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JUPITER: Best CVD event reduction in patients with very
low LDL-cholesterol levels
 
 
  Ridker said he emphasizes diet, exercise, smoking cessation, and long-term compliance with statin therapy. In JUPITER, low levels of both on-treatment LDL cholesterol and low levels of on-treatment hs-CRP were both crucial for maximizing the benefits of therapy, he said. Asked how comfortable general physicians would feel with decreasing LDL-cholesterol levels to such low targets, Ridker said doctors should emphasize the importance of compliance for their patients, and that if "clinicians understand that getting LDL cholesterol as low as 50 mg/dL is safe and effective, then perhaps we can get larger proportions of patients to our current targets of <100 mg/dL and <70 mg/dL."
 
April 15, 2011 Michael O'Riordan
 
Wilmington, DE - A new analysis from Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) suggests even greater reductions in the risk of major cardiovascular events among individuals who achieve very low levels of LDL cholesterol [1].
 
In this case, individuals with elevated levels of high-sensitivity C-reactive protein (hs-CRP) who achieved LDL-cholesterol levels <50 mg/dL when treated with rosuvastatin (Crestor, AstraZeneca) had a 65% reduction in the risk of cardiovascular events and a 46% reduction in total mortality, both reductions larger than observed in the overall cohort. Importantly, there was no increased risk of adverse events among those who achieved very low levels of LDL cholesterol, although the incidence of new-onset diabetes was more common, a trend that did not reach statistical significance
 
To heartwire, senior investigator Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) called the results reassuring, saying they offer some insight into what the potential for cardiovascular-disease prevention might really be. "We know that societies living away from Western diets often have LDL-cholesterol levels in this very low range and have relatively little atherosclerotic disease," he said. "What these new data from JUPITER suggest is that very low levels of LDL cholesterol can be safely achieved with aggressive statin therapy, along with diet and exercise."
 
Commenting on the results for heartwire, Dr Steven Nissen (Cleveland Clinic, OH) said, "This finding is consistent with other substudies of statin trials that demonstrate that patients achieving very low LDL levels have no increase in adverse events and similar or greater benefits in cardiovascular risk reduction." While he urged caution in interpreting subgroup analyses in clinical trials, he suspects this analysis, as well as others, will "weight heavily" when the National Cholesterol Education Panel (NCEP) guidelines committee meets later this year to consider the next iteration of the cholesterol guidelines. The results are published, with first author Dr Judith Hsia (AstraZeneca, Wilmington, DE), in the April 19, 2011 issue of the Journal of the American College of Cardiology.
 
The JUPITER trial
 
Previously reported by heartwire, the JUPITER study was a landmark primary-prevention trial testing the hypothesis that a strategy of treating intermediate-risk patients with normal LDL-cholesterol levels but elevated CRP levels would significantly reduce the risk of cardiovascular events. Treatment with rosuvastatin 20 mg significantly reduced the primary end point-a composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes-by 44% compared with individuals treated with placebo.
 
In this newest analysis, the investigators report that treatment with rosuvastatin in patients who achieved LDL-cholesterol levels <50 mg/dL-the approximate median on-treatment LDL-cholesterol level in JUPITER-reduced the primary end point 65% when compared with placebo-treated patients (hazard ratio [HR] 0.35; 95% CI 0.25-0.49). Comparatively, those who failed to achieve LDL-cholesterol levels <50 mg/dL had a smaller reduction in the primary end point, that being a 24% reduction in risk compared with placebo-treated patients (HR 0.76; 95% CI 0.57-1.00).
 
Similarly, those treated to LDL-cholesterol levels <50 mg/dL had larger reductions in the risk of MI, stroke, or cardiovascular death compared with patients who did not achieve the lower LDL thresholds. For total mortality, there was a 46% reduction among those treated to LDL cholesterol <50 mg/dL, a larger reduction than the 20% observed in the entire cohort.
 
The investigators also presented data showing that the relative risk reduction in the primary end point was not associated with baseline LDL-cholesterol levels, showing similar reductions in risk among patients with LDL cholesterol <130 mg/dL, <100 mg/dL, and <70 mg/dL, among other LDL cutoff points.
 
"This challenges a great deal of dogma in our prevention guidelines, since it demonstrates that the JUPITER investigators would have gotten the exact same result even if the trial had been conducted exclusively among those with native LDL cholesterol levels <70 mg/dL, as long as they had elevated hs-CRP," noted Ridker. "It is a really good demonstration of why our guidelines need to be based on hard trial evidence rather than a priori beliefs."
 
There was no difference in the rates of myalgia, muscle weakness, and myopathy in those who achieved the low LDL target and those who did not. Diabetes was reported more frequently among patients with LDL-cholesterol levels <50 mg/dL, but this increase was not statistically significant. The rate of diabetes mellitus was 1.6 per 100 person-years among those with LDL <50 mg/dL and 1.2 per 100 person-years among those who did not achieve the low LDL target. Rates of psychiatric events, cancer, proteinuria, hematuria, and renal failure, among other adverse events, were no different between the two LDL-cholesterol-threshold groups. Regarding the risk of hemorrhagic stroke, which occurred infrequently in JUPITER, the investigators found no increase with rosuvastatin, even among patients with LDL-cholesterol levels <50 mg/dL.
 
What happens next?
 
To heartwire, Ridker said he emphasizes diet, exercise, smoking cessation, and long-term compliance with statin therapy. In JUPITER, low levels of both on-treatment LDL cholesterol and low levels of on-treatment hs-CRP were both crucial for maximizing the benefits of therapy, he said. Asked how comfortable general physicians would feel with decreasing LDL-cholesterol levels to such low targets, Ridker said doctors should emphasize the importance of compliance for their patients, and that if "clinicians understand that getting LDL cholesterol as low as 50 mg/dL is safe and effective, then perhaps we can get larger proportions of patients to our current targets of <100 mg/dL and <70 mg/dL."
 
The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was launched this week and will directly test the inflammatory hypothesis of atherothrombosis among patients with persistent inflammation. Canakinumab is an interleukin-1-beta inhibitor that does not alter lipid levels or coagulation and has been tested in other inflammatory conditions, such as gout and arthritis. Ridker is the primary investigator of CANTOS, an investigator-initiated study funded by Novartis.
 
AstraZeneca sponsored the JUPITER study and employs lead investigator Hsia. Ridker reports research grant support from AstraZeneca, Novartis, Merck, Abbott, Roche, and Sanofi-Aventis and consulting and/or lecture fees from AstraZeneca, Novartis, Merck/Schering-Plough, Sanofi-Aventis, ISIS, and Vascular Biogenics; he is listed as a coinventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease. These patents have been licensed to several entities, including AstraZeneca.
 
Source
 
1. Hsia J, MacFayden JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dL with rosuvastatin. J Am Coll Cardiol 2011; 57: 1666-1675.
 
Related links
 
· CRP testing plus statin therapy cost-effective in primary-prevention patients: JUPITER [Lipid/Metabolic > Lipid/Metabolic; Feb 08, 2011] · Cochrane review stirs controversy over statins in primary prevention [Lipid/Metabolic > Lipid/Metabolic; Jan 20, 2011] · ASCOT analysis fuels debate over JUPITER-based CRP indication for statins [Lipid/Metabolic > Lipid/Metabolic; Nov 18, 2010] · JUPITER: Low LDL and low CRP best for reducing events in primary prevention [Lipid/Metabolic > Lipid/Metabolic; Mar 29, 2009] JUPITER hits New Orleans: Landmark study shows statins benefit healthy individuals with high CRP levels [Clinical cardiology > Clinical cardiology; Nov 09, 2008]
 
 
 
 
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