Reducing Inflammation

Abstract

An elevated C-reactive protein level is an inflammatory marker associated with an increased risk in cardiovascular disease. Regular long-term exercise, a cholesterol-lowering diet (a diet low in saturated fat and high in viscous fiber and plant sterols), and statin pharmacotherapy have all been shown to reduce C-reactive protein levels. The purpose of this article is to describe the research available regarding lowering of C-reactive protein levels and reducing incidence of cardiovascular disease. Specifically, the article will compare the use of statin therapy, regular physical activity, and a cholesterol-lowering diet. The effectiveness of each intervention will be evaluated along with the risks and benefits associated with treatment.

Numerous studies have established that the anti-inflammatory marker C-reactive protein (CRP) can be used to predict the risk of future CVD [cardiovascular disease] in healthy individuals independent of traditional risk factors.

Traditional risk factors for developing cardiovascular disease (CVD) include age, gender, blood pressure, total cholesterol, high-density lipoprotein cholesterol, tobacco use, low-density lipoprotein (LDL) cholesterol, and family history. ¹ Yet a proportion of patients void of any traditional risk factors will go on to develop CVD. ² Numerous studies have established that the anti-inflammatory marker C-reactive protein (CRP) can be used to predict the risk of future CVD in healthy individuals independent of traditional risk factors.^3-5 Results from trials such as JUPITER (Justification for the Use of statin in Primary prevention: an Interventional Trial Evaluating Rosuvastatin) suggest CRP may be an additional therapeutic target in the prevention of CVD and that statin pharmacotherapy can be used to address this target. ⁶

The findings from JUPITER could have a major impact on guidelines and health care costs associated with preventing CVD. However, statin therapy is not the only intervention to lower CRP levels. Current evidence also exists that a diet low in saturated fat together with plant sterols and viscous fiber as well as regular physical activity can reduce CRP levels.^7,8 The purpose of this article is to describe what can be concluded from the findings of the JUPITER trial and compare lifestyle modifications to statin therapy for the reduction of CRP levels to prevent CVD in lower risk patients.

The JUPITER trial was a large, randomized, placebo-controlled study that evaluated the effects of rosuvastatin on prevention of vascular events in relatively healthy men and women with elevated CRP levels. ⁶ Inclusion criteria included women aged ≥60 years, men aged ≥50 years, a high-sensitivity C-reactive protein (hs-CRP) level of ≥2 mg/L, and an LDL level of <120 mg/dL. Because of the low LDL level, the population of patients assessed would not qualify for statin therapy under the current Adult Treatment Panel III (ATP III) guidelines. ⁹ The participants were considered “relatively healthy” because they had no past medical history of myocardial infarction, stroke, arterial revascularization, or other coronary risk equivalents. ¹⁰ However, there was a high proportion of participants with risk factors for CVD. For example, 58% of the study population had hypertension and 16% smoked cigarettes. ¹⁰

The results from JUPITER found that relative to baseline, median hs-CRP levels were decreased by 48% to 57% following treatment with rosuvastatin 20 mg daily. ⁶ Additionally, the occurrence of first major cardiovascular event was significantly reduced in the statin group (P < .0001). The study was terminated early due to these significant findings.

Following published results from JUPITER, the FDA expanded the indications for rosuvastatin to include primary prevention of CVD. The indication further specifies the target population to include patients at risk of CVD based on age (women ≥60 years, men ≥50 years), hs-CRP level ≥2 mg/L, and the presence of at least one other CVD risk factor (eg, hypertension, smoking, or family history of premature coronary heart disease). ¹¹ In addition, the Centers for Disease Control and Prevention/American Heart Association guidelines support the use of hs-CRP level as a marker of CVD risk in specific populations determined to be at intermediate risk when traditional risk factors are taken into account. ¹² The ATP III guidelines do not make therapy recommendations based on hs-CRP level. However, the guidelines have not been updated since 2004, four years before the results from JUPITER were presented.

Screening hs-CRP and statin treatment for patients based on CRP levels remains controversial. Following JUPITER, the Heart Protection Study published findings contradictory to those from the JUPITER trial. ¹³ High-risk patients were assigned to simvastatin or placebo for 5 years. Patients were categorized into groups based on baseline CRP levels. The study found that baseline CRP concentration does not modify the vascular benefits of statin therapy. The high-risk population in the Heart Protection Study was different from the low-risk population in JUPTIER, and a different, less potent statin (simvastatin vs rosuvastatin, respectively) was used. These variables must be taken into account when evaluating the results; however, it raises question to the findings in JUPITER.

Another concern is whether the mechanism of benefit of rosuvastatin in JUPITER was due solely to reduced inflammation. Statin therapy is associated with several beneficial pleotropic effects including improvement of endothelial dysfunction, increased nitric oxide availability, antioxidant properties, and stabilization of existing atherosclerotic plaques. ¹⁴ It is difficult to determine whether the patients randomized to statin therapy in JUPITER exhibited lower CVD risk due to a reduced CRP level or due to other pleotropic effects from rosuvastatin.

Cost-effectiveness must also be considered. The cost of hs-CRP screening is variable. One study found the range to be between $45 and $85 per test. ¹⁵ The cost of statin therapy also varies. A cost-effectiveness model from 2010 estimated statin costs from $0.25 per day to more than $3.85 per day for branded rosuvastatin. ¹⁶ A study using National Health and Nutrition Examination Survey data suggests that an additional 6.5 million people in America would qualify for statin treatment if hs-CRP screening data were used to make risk interventions. ¹⁶

Furthermore, pharmacotherapy carries risk of adverse events. Although statins are fairly well tolerated, minor side effects such as muscle pain are reported by 15% to 20% of initial users. ¹⁶ Recent information also proposes a possible increased risk of new onset diabetes. ¹⁷ In the JUPITER trial, there were 270 physician-reported new cases in diabetes when compared with 216 in the placebo group. ⁶ This finding was significant with a P value of .01.

Population-based information suggests that if JUPITER strategies were implemented in primary prevention of CVD, an additional 20% of middle-aged to elderly patients would qualify for statin treatment. ¹⁸ Several questions remain unanswered as to whether statins are appropriate for administration to this cohort based solely on JUPITER results. Until these questions are answered, an appropriate and efficacious alternative in lowering CRP levels in this population is promoting exercise and a cholesterol-lowering diet.

Lifestyle interventions such as regular physical activity and cholesterol-lowering diets are efficacious in lowering CRP levels. Studies have demonstrated a 41% reduction in CRP levels following long-term exercise training. ⁸ This finding is impressive considering potent statin pharmacotherapy reduced CRP levels just 7% to 16% more in the JUPITER trial. One nutritional study evaluated the CRP-lowering potential of a cholesterol-lowering diet compared directly with statin use. ⁷ The cholesterol-lowering diet consisted of low saturated fat and high amounts of plant sterols and viscous fibers. There was no significant difference in CRP reductions between the 2 groups. Although the statin used in this study, lovastatin, is less potent than the statin used in the JUPITER trial (rosuvastatin), the findings of noninferiority with proper nutrition is also impressive.

There are numerous questions yet to be answered regarding how to apply findings from the JUPITER trial to clinical practice. Lifestyle behaviors such as regular exercise and healthy nutrition are the cornerstone to primary prevention and reducing CVD risk. Until more concrete evidence is available to promote statin use in patients with normal cholesterol and before millions of “relatively healthy” patients are started on a new medication for a lifetime, strong consideration should be given to alternatives such as lifestyle modifications. Physical activity and nutrition have far-reaching benefits that are tried and true and in some ways more efficacious than pharmacotherapy.