We are led to believe that statins are the greatest drugs the pharmaceutical industry has ever developed. It is true that they are the most profitable drugs ever developed, but they only reduce cardiovascular mortality by about 20 percent compared to a placebo. This means that about 80 percent of the people taking statins to reduce elevated cholesterol will see no impact on their mortality from heart disease. Furthermore, nearly 50 percent of individuals who have heart attacks also have normal cholesterol levels. So much for the major marketing message sent to Americans that cholesterol causes heart disease.
Nonetheless, an advisory panel to the FDA has recommended that existing guidelines for statin use should be expanded to individuals with normal cholesterol levels if they have high levels of C-reactive protein (CRP), which is a marker for inflammation. This would mark for the first time that an expensive drug with numerous side effects is being recommended for life-time use for people without any sign of disease. This type of off-the-wall thinking comes from the recent JUPITER trial in which it was shown that subjects with normal LDL levels and no sign of heart disease but with slightly elevated CRP levels had significant reductions in cardiovascular mortality by taking a new powerful statin drug known as Crestor (1). This is potentially great news for the drug companies since another potential six million patients could be placed on statin therapy.
If inflammation is the problem that is causing cardiovascular mortality, then there are much better, less expensive solutions with much lower side-effect profiles. One of these is fish oil. In a large analysis of every clinical trial using either a statin or fish oil supplementation to prevent cardiovascular death (a very easy end point to measure), it was found that fish oil is superior to statins (2). And isn’t the reduction of death the primary reason to take a statin? Furthermore, there are more than 200 risk factors for developing heart disease besides cholesterol. But as I stated above, half the people who get heart attacks don’t have high cholesterol levels, which only emphasizes the central lack of importance of cholesterol.
Now it turns out that statins probably do work, not by lowering cholesterol levels, but by reducing inflammation (3). To understand why, you have to know something about the most primitive part of our immune system, known as the innate immune system. The central lynch pin for activation of inflammation is controlled by a genetic transcription factor known as Nuclear Factor kappa B (NF-κB). This is the master switch that turns on inflammation. Once activated, it goes into DNA and causes the expression of the inflammatory enzymes (like COX-2) and inflammatory cytokines (like IL-6 and TNF) that amplify inflammation in nearby cells. The unexpected benefit of statins is their ability to inhibit this master inflammation switch. A few other drugs like aspirin can also inhibit the activation of NF-κB. Unfortunately, you have to use very high levels of either drug to do so. That’s why Crestor was used in the JUPITER study. It is more powerful than other statins, but that also means it has more side effects. That’s why the JUPITER study demonstrated a greater number of individuals either developing diabetes, dying from gastrointestinal disorders, or having neurological problems than those on the placebo.
On the other hand, fish oil rich in EPA and polyphenols also inhibits NF-κB (4,5), and the side-effect profile is virtually nil (other than making you smarter in the case of fish oils). However, the best way to inhibit this master inflammatory switch from being activated is simply to reduce the levels of arachidonic acid in the body (6). This can only be done by following a strict anti-inflammatory diet that is very low in omega-6 fatty acids, has a low glycemic load, provides adequate protein and is rich in polyphenols (the chemicals that give fruits and vegetables their color). Not surprisingly, that is the exact description of the Zone Diet. Maybe before the FDA gives the drug companies the OK to sell more statins to people with no evidence of heart disease, the government might want to consider recommending anti-inflammatory diets and have insurance companies reimburse patients who successfully use them.
References
1. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, and the JUPITER Study Group. “Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.” N Engl J Med. 359: 2195-2207 (2008)
2. Briel M, Studer M, Glass TR, and Bucher HC. “Effects of statins on stroke prevention in patients with and without coronary heart disease: a meta-analysis of randomized controlled trials.” Am J Med. 117: 596-606 (2004)
3. Dichtl W, Dulak J, Frick M, Alber HF, Schwarzacher SP, Ares MP, Nilsson J, Pachinger O, and Weidinger F. “HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells.” Arterioscler Thromb Vasc Biol 23: 58-63 (2003)
4. Ross JA, Maingay JP, Fearon KC, Sangster K, and Powell JJ. “Eicosapentaenoic acid perturbs signaling via the NF-kappaB transcriptional pathway in pancreatic tumor cells.” Int J Oncol 23: 1733-1738 (2003)
5. Romier-Crouzet B, Van De Walle J, During A, Joly A, Rousseau C, Henry O, Larondelle Y, and Schneider YJ. “Inhibition of inflammatory mediators by polyphenolic plant extracts in human intestinal Caco-2 cells.” Food Chem Toxicol 47: 1221-1230 (2009)
6. Ramakers JD, Mensink RP, Schaart G, and Plat J. “Arachidonic acid but not eicosapentaenoic acid (EPA) and oleic acid activates NF-kappaB and elevates ICAM-1 expression in Caco-2 cells.” Lipids 42: 687-698 (2007)