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Helen M Colhoun - One of the best experts on this subject based on the ideXlab platform.

  • effect of Alirocumab on individuals with type 2 diabetes high triglycerides and low high density lipoprotein cholesterol
    Cardiovascular Diabetology, 2020
    Co-Authors: Helen M Colhoun, Kausik K Ray, Lawrence A Leiter, Dirk Mullerwieland, Bertrand Cariou, Francisco J Tinahones, Catherine Domenger, Alexia Letierce, Marc Israel, Rita Samuel
    Abstract:

    Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM. The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of Alirocumab on individuals with non‐HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of Alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Alirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), − 35.0% (3.9)], ApoB [LS mean difference (SE), − 34.7% (3.6)], LDL-C [LS mean difference (SE), − 47.3% (5.2)], LDL particle number [LS mean difference (SE), − 40.8% (4.1)], and Lp(a) [LS mean difference (SE), − 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for Alirocumab versus usual care. TG reductions were similar between Alirocumab and usual care (no significant difference), but greater with fenofibrate versus Alirocumab (P = 0.3371). Overall, Alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with Alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving Alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between Alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of Alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed. Alirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with Alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159

  • Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease analysis of the odyssey dm dyslipidemia and dm insulin studies
    Cardiovascular Diabetology, 2019
    Co-Authors: Kausik K Ray, Dirk Mullerwieland, Bertrand Cariou, Helen M Colhoun, Francisco J Tinahones, Catherine Domenger, Alexia Letierce, Jonas Mandel, Stefano Del Prato, Rita Samuel
    Abstract:

    Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label Alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to Alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, Alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% Alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% Alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% Alirocumab/35.4% UC and 76.8% Alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (Alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with Alirocumab versus controls. Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, Alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015

  • relationship between Alirocumab pcsk9 and ldl c levels in four phase 3 odyssey trials using 75 and 150 mg doses
    Journal of Clinical Lipidology, 2019
    Co-Authors: Jennifer G Robinson, Eli M Roth, John J P Kastelein, Michel Farnier, Thomas A Dicioccio, Aurelie Brunet, Helen M Colhoun, Marjariitta Taskinen, Guillaume Lecorps, Robert Pordy
    Abstract:

    Background Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). Objective Changes in PCSK9, Alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with Alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). Methods Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated Alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied Alirocumab 150 mg Q2W. Results Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After Alirocumab administration, increased Alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:Alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with Alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as Alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. Conclusions Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production.

  • efficacy and safety of Alirocumab in individuals with type 2 diabetes mellitus with or without mixed dyslipidaemia analysis of the odyssey long term trial
    Atherosclerosis, 2018
    Co-Authors: Marjariitta Taskinen, Maja Bujasbobanovic, Alexia Letierce, Michael J Louie, Stefano Del Prato, Desmond Thompson, Helen M Colhoun
    Abstract:

    Abstract Background and aims Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, significantly reduces low-density lipoprotein cholesterol (LDL-C). We evaluated the efficacy and safety of Alirocumab in individuals with type 2 diabetes mellitus (T2DM) with versus without mixed dyslipidaemia (MDL, defined as baseline LDL-C ≥70 mg/dL [1.8 mmol/L] and triglycerides ≥150 mg/dL [1.7 mmol/L]). Methods Data from 812 individuals with T2DM, from the placebo-controlled, 78-week, Phase 3 ODYSSEY LONG TERM trial of Alirocumab 150 mg every 2 weeks (Q2W), on a background of maximally tolerated statins ± other lipid-lowering therapies, were pooled according to MDL status. Efficacy endpoints included percentage change from baseline to Week 24 in calculated LDL-C and other lipids/lipoproteins. Results In individuals with T2DM who received Alirocumab 150 mg Q2W, mean LDL-C changes from baseline to Week 24 were −62.6% (vs. −6.0% with placebo) in those with MDL and −56.1% (vs. 5.6%) in those without MDL, with no significant between-group difference (p-interaction = 0.0842). Risk-based LDL-C goals ( Conclusions Reductions in LDL-C and other lipids with Alirocumab, as well as safety and tolerability, were comparable between individuals with T2DM and with versus without MDL.

  • Alirocumab vs usual lipid lowering care as add on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia the odyssey dm dyslipidemia randomized trial
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Kausik K Ray, Lawrence A Leiter, Dirk Mullerwieland, Bertrand Cariou, Helen M Colhoun, Robert R Henry, Francisco J Tinahones, Maja Bujasbobanovic, Catherine Domenger, Alexia Letierce
    Abstract:

    Aims Individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia represent a high-risk and difficult-to-treat population. ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) compared Alirocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, with usual care (UC) in individuals with T2DM and mixed dyslipidaemia not optimally managed by maximally-tolerated statins. Materials and Methods UC options (no additional lipid-lowering therapy; fenofibrate; ezetimibe; omega-3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open-label Alirocumab 75 mg every 2 weeks (Q2W; with increase to 150 mg Q2W at Week [W]12 if W8 non-high-density lipoprotein cholesterol [non-HDL-C] was ≥2.59 mmol/L [100 mg/dL]) or UC for 24 weeks. Primary efficacy endpoint was percentage change in non-HDL-C from baseline to W24. Results The randomized population comprised 413 individuals (409 intention-to-treat; 412 safety). At W24, mean non-HDL-C reductions were superior with Alirocumab (-32.5% difference vs UC; 97.5% confidence interval: -38.1 to -27.0; P<.0001). Overall, 63.6% of Alirocumab-treated individuals were maintained on 75 mg Q2W. Alirocumab also reduced low-density lipoprotein cholesterol (-43.0%), apolipoprotein B (-32.3%), total cholesterol (-24.6%), and LDL particle number (-37.8%) at W24 vs UC (all P<.0001). Consistent with the overall trial comparison, Alirocumab reduced non-HDL-C to a greater degree within each UC stratum at W24. Incidence of treatment-emergent adverse events was 68.4% (Alirocumab) and 66.4% (UC). No clinically meaningful effect on glycated hemoglobin, or change in number of glucose-lowering agents, was seen. Conclusions In individuals with T2DM and mixed dyslipidaemia on maximally tolerated statin, Alirocumab showed superiority in non-HDL-C reduction vs UC and was generally well tolerated.

Lawrence A Leiter - One of the best experts on this subject based on the ideXlab platform.

  • Alirocumab efficacy and safety by body mass index a pooled analysis from 10 phase 3 odyssey trials
    Diabetes & Metabolism, 2020
    Co-Authors: Francisco J Tinahones, Bertrand Cariou, Michael J Louie, Desmond Thompson, U Laufs, J Yang, Lawrence A Leiter
    Abstract:

    Abstract Aims Increased body mass index (BMI) contributes to cardiovascular risk and may influence efficacy of therapeutic antibodies. We investigated the effect of baseline BMI on efficacy and safety of Alirocumab, a PCSK9 monoclonal antibody. Methods In a post-hoc analysis, data were pooled from 10 Phase 3 trials (n = 4975) of Alirocumab vs. placebo/ezetimibe controls. Alirocumab dose was 150 mg every 2 weeks in two trials, and 75 mg every 2 weeks with possible increase to 150 mg at 12 weeks (based on Week 8 low-density lipoprotein cholesterol [LDL-C]) in eight trials. Efficacy/safety data were assessed in baseline BMI subgroups of ≤ 25, > 25 to 30, > 30 to 35, and > 35 kg/m2. Results Baseline LDL-C levels were lower among patients in the higher BMI subgroups. Significant LDL-C reductions from baseline were observed at Weeks 12 and 24 for Alirocumab vs. controls, of similar magnitude regardless of baseline BMI (interaction P-value = 0.7119). LDL-C   25 to 30, > 30 to 35, and > 35 kg/m2, respectively. Adverse event frequencies were similar regardless of BMI; injection-site reaction frequency was higher with Alirocumab (5.1–8.2% across BMI categories) vs. controls (3.6–4.8%). Conclusions Alirocumab provided consistent LDL-C reductions, with similar safety findings across BMI subgroups.

  • effect of Alirocumab on individuals with type 2 diabetes high triglycerides and low high density lipoprotein cholesterol
    Cardiovascular Diabetology, 2020
    Co-Authors: Helen M Colhoun, Kausik K Ray, Lawrence A Leiter, Dirk Mullerwieland, Bertrand Cariou, Francisco J Tinahones, Catherine Domenger, Alexia Letierce, Marc Israel, Rita Samuel
    Abstract:

    Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM. The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of Alirocumab on individuals with non‐HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of Alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Alirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), − 35.0% (3.9)], ApoB [LS mean difference (SE), − 34.7% (3.6)], LDL-C [LS mean difference (SE), − 47.3% (5.2)], LDL particle number [LS mean difference (SE), − 40.8% (4.1)], and Lp(a) [LS mean difference (SE), − 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for Alirocumab versus usual care. TG reductions were similar between Alirocumab and usual care (no significant difference), but greater with fenofibrate versus Alirocumab (P = 0.3371). Overall, Alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with Alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving Alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between Alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of Alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed. Alirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with Alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159

  • Alirocumab safety in people with and without diabetes mellitus pooled data from 14 odyssey trials
    Diabetic Medicine, 2018
    Co-Authors: Lawrence A Leiter, Francisco J Tinahones, Maja Bujasbobanovic, Alexia Letierce, Rita Samuel, Dean G Karalis, Jonas Mandel, P Jones
    Abstract:

    Aim To evaluate the safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor Alirocumab according to diabetes mellitus status. Methods Safety data from 14 trials (8-104-week durations) were analysed by treatment (Alirocumab or placebo/ezetimibe control) and diabetes status (yes/no, defined by medical history). Adverse event data were assessed using descriptive statistics and Cox models. Results Of the 5234 trial participants, 1554 (29.7%) had diabetes. Overall, treatment-emergent adverse events were similar in the Alirocumab and control groups, except for more frequent local injection site reactions with Alirocumab. Fewer people with diabetes experienced local injection site reactions [Alirocumab, 3.5%, control, 2.9%; hazard ratio 1.24 (95% CI 0.68-2.25)] than those without diabetes [Alirocumab, 7.5%; control, 4.9%; hazard ratio 1.51 (95% CI 1.13-2.01)]. Those with diabetes reported a greater number of serious adverse events (Alirocumab, 19.4%; control, 19.7%) than those without diabetes (Alirocumab, 14.5%; control, 13.5%). In people with diabetes, major adverse cardiac events occurred in 2.7% of Alirocumab-treated people [control, 3.3%; hazard ratio 0.74 (95% CI 0.41-1.35)]; in those without diabetes, 1.8% of Alirocumab-treated people had major adverse cardiac events [control, 1.7%; hazard ratio 0.95 (95% CI 0.56-1.62)]. Overall, no increase in HbA1c or fasting plasma glucose vs control treatment groups was observed, regardless of diabetes status. Conclusion This pooled analysis across 14 trials demonstrated similar safety for Alirocumab vs control treatment, irrespective of diabetes status, except for more frequent local injection site reactions with Alirocumab. People with diabetes reported fewer local injection site reactions than those without diabetes.

  • efficacy and safety of Alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the odyssey phase 3 trials
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Om P Ganda, Maja Bujasbobanovic, Alexia Letierce, Jonas Mandel, Jorge Plutzky, Santosh K Sanganalmath, Andrew Koren, Lawrence A Leiter
    Abstract:

    AIMS Individuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post-hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor Alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials. MATERIALS AND METHODS Changes in low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to Week 24 were analysed (intention-to-treat) in four pools by Alirocumab dosage (150 mg every 2 weeks [150] or 75 mg with possible increase to 150 mg every 2 weeks [75/150]), control (placebo/ezetimibe) and background statin usage (yes/no). RESULTS At Week 24, LDL-C changes from baseline in pools with background statins were -61.5% with Alirocumab 150 (vs -1.0% with placebo), -46.4% with Alirocumab 75/150 (vs +6.3% with placebo) and -48.7% with Alirocumab 75/150 (vs -20.6% with ezetimibe), and -54.9% with Alirocumab 75/150 (vs +4.0% with ezetimibe) without background statins. A greater proportion of Alirocumab recipients achieved LDL-C < 70 and < 55 mg/dL at Week 24 vs controls. Alirocumab also resulted in significant reductions in non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) vs controls. Alirocumab did not appear to affect glycaemia over 78-104 weeks. Overall safety was similar between treatment groups, with a higher injection-site reaction frequency (mostly mild) with Alirocumab. CONCLUSION Alirocumab significantly reduced LDL-C and other atherogenic lipid parameters, and was generally well tolerated in individuals with DM and ASCVD.

  • Alirocumab vs usual lipid lowering care as add on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia the odyssey dm dyslipidemia randomized trial
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Kausik K Ray, Lawrence A Leiter, Dirk Mullerwieland, Bertrand Cariou, Helen M Colhoun, Robert R Henry, Francisco J Tinahones, Maja Bujasbobanovic, Catherine Domenger, Alexia Letierce
    Abstract:

    Aims Individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia represent a high-risk and difficult-to-treat population. ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) compared Alirocumab, a proprotein convertase subtilisin-kexin type 9 inhibitor, with usual care (UC) in individuals with T2DM and mixed dyslipidaemia not optimally managed by maximally-tolerated statins. Materials and Methods UC options (no additional lipid-lowering therapy; fenofibrate; ezetimibe; omega-3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open-label Alirocumab 75 mg every 2 weeks (Q2W; with increase to 150 mg Q2W at Week [W]12 if W8 non-high-density lipoprotein cholesterol [non-HDL-C] was ≥2.59 mmol/L [100 mg/dL]) or UC for 24 weeks. Primary efficacy endpoint was percentage change in non-HDL-C from baseline to W24. Results The randomized population comprised 413 individuals (409 intention-to-treat; 412 safety). At W24, mean non-HDL-C reductions were superior with Alirocumab (-32.5% difference vs UC; 97.5% confidence interval: -38.1 to -27.0; P<.0001). Overall, 63.6% of Alirocumab-treated individuals were maintained on 75 mg Q2W. Alirocumab also reduced low-density lipoprotein cholesterol (-43.0%), apolipoprotein B (-32.3%), total cholesterol (-24.6%), and LDL particle number (-37.8%) at W24 vs UC (all P<.0001). Consistent with the overall trial comparison, Alirocumab reduced non-HDL-C to a greater degree within each UC stratum at W24. Incidence of treatment-emergent adverse events was 68.4% (Alirocumab) and 66.4% (UC). No clinically meaningful effect on glycated hemoglobin, or change in number of glucose-lowering agents, was seen. Conclusions In individuals with T2DM and mixed dyslipidaemia on maximally tolerated statin, Alirocumab showed superiority in non-HDL-C reduction vs UC and was generally well tolerated.

Jennifer G Robinson - One of the best experts on this subject based on the ideXlab platform.

  • relationship between Alirocumab pcsk9 and ldl c levels in four phase 3 odyssey trials using 75 and 150 mg doses
    Journal of Clinical Lipidology, 2019
    Co-Authors: Jennifer G Robinson, Eli M Roth, John J P Kastelein, Michel Farnier, Thomas A Dicioccio, Aurelie Brunet, Helen M Colhoun, Marjariitta Taskinen, Guillaume Lecorps, Robert Pordy
    Abstract:

    Background Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). Objective Changes in PCSK9, Alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with Alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). Methods Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated Alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied Alirocumab 150 mg Q2W. Results Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After Alirocumab administration, increased Alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:Alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with Alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as Alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. Conclusions Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production.

  • efficacy and safety of Alirocumab in individuals with diabetes mellitus pooled analyses from five placebo controlled phase 3 studies
    Diabetes Therapy, 2018
    Co-Authors: Henry N Ginsberg, Christopher P Cannon, Michel Farnier, Marie T Baccaradinet, Maja Bujasbobanovic, Alexia Letierce, Jennifer G Robinson, Michael J Louie, Naveed Sattar, Helen M Colhoun
    Abstract:

    Diabetes mellitus (DM) carries an elevated risk for cardiovascular disease. Here, we assessed Alirocumab efficacy and safety in people with/without DM from five placebo-controlled phase 3 studies. Data from up to 78 weeks were analyzed in individuals on maximally tolerated background statin. In three studies, Alirocumab 75 mg every 2 weeks (Q2W) was increased to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dL; two studies used Alirocumab 150 mg Q2W throughout. The primary endpoint was percentage change in LDL-C from baseline to week 24. In the Alirocumab 150 mg pool (n = 2416), baseline LDL-C levels were 117.4 mg/dL (DM) and 130.6 mg/dL (without DM), and in the 75/150 mg pool (n = 1043) 112.8 mg/dL (DM) and 133.0 mg/dL (without DM). In the 150 mg Q2W group, week 24 LDL-C reductions from baseline were observed in persons with DM (− 59.9%; placebo, − 1.4%) and without DM (− 60.6%; placebo, + 1.5%); 77.7% (DM) and 76.8% (without DM) of subjects achieved LDL-C < 70 mg/dL. In the Alirocumab 75/150 mg group, 26% (DM) and 36% (without DM) of subjects received dose increase. In this group, week 24 LDL-C levels changed from baseline by − 43.8% (DM; placebo, + 0.3%) and − 49.7% (without DM; placebo, + 5.1%); LDL-C < 70 mg/dL was achieved by 68.3% and 65.8% of individuals, respectively. At week 24, Alirocumab was also associated with improved levels of other lipids. Adverse event rates were generally comparable in all groups (79.8–82.0%). Regardless of DM status, Alirocumab significantly reduced LDL-C levels; safety was generally similar. Sanofi and Regeneron Pharmaceuticals, Inc. Plain language summary available for this article.

  • long term treatment adherence to the proprotein convertase subtilisin kexin type 9 inhibitor Alirocumab in 6 odyssey phase iii clinical studies with treatment duration of 1 to 2 years
    Journal of Clinical Lipidology, 2017
    Co-Authors: Michel Farnier, William J Sasiela, Helen M Colhoun, Jay M Edelberg, Gaelle Asset, Jennifer G Robinson
    Abstract:

    Background Nonadherence to cardiovascular medications, including daily, oral statin therapy, negatively impacts outcomes in patients requiring low-density lipoprotein cholesterol (LDL-C)-lowering therapy. The proprotein convertase subtilisin/kexin type 9 inhibitor Alirocumab also reduces LDL-C, but has a different mode of administration (subcutaneous injection). Objective The objective of the study was to assess long-term adherence to Alirocumab 75 or 150 mg, given every 2 weeks, in phase III trials of patients with sub-optimally controlled hypercholesterolemia. Methods Data were pooled from 6 ODYSSEY trials (n = 4212) with double-blind treatment durations of 52 to 104 weeks. Adherence was reported as percentage of days receiving injections according to dosing schedule and categorized into 100% adherence, below-planned dosing, above-planned dosing, and both below- and above-planned dosing. Overall adherence was calculated as 100 − (percentage of days with below-planned dosing + percentage of days with above-planned dosing). Safety of Alirocumab and effect on LDL-C levels were also evaluated. Results Adherence was analyzed for 4197 patients (n = 2786 Alirocumab; n = 1411 control). Mean overall adherence was high (Alirocumab 98.0%; control 97.8%). Among patients receiving Alirocumab, 45.7% were 100% adherent, 20.4% had below-planned dosing, 2.9% had above-planned dosing, and 31.1% had both below- and above-planned dosing. Mean percentage reduction in LDL-C (baseline to Week 52) was 45.8% to 61.9%, depending on Alirocumab dose, and was comparable across adherence categories. Treatment-emergent adverse events leading to Alirocumab discontinuation were infrequent and included myalgia and injection-site reactions ( Conclusions Alirocumab injections were associated with a high level of adherence over ≥1 year. Infrequent below- or above-planned dosing had minimal impact on LDL-C reductions.

  • safety of very low low density lipoprotein cholesterol levels with Alirocumab pooled data from randomized trials
    Journal of the American College of Cardiology, 2017
    Co-Authors: Jennifer G Robinson, Michel Farnier, William J Sasiela, Umesh Chaudhari, Kathryn Miller, Robert S Rosenson, Laurence Merlet, John J P Kastelein
    Abstract:

    Abstract Background Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies can reduce low-density lipoprotein cholesterol (LDL-C) to very low levels when added to background lipid-lowering therapy. Objectives The safety of Alirocumab was evaluated in patients with at least 2 consecutive LDL-C values  Methods Pooled data from 14 trials were analyzed (double-blind treatment 8 to 104 weeks; n = 3,340 Alirocumab, n = 1,894 control [placebo or ezetimibe]; representing 4,029 [Alirocumab] and 2,114 [control] double-blind patient-years’ exposure). Results In Alirocumab-treated patients, 839 (25.1%) achieved 2 consecutive LDL-C values  Conclusions LDL-C levels  NCT01288443 , NCT01288469 , NCT01266876 , NCT01812707 , NCT01507831 , NCT01617655 , NCT01623115 , NCT01709500 , NCT01644175 , NCT01644188 , NCT01730040 , NCT01730053 , NCT01644474 , and NCT01709513 )

  • effect of Alirocumab on lipoprotein a over 1 5 years from the phase 3 odyssey program
    American Journal of Cardiology, 2017
    Co-Authors: Daniel Gaudet, William J Sasiela, Jennifer G Robinson, Gerald F Watts, Pascal Minini, Jay M Edelberg, Michael J Louie, Frederick J Raal
    Abstract:

    Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between Alirocumab and controls. We evaluated the effect of Alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated Alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated Alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with Alirocumab 75/150-mg Q2W and 29% with Alirocumab 150-mg Q2W (all comparisons p

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  • effect of Alirocumab on individuals with type 2 diabetes high triglycerides and low high density lipoprotein cholesterol
    Cardiovascular Diabetology, 2020
    Co-Authors: Helen M Colhoun, Kausik K Ray, Lawrence A Leiter, Dirk Mullerwieland, Bertrand Cariou, Francisco J Tinahones, Catherine Domenger, Alexia Letierce, Marc Israel, Rita Samuel
    Abstract:

    Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM. The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of Alirocumab on individuals with non‐HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of Alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Alirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), − 35.0% (3.9)], ApoB [LS mean difference (SE), − 34.7% (3.6)], LDL-C [LS mean difference (SE), − 47.3% (5.2)], LDL particle number [LS mean difference (SE), − 40.8% (4.1)], and Lp(a) [LS mean difference (SE), − 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for Alirocumab versus usual care. TG reductions were similar between Alirocumab and usual care (no significant difference), but greater with fenofibrate versus Alirocumab (P = 0.3371). Overall, Alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with Alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving Alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between Alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of Alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed. Alirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with Alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159

  • Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease analysis of the odyssey dm dyslipidemia and dm insulin studies
    Cardiovascular Diabetology, 2019
    Co-Authors: Kausik K Ray, Dirk Mullerwieland, Bertrand Cariou, Helen M Colhoun, Francisco J Tinahones, Catherine Domenger, Alexia Letierce, Jonas Mandel, Stefano Del Prato, Rita Samuel
    Abstract:

    Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label Alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to Alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, Alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% Alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% Alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% Alirocumab/35.4% UC and 76.8% Alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (Alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with Alirocumab versus controls. Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, Alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015

  • pcsk9 inhibition in patients with and without prior myocardial infarction or ischemic stroke a pooled analysis of nine randomized controlled studies of Alirocumab
    Journal of Clinical Lipidology, 2019
    Co-Authors: Eric Bruckert, Alexia Letierce, Michael J Louie, Kathryn Miller, Michael J Koren, Dean J Kereiakes, Christopher P Cannon
    Abstract:

    Background Patients with prior cardiovascular events are at very high risk of recurrent events and may benefit from low-density lipoprotein cholesterol (LDL-C) lowering beyond that achieved with maximally tolerated statins. Objective To assess potential differences between the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor, Alirocumab, in patients with vs without prior myocardial infarction (MI)/ischemic stroke. Methods Data (n = 4880) were pooled from nine ODYSSEY phase 3 trials of Alirocumab 75/150 mg or 150 mg every 2 weeks, mostly on background statins ± other lipid-lowering therapies. Analyses were performed according to statin status, Alirocumab dose, and control (placebo or ezetimibe). Results Baseline LDL-C, non–high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B levels were lower and lipoprotein(a) higher in patients with than without prior MI/ischemic stroke. LDL-C levels were reduced from baseline to week 24 in patients with (51.1%–62.9%) and without (43.6%–58.3%) prior MI/ischemic stroke, with no significant interaction between prior MI/ischemic stroke status and LDL-C–lowering efficacy of Alirocumab vs controls. Alirocumab significantly reduced other lipid/lipoproteins (including lipoprotein[a]) similarly in patients with/without MI/ischemic stroke. Week 24 LDL-C goal attainment rates for subgroups with/without prior MI/ischemic stroke on background statins were 74.1%–84.8% and 63.7%–74.7%, respectively. The safety profile of Alirocumab was generally similar regardless of prior MI/ischemic stroke status. Conclusions Alirocumab significantly reduced LDL-C and other atherogenic lipids/lipoproteins in patients with prior MI/ischemic stroke, and the majority of this very high cardiovascular risk population achieved LDL-C goals; efficacy and safety results were similar in patients without prior MI/ischemic stroke.

  • Alirocumab safety in people with and without diabetes mellitus pooled data from 14 odyssey trials
    Diabetic Medicine, 2018
    Co-Authors: Lawrence A Leiter, Francisco J Tinahones, Maja Bujasbobanovic, Alexia Letierce, Rita Samuel, Dean G Karalis, Jonas Mandel, P Jones
    Abstract:

    Aim To evaluate the safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor Alirocumab according to diabetes mellitus status. Methods Safety data from 14 trials (8-104-week durations) were analysed by treatment (Alirocumab or placebo/ezetimibe control) and diabetes status (yes/no, defined by medical history). Adverse event data were assessed using descriptive statistics and Cox models. Results Of the 5234 trial participants, 1554 (29.7%) had diabetes. Overall, treatment-emergent adverse events were similar in the Alirocumab and control groups, except for more frequent local injection site reactions with Alirocumab. Fewer people with diabetes experienced local injection site reactions [Alirocumab, 3.5%, control, 2.9%; hazard ratio 1.24 (95% CI 0.68-2.25)] than those without diabetes [Alirocumab, 7.5%; control, 4.9%; hazard ratio 1.51 (95% CI 1.13-2.01)]. Those with diabetes reported a greater number of serious adverse events (Alirocumab, 19.4%; control, 19.7%) than those without diabetes (Alirocumab, 14.5%; control, 13.5%). In people with diabetes, major adverse cardiac events occurred in 2.7% of Alirocumab-treated people [control, 3.3%; hazard ratio 0.74 (95% CI 0.41-1.35)]; in those without diabetes, 1.8% of Alirocumab-treated people had major adverse cardiac events [control, 1.7%; hazard ratio 0.95 (95% CI 0.56-1.62)]. Overall, no increase in HbA1c or fasting plasma glucose vs control treatment groups was observed, regardless of diabetes status. Conclusion This pooled analysis across 14 trials demonstrated similar safety for Alirocumab vs control treatment, irrespective of diabetes status, except for more frequent local injection site reactions with Alirocumab. People with diabetes reported fewer local injection site reactions than those without diabetes.

  • efficacy and safety of Alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the odyssey phase 3 trials
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Om P Ganda, Maja Bujasbobanovic, Alexia Letierce, Jonas Mandel, Jorge Plutzky, Santosh K Sanganalmath, Andrew Koren, Lawrence A Leiter
    Abstract:

    AIMS Individuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post-hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor Alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials. MATERIALS AND METHODS Changes in low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to Week 24 were analysed (intention-to-treat) in four pools by Alirocumab dosage (150 mg every 2 weeks [150] or 75 mg with possible increase to 150 mg every 2 weeks [75/150]), control (placebo/ezetimibe) and background statin usage (yes/no). RESULTS At Week 24, LDL-C changes from baseline in pools with background statins were -61.5% with Alirocumab 150 (vs -1.0% with placebo), -46.4% with Alirocumab 75/150 (vs +6.3% with placebo) and -48.7% with Alirocumab 75/150 (vs -20.6% with ezetimibe), and -54.9% with Alirocumab 75/150 (vs +4.0% with ezetimibe) without background statins. A greater proportion of Alirocumab recipients achieved LDL-C < 70 and < 55 mg/dL at Week 24 vs controls. Alirocumab also resulted in significant reductions in non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) vs controls. Alirocumab did not appear to affect glycaemia over 78-104 weeks. Overall safety was similar between treatment groups, with a higher injection-site reaction frequency (mostly mild) with Alirocumab. CONCLUSION Alirocumab significantly reduced LDL-C and other atherogenic lipid parameters, and was generally well tolerated in individuals with DM and ASCVD.

Bertrand Cariou - One of the best experts on this subject based on the ideXlab platform.

  • Alirocumab efficacy and safety by body mass index a pooled analysis from 10 phase 3 odyssey trials
    Diabetes & Metabolism, 2020
    Co-Authors: Francisco J Tinahones, Bertrand Cariou, Michael J Louie, Desmond Thompson, U Laufs, J Yang, Lawrence A Leiter
    Abstract:

    Abstract Aims Increased body mass index (BMI) contributes to cardiovascular risk and may influence efficacy of therapeutic antibodies. We investigated the effect of baseline BMI on efficacy and safety of Alirocumab, a PCSK9 monoclonal antibody. Methods In a post-hoc analysis, data were pooled from 10 Phase 3 trials (n = 4975) of Alirocumab vs. placebo/ezetimibe controls. Alirocumab dose was 150 mg every 2 weeks in two trials, and 75 mg every 2 weeks with possible increase to 150 mg at 12 weeks (based on Week 8 low-density lipoprotein cholesterol [LDL-C]) in eight trials. Efficacy/safety data were assessed in baseline BMI subgroups of ≤ 25, > 25 to 30, > 30 to 35, and > 35 kg/m2. Results Baseline LDL-C levels were lower among patients in the higher BMI subgroups. Significant LDL-C reductions from baseline were observed at Weeks 12 and 24 for Alirocumab vs. controls, of similar magnitude regardless of baseline BMI (interaction P-value = 0.7119). LDL-C   25 to 30, > 30 to 35, and > 35 kg/m2, respectively. Adverse event frequencies were similar regardless of BMI; injection-site reaction frequency was higher with Alirocumab (5.1–8.2% across BMI categories) vs. controls (3.6–4.8%). Conclusions Alirocumab provided consistent LDL-C reductions, with similar safety findings across BMI subgroups.

  • effect of Alirocumab on individuals with type 2 diabetes high triglycerides and low high density lipoprotein cholesterol
    Cardiovascular Diabetology, 2020
    Co-Authors: Helen M Colhoun, Kausik K Ray, Lawrence A Leiter, Dirk Mullerwieland, Bertrand Cariou, Francisco J Tinahones, Catherine Domenger, Alexia Letierce, Marc Israel, Rita Samuel
    Abstract:

    Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM. The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of Alirocumab on individuals with non‐HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of Alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Alirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), − 35.0% (3.9)], ApoB [LS mean difference (SE), − 34.7% (3.6)], LDL-C [LS mean difference (SE), − 47.3% (5.2)], LDL particle number [LS mean difference (SE), − 40.8% (4.1)], and Lp(a) [LS mean difference (SE), − 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for Alirocumab versus usual care. TG reductions were similar between Alirocumab and usual care (no significant difference), but greater with fenofibrate versus Alirocumab (P = 0.3371). Overall, Alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with Alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving Alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between Alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of Alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed. Alirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with Alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159

  • Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease analysis of the odyssey dm dyslipidemia and dm insulin studies
    Cardiovascular Diabetology, 2019
    Co-Authors: Kausik K Ray, Dirk Mullerwieland, Bertrand Cariou, Helen M Colhoun, Francisco J Tinahones, Catherine Domenger, Alexia Letierce, Jonas Mandel, Stefano Del Prato, Rita Samuel
    Abstract:

    Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label Alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to Alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, Alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% Alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% Alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% Alirocumab/35.4% UC and 76.8% Alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (Alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with Alirocumab versus controls. Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, Alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015

  • impact of age on the efficacy and safety of Alirocumab in patients with heterozygous familial hypercholesterolemia
    Cardiovascular Drugs and Therapy, 2019
    Co-Authors: Henry N Ginsberg, Bertrand Cariou, Santosh K Sanganalmath, Andrew Koren, Jaakko Tuomilehto, Raul D Santos, Kees G Hovingh, Alan S Brown, Desmond Thompson
    Abstract:

    Purpose: This post-hoc analysis examined whether age modified the efficacy and safety of Alirocumab, a PCSK9 inhibitor, in patients with heterozygous familial hypercholesterolemia (HeFH), using pooled data from four 78-week placebo-controlled phase 3 trials (ODYSSEY FH I, FH II, LONG TERM, and HIGH FH). Methods: Data from 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies were analyzed by an Alirocumab dose regimen and by age subgroups (18 to < 45, 45 to < 55, 55 to < 65, and ≥ 65 years). In the FH I and II trials, patients received 75 mg subcutaneously every 2 weeks (Q2W), with dose increase to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dl. In HIGH FH and LONG TERM, patients received 150 mg Alirocumab Q2W. Results: Baseline characteristics were similar between treatment groups across all age groups; the proportion of males decreased whereas the proportion of patients with coronary heart disease, diabetes, hypertension, and declining renal function increased with increasing age. Mean LDL-C reductions at week 24 were consistent across age groups (50.6–61.0% and 51.1–65.8% vs. placebo for the 75/150 and 150 mg Alirocumab dose regimens, respectively; both non-significant interaction P-values). Treatment-emergent adverse events occurred in similar frequency in Alirocumab- and placebo-treated patients regardless of age, except for injection-site reactions, which were more common in Alirocumab than placebo but declined in frequency with age. Conclusions: Alirocumab treatment resulted in significant LDL-C reductions at weeks 12 and 24 and was generally well tolerated in patients with HeFH across all age groups studied.

  • impact of age on the efficacy and safety of Alirocumab in patients with heterozygous familial hypercholesterolemia
    WOS, 2019
    Co-Authors: Henry N Ginsberg, Bertrand Cariou, Santosh K Sanganalmath, Andrew Koren, Jaakko Tuomilehto, Raul D Santos, Kees G Hovingh, Alan S Brown, Desmond Thompson
    Abstract:

    This post-hoc analysis examined whether age modified the efficacy and safety of Alirocumab, a PCSK9 inhibitor, in patients with heterozygous familial hypercholesterolemia (HeFH), using pooled data from four 78-week placebo-controlled phase 3 trials (ODYSSEY FH I, FH II, LONG TERM, and HIGH FH). Data from 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies were analyzed by an Alirocumab dose regimen and by age subgroups (18 to < 45, 45 to < 55, 55 to < 65, and ≥ 65 years). In the FH I and II trials, patients received 75 mg subcutaneously every 2 weeks (Q2W), with dose increase to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dl. In HIGH FH and LONG TERM, patients received 150 mg Alirocumab Q2W. Baseline characteristics were similar between treatment groups across all age groups; the proportion of males decreased whereas the proportion of patients with coronary heart disease, diabetes, hypertension, and declining renal function increased with increasing age. Mean LDL-C reductions at week 24 were consistent across age groups (50.6–61.0% and 51.1–65.8% vs. placebo for the 75/150 and 150 mg Alirocumab dose regimens, respectively; both non-significant interaction P-values). Treatment-emergent adverse events occurred in similar frequency in Alirocumab- and placebo-treated patients regardless of age, except for injection-site reactions, which were more common in Alirocumab than placebo but declined in frequency with age. Alirocumab treatment resulted in significant LDL-C reductions at weeks 12 and 24 and was generally well tolerated in patients with HeFH across all age groups studied.