novel, topical antibacterial of the pleuromutilin class in develop... more Introduction: Retapamulin is a novel, topical antibacterial of the pleuromutilin class in development for the treatment of secondarily infected traumatic lesions of the skin.Methods: The efficacy, safety, and tolerability of topical retapamulin ointment, 1% for 5 days twice daily was evaluated in 2 identical, randomized, double-blind, double-dummy, multicenter studies vs oral cephalexin, 500 mg twice daily for 10 days, in 1904 patients with secondarily infected traumatic lesions.Results: Clinical success rates were 89.5% in protocol-adherent patients receiving retapamulin compared with 91.9% for cephalexin (treatment difference, −2.5% [95% confidence interval, −5.4% to 0.5%]). In patients with Staphylococcus aureus or Streptococcus pyogenes at baseline, clinical success was 89.2% (365/409) for retapamulin and 92.6% (63/68) for cephalexin. Safety and tolerability were similar between treatments. Noncompliance (defined as using or taking <80% of doses) was recorded in 8.0% (51/636) of patients taking cephalexin compared with 0.39% (5/1268) of patients receiving retapamulin.Conclusions: Retapamulin offers a novel, effective, and convenient topical treatment for secondarily infected traumatic lesions.
Statins have been the cornerstone of lipid therapy for the last two decades, but despite signific... more Statins have been the cornerstone of lipid therapy for the last two decades, but despite significant clinical efficacy in the majority of patients, a large residual risk remains for the development of initial or recurrent atherosclerotic cardiovascular disease. In addition, owing to side effects, a significant percentage of patients cannot tolerate any statin dose or a high enough statin dose to reach their recommended LDL cholesterol goals. Monoclonal antibodies (mAbs) to PCSK9 have recently been shown to be highly efficacious in lowering LDL cholesterol, while demonstrating a favorable adverse event profile in early clinical trials. This review of alirocumab (formerly REGN727/SAR236553) explains the physiology and pharmacodynamics of PCSK9 inhibition with a mAb, as well as the Phase I and II clinical trial results of alirocumab and the ongoing Phase III trial designs. Several mAbs to PCSK9 are currently in development and approval may be 1-3 years away. We will focus this review on alirocumab, but mAbs to PCSK9 are the most promising cholesterol-lowering medication since statins and have the potential to significantly reduce further the occurrence of atherosclerotic cardiovascular disease.
Background and Objectives: Long-term (>1 year) safety and efficacy studies of combination lipid t... more Background and Objectives: Long-term (>1 year) safety and efficacy studies of combination lipid therapy are lacking. This year 2 study evaluated fenofibric acid 135 mg in combination with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg) in patients with mixed dyslipidaemia. Methods: This was a phase 3, open-label, year 2 extension study in patients who had completed one of three double-blind, 12-week, controlled studies and the subsequent open-label, year 1 extension study. Patients in this study had mixed dyslipidaemia (high-density lipoprotein cholesterol [HDL-C] <40 mg/dL [<1.02 mmol/L] for men or <50 mg/dL [<1.28 mmol/L] for women, triglycerides [TG] ‡150 mg/dL [ ‡1.69 mmol/L], and low-density lipoprotein cholesterol [LDL-C] ‡130 mg/dL [ ‡3.37 mmol/L]) at the start of the controlled study, and had completed the year 1 extension study. Treatment was once-daily oral coadministration of fenofibric acid 135 mg and moderatedose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg), and was identical to the treatment received in the year 1 study. The year 2 population safety data were summarized for the entire duration of fenofibric acid + statin therapy. Efficacy data were summarized by combination therapy group, as well as pooled across combination therapies, and summarized across the controlled and open-label studies. Results: Of the 310 patients enrolled into the year 2 study, 287 (93%) completed therapy. The mean cumulative exposure to combination therapy was 743 days across the studies. Adverse event rates were similar for all three combination therapy groups. No deaths or treatment-related serious adverse events occurred. The incidence of discontinuation due to adverse events was 2.9% overall. Rhabdomyolysis was not reported in any group. Overall, fenofibric acid + moderate-dose statin for ‡2 years resulted in sustained improvements in HDL-C (+17.4%), TG (-46.4%) and LDL-C (-40.4%).
... Cardiol. Harold E. Bays, Eli M. Roth, Iain Dukes, Gloria Lin-Luo, Neil Cowen, and Yu Liu META... more ... Cardiol. Harold E. Bays, Eli M. Roth, Iain Dukes, Gloria Lin-Luo, Neil Cowen, and Yu Liu METABOLIC EFFECTS HYPERTRIGLYCERIDEMIC SUBJECTS: LIPID AND OTHER DIAZOXIDE CHOLINE CONTROLLED RELEASE IN This information is current as of April 19, 2010 ...
To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric aci... more To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric acid (R/F), compared with simvastatin (S) in patients with high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG).
Aims To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO)... more Aims To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia. Methods and results This was a multicentre, randomized, double-blind, placebocontrolled, parallel arm trial in patients with mixed hyperlipidaemia [LDL-cholesterol (LDL-C), 3.4-5.7 mmol/L (2.6-4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3-5.7 mmol/L] and no history of coronary heart disease (CHD), CHDequivalent disease (except for type 2 diabetes), or CHD risk score .20%. A total of 625 patients was randomized in a 1:3 :3: 3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO þ EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO þ EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P , 0.001) reduced with FENO þ EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO þ EZE and FENO treatments when compared with placebo (P , 0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline, .70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO þ EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated. Conclusion Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.
The Journal of Clinical Endocrinology & Metabolism
Context In the ODYSSEY CHOICE I trial, alirocumab 300 mg every 4 weeks (Q4W) was assessed in pati... more Context In the ODYSSEY CHOICE I trial, alirocumab 300 mg every 4 weeks (Q4W) was assessed in patients with hypercholesterolemia. Alirocumab efficacy and safety were evaluated in a patient subgroup with type 2 diabetes mellitus (T2DM) and who were receiving maximally tolerated statins with or without other lipid-lowering therapies. Methods Participants received either alirocumab 300 mg Q4W (n = 458, including 96 with T2DM) or placebo (n = 230, including 50 with T2DM) for 48 weeks, with alirocumab dose adjustment to 150 mg every 2 weeks at Week (W) 12 if W8 low-density lipoprotein cholesterol (LDL-C) levels were ≥70 mg/dL or ≥ 100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline. Efficacy end points included percentage change from baseline to W24 for lipids, and time-averaged LDL-C over W21 to W24. Results In individuals with T2DM, LDL-C reductions from baseline to W24 and the average of W21 to W24 were significantly greater with alirocumab (−61...
Background: At least 4 grams of prescription omega-3 ethyl esters (EE) are required to lower non-... more Background: At least 4 grams of prescription omega-3 ethyl esters (EE) are required to lower non-high density lipoprotein cholesterol (non-HDL-c) in patients treated with a statin with triglycerides (TG) between 200-499 mg/dL. Omega-3 EE require hydrolysis to free-fatty acids (FFA) by pancreatic lipases for absorption. Epanova, a novel omega-3 FFA does not require hydrolysis and has been shown to have up to 5-fold greater bioavailability (BA) than the EE form. This improvement in BA may lead to a lower daily dosage compared to EE formulations. The ESPRIT trial evaluated a 2 g/d dosage as well as a 4 g/d of Epanova compared to olive oil (OO) in patients with persistent high TG (HTG) and high risk for cardiovascular disease.
Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited tre... more Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled phase 2 studies of 8 or 12 weeks duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, NCT01288443). Data were available for 102/108 patients who received alirocumab 150 mg Q2W and 74/77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (-30.3% versus -0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that less than 5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C). In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of LDL-C lowering.
ABSTRACT Alirocumab is a fully human monoclonal antibody to PCSK9. The ODYSSEY MONO study was th... more ABSTRACT Alirocumab is a fully human monoclonal antibody to PCSK9. The ODYSSEY MONO study was the first alirocumab Phase III study to test a previously unused dose of 75 mg subcutaneously every 2 weeks in a population on no lipid-lowering therapy. A total of 103 patients were randomly assigned to alirocumab starting at 75 mg subcutaneously every 2 weeks or ezetimibe 10 mg per os every day with alirocumab dose uptitration at 12 weeks based on achieved LDL-cholesterol level at week 8 and followed to week 24. At the week-24 primary end point, the alirocumab intent-to-treat group showed a 47.2% (least square [LS] mean) reduction in LDL-cholesterol compared with a 15.6% (LS mean) reduction with ezetimibe (LS mean difference of 31.6%; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Safety parameters and adverse events were similar between the two groups.
Background: Xuezhikang (XZK) is an extract of fermented red yeast rice that has lipidlowering pro... more Background: Xuezhikang (XZK) is an extract of fermented red yeast rice that has lipidlowering properties.
Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PC... more Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.).
Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) rec... more Serum proprotein convertase subtilisin/kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation. REGN727/SAR236553 (designated here as SAR236553), a fully human PCSK9 monoclonal antibody, increases the recycling of LDL receptors and reduces LDL cholesterol levels.
increases in FG levels that appeared to decline over time in non-diabetic, hypercholesterolemic p... more increases in FG levels that appeared to decline over time in non-diabetic, hypercholesterolemic patients, whereas Eze monotherapy had no significant effects. These data suggest that coadministration of Eze with statin therapy does not further increase FG levels beyond those observed with statin monotherapy. Additional analyses are in progress to assess the relationships between various baseline factors and FG changes in these patients.
Introduction: Retapamulin is a novel, topical antibacterial of the pleuromutilin class in develop... more Introduction: Retapamulin is a novel, topical antibacterial of the pleuromutilin class in development for the treatment of secondarily infected traumatic lesions of the skin.Methods: The efficacy, safety, and tolerability of topical retapamulin ointment, 1% for 5 days twice daily was evaluated in 2 identical, randomized, double-blind, double-dummy, multicenter studies vs oral cephalexin, 500 mg twice daily for 10 days, in 1904 patients with secondarily infected traumatic lesions.Results: Clinical success rates were 89.5% in protocol-adherent patients receiving retapamulin compared with 91.9% for cephalexin (treatment difference, −2.5% [95% confidence interval, −5.4% to 0.5%]). In patients with Staphylococcus aureus or Streptococcus pyogenes at baseline, clinical success was 89.2% (365/409) for retapamulin and 92.6% (63/68) for cephalexin. Safety and tolerability were similar between treatments. Noncompliance (defined as using or taking <80% of doses) was recorded in 8.0% (51/636) of patients taking cephalexin compared with 0.39% (5/1268) of patients receiving retapamulin.Conclusions: Retapamulin offers a novel, effective, and convenient topical treatment for secondarily infected traumatic lesions.
Statins have been the cornerstone of lipid therapy for the last two decades, but despite signific... more Statins have been the cornerstone of lipid therapy for the last two decades, but despite significant clinical efficacy in the majority of patients, a large residual risk remains for the development of initial or recurrent atherosclerotic cardiovascular disease. In addition, owing to side effects, a significant percentage of patients cannot tolerate any statin dose or a high enough statin dose to reach their recommended LDL cholesterol goals. Monoclonal antibodies (mAbs) to PCSK9 have recently been shown to be highly efficacious in lowering LDL cholesterol, while demonstrating a favorable adverse event profile in early clinical trials. This review of alirocumab (formerly REGN727/SAR236553) explains the physiology and pharmacodynamics of PCSK9 inhibition with a mAb, as well as the Phase I and II clinical trial results of alirocumab and the ongoing Phase III trial designs. Several mAbs to PCSK9 are currently in development and approval may be 1-3 years away. We will focus this review on alirocumab, but mAbs to PCSK9 are the most promising cholesterol-lowering medication since statins and have the potential to significantly reduce further the occurrence of atherosclerotic cardiovascular disease.
Background and Objectives: Long-term (>1 year) safety and efficacy studies of combination lipid t... more Background and Objectives: Long-term (>1 year) safety and efficacy studies of combination lipid therapy are lacking. This year 2 study evaluated fenofibric acid 135 mg in combination with moderate-dose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg) in patients with mixed dyslipidaemia. Methods: This was a phase 3, open-label, year 2 extension study in patients who had completed one of three double-blind, 12-week, controlled studies and the subsequent open-label, year 1 extension study. Patients in this study had mixed dyslipidaemia (high-density lipoprotein cholesterol [HDL-C] <40 mg/dL [<1.02 mmol/L] for men or <50 mg/dL [<1.28 mmol/L] for women, triglycerides [TG] ‡150 mg/dL [ ‡1.69 mmol/L], and low-density lipoprotein cholesterol [LDL-C] ‡130 mg/dL [ ‡3.37 mmol/L]) at the start of the controlled study, and had completed the year 1 extension study. Treatment was once-daily oral coadministration of fenofibric acid 135 mg and moderatedose statin (rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg), and was identical to the treatment received in the year 1 study. The year 2 population safety data were summarized for the entire duration of fenofibric acid + statin therapy. Efficacy data were summarized by combination therapy group, as well as pooled across combination therapies, and summarized across the controlled and open-label studies. Results: Of the 310 patients enrolled into the year 2 study, 287 (93%) completed therapy. The mean cumulative exposure to combination therapy was 743 days across the studies. Adverse event rates were similar for all three combination therapy groups. No deaths or treatment-related serious adverse events occurred. The incidence of discontinuation due to adverse events was 2.9% overall. Rhabdomyolysis was not reported in any group. Overall, fenofibric acid + moderate-dose statin for ‡2 years resulted in sustained improvements in HDL-C (+17.4%), TG (-46.4%) and LDL-C (-40.4%).
... Cardiol. Harold E. Bays, Eli M. Roth, Iain Dukes, Gloria Lin-Luo, Neil Cowen, and Yu Liu META... more ... Cardiol. Harold E. Bays, Eli M. Roth, Iain Dukes, Gloria Lin-Luo, Neil Cowen, and Yu Liu METABOLIC EFFECTS HYPERTRIGLYCERIDEMIC SUBJECTS: LIPID AND OTHER DIAZOXIDE CHOLINE CONTROLLED RELEASE IN This information is current as of April 19, 2010 ...
To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric aci... more To evaluate the efficacy and safety of fixed-dose combinations of rosuvastatin and fenofibric acid (R/F), compared with simvastatin (S) in patients with high levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG).
Aims To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO)... more Aims To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia. Methods and results This was a multicentre, randomized, double-blind, placebocontrolled, parallel arm trial in patients with mixed hyperlipidaemia [LDL-cholesterol (LDL-C), 3.4-5.7 mmol/L (2.6-4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3-5.7 mmol/L] and no history of coronary heart disease (CHD), CHDequivalent disease (except for type 2 diabetes), or CHD risk score .20%. A total of 625 patients was randomized in a 1:3 :3: 3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO þ EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO þ EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P , 0.001) reduced with FENO þ EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO þ EZE and FENO treatments when compared with placebo (P , 0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline, .70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO þ EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated. Conclusion Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.
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