Jay S. Cohen M.D.       http://medicationsense.com      1337 Camino Del Mar   Suite C       Del Mar, CA 92014       Phone: 858.345.1760       Fax: 858.509.8944


The Crestor for C-Reactive Protein Study: Limited Benefits and Serious Risks

What are the implications as doctors place millions of patients on this powerful, cholesterol-lowering statin drug?

If you read a newspaper or watched television news on December 10, 2008, you would have thought that Crestor, a cholesterol-lowering statin medication, was a wonder drug.

Of course, a few years ago you would have thought the same thing after the heavy news coverage for another powerful statin, Lipitor. Yet, my analyses at MedicationSense (2005, 2006) revealed that the Lipitor studies demonstrated limited benefits and worrisome adverse effects.

The new Crestor study, which involved more than 17,000 subjects, examined the drug's effectiveness in reducing elevated blood levels of C-reactive protein (CRP), a marker for cardiovascular inflammation.1 It is currently believed that increased levels of inflammation are associated with a higher incidence of heart attacks and strokes (more on CRP below).

Crestor Study Results -- and What They Really Mean
The authors of the Crestor-CRP study reported that over the 1.9 years of the study, there was a 44% reduction in cardiac events (defined as heart attack, stroke, severe angina, or cardiac death) among the subjects taking Crestor versus those taking a placebo. A 44% reduction sounds very impressive, but it is misleading.

Here on the actual numbers from the study. Over 2 years, 1.36% of subjects in the placebo group experienced a cardiac event; 0.77% of subjects in the Crestor group experienced an event. The difference was 0.59%. That is, less than 1%, a tiny difference.

The difference was so tiny that it will require 120 individuals with elevated CRP to take Crestor every day for two years for just one person to obtain benefit.2 Meanwhile, the other 119 individuals taking and paying for Crestor for two years will obtain no protection from a cardiovascular event.

Why would the results of the Crestor-CRP study be proclaimed so loudly nationwide despite being so tiny? The Crestor-CRP study was underwritten by AstraZeneca, the manufacturer of Crestor. We have seen previously that the marketing departments of drug companies are masters at obtaining maximum media coverage for their studies even if the results are unimpressive. Wide exposure means increased sales and big profits.

One media outlet took a critical stance. ABCNEWS.com boldly offered a dissenting opinion. In "Doctor Urges Caution in Interpreting New Findings on Cholesterol Drug," Dr. Nortin Hadler wrote, "The benefit shown in this study is tiny, and if [the Crestor-CRP study] were repeated, there might be no benefit at all. I never leap to act on the basis of such small effects."3

Serious Side Effects Downplayed
In Crestor-CRP, the drug displayed many of the common adverse effects of other statin medications (Lipitor, Zocor, Pravachol, Mevacor, Lescol). Typical side effects include abdominal pain, muscle pain, serious muscle breakdown (rhabdomyolysis), renal disorders, and liver disorders. More subjects in the Crestor group experienced these side effects than subjects in the placebo group.

A far more serious adverse effect occurred with Crestor: 270 cases of newly diagnosed diabetes were reported among Crestor users, and 216 cases were reported among placebo users. The 54 more cases of diabetes in the Crestor group was a significant and worrisome finding. Diabetes is one of the most destructive, life-shortening disorders of our time. It also is a leading cause of heart attacks and strokes. Imagine, taking Crestor to prevent a heart attack and getting diabetes instead.

When the FDA decides whether to approve a new drug, it makes it decision based on whether the drug will produce significantly more benefit than risk. If Crestor were being evaluated today for approval by the FDA, I believe Crestor would not be approved because its use in the Crestor-CRP study was associated with many new cases of diabetes.

Should I Be Tested for Elevated CRP?
Half of all cardiac deaths occur in people with normal cholesterol levels, so other factors cleary are involved in the development of cardiovascular disease. New studies suggest that an elevated level of CRP may be as important an indicator of cardiac risk as cholesterol levels.4.5

"Forward-thinking cardiologists suspect that internal inflammation is the root cause of many diseases including those of the heart and blood vessels," states cardiologist Stephen Sinatra. "Studies have shown that people with elevated CRP run two times the risk of dying from a cardiovascular-related problem compared with those who have high cholesterol levels. Combine a cholesterol burden with a markedly elevated CRP and your risk of heart attack and stroke increases by a factor of nine."6

Despite this, experts still disagree on whether the entire population should be tested for elevated CRP. I believe that anyone who has cardiovascular disease or is at risk for it should be tested for elevated CRP. Furthermore, I also encourage anyone interested in prevention to have a CRP test.

A CRP level below 1 is low-risk; 1-3 moderate-risk; above 3 high-risk.

Should My Elevated CRP Be Treated?
If your CRP level is elevated, it should not be ignored. Yet this does not mean that your doctor should immediately prescribe you a statin. As Dr. James Ehrlich, a pioneer in cardiovascular disease screening, said, an elevated CRP "is a call for more information, not an invitation to take an automation-like approach to prescribing life-long statins."7

An elevated CRP indicates a higher than normal level of inflammation in the body. Many medical conditions can produce inflammation. Your doctor should examine you for signs of infection: teeth, sinuses, bladder, ovaries or prostate. A recent cold or bout of the flu can also elevate CRP. Inflammatory disorders such as rheumatoid arthritis may cause an elevated CRP.

If no other causes of infection are found, the elevated CRP likely reflects cardiovascular inflammation. Should it be treated? Experts differ on this, but in general I recommend treatment.

Is Crestor the Only Treatment for Elevated CRP?
No. There are many choices, pharmaceutical and natural. This section will discuss statin therapy.

We have known for a decade that the effects of all statins are similar. This means that all statins can reduce elevated CRP.

In the Crestor-CRP study, 20 mg of Crestor was used. This is a powerful dose, and because Crestor is only available as a brand-need drug, it is expensive. At a nationwide discount pharmacy, 100 pills of 20-mg Crestor costs $340. The cost over one year is approximately $1360. Over 20 years, the cost of Crestor 20 mg per day is approximately $27,000.8 An equally powerful dose, 80 mg, of Zocor is available as a generic (simvastatin), and it costs about 90% less.

Just because the Crestor-CRP study used a powerful dose of Crestor does not mean that only a powerful dose will reduce elevated CRP. Some experts believe that it is not necessary to use the same strong statin doses that doctors frequently prescribe to reduce cholesterol levels. Elevated levels of CRP may not require such strong treatment. According to Dr. Uve Ravnskov, "It may be wiser to search for the lowest effective dose instead of the dose with maximal effect on LDL-cholesterol."9

If you are prone to getting side effects with medications, or if you simply want to reduce your risk of side effects, ask your doctor about starting with the lowest dose of simvastatin. If this does not adequately reduce your elevated CRP level, ask your doctor to increase the dose gradually until you arrive at the amount that works. With Zocor (simvastatin), the lowest dose is 10 mg.

Natural Approaches
Integrative doctors recommend a variety of natural approaches to reduce elevated CRP. Because smoking increases CRP, the first step for any smoker is to stop smoking. Being overweight increases CRP, so weight loss is also important. Healthy eating and exercise can also reduce CRP levels.

Women taking hormone replacement therapy should be aware that the therapy can increase CRP levels.10 Check with your doctor.

There are several natural supplements that have anti-inflammatory qualities. Alternative doctors often include one, such as curcumin or ginger, in their combination treatment for elevated CRP. Some alternative doctors include aspirin because of its proven anti-inflammatory effect.

Vitamin C might also be included in the treatment of elevated CRP. A study in the Journal of the American College of Nutrition demonstrated that 515 mg/day of vitamin C reduced CRP 24%.11 In comparison, in the Crestor-CRP study, Crestor reduced CRP levels by an average up 37%. Vitamin C plus other therapies mentioned in this section might rival or exceed this result.

Vitamin E, with its natural anti-inflammatory effects, might also help reduce elevated CRP.

Omega-3 fatty acids (fish oils) have proven anti-inflammatory effects. Studies have shown that daily intake of omega-3 fatty acids reduce the risk of cardiac death and also reduce the pain of rheumatoid arthritis.12,13 Fish oils should be a standard part of the treatment of elevated CRP. Because fish oils and aspirin taken together can increase the body's tendency for bleeding, check with your doctor before taking these therapies together.

A natural supplement with properties similar to prescription statins is red yeast rice. This fermentation product contains small amounts of several statin-like compounds. It works like a mild statin and, like prescription statins, reduces vascular inflammation and elevated CRP. Red yeast rice can also reduce cholesterol levels. Like prescription statins, red yeast rice can cause adverse effects, but the risk is low and, if side effects occur, they are usually milder than with prescription statins.

Jay S. Cohen M.D. is a nationally recognized expert on medications and side effects. He is an adjunct associate professor of preventive medicine and author of What You Need to Know about Statin Drugs and Their Natural Alternatives (Square One Publishers 2005). Dr. Cohen provides consultations to people across America who are interested in statin drugs or natural alternatives for reducing elevated CRP or cholesterol, or who are interested in cardiovascular health and methods of prevention.

References

1. Ridker PM, Danielson E, Fonseca FAH, et al (for the JUPITER Study Group). Rosuvastatin to prevent vascular events in men and women with elevated C?reactive protein. The New England Journal of Medicine, Nov. 20, 2008;359(21):2195?2207.

2. Hlatky MA. Expanding the Orbit of Primary Prevention ?? Moving beyond JUPITER. New England Journal of Medicine, Nov. 20, 2008;359 (21):2280?82.

3. Hadler NM. Crestor, by Jove... or Not. Doctor urges caution in interpreting new findings on cholesterol drug. ABC News, Nov. 10, 2008:http://abcnews.go.com.

4. Ridker, PM, Rifai, N, Rose, L, et al. R. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. New England Journal of Medicine 2002;347:1557-1565.

5. Albert, MA, Glynn, RJ, Ridker, PM. Plasma concentration of C-reactive protein and the calculated. Framingham Coronary Heart Disease Risk Score. Circulation 2003;108(2):161?5.

6. Sinatra, S. Statins: grossly overprescribed for cholesterol and underprescribed for internal inflammation. The Sinatra Health Report, Sept. 2002;8:1.

7. West A. JUPITER: separating the solid clinical matter from the hot gas. Holistic Primary Care, Winter 2008;9(4):1-2.

8. Crestor costs. Costco pharmacy, Dec. 20, 2008:www.costco.com.

9. Ravnskov, U. Is atherosclerosis caused by high cholesterol? QJM (Quarterly Journal of Medicine) 2002;95:397-403.

10. Walsh, BW, Paul, S, Wild RA, et al. The Effects of Hormone Replacement Therapy and Raloxifene on C?Reactive Protein and Homocysteine in Healthy Postmenopausal Women: A Randomized, Controlled Trial. Journal of Clinical Endocrinology and Metabolism 2004;85:214?218.

11. Block, G, Jensen, C, Dietrich, M, et al. Plasma C-reactive protein concentrations in active and passive smokers: influence of antioxidant supplementation. Journal of the American College of Nutrition 2004;23:141-147.

12. Simopoulos, AP. Essential Fatty Acids in Health and Chronic Disease. American Journal of Clinical Nutrition 1999;70(suppl):560S-569S.

13. Simopoulos, AP. The Mediterranean diets: What is so special about the diet of Greece? Journal of Nutrition 2001;131:3065S-3073S.


NOTE TO READERS: The purpose of this E-Letter is solely informational and educational. The information herein should not be considered to be a substitute for the direct medical advice of your doctor, nor is it meant to encourage the diagnosis or treatment of any illness, disease, or other medical problem by laypersons. If you are under a physician's care for any condition, he or she can advise you whether the information in this E-Letter is suitable for you. Readers should not make any changes in drugs, doses, or any other aspects of their medical treatment unless specifically directed to do so by their own doctors.

If you have questions about your medications or medical care, Dr. Cohen is available for consultation at his office or by telephone.

If you find this article informative, please tell your friends, family members, colleagues, and doctors about www.MedicationSense.com and the free MedicationSense E-Newsletter.