The JUPITER study: statins for the primary prevention of cardiovascular events in patients with inflammatory rheumatic diseases?

Patients with inflammatory rheumatic diseases have an increased risk of cardiovascular disease, raising questions of whether primary prevention strategies that are more aggressive than cardiac risk factor modification alone should be implemented. Recent trials demonstrating the efficacy of statins in reducing rates of cardiovascular events in healthy persons with elevated levels of C-reactive protein broaden the potential protective mechanisms of statins, but do not directly translate to primary cardiovascular disease prevention in patients with inflammatory rheumatic diseases.

Introduction and context

The risk of cardiovascular disease and cardiovascular mortality is increased in patients with inflammatory rheumatic diseases compared to the general population or to persons without these diseases. Although an increased risk is most well established for patients with systemic lupus erythematosus and rheumatoid arthritis, some evidence suggests an increased risk also exists for patients with ankylosing spondylitis, psoriasis, and psoriatic arthritis [1-5]. Although the reasons for this increased risk are not completely understood, the association between markers of inflammation, in particular, high-sensitivity C-reactive protein (hs-CRP), and cardiovascular risk in patients without known inflammatory disease has led to speculation that systemic inflammation itself may be etiologic [6-9]. Evidence that cardiovascular events are reduced in patients who respond to anti-inflammatory treatment supports this view [10].

Recent advances

The JUPITER study (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) tested whether treatment with rosuvastatin altered the risk of incident cardiovascular events compared to placebo in persons with a normal level of low-density lipoprotein (LDL) cholesterol (less than 130 mg/ml) but an elevated level of hs-CRP (2.0 mg/l or higher) [11]. Persons with systemic inflammatory diseases, including severe arthritis and systemic lupus erythematosus, were excluded, as were those being treated with prednisone and other immunosuppressive medications. Subjects (n = 17,802) were randomized to receive either 20 mg rosuvastatin daily or placebo, for a planned duration of 5 years. The study's primary endpoint was the occurrence of a first major cardiovascular event, including myocardial infarction, stroke, hospitalization for unstable angina or arterial revascularization, or death from a cardiovascular cause.

The study was stopped prematurely when an interim analysis found that cardiovascular events were significantly less frequent in the group receiving rosuvastatin. The primary endpoint was 44% less likely in the rosuvastatin group than in the placebo group, although the rates of events were low in both groups. Reduced risks of similar magnitude were present for each condition comprising the primary endpoint. There was also a modest reduction in all-cause mortality in the rosuvastatin group. At 12 months, the median hs-CRP level was 37% lower in the rosuvastatin group compared to placebo, from a baseline level of 2.2 mg/l, and median LDL cholesterol was 50% lower in the rosuvastatin group compared to placebo, from a baseline level of 186 mg/dl.

These results indicate that treatment with rosuvastatin can decrease cardiovascular events among patients with an elevated hs-CRP level who do not have cholesterol levels elevated to the threshold customarily used to begin treatment. One possible implication of these results is that primary prevention strategies should be broadened to treat with statins those whose only cardiac risk factor is an elevated hs-CRP level. But is this an appropriate conclusion? Although subjects were selected based on both an elevated hs-CRP level and a normal LDL cholesterol level, the trial did not include a group with low hs-CRP levels and, therefore, did not isolate the benefit to patients with elevated hs-CRP levels specifically. Nor did it test hs-CRP as a screening tool to target treatment, which would have required a parallel arm of subjects who had not been tested for hs-CRP and were treated without regard to hs-CRP level. In the strictest interpretation, the JUPITER trial expands the potential mechanisms by which statins reduce cardiovascular events to include reductions in hs-CRP levels. Whether this effect is completely independent of the hypocholersterolemic effect is uncertain.

Implications for clinical practice

Given the elevated cardiovascular risk experienced by patients with inflammatory rheumatic diseases, and the association of elevated CRP levels with cardiovascular disease, how should the results of the JUPITER trial be applied to patients with inflammatory rheumatic diseases? If hs-CRP levels in persons without inflammatory diseases reflect inflammation in atherosclerotic endothelial lesions, while hs-CRP (or CRP) levels in patients with inflammatory diseases primarily reflect inflammation outside the atherosclerotic endothelial lesions, elevated hs-CRP levels would not be specific to the etiologic target in patients with inflammatory diseases. In this case, targeting treatment based on hs-CRP would not be helpful, and treatment might not be expected to have the same effects. Statins have multiple immunomodulatory actions, which may have a role in their cardioprotective effects [12]. Differences in activation or regulation of these immune and inflammatory pathways between patients with chronic inflammatory rheumatic diseases and people without these diseases complicate using the findings in non-rheumatic cohorts to predict effects in rheumatic disease cohorts. Also to be considered is whether any benefit of statins for primary prevention would be attenuated or negated by anti-rheumatic treatments, particularly chronic corticosteroids. Lastly, the long-term safety of statins and unknown risks of prolonged marked hypocholesterolemia would need to be balanced against the potential benefits.

Given the difficulty applying the results of the JUPITER trial to patients with inflammatory diseases, it would be premature to recommend statins for primary prevention of cardiovascular events in patients with inflammatory rheumatic diseases. Rather, cardiac risk factor assessment and modification should be enforced, while awaiting the results of ongoing or recently completed studies specifically investigating statins for primary cardiovascular disease prevention in systemic lupus erythematosus and rheumatoid arthritis [13-15].