Commentary by Ilana Bragin MD, PGY-3
This week online in the NEJM, the results of a trial known as Jupiter were presented in an article that will likely change the way we approach cardiovascular health protection. The Jupiter trial attempts to answer this perturbing question: “Why do half of all myocardial infarctions and strokes occur in apparently healthy men and women with levels of LDL that are below currently recommended thresholds of treatment?” The study addresses the biomarker C-reactive protein, an inflammatory marker that has long been linked to an increased risk of adverse cardiovascular events. While cholesterol has been a target for decreasing cardiovascular risk, physicians have known less what to do about elevated CRPs, using it more as a harbinger of trouble, than as an indication for action. Statins have been previously shown to decrease levels of CRP as well as lipids, and the magnitude of the benefit of statin therapy is known to be in part due to its lowering of CRP. However, while we have guidelines for lowering cholesterol, lowering CRP alone has not been a target of therapy. The study, sponsored by AstroZeneca, thus took individuals who did not have elevated LDL by current treatment guidelines, but did have elevated CRP, treated them with a statin, and then monitored them for cardiovascular events.
More specifically, 17,802 patients with low LDL levels <130mg/deciliter and high sensitivity C-reactive proteins 2.0 mg/liter or higher, were randomized to receive either 20 mg of rosuvastatin daily or placebo. Men above the age of 50 and women above the age of 60 with these criteria were eligible. Patients with a history of cardiovascular disease were excluded. Also excluded were patients on hormonal therapy, with evidence of liver disease, with an elevated CK or elevated Cr (Cr>2), patients with diabetes, uncontrolled hypertension, cancer (other than basal or squamous skin cancer) within 5 years of enrollment, uncontrolled hypothyroidism, recent drug or alcohol history, or any patients with inflammatory conditions, such as lupus, severe arthritis, or inflammatory bowel disease as well as anyone taking immunosuppressive medications or long term glucocorticoids.
The study results were impressive. Although the study was designed to be continued for 5 years or until a primary cardiac event; namely myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes; when a prespecified interim efficacy analysis was performed after less than 2 years, the trial was terminated given the markedly beneficial results of the statin.
After 1 year of therapy, as compared with the placebo group, the rosuvastatin group had a 50% lower average LDL and a 37% lower CRP level. At the time of the termination of the study, 142 first major cardiovascular events had occurred in the rosuvastatin group as compared with 251 in the placebo group. Rosuvastatin also decreased the number of deaths from any cause (hazard ratio for the rosuvastatin group, 0.80; 95% CI, 0.67 to 0.97; P=0.02) With Kaplan-Meir estimates, the number of patients needed to treat with rosuvastatin for 2 years in order to prevent one primary endpoint is 95, and if the risk is projected over a 5 year period, the number needed to treat to prevent the occurrence of one primary endpoint, is 25.
Given that few adverse events occurred with the rosuvastatin group (increased physician-reported diabetes was reported in the rosuvastatin group; although there were no significant elevations of fasting blood glucose and only minimal differences in HgA1c), this could significantly impact how we risk stratify patients and subsequently initiate treatment with statins for cardiovascular prevention.
Some questions remain to be addressed. Does this study mean we should test for CRP levels in all patients, even those who have no other cardiovascular risk? Should the test only be initiated in individuals above the age criteria in this trial (men >50, women>60)? And given that cardiovascular disease is such a multifactorial illness (obesity, HTN, smoking, cholesterol, all play a part), how does CRP, when looked at alone without the other risk factors, fit in? Also, the study, in addition to cutting CRP levels, also cut down LDL from low levels to even lower levels—perhaps that effect is greater than the effect of the lower CRP? And lastly, perhaps this study paved the way for looking more at the inflammatory nature of heart disease, and potentially the benefit of other anti-inflammatory medications on lowering heart disease.
3 comments on “Breaking News: The Jupiter Trial”
what is the proposed mechanism by which rosuvastatin lowers CRP? is there one?
Facts Believed to be Associated With All Statin Medications:
Statins are a class of medications specifically prescribed to lower LDL- one of five lipid parameters of a person’s lipid profile. There are 6 available statins to choose- with three that are combination drugs that have a statin as a component of these medications. There are other classes of medications for lipid management, such as bile acid sequestrants and nicotinic acid, which is known as niacin. Yet the side effect profile is more unfavorable of these classes of medications compared with the statin class.
One’s cholesterol level is primarily due to how they produce cholesterol in their liver, which is overall genetically determined. This level is also determined by one’s lifestyle and diet as well. If a person has too much cholesterol in their blood, it can lead to hardening and narrowing of their arteries, which can lead to cardiovascular events.
To measure one’s cholesterol, a blood test called a lipid profile is obtained from a person after they have fasted for at least 12 hours. The test should also be performed only if the person is free of any acute illness, as this may affect true lipid measures. If the results prove to be abnormal, lipid lowering therapy may be initiated, according to the discretion of the person’s health care provider. This therapy usually involves a statin medication.
Adverse events associated with the statin class of pharmaceuticals are thought to occur more often than they are reported- with high doses of statins prescribed to patients in particular at times that may not be necessary to control their dyslipidemia based on their lipid profile. However, since this class of drugs has existed for use for over 20 years, statins are considered safe and effective for enhancing the clearance of LDL noted to be elevated in the lipid profiles of patients. Also, they have proven to reduce cardiovascular mortality with one who is treated with a statin that has dyslipidemia. In addition to lowering LDL by up to 60 percent- depending on the statin- this class of drugs also raises HDL and lowers triglycerides, which are two other lipid parameters. Both of these effects from taking a statin drug are beneficial for the patient on a statin drug for lipid management.
Statin therapy is also recommended for those patients who have a greater than twenty percent risk of developing cardiovascular disease, or those patients that have clinical evidence of this disease
Additionally, there appears to be no comparable reduction in cardiovascular morbidity or mortality, as well as a difference in the increase of one’s lifespan, if one is on any particular statin medication for their lipid management over another, others have concluded. So caution should perhaps be considered if one chooses to prescribe a statin for a patient if they are absent of, or have only mild dyslipidemia to a significant degree. Furthermore, research should be done by the health care provider if they are under the belief that one statin medication provides a greater cardiovascular benefit over another. In other words, the health care provider should be assured that any choice of statin therapy for their patients is considered reasonable and necessary if the LDL in their patients need to be reduced, and the statin selection should be determined by the results that have been shown with a particular statin.
Abstract etiologies for those who choose to prescribe statin drugs on occasion for reasons not indicated by these statin drugs- such as reducing CRP levels, or for Alzheimer’s treatment, or anything else not involved with LDL reduction with prevention if not delaying the progression of cardiovascular disease, should be thoroughly evaluated by the health care provider. As statin therapy for such patients may not be considered appropriate prophylaxis at this point for any patient who does not have the indications for which statins are approved for and treat with patients. All other benefits that appear to have favorable effects in such areas are speculative at this point due to minimal research in other areas aside from lipid management, and require further research for these disease states aside from dyslipidemia, according to many.
Statins as a particular class of drugs that seem to in fact decrease the risk of cardiovascular events significantly, it has been proven. Statins also decrease thrombus formation as well as modulate inflammatory responses (CRP) as additional benefits of the medication. For those patients with dyslipidemia who are placed on a statin, the effects of that statin on reducing a patient’s LDL level can be measured after about five weeks of therapy on a particular statin drug.
Liver Function blood tests are recommended for those patients on continued statin therapy, and most are chronically taking statins for the rest of their lives to manage their lipid profile in regards to maintaining the suitable LDL level for a particular patient presently. Patients should be made aware of potential additional side effects as well, such as muscular issues.
Yet some have said that about half of all strokes and heart attacks that do occur are not because of increased cholesterol levels of these patients. Others believe that it is oxidized cholesterol that causes vulnerable plaques to form on coronary arterial walls, which is the catalyst for a heart attack, and that there is no medicinal treatment for the formation or stabilization of these plaques to prevent heart attacks or strokes. Others who promote and support statin medicinal therapy claim that these drugs, do, in fact, stabilize these plaques, and therefore are beneficial.
As stated previously, in regards to other uses of statins besides just primarily LDL reduction, there is some evidence to suggest that statins have other benefits besides lowering LDL. These other disease states include aside from what has been stated already, those patients with dementia or Parkinson’s disease, as well as those patients who may have certain types of cancer or even cataracts. Yet again, these other roles for statin therapy have only been minimally explored, comparatively speaking. Because of the limited evidence regarding additional benefits of statin medications, the drug should again be prescribed for those with dyslipidemia only at this time involving elevated LDL levels as detected in the patient’s bloodstream.
Yet overall, the existing cholesterol lowering recommendations or guidelines should possibly be re-evaluated, as they may be over-exaggerated upon tacit suggestions from the makers of statins to those who create these current lipid lowering guidelines. This is notable if one chooses to compare these cholesterol guidelines with others in the past. The cholesterol guidelines that exist now are considered by many health care providers and experts to be rather unreasonable, unnecessary, and possibly detrimental to a patient’s health, according to others. Yet statins are beneficial medications for those many people that exist with elevated LDL levels that can cause cardiovascular events to occur because of this abnormality. What that ideal LDL level is may have yet to be empirically determined.
Finally, a focus on children and their lifestyles should be amplified so their arteries do not become those of one who is middle-aged, and this may prevent them from being candidates for statin therapy now and in the future, regarding the high cholesterol issue. Treating children with a statin drug for dyslipidemia is controversial presently.
Dietary management should be the first consideration in regards to correcting lipid dysfunctions that may exist in patients,
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