It is amazing that only after the patent expiration of the best-selling statin drug of all time (i.e. Lipitor) that the FDA finally admitted that maybe the drug class that many physicians wanted to put into the drinking water might have some problems after all (1). In particular, the FDA issued a warning that use of statins increases the risk of memory loss and diabetes. The FDA said the risk of diabetes is “small;” however, they were playing fast and loose with the data. This is because the weaker the statin, the less the side-effect profile. The stronger (and better selling) the statin, the greater the side effects are (like diabetes and memory loss). You would think that after having Americans spend more than $50 billion in statin sales that the FDA would have asked these safety questions earlier.
How could statins cause memory loss and diabetes? It has been known for nearly 20 years that statins are the only drug that increase the levels of arachidonic acid (AA) by stimulating the enzyme delta 5-desaturase (2-4). This means greater cellular inflammation that leads to insulin resistance (thus increasing diabetes) and disturbances in signaling mechanisms in nerve cells (thus decreasing memory). I guarantee that no physician knows these facts because the drug companies had no reason to lose a potential sale to disclose that information. Apparently the FDA agreed with the drug companies, since that relevant information was never mentioned in any of the side-effect profiles until now.
The drug industry developed a great marketing pitch for statins: “If your cholesterol is high, you are going to die”. Unfortunately, the data never supported that spiffy slogan. Epidemiological studies do indicate that if your cholesterol levels are high and you are less than 50 years of age, then there is an increased risk for mortality. After age 50, that risk of increased mortality with high cholesterol disappears (5).
Furthermore, keep in mind that statins were not the first drugs to lower cholesterol. There were many other drugs before the statins, but they had the unfortunate side-effect of increasing mortality. It was only with use of the first statin drugs that decreased mortality was finally shown in those having had a prior heart attack. This is called secondary prevention trial. Aspirin and fish oil are also effective in secondary prevention trials, but neither of those interventions reduces cholesterol (6). However, in primary prevention trials (done with people with no history of heart attacks), statins aren’t very good. This is estimated by looking at a number known as “number needed to treat” or NNT. This number indicates how many people have to take a drug to prevent a single heart attack. With the newest statins, the NNT is usually 2 percent. That means you have to treat 100 people to prevent two heart attacks. Unfortunately you have no idea who those two people are, which means the other 98 people will have a lifetime of side effects. One of those side effects is developing diabetes, which occurs in about 1 percent of the patients (forget the other side effects, such as memory loss, muscle fatigue, etc). Who that one person is out of 100 who will develop diabetes is also unknown. Therefore your chances of reducing a heart attack are significantly cut by the likelihood of increasing your chances of developing diabetes. Some wonder drug!
Finally, defenders of statins for the primary prevention of heart disease point to the recent JUPITER trial (7). This clinical trial used people that had normal levels of LDL cholesterol, but very high levels of C-reactive protein (CRP). These people were already inflamed. It should be noted that the drug company that markets the statin drug used in the study funded this particular study. In fact, the government had no interest in the trial. Maybe government officials knew from previous statin trials that in people with normal LDL cholesterol levels and normal levels of CRP that statins had absolutely no benefit in reducing future heart attacks (8). Nonetheless in this small subsection of the population (more than 80 percent of the screened patients were rejected), there was a reduction in first-time heart attacks. But since the patients were highly inflamed to begin with, this means that aspirin or fish oil would probably have given the same result had the same population been tested (9,10). In fact, the JELIS study in Japan confirmed this hypothesis (11). Using the same number of patients, with high cholesterol and lows levels of inflammation (as measured by the AA/EPA ratio), it was demonstrated that those patients given more EPA to lower the AA/EPA ratio had significant reduction in future cardiovascular events. I will make a leap of faith that if the population in the JELIS study was as inflamed as that in the JUPITER study, the results with omega-3 fatty acids would have been even more dramatic.
Lost in all this marketing hype is what actually causes LDL cholesterol to increase in the first place. The answer was known in the 1970s. It’s high levels of insulin (12). This is because insulin activates the same enzyme that statins inhibit. Call me crazy, but it seems to make more sense to lower insulin by the diet rather than taking statins for a lifetime if your goal is to live longer. The best way to lower insulin is the anti-inflammatory Zone Diet coupled with enough fish oil to reduce the AA/EPA ratio to the in the Japanese population range. That’s just good science, not good marketing.
References:
- Harris G. “Safety alerts cite cholesterol drugs’ side effects.” New York Times, Feb 28. (2012).
- Hrboticky N, Tang L, Zimmer B, Lux I, Weber PC. “Lovastatin increases arachidonic acid levels and stimulates thromboxane synthesis in human liver and monocytic cell lines. J Clin Invest 93: 195-203 (1994).
- Rise P, Pazzucconi F, Sirtori CR, and Galli C. “Statins enhance arachidonic acid synthesis in hypercholesterolemic patients.”
- Nutr Metab Cardiovasc Dis 11:88-94 (2001).
- Rise P, Ghezzi S, and Galli C. “Relative potencies of statins in reducing cholesterol synthesis and enhancing linoleic acid metabolism.” Eur J Pharmacol 467:73-75 (2003).
- Anderson KM, Castelli WP, and Levy D. “Cholesterol and mortality. 30 years of follow-up from the Framingham study.” JAMA 1987 257:2176-2180 (1987).
- Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, and Zanchetti A. “Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.” Lancet 373:1849-1860 (2009).
- Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. “Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.” Lancet 354:447-455 (1999).
- Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, and Lau J. “n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.” Am J Clin Nutr 84:5-17 (2006).
- Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, and Glynn RJ. “Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.” N Engl J Med 359:2195-2207 (2008).
- Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, and Gotto AM. “Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.” N Engl J Med 344:1959-1965 (2001).
- Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and Shirato K. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.” Lancet 369:1090-1098 (2007).
- Lakshmanan MR, Nepokroeff CM, Ness GC, Dugan RE, and; Porter JW. “Stimulation by insulin of rat liver hydroxy-β-methylglutaryl coenzyme A reductase and cholesterol-synthesizing activities.” Biochem Biophys Res Commun 50:704-710 (1973).
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