Science

LDL-C is a Causal factor for CVD

Guideline from American College of Cardiology (ACC) and American Heart Association (AHA) considers LDL-C as a primary cause of atherosclerosis. According to this guideline, randomized clinical trials of cholesterol-lowering drugs in high-risk patients confirm that LDL-C lowering produces marked reductions in atherosclerotic cardiovascular disease (ASCVD). This confirms the general principle that “lower is better” for LDL-C. [Grundy et al. 2018 Cholesterol Clinical Practice Guideline]

European Atherosclerosis Society (EAS) placed a consensus statement stating that LDL-C is a cause of ASCVD, based on the Mendelian research data that emphasized:

 

  • LDL lowering is directly correlated with cardiovascular events, with source of LDL lowering not being relevant.

  • The duration of lower LDL is directly related with cardiovascular events; that is, the longer the individuals maintain a lower LDL, the lower the risk of cardiovascular events.

Clinical data for Rosuvastatin and ezetimibe in combination

Note: Rosuvastatin/ezetimibe fixed combination as a medicinal product is neither approved for any use nor is commercially available in the United States of America. Please refer to local country registration authority or contact us for country specific information.

Primary prospective clinical trials published in peer-reviewed journals: The ACTE study (Bays et al., 2011), the EXPLORER study (Ballantyne et al., 2007), and the GRAVITY study (Ballantyne et al., 2014). These studies have been conducted according to GCP guidelines and are summarized in the European SmPC of the approved combination medicinal products comprising rosuvastatin and ezetimibe.

1. Bays et al., 2011: In a multicenter, 6-week, randomized, double-blind, parallel-group clinical trial, 440 patients were evaluated to assess the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg. Subjects were centrally randomized into equal-size double-blind treatment groups of ezetimibe 10 mg added to the run-in dose of rosuvastatin or up-titration of the run-in dose of rosuvastatin for 6 weeks. The primary efficacy end point was the % change from LDL-C baseline evaluated in the overall population and secondary point was % of subjects reaching the NCEP ATP III LDL-C targets. [PubMed]

Summary of Key Results:

  • Compared to rosuvastatin up-titration, ezetimibe add-on allowed significantly greater percent of patients to achieve prespecified individualized LDL-C targets of < 70 or <100 mg/dL (59.4% vs 30.9%, p <0.001) and more of them to achieve a threshold <70 mg/dL (43.8% vs 17.5%, p<0.001).

  • Ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21.0%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (p <0.001).

  • The combination cohort also demonstrated significantly greater reductions in TC, non-HDLC and Apo B.

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2. Ballantyne et al., 2014: In an open-label, randomized study, 833 patients were examined to assess the efficacy and safety of 10 mg of rosuvastatin or 20 mg of rosuvastatin along with 10 mg of ezetimibe and compare these with significantly higher dosages of simvastatin 40 mg or simvastatin 80 mg along with 10 mg of ezetimibe. After a 6-week dietary lead-in and washout of lipid-lowering drugs, patients received rosuvastatin 10 mg, rosuvastatin 20 mg, simvastatin 40 mg, or simvastatin 80 mg monotherapy for 6 weeks. Ezetimibe 10 mg was then added to each regimen for a further 6 weeks. Primary outcome studied was % change from baseline LDL-C at week 12 of the study. [PubMed]

Summary of Key Results:

  • 93.3% of patients reached the NCEP ATP III goal of LDL-C < 100 mg/dL with the treatment with rosuvastatin 10 mg and ezetimibe 10 mg, and 67.1% reached goal of LDL-C < 70 mg/dl; 95.6% of patients reached NCEP ATP III goal of LDL-C < 100 mg/dl with the treatment with rosuvastatin 20 mg and ezetimibe 10 mg, and 77.0% reached goal of LDL-C < 70 mg/dl.

  • Rosuvastatin 10 mg and ezetimibe 10 mg combined treatment significantly reduced LDL-C, TG, non HDL-C, and Apo-B compared with simvastatin 40 mg and ezetimibe 10 mg; as did rosuvastatin 20 mg and ezetimibe 10 mg versus either dose of simvastatin with ezetimibe 10 mg.

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3. Ballantyne et al., 2007: In a multicenter, 6-week, randomized, double-blind, study, 469 patients were evaluated to assess the efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe 10 mg in patients at high risk of coronary heart disease. Patients were randomly assigned to rosuvastatin alone or in combination with ezetimibe for 6 weeks. The primary end point was the % of patients achieving ATPIII LDL-C goal (< 100 mg/dL) at week 6. [PubMed]

Summary of Key Results:

  • Significantly more patients receiving rosuvastatin/ezetimibe than rosuvastatin alone achieved ATP III LDL-C goal (<100 mg/dl, 94.0% vs 79.1%, p<0.001) as well as the optional LDLC goal (<70 mg/dl) for high risk patients (79.6% vs 35.0%, p<0.001).

  • The combination of rosuvastatin/ezetimibe reduced LDL-C significantly more than rosuvastatin (69.8% vs. 57.1%, p<0.001).

  • Other components of the lipid profile were also significantly (p<0.001) improved with rosuvastatin/ezetimibe.

 

 

Clinical data for Ezetimibe and Atorvastatin in combination

 

Note: Ezetimibe/Atorvastatin tablets is an approved product in the United States of America and is anticipated to be commercially available to patients in 2021. For countries outside the US, please refer to local country registration authority or contact us for country specific information.

Primary prospective clinical trials published in peer-reviewed journals are summarized below:

4. Ballantyne et al., 2003: In a multicenter, 12-week, randomized, double-blind, study, 628 patients were evaluated to assess the efficacy and safety of atorvastatin (10, 20, 40 or 80 mg / day) and ezetimibe (10 mg / day) in combination versus atorvastatin alone, ezetimibe alone or placebo in patients with primary hypercholesteremia and LDL-C levels between 145 and 250 mg/dL and triglyceride levels ≤350 mg/dL. Patients were randomly assigned to each dose of atorvastatin alone or in combination with ezetimibe, ezetimibe alone or placebo for 12 weeks. The primary end point was the percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment at week 12. [PubMed]

Summary of Key Results:

  • Ezetimibe plus atorvastatin significantly improved LDL-C, HDL cholesterol (HDL-C), triglycerides, total cholesterol, HDL-C, and high-sensitivity C-reactive protein (hs-CRP) compared with atorvastatin alone (P<0.01).

  • Ezetimibe plus atorvastatin provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction, and 10% hs-CRP reduction versus atorvastatin alone.

  • Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose versus atorvastatin alone.

  • LDL-C reductions with ezetimibe plus the lowest dose atorvastatin (10/10 mg; 50% reduction) were similar to reductions from the highest dose of atorvastatin alone (80 mg; 51% reduction).

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5. Stein et al., 2004: In a multicenter, 14-week, randomized, double-blind, parallel-group study, 621 patients heterozygous familial hypercholesterolemia (HeFH), coronary heart disease (CHD), or multiple cardiovascular risk factors (≥2) who were treated with atorvastatin 10 mg for at least 4 weeks prior to randomization were evaluated to assess the efficacy of switching to ezetimibe/atorvastatin 10/10 mg versus titrating up to atorvastatin 20 mg dose. Patients were evaluated for LDL-C target goal achievement after 4 and/or 9 weeks of treatment and their atorvastatin dose was doubled at each evaluation if they were not at goal. The primary end point was the percentage of patients reaching a target LDL-C goal. A key secondary endpoint was the percentage LDL-C reduction at 4 weeks, when a direct comparison can be made between the addition of ezetimibe to the starting dose of atorvastatin versus doubling the dose of atorvastatin. [PubMed]

Summary of Key Results:

  • After 14 weeks of treatment, significantly more patients in the ezetimibe group than in the atorvastatin monotherapy group reached LDL-C goal of ≤ 100 mg/dL (22% versus 7%; P < 0.01).

  • At week 4, LDL-C was reduced 22.8% in patients receiving ezetimibe 10 mg plus atorvastatin 10 mg and 8.6% in patients receiving atorvastatin 20 mg (P < 0·01).

  • Approximately four times as many patients reached LDL-C goal at week 4 when receiving ezetimibe 10 mg plus atorvastatin 10 mg versus when receiving atorvastatin 20 mg (17% versus 4%; P < 0·01).

 

6. Conrad et al., 2008: In a multicenter, 6-week, randomized, double-blind, parallel-group study, 184 patients with an LDL-C level ≥100 mg/dL and ≤160 mg/dL (≥2.6 mmol/L and ≤4.1 mmol/L) and at moderate high risk for coronary heart disease (CHD) who were treated with atorvastatin 20 mg for at least 4 weeks prior to randomization were evaluated to assess the efficacy of switching to ezetimibe/atorvastatin 10/20 mg versus titrating up to atorvastatin 40 mg dose. The primary end point was the percentage reduction in LDL-C. [PubMed]

Summary of Key Results:

  • Adding ezetimibe 10 mg to atorvastatin 20 mg produced significantly greater reductions in LDL cholesterol than increasing atorvastatin to 40 mg (-31% vs -11%, p <0.001).

  • Significantly greater reductions were also seen in non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B (p <0.001).

  • Significantly more patients reached LDL cholesterol levels <100 mg/dl with atorvastatin 20 mg plus ezetimibe compared with atorvastatin 40 mg (84% vs 49%, p <0.001).

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7. Leiter et al., 2008: In a multicenter, 6-week, randomized, double-blind, parallel-group study, 556 patients LDL-C level ≥70 mg/dL and ≤160 mg/dL and at high risk for coronary heart disease (CHD) who were treated with atorvastatin 40 mg for at least 4 weeks prior to randomization were evaluated to assess the efficacy of switching to ezetimibe/atorvastatin 10/40 mg versus titrating up to atorvastatin 80 mg dose. The primary end point was the percentage reduction in LDL-C. [PubMed]

Summary of Key Results:

  • Ezetimibe/atorvastatin 10/40 mg significantly reduced the primary end point of LDL cholesterol by 27% versus atorvastatin 80 mg which reduced LDL-C by 11% (p <0.001).

  • Ezetimibe/atorvastatin 10/40 mg also reduced non-high-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and triglycerides significantly more than atorvastatin 80 mg (all p <0.001)

  • Significantly more patients treated with ezetimibe/atorvastatin 10/40 mg reached LDL cholesterol <70 mg/dl versus patients treated with atorvastatin 80 mg (74% vs 32%; p <0.001)

 

 

References:

 

1. Bays H. E., Davidson M. H., Massaad R., Flaim D., Lowe R. S., Tershakovec A. M., Jones-Burton C. Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study). Am J Cardiol. 2011 Aug 15;108(4):523-30. doi: 10.1016/j.amjcard.2011.03.079. Epub 2011 May 17.


2. Ballantyne C. M., Hoogeveen R. C., Raya J. L., Cain V. A., Palmer M. K., Karlson B. W., GRAVITY Study Investigators. Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: Results of the GRAVITY randomized study. Atherosclerosis. 2014 Jan;232(1):86-93. doi: 10.1016/j.atherosclerosis.2013.10.022. Epub 2013 Nov 1.


3. Ballantyne C. M., Weiss R., Moccetti T., Vogt A., Eber B., Sosef F., Duffield E., EXPLORER Study Investigators. Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol. 2007 Mar 1;99(5):673-80. doi: 10.1016/j.amjcard.2006.10.022. Epub 2007 Jan 4.


4. Ballantyne C. M., Houri J., Notarbartolo A., Melani L., Lipka L. J., Suresh R., Sun S., LeBeaut A. P., Sager P. T., Veltri E. P., Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003 May 20;107(19):2409-15. doi: 10.1161/01.CIR.0000068312.21969.C8. Epub 2003 Apr 28.


5. Stein E., Stender S., Mata P., Sager P., Ponsonnet D., Melani L., Lipka L., Suresh R., Maccubbin D., Veltri E., Ezetimibe Study Group. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J. 2004 Sep;148(3):447-55. doi: 10.1016/j.ahj.2004.03.052.


6. Conard S. E., Bays H. E., Leiter L. A., Bird S. R., Rubino J., Lowe R. S., Tomassini J. E., Tershakovec A. M. Efficacy and safety of ezetimibe added on to atorvastatin (20 mg) versus uptitration of atorvastatin (to 40 mg) in hypercholesterolemic patients at moderately high risk for coronary heart disease. Am J Cardiol. 2008 Dec 1;102(11):1489-94. doi: 10.1016/j.amjcard.2008.09.075. Epub 2008 Oct 23.


7. Leiter L. A., Bays H., Conard S., Bird S., Rubino J., Hanson M. E., Tomassini J. E., Tershakovec A. M. Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with uptitration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol. 2008 Dec 1;102(11):1495-501. doi: 10.1016/j.amjcard.2008.09.076. Epub 2008 Oct 23.