Blog | Friday, May 13, 2016

Is it time to reconsider the cholesterol hypothesis?


This post is purposely controversial. I write it because I believe that mounting evidence suggests that we should encourage “out of the box” thinking about this issue. This post is hypothesis challenging. I may be right or I may be wrong. I hope we get some debate on my speculations.

The latest blow to the cholesterol hypothesis is the New York Times article, “Dashing Hopes, Study Shows a Cholesterol Drug Had No Effect on Heart Health,” which states:

“We had an agent that seemed to do all the right things,” said Dr. Stephen J. Nicholls, the study's principal investigator and the deputy director of the South Australian Health and Medical Research Institute in Adelaide. “It's the most mind-boggling question. How can a drug that lowers something that is associated with benefit not show any benefit?” he said, referring to the 37 percent drop in LDL levels with the drug.

Two other drugs in the same class as evacetrapib, known as CETP inhibitors, have also failed: One, which lowered LDL levels by only 20 percent, had toxic side effects. The other raised HDL levels but did not lower LDL levels at all. Cardiologists thought evacetrapib, a safe and potent drug, would be different.

“All of us would have put money on it,” said Dr. Peter Libby, a Harvard cardiologist. The drug, he said, “was the great hope.”

But previous studies had already foreshadowed these results. Adding ezetimibe to a statin does not improve outcomes. Only statins show significant clinical benefits. Statins help patients after myocardial infarctions regardless of their initial cholesterol levels.

Perhaps we have overstated the cholesterol hypothesis. Some believe that statins achieve clinical benefits because of their pleiotropic effects of stabilizing plaques. Statins have an anti-inflammatory impact on the endothelium (as I understand it) and perhaps that is where the real action is.

Perhaps these cardiologists need to examine their paradigm. I am clearly not an expert in this field, but we have too much data challenging the paradigm. At what point do we continue running expensive studies for a failing hypothesis. These studies recall the 80s when they kept trying to improve myocardial contractility in patients with systolic dysfunction, and drug after drug causes increased mortality.

The cardiologists have made us all obsessed with the LDL and HDL numbers. While they do predict heart disease risk, we really do not have appropriate evidence that changing the numbers changes our risk. Perhaps they should re-examine their obsession.

db is the nickname for Robert M. Centor, MD, FACP. db stands both for Dr. Bob and da boss. He is an academic general internist at the University of Alabama School of Medicine, and is the Regional Associate Dean for the Huntsville Regional Medical Campus of UASOM. He still makes inpatient rounds over 100 days each year. This post originally appeared at his blog, db's Medical Rants.