#23–Tom Dayspring Part IV of V: statins, Zetia, PCSK9 inhibitors, niacin, cholesterol & the brain

KEYPOINTS

• 01

  Early cholesterol drugs proved that lowering cholesterol reduces events, and then the field fixated on cholesterol numbers.

  Before statins there was immediate-release niacin, which most people couldn't tolerate, and an antibiotic that disrupted cholesterol recirculation through bile. Then came bile acid sequestrants, whose long outcome trial showed modest benefit. Dayspring calls the result a tragedy: for 20–30 years drug companies chased cholesterol numbers, including sequestrants' trivial one- or two-point rises in HDL cholesterol.

• 02

  Statins began with a fungus and were proven in patients with familial hypercholesterolemia.

  Dayspring credits Japanese mycologist Akira Endo, who he says deserves a Nobel Prize. Lovastatin was approved in 1987. The first outcome trials enrolled people with LDL cholesterol around 180–190, likely familial hypercholesterolemia: Swedish heart-attack survivors on simvastatin, then Scottish men without prior events on pravastatin in the West of Scotland trial. Both cut events by about 25%, with Dayspring recalling a number needed to treat of roughly 40–50 for West of Scotland.

• 03

  Five-year trials underestimate a disease that develops over 50 years.

  Attia credits Allan Sniderman for teaching him that lipid trials give a drug about five years to change the course of a disease that began at birth. Because statins work, it is now unethical to withhold them from high-risk patients. New drugs therefore get tested on top of statins, which, as both point out, raises the bar for showing benefit.

• 04

  Ezetimibe works in both the gut and the liver.

  Dayspring explains that NPC1L1, the transporter ezetimibe blocks, sits on intestinal cells and on the liver's bile-facing surface, where the liver can reclaim cholesterol from bile. Blocking both drains liver cholesterol and switches on LDL receptor production through SREBP. Attia admits this weakens his habit of reserving ezetimibe for people who over-absorb cholesterol, though Dayspring says plant-sterol over-absorption still matters.

• 05

  Ezetimibe was hurt by trials that measured the wrong thing.

  Dayspring says early imaging studies measured artery wall thickness (carotid IMT), which in his view was the wrong surrogate, and ignored the extra reductions in apoB, triglycerides and CRP. That led cardiologists to write the drug off. He also points to aortic stenosis trials that could test ezetimibe without a statin.

• 06

  PCSK9 inhibitors cut events even in patients who were already low.

  Attia calls the FOURIER trial one of the most remarkable results in cardiovascular medicine. Patients on statins with an average LDL cholesterol of 92 mg/dL, around the 10th percentile of the Framingham population, still had fewer events with Repatha within about 2.2 years. Amgen's stock was hammered because the cost per life saved looked like $1 million or more. Attia stresses that this is a separate question from the science.

• 07

  Gemfibrozil has outcome data on its own, and its benefit tracked particle numbers.

  The VA-HIT trial in veterans with heart disease, low HDL cholesterol and roughly normal LDL showed event reductions as large as any statin trial, despite only about a 1.5-point rise in HDL cholesterol. Dayspring says James Otvos's post hoc NMR analysis explained the benefit by lower LDL particle counts and higher HDL particle counts. Fenofibrate trials missed their primary endpoints, which he blames partly on many participants also taking statins.

• 08

  Dayspring regards niacin as having failed every rigorous test.

  In the 1960s Coronary Drug Project, niacin did not improve its primary endpoint, mortality, and trended the wrong way. Other arms of that trial gave men estrogen, which triggered heart attacks, and thyroid hormone, which killed people. A follow-up a decade or more later claiming a mortality benefit is, he says, a post hoc analysis that 'would be laughed at' today. Later trials also failed, and insurers stopped paying.

• 09

  Statins and brain cholesterol: a subset of patients may be at risk.

  The brain makes all its own cholesterol, mainly through the desmosterol pathway. Dayspring says blood desmosterol tracks spinal-fluid levels closely, and statins are the leading cause of suppressed desmosterol. Both stress that population data do not show statins causing dementia. Attia's concern is patients with unmeasurably low desmosterol, such as someone with LDL cholesterol of 40 and LDL particle number of 500.