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JUPITER in clinical context: challenging traditional thinking
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The findings of the JUPITER trial have created a substantial effect amongst clinicians. It has made us consider several issues that could be viewed as evolutionary in the realm of preventive cardiology.
First and probably most important is that our traditional views on levels of LDL in predicting risk must be reconsidered, which was first demonstrated in the ASCOT trial. Namely, the presence of co-morbidities or multiple risks for CVD will modify the level of LDL that we could expect to be associated with low CV risk.
In JUPITER, treatment with rosuvastatin (Crestor, AstraZeneca) 20 mg daily in people with a median LDL level of 108 mg/dL resulted in substantial reduction in CV events. Also, the mean baseline systolic BP of 134 mmHg has been suggested to confer additional CV risk in contrast to readings that are “normal,” namely below 120 mmHg systolic.
Secondly, we may have to accept what many have been espousing over the past several years: that optimal levels of LDL are much lower than our older guidelines have predicted. This stems from end treatment LDL’s in the mid 50’s mg/dL, with one-quarter of the people achieving LDL’s of less than 45 mg/dL.
Some concern has been voiced about the premature cessation of the study preventing an adequate assessment of the safety of such low LDL levels. However, no safety signal emerged in the data and the number of malignancies was actually reduced.
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Finally, we are now faced with the notion of whether we should be routinely measuring levels of inflammatory markers when we evaluate risk. In JUPITER the entry criteria of levels of hs-CRP greater than 2 mg/dL appears to have identified a cohort at greater risk for events. In fact, when increased hs-CRP was the only “risk factor” there was still robust benefit from the study medication. However, the data from JUPITER do not permit evaluation of the weighted effect of LDL vs. CRP.
Many have suggested that the large number of patients with metabolic syndrome (42%), the pre-hypertensive systolic BPs (134 mm Hg/80 mm Hg) and average BMI’s (28) could be adequate to predict risk in the absence of increased CRP. Unfortunately, since increased levels of the inflammatory marker were inclusion criteria, we will not be able to determine whether those with the above findings with normal CRP were at equal risk.
In addition, the recent publication in the New England Journal of Medicine on CRP polymorphisms raises questions about CRP’s actual role in the process of plaque development. In this trial those with higher levels of CRP due to genetic mutations were not found to have the increased CV risk that would have been expected if the risk was actually caused by CRP.
How should JUPITER change practice?
The question now is what effect JUPITER should have on the way a clinician approaches patients. Many physicians have already been asked by their patients to include hs-CRP on the next laboratory exam. Is this something that should be universally included?
In JUPITER, only men older than 50 and women older than 60 were allowed to be screened. This quickly increases the baseline risk from other studies that have allowed enrollment of people older than 45. In addition, participants had to be naïve to any prior hypolipidemic drug exposure, and women could not be users of hormone replacement therapy. Other exclusion factors were in place to prevent consideration of patients with elevated levels of hs-CRP on a non-vascular basis. This was a relatively select group of participants that permitted the assessment of risk and potential benefit of treatment with a statin.
There is also reason to wonder if these effects can be generalized to the entire statin class. This is hard to determine, but if lowering levels of inflammatory biomarkers as well as LDL are to be considered as an important predictors of benefit, then we may have to accept that some statins have greater clinical efficacy than others in this regard. Certainly, there are only two (rosuvastatin and atorvastatin [Lipitor, Pfizer]) that can safely achieve greater than 50% drops in LDL as seen in JUPITER. There was an increased risk of myopathy associated with use of simvastatin (Zocor, Merck) 80 mg in both the A to Z and SEARCH trials.
There was a benefit of unanticipated magnitude derived from treating patients deemed at relatively low risk (on the basis of traditional risk factors) with a potent statin that significantly reduced levels of LDL, triglycerides and hs-CRP. The key now is to consider application of these findings to others with similar risk attributes to optimally take advantage of the marked risk reduction that may be realized.
Howard Weintraub, MD, is Clinical Associate Professor of Medicine, New York University School of Medicine and Clinical Director, Center for the Prevention of CVD at New York University Medical Center.