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Peter Attia MD#23–Tom Dayspring Part IV of V: statins, Zetia, PCSK9 inhibitors, niacin, cholesterol & the brain
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CHAPTERS
- 0:04 – 9:16
Early cholesterol drugs and the first statin outcome trials
Peter Attia asks what the first cholesterol-targeting drug was. Tom Dayspring walks through niacin, neomycin, bile acid sequestrants and the LRC trial, then Akira Endo's discovery of statins and the early 4S and West of Scotland outcome trials. They also discuss why lipid trials are handicapped by short duration and why mortality is a poor endpoint.
- •Bile acid sequestrants and the LRC study gave early proof that lowering cholesterol reduces events
- •Statins came from Akira Endo's fungus discovery, and lovastatin was approved in 1987
- •The first statin outcome trials enrolled FH-like patients, in secondary prevention (simvastatin) and then primary prevention (pravastatin)
- •Trials of about five years can't undo decades of disease, so mortality is a meaningless endpoint for lipid drugs
- 9:16 – 15:20
Triparanol, HMG-CoA reductase and why LDL-receptor drugs work
The conversation contrasts statins with triparanol, which blocked the last step of cholesterol synthesis and was pulled off the market after harm appeared as desmosterol rose. Dayspring explains that statins act high in the pathway and are liver-selective. He argues that drugs which enhance LDL receptor expression are the ones that have safely reduced events.
- •Triparanol inhibited delta 24 desaturase, raised desmosterol and was withdrawn after atherosclerosis, cataracts and other problems
- •Statins act early in the pathway, where other routes can compensate
- •The liver is the key place to inhibit synthesis because it can upregulate the most LDL receptors
- •Statins, ezetimibe, bile acid sequestrants and PCSK9 inhibitors all work by expressing more LDL receptors
- •Brown and Goldstein's LDL receptor discovery guided this approach
- 15:20 – 21:24
How ezetimibe works in both gut and liver
Dayspring disputes the view that ezetimibe acts mainly in the gut, saying the Niemann-Pick C1-like protein is also on the liver's biliary surface. Ezetimibe therefore blocks both intestinal absorption and the liver's re-uptake of biliary cholesterol. Attia says this changes his view of a drug he has regarded as too weak.
- •Niemann-Pick C1-like protein sits in the intestine and on the hepatobiliary surface
- •Depleting liver cholesterol triggers SREBP and more LDL receptor expression
- •Attia says he has seen Zetia as too impotent and used it mainly for hyperabsorbers or statin-intolerant patients
- •Dayspring notes Merck simplified the message to gut absorption and that no monotherapy outcome trial was done
- •The VIP bouncer analogy illustrates the liver as a backup to the gut
- 21:24 – 28:28
Ezetimibe trials: IMT, SEAS, SHARP and IMPROVE-IT
Dayspring explains that Merck's IMT-based ezetimibe trials were the wrong shortcut and soured cardiologists on the drug. They discuss the ethics of studying a drug without background statins, then the SEAS, SHARP and IMPROVE-IT trials. The IMPROVE-IT result is called miraculous in highly treated patients.
- •IMT trials showed no change despite better ApoB and inflammatory markers, and IMT is a poor surrogate
- •Attia says adding a drug to statins is now the only ethical design except in statin-intolerant patients
- •SEAS in aortic stenosis was negative on its main endpoints, with ischemic benefits only post hoc
- •SHARP in renal patients showed a statin plus ezetimibe reduced events
- •IMPROVE-IT showed that a little extra ApoB lowering matters in very high-risk patients
- 28:28 – 36:57
FOURIER and the noise around statins and PCSK9
Attia and Dayspring marvel that FOURIER reduced events in patients already on statins with an average LDL-C of 92 in under 2.5 years. Attia comments on the market's reaction and on his own patients on PCSK9 inhibitors. They then turn to internet misinformation, the pharma over-simplification of the message, and the need to individualize therapy.
- •FOURIER cut events in low-LDL statin-treated patients in about 2.2 years
- •Attia says the market's reaction reflected cost per life saved, not scientific merit
- •Attia's PCSK9 patients are those he previously treated inadequately with niacin, weak monotherapy or tiny statin doses
- •Both the 'statins in the drinking water' and 'statins cause everything' views are rejected
- •Dayspring stresses individualizing care and understanding clinical chemistry and biomarkers
- 36:57 – 41:18
Lab assays, phytosterols and ezetimibe as reverse cholesterol transport
The two discuss how labs measure analytes: triglycerides are calculated from glycerol, and LDL-C assays detect any sterol, including phytosterols and desmosterol. Dayspring argues that ezetimibe is the top drug for moving cholesterol out of the body and says he would pick it over a statin for the water supply. He adds that ApoB usually needs more lowering than ezetimibe alone can give.
- •Labs measure glycerol and calculate triglycerides
- •LDL-C includes sitosterol, campesterol and desmosterol, which matters most in phytosterolemia
- •Dayspring says ezetimibe is the number one agent increasing stool cholesterol excretion
- •He calls his drinking-water remark controversial and says the FDA and evidence-based critics would object
- •Most patients still need more ApoB lowering than ezetimibe alone
- 41:18 – 1:05:28
Fibrates: gemfibrozil, fenofibrate and who benefits
Attia introduces fibrates, and Dayspring explains the differences between gemfibrozil and fenofibrate and the trials behind them (VA-HIT, Helsinki, FIELD). He covers how fibrates reduce VLDL synthesis, their possible microvascular benefits in diabetics and the best candidates (high ApoB and triglycerides). He also discusses side effects, drug interactions with Coumadin and statins, and fish oil EPA versus DHA.
- •Gemfibrozil had outcome benefit in VA-HIT and Helsinki, and Otvos's NMR analysis tied the benefit to LDL and HDL particle changes
- •Fenofibrate trials missed primary endpoints, which Dayspring attributes to enrolling the wrong people and heavy statin contamination
- •Fenofibrate showed secondary microvascular benefits in diabetics (retinopathy, amputations, renal outcomes) that were not primary endpoints
- •Fenofibrate is well tolerated, interacts with Coumadin, and should be chosen over gemfibrozil when combined with a statin
- •Dayspring says DHA acts on triglycerides via ApoC3 while EPA lowers ApoB more, and he monitors omega-3 levels
- 1:05:28 – 1:23:44
Niacin: forms, trials and why it failed
Attia raises niacin for patients who cannot use mainstream options, and Dayspring describes its formulations and cost. He reviews the Coronary Drug Project, HATS, AIM-HIGH and THRIVE, arguing there is no real outcome evidence and that niacin worsens insulin resistance and glucose. Attia questions whether worsened insulin resistance could explain the lack of benefit despite lower ApoB.
- •Niacin exists as immediate, extended and sustained release forms, with more hepatotoxicity in the sustained release form
- •The Coronary Drug Project had mortality as its primary endpoint and niacin went in the wrong direction
- •HATS was a small uncontrolled angiographic study whose 90% event reduction claim was disingenuous
- •AIM-HIGH and THRIVE lowered ApoB further and raised HDL-C yet produced no outcome benefit and notable toxicity
- •Dayspring says niacin is cited as favored while fibrates, which have randomized trial data, are bashed
- 1:23:44 – 1:29:29
PCSK9 genetics and mechanism of action
Attia introduces Repatha and Praluent and the genetics behind them. Gain-of-function PCSK9 variants cause very high LDL and events, while loss-of-function variants give LDL of 10 to 30 with far fewer events and no apparent hormonal deficits. Dayspring explains how PCSK9 controls LDL receptor recycling and that inhibiting it clears all ApoB particles including remnants.
- •Gain-of-function PCSK9 variants account for a small share of familial hypercholesterolemia, which is a phenotype rather than a single genotype
- •Loss-of-function carriers had LDL of 10 to 30 and dramatically fewer events
- •Very low LDL has not impaired reproductive or adrenal hormones, because glands make their own cholesterol and obtain it from HDL
- •PCSK9 determines how quickly LDL receptors are recycled or degraded
- •PCSK9 inhibition clears remnants as well as LDL
- 1:29:29 – 1:34:58
Statin choice and the case for hepatoselectivity
Attia and Dayspring discuss how LDL can be lowered by blocking synthesis or boosting clearance, and Attia questions the 'lower is always better' idea if synthesis is suppressed too much. They review which statins are used under current guidelines and their drug interactions. Dayspring explains that hydrophilic statins like rosuvastatin and pravastatin are liver-selective and that he titrates to ApoB.
- •Statins reduce synthesis and raise clearance, while PCSK9 inhibitors act directly on clearance
- •Attia questions whether heavy synthesis inhibition affects other organs such as the brain
- •Guideline-level choices are high-intensity atorvastatin or rosuvastatin, and simvastatin has many drug interactions
- •Dayspring says pravastatin has the most outcome data and rosuvastatin 5 mg is enough for many people
- •Dayspring says to use whatever dose gets ApoB down rather than rigidly following guideline doses
- 1:34:58 – 1:50:13
Statins, desmosterol and brain cholesterol
Dayspring says all statins reach the brain, but lipophilic ones such as atorvastatin and simvastatin cross more easily. The brain makes all its own cholesterol, mostly via the desmosterol pathway, and serum desmosterol correlates with CSF desmosterol. Low desmosterol is linked with cognitive impairment, and both speakers argue for individualizing therapy while rejecting anti-statin extremism.
- •Lipophilic statins cross the blood-brain barrier more easily than hydrophilic ones like pravastatin, rosuvastatin and pitavastatin
- •Serum desmosterol correlated closely with CSF desmosterol in one trial and can serve as a biomarker of brain synthesis
- •Dayspring says statin use is by far the biggest reason for suppressed desmosterol, and low levels were tied to Alzheimer's and mild cognitive impairment, though this is hypothesis-level
- •Attia suggests a vascular benefit on average but harm in a subset of hyposynthesizers who are over-suppressed
- •Dayspring prefers a low-dose statin plus ezetimibe, which gives the same ApoB reduction with less synthesis suppression
- 1:50:13 – 1:55:26
CK and liver enzymes are poor statin monitors
Discussing his statin choices, Attia mentions asymptomatic CK bumps, and Dayspring says CK elevation is a poor biomarker of statin toxicity; stop a statin for muscle symptoms instead. They then debate transaminases: Dayspring cites package inserts and large analyses, while Attia describes patients whose transaminases doubled after adding Zetia. Both agree on individualized decisions.
- •Attia says he has moved toward Crestor and pravastatin and dislikes CK bumps even without symptoms
- •Dayspring says to get a baseline CK, that CK elevations are not useful, and that muscle symptoms should dictate stopping
- •Dayspring says package inserts don't call for following liver enzymes to judge statin toxicity
- •Attia reports several cases where transaminases doubled after adding Zetia and normalized after stopping it
- •Both agree it is an individual decision and shouldn't be generalized
- 1:55:26 – 2:00:15
Synthesis reflexes, ezetimibe and personalizing therapy
Attia clarifies that the message isn't that statins cause dementia but that a subset may be at risk when synthesis is overly suppressed. Dayspring explains the reflex relationship between synthesis and absorption: ezetimibe monotherapy raises synthesis and statins raise absorption. Dayspring argues that even normal absorbers may gain from ezetimibe's ApoB lowering.
- •Attia says the aim is to identify the subset of patients overly suppressed on statins, not to claim statins cause dementia
- •Cellular synthesis is unrelated to blood cholesterol and is not directly affected by PCSK9 inhibitors
- •Ezetimibe monotherapy causes a reflex rise in synthesis, and statin monotherapy causes hyperabsorption
- •Attia sometimes uses ezetimibe to boost synthesis in patients with an LDL clearance deficiency
- •Dayspring says even normal absorbers get extra ApoB lowering and the genetic longevity model of reduced NPC1L1 function
