JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean?

Better markers are needed

Even with a nonspecific marker such as hs-CRP, patients at higher global risk and with LDL-C below the recommended levels could be identified and treated aggressively. This benefit, however, required that approximately 100 people be treated with rosuvastatin for 2 years to prevent one event. Additionally, only 20% of all patients screened were eligible for the trial. Therefore, one could argue that its generalizability is limited.

Markers of risk that are more specific and sensitive are needed to identify people at higher global risk who would otherwise be considered to be at low risk with the current risk assessment tools. A number of such inflammatory and oxidative markers are under development.^54–60

Absolute vs relative risk reduction and the public health burden

The 44% reduction in the number of primary end point events in the rosuvastatin group was considerable in relative terms. However, in absolute terms, 95 people had to be treated for up to 2 years in order to prevent one event.⁵³ In making recommendations, the United States Department of Health and Human Services has to consider the clinical benefit of a test or a drug in light of its cost. With health care costs increasing, many agencies are refusing to pay for therapies on the basis of cost or small absolute benefit.

While we do not have the answer as to whether treating 95 people for 2 years to see one benefit is cost-effective, one thing is clear: the field of medicine is in desperate need of a better way to identify individuals who may benefit from a test or therapy.⁶¹ Additionally, we think it is important to note that the “numbers-needed-to-treat” (95 at 2 years and 25 at 5 years) derived from JUPITER are actually smaller than the values observed in the AFCAPS/TexCAPS and the West of Scotland Coronary Prevention Study.^62,63 This suggests that statin therapy is at least as cost-effective in those with elevated hs-CRP as in those with elevated LDL-C. Even our most robust therapies are effective in only a minority of patients treated.⁶¹

Should ‘healthy’ people be tested for hs-CRP?

In 2003, we wrote in this journal²¹ that measuring hs-CRP may add to the current risk-prediction models by identifying people at increased risk who would otherwise not be considered as such by current risk models. The US Centers for Disease Control and Prevention and the American Heart Association have also stated that measuring hs-CRP in those at intermediate risk may be reasonable.²⁶

The JUPITER investigators intended to study a relatively healthy population, but, as we mentioned, a close look at the cohort’s baseline characteristics indicates a substantial proportion met the criteria for metabolic syndrome. Therefore, one could challenge whether we really need hs-CRP in such a population to identify who will benefit from statin therapy.

We agree with the recommendation from the Centers for Disease Control and Prevention and the American Heart Association that measuring hs-CRP in people at intermediate risk is a reasonable option.²⁶ We also believe that hs-CRP should be tested as a secondary risk factor, in combination with blood pressure, lipids, diabetes, smoking, serum creatinine, and fasting blood glucose. Factors such as obesity, sedentary lifestyle, family history of heart disease, and emotional and physical stress should also be considered.

Safety of high-dose statin therapy

High-dose statin therapy has been well tolerated in clinical trials, but rates of discontinuation have been higher (7%–10%) than with moderate-dose therapy (4%–5%).⁶⁴ Fortunately, the rates of serious adverse events have in general been low. For example, with simvastatin 80 mg, the rates of myopathy and rhabdomyolysis were quite low.³¹

Rates of elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with high-dose statin therapy have been reported to be below 1.3%. Studies have shown that reducing LDL-C to below 100 mg/dL is associated with a higher incidence of ALT and AST elevations. However, these elevations have usually been benign and often return to normal when the drug is reduced in dose or withdrawn.

In previous studies of rosuvastatin,⁶⁵ the incidence of myopathy and liver function abnormalities was less than 0.1%. Rates of proteinuria were similarly low, and in many patients renal function actually improved on rosuvastatin.^66,67 Furthermore, rosuvastatin may have different pharmacokinetic properties than atorvastatin (Lipitor) and simvastatin, which may result in a lower incidence of musculoskeletal toxicity.^68,69

In general, the incidence of cancer has been similar in those treated with high-dose statins and those treated with placebo. The Treating to New Targets trial⁷⁰ suggested that the incidence of cancer was higher with atorvastatin 80 mg daily than with 20 mg daily. However, a meta-analysis of 14 trials of moderate-dose statin therapy did not show any evidence of increased cancer rates with these agents.⁷⁰ Indeed, in JUPITER, there was a reduction in cancer-related mortality rates, which could have been due to chance.

The JUPITER trial also showed an increase in the physician-reported incidence of diabetes mellitus with rosuvastatin. This is an important finding, and it may be a class effect because modest increases have similarly been reported with other statins in other major trials, eg, with pravastatin (Pravachol) in PROSPER, simvastatin in the Heart Protection Study, and atorvastatin in PROVE-IT. However, even in those with diabetes or impaired fasting glucose, the reduction in the rate of major adverse events is significant. For example, in JUPITER, almost all of the cases of “incident diabetes” were in those with impaired fasting glucose at baseline, and this group had nearly a 50% reduction in rates of myocardial infarction, stroke, and cardiovascular death. Therefore, on balance, the modest risk of earlier diagnosis of diabetes with statin therapy seems substantially offset by the marked reduction in rates of major adverse cardiovascular events in people with diabetes and impaired fasting glucose on statin therapy.

TAKE-HOME POINTS

The JUPITER trial, like previous high-dose statin trials, calls into question whether current LDL-C guidelines are appropriate for people at higher global risk with otherwise “normal” LDL-C levels.^27,28 This trial heralds a new era in preventive therapy because it extends beyond LDL-C as an indication for statin therapy within the primary prevention setting. Statins have revolutionized the therapy of cardiovascular disease, and they continue to show benefit even in the “healthy.”

Clearly, hs-CRP serves as a nonlipid marker to identify those who may benefit from statin therapy. Nonetheless, more specific and sensitive markers (or panels) of cardiovascular risk are necessary. In the future, we will need markers that not only identify people at higher global risk, but that also tell us who would benefit from certain medical or surgical therapies. Elevated hs-CRP in a patient who otherwise would not be a candidate for statin therapy should trigger a reassessment of the risks vs benefits of statin therapy—JUPITER teaches us that statin therapy will benefit these patients.

Aggressive lifestyle modification that encompasses a balanced diet, routine exercise, and smoking cessation should be applied in both primary and secondary prevention. Additionally, risk factors such as elevated blood pressure and hyperlipidemia should be aggressively treated with appropriate medications.