As a practicing internist and lipidologist, I have long been trained to believe in the cholesterol hypothesis. Statins were not just recommended; they were the gospel. Lower LDL, save lives. That mantra was repeated at every lecture, every conference, every guideline committee.

But like many dogmas in medicine, the cracks are there if you dare to look. And some of the most damning cracks are found in a set of randomized trials that rarely get mentioned in the statin narrative.

These are the ignored trials. Left out of the widely-cited meta-analysis by Silverman et al, they tell a story that should shake every clinician who still reflexively reaches for a statin prescription.

The shocking numbers

• In the EXCEL trial, all three pravastatin dose groups (20, 40, and 80 mg/day) showed more CHD deaths than placebo.
• Example: 0.50 percent vs 0.20 percent CHD mortality, a 150 percent relative risk increase for patients on pravastatin.
• In DEBATE, mortality was higher on the statin: 18.1 percent vs 17.4 percent total deaths, and CHD deaths were also worse (7.5 percent vs 6.0 percent).
• In GISSI-HF, rosuvastatin did not reduce death in patients with heart failure. In fact, total mortality was 28.75 percent vs 28.13 percent, a 2.2 percent relative risk increase with Crestor.
• SEAS and CORONA fared no better: slight excess mortality on the drug side, with no life-saving signal.

And then comes the kicker: IMPROVE-IT, the largest ignored trial, with approximately 18,000 post-ACS patients. Adding ezetimibe to simvastatin reduced LDL a bit further but had no impact on total mortality (13.40 percent vs 13.56 percent).

Placebo as the “better choice”

Put bluntly: In these studies, placebo did as well, or better, than statins when it came to keeping patients alive. Not one showed a clear reduction in all-cause mortality. Some showed the opposite: more deaths on the drug.

This is not the story the public, or most of our colleagues, hear. Instead, statins are sold as life-savers, when the uncomfortable truth is that in several large, well-run trials, they failed the most basic test: prolonging life.

Why were we not told?

Why were these trials sidelined? Why do guidelines and meta-analyses trumpet a selective version of the evidence, while ignoring the studies that do not fit the narrative?

The answer, of course, is money. Billions of dollars, blockbuster drugs, careers, reputations, all at stake. It is far easier to bury inconvenient numbers than to confront them.

A call to my colleagues

I am not saying never prescribe a statin. But I am saying we owe our patients the truth:

• The evidence that statins save lives is far shakier than advertised.
• Some trials suggest the opposite, that patients may actually fare worse on drug than on placebo.
• And yet we continue to prescribe them reflexively, as though they were vitamin pills.

At the very least, we must stop pretending the cholesterol hypothesis is settled science. If anything, these ignored trials should force us to re-examine whether lowering LDL is the right target at all.

If you want to live

It sounds heretical, but here is what the numbers show: If you want to live longer, in trial after trial, placebo was the better bet than the statin.

That should give every one of us pause.

Larry Kaskel is an internist and “lipidologist in recovery” who has been practicing medicine for more than thirty-five years. He operates a concierge practice in the Chicago area and serves on the teaching faculty at the Northwestern University Feinberg School of Medicine. In addition, he is affiliated with Northwestern Lake Forest Hospital.

Before podcasts entered mainstream culture, Dr. Kaskel hosted Lipid Luminations on ReachMD, where he produced a library of more than four hundred programs featuring leading voices in cardiology, lipidology, and preventive medicine.

He is the author of Dr. Kaskel’s Living in Wellness, Volume One: Let Food Be Thy Medicine, works that combine evidence-based medical practice with accessible strategies for improving healthspan. His current projects focus on reevaluating the cholesterol hypothesis and investigating the infectious origins of atherosclerosis. More information is available at larrykaskel.com.