Saturday, August 23, 2014

Drug Wars (short version)

A July 2014 article in the New England Journal of Medicine (NEJM) discussed research that found niacin, which for 60 years was the best option for lowering cholesterol and improving cardiovascular health, was ineffective and that it may be dangerous in large doses.

Soon thereafter, the media, following NEJM’s lead, was awash in warnings with headlines like “New study finds niacin harmful for health” (The Utah People’s Post), “Excessive niacin consumption is harmful, study says” (, San Francisco), and “The dangers of niacin” (NBC news).

Niacin, a B-complex vitamin, is an essential nutrient in the human diet. A niacin deficiency causes pellagra whose symptoms include dermatitis, diarrhea, dementia, and death - the “4 D’s”. Niacin has been used without prescription as a nutritional supplement for decades, and in large doses in the treatment of cardiovascular disease and schizophrenia. It is safe and, except for skin flushing when used in larger doses, has no adverse side effects.

What happened?

The research, funded by pharmaceutical company Merck, was designed to test the effects of its drug, Tredaptive, on test subjects’ cardiovascular parameters. Tredaptive contains 1000 milligrams of extended-release niacin in combination with the drug laropiprant.

Laropiprant is a drug that inhibits hormone-like substances in the body called prostaglandins, specifically the ones that mediate niacin’s flushing reaction. Since the harmless flushing reaction is uncomfortable for some, laropiprant was combined with high-dose niacin to improve test subject compliance.

However, laropiprant has not been approved by the FDA. FDA’s reasons for non-approval have not been published, but some speculate that FDA was concerned about laropiprant’s safety. The Merck project was carried out in Europe.

The prostaglandins inhibited by laropiprant have several functions including causing blood vessels to relax. In other words, laropiprant makes it harder for blood vessels to relax. It’s this function, dilation or relaxing of blood vessels that niacin causes, that laropiprant inhibits.

In the Merck study, test subjects - over 29,000 high-risk cardiovascular patients age 50 to 80 years whose cholesterol had been lowered as a preparatory measure by a statin drug or statin in combination with a drug called ezetimibe - were given Tredaptive, Merck’s extended-release, high-dose niacin with laropiprant.

Ezetimibe is a drug that prevents absorption from the intestine of cholesterol in the diet. Though ezetimibe is an FDA-approved drug it, too, is controversial. Ezetimibe is effective at lowering cholesterol, but it has no effect in reducing atherosclerotic plaque that accumulates in arteries, and it’s associated with an increase in cardiovascular disease parameters. In fact, in a different study, a “paradoxical increase” in carotid plaque was found in patients who had the greatest reduction in cholesterol using ezetimibe. Results of research supported by pharmaceutical company Abbott published in NEJM in November 2009, using Abbott’s mega-dose, extended-release niacin (without laropiprant) found “[M]ajor cardiovascular events occurred at a significantly higher incidence in the ezetimibe group…” They concluded that their study “...demonstrates the superiority of extended-release niacin over ezetimibe when combined with statin therapy.”

Statin drugs lower cholesterol by inhibiting an enzyme in an important metabolic pathway. Cholesterol is the precursor of critical stress and sex hormones and vitamin D. Though statins are considered safe they are known to have side effects, including muscle pain and weakness, diabetes, sexual dysfunction, cognitive loss, neuropathy, and others. Further, it’s recognized that statins’ side-effects can be potentiated when used in combination with other cholesterol lowering drugs - ezetimibe, for example.

Statins earn drug companies billions of dollars a year. Merck’s Vytorin, the combination simvastatin and ezetimibe, and its Zetia, which is its ezetimibe alone, earned $4.6 billion in 2008.

We must question the quality of the journalism that reported Merck’s study and the credibility of Merck’s interpretation of its own results. Test subjects were older people with serious cardiovascular disease. To lower cholesterol in preparation for the study, test subjects were administered a statin drug, which inhibits an important metabolic pathway and can cause complicating side-effects. In combination with the statin, some test subjects were given a drug that has been shown to contribute to cardiovascular events even though it lowers cholesterol. Finally, test subjects were administered another drug, the test drug Tredaptive, that is a combination of a substance - not approved by the FDA - that inhibits another important metabolic pathway and whose effect is to limit the ability of arteries to relax, and the essential nutrient niacin in an extended-release mega dose.

The conclusion reported by Merck and the media was that niacin is harmful. But as it goes with drug wars, because the stakes are so high it’s hard to know what the truth is.

William Conder, August 2014.

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