What is the significance of the Jupiter trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)?

From the Guidelines

The JUPITER trial was a landmark study that demonstrated the effectiveness of rosuvastatin in preventing cardiovascular events in individuals with normal LDL cholesterol but elevated high-sensitivity C-reactive protein (hsCRP), with a significant 44% reduction in the primary endpoint of major cardiovascular events in the rosuvastatin group 1. The trial's main strength was its large sample size of nearly 18,000 participants and its robust randomized, double-blind, placebo-controlled design.

• The JUPITER trial was terminated early (after approximately 1.9 years instead of the planned 5 years) due to the significant reduction in major cardiovascular events in the rosuvastatin group 1.
• This early termination provided compelling evidence for statin therapy in primary prevention for patients with inflammation but normal cholesterol levels.
• The trial expanded our understanding of cardiovascular risk beyond traditional lipid profiles by highlighting inflammation (measured by hsCRP) as an important risk factor.
• JUPITER also demonstrated benefits across diverse subgroups, including women and older adults, showing consistent risk reduction regardless of baseline characteristics 1. The most recent and highest quality study, the 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease, supports the use of high-intensity statins to lower LDL-C by ≥50% for maximal ASCVD risk reduction, especially when 10-year ASCVD risk is ≥20% 1.
• The JUPITER trial fundamentally changed preventive cardiology by supporting the use of statins in patients who wouldn't qualify for treatment under previous cholesterol-focused guidelines.
• The trial's findings have been corroborated by meta-analyses demonstrating that in those at risk, the net benefit of LDL-C-lowering therapy is greater with greater reductions in LDL-C 1.

From the FDA Drug Label

In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study, the effect of Atorvastatin on the occurrence of major CV disease events was assessed in 17,802 males (≥50 years) and females (≥60 years) who had no clinically evident CV disease, LDL-C levels <130 mg/dL and hsCRP levels ≥2 mg/L.

The study population had an estimated baseline coronary heart disease risk of 11. 6% over 10 years based on the Framingham risk criteria and included a high percentage of patients with additional risk factors such as hypertension (58%), low HDL-C levels (23%), cigarette smoking (16%), or a family history of premature CHD (12%).

Patients had a median baseline LDL-C of 108 mg/dL and hsCRP of 4. 3 mg/L. Patients were randomly assigned to placebo (n=8901) or rosuvastatin 20 mg once daily (n=8901) and were followed for a mean duration of 2 years.

The strength of the Jupiter trial can be described in terms of its large sample size of 17,802 patients, long duration of 2 years, and robust study design that included a placebo-controlled group. The trial demonstrated a statistically significant reduction in major CV events, with a relative risk reduction of 44% and an absolute risk reduction of 1.2%. Key points about the trial's strength include:

• Large sample size: 17,802 patients were enrolled in the study.
• Long duration: The study lasted for a mean duration of 2 years.
• Robust study design: The trial included a placebo-controlled group, allowing for a comparison of outcomes between the treatment and control groups.
• Statistically significant results: The trial demonstrated a significant reduction in major CV events, with a relative risk reduction of 44% and an absolute risk reduction of 1.2% 2.

From the Research

Study Design and Population

• The JUPITER trial was a randomized, double-blind, placebo-controlled primary prevention trial of statin therapy among persons with average to low levels of low-density lipoprotein (LDL) cholesterol who are at increased cardiovascular risk due to elevated plasma concentrations of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) 3.
• A total of 17,802 persons with LDL cholesterol <130 mg/dl (3.36 mmol/L) and hs-CRP ≥2 mg/L were recruited from 26 countries and randomly allocated to 20 mg/day rosuvastatin or placebo 3.
• The trial included 6,801 women (38.2%) and 5,577 participants with metabolic syndrome (32.1%) 3.

Efficacy of Rosuvastatin

• Rosuvastatin 20 mg significantly reduced major cardiovascular events among men and women with elevated hs-CRP and "intermediate risk" defined either as 5% to 10% or 10% to 20% 10-year risk 4.
• The rate of myocardial infarction/stroke/cardiovascular death was 9.4 and 18.2 per 1000 person-years in rosuvastatin and placebo-allocated patients, respectively, with a hazard ratio (HR) of 0.50 (95% CI: 0.27-0.93, P = 0.028) 5.
• Among patients with SCORE risk ≥5%, the corresponding rates were 6.9 and 12.0 using a model extrapolating risk for age ≥65 years (HR: 0.57,95% CI: 0.43-0.78, P = 0.0003) 5.

Reduction in C-Reactive Protein and LDL Cholesterol

• Rosuvastatin reduced LDL cholesterol by up to 50% and achieved hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1.8 mmol/L (<70 mg/dL) 6.
• Participants allocated to rosuvastatin who achieved LDL cholesterol less than 1.8 mmol/L had a 55% reduction in vascular events (event rate 1.11 vs 0.51 per 100 person-years; hazard ratio [HR] 0.45,95% CI 0.34-0.60, p<0.0001) 6.
• Those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0.42 per 100 person-years; HR 0.38,95% CI 0.26-0.56, p<0.0001) 6.

Critique and Implications

• The interpretation and clinical implications of the JUPITER trial have been questioned and remain controversial 7.
• The trial demonstrates that rosuvastatin 20 mg significantly reduces major cardiovascular events among men and women with elevated hsCRP and "intermediate risk" defined either as 5% to 10% or 10% to 20% 10-year risk 4.