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

A statin that reduced clinical events in Swedish MI survivors by 25%. Its 80mg dose was later taken off the market due to drug interactions.

An anticoagulant drug that has a serious interaction with fenofibrate, requiring a reduction in Coumadin dose if co-administered.

A class of drugs that enhance the clearance of apoB-containing particles by preventing the degradation of LDL receptors, leading to significantly lower LDL cholesterol and reduced cardiovascular events, even in patients already on statins.

The first statin approved in 1987, marketed as Mevacor, which significantly lowers LDL cholesterol.

A fibrate which is a prodrug converted into an active acid. It has shown efficacy in mono therapy outcome trials for veterans with coronary artery disease, low HDL, and high triglycerides.

Drugs that inhibit HMG-CoA reductase, leading to reduced cholesterol synthesis in the liver and upregulation of LDL receptors, effectively lowering LDL cholesterol and significantly reducing cardiovascular events. Different statins have varying lipophilicity and drug interaction profiles.

A high-potency, hydrophilic statin, considered hepatoselective, which helps upregulate LDL receptors with lower doses. It is favored due to its cleaner pharmacokinetics and potentially less CNS penetration compared to lipophilic statins.

A statin mentioned as an option for patients who are very sensitive to other statins, and a non-lipophilic statin.

A selective estrogen receptor modulator (SERM) that came to market and was observed to lower ApoB, potentially offering cardiovascular benefits, although a large outcome trial did not show event reduction in the overall population.

Also known as Zetia, this drug inhibits the Niemann-Pick C1-like protein, reducing cholesterol absorption in the gut and preventing the liver from reabsorbing cholesterol from bile, leading to depletion of liver cholesterol and increased LDL receptor expression.

A class of drugs including fenofibrate and gemfibrozil, which reduce triglyceride-rich LDL particles, modulate HDL particles, and have shown benefits in reducing microvascular endpoints in diabetics, though trials can be confounded by statin use.

A high-potency statin that is lipophilic and crosses the blood-brain barrier more easily, potentially leading to increased cognitive impairment in certain patients if over-prescribed.

A fibrate available generically, which is the active form and has similar outcome data to statins in specific populations, and is particularly effective for patients with elevated ApoB and triglycerides, especially for microvascular endpoints in diabetics.

A weaker statin (compared to simvastatin) sold as Pravachol, which also showed significant reduction in clinical events in primary prevention trials and is a hydrophilic, hepatoselective statin often chosen due to fewer drug interactions and potential CNS concerns.

Another PCSK9 inhibitor.

A large randomized, prospective, blinded trial designed to test the effect of adding niacin to statin therapy to raise HDL-C in patients with optimized LDL-C. It failed to show additional cardiovascular event reduction despite lowering ApoB.

A study that identified individuals, particularly African Americans, with hypo-functioning PCSK9 and very low LDL cholesterol levels (10-30 mg/dL) who were largely event-free, validating the genetic model for PCSK9 inhibition.

A trial that provided outcome data for gemfibrozil.

A small angiographic trial (around 100 subjects) that studied niacin and indicated improved lumen of arteries in people with CAD, but its claims of 90% event reduction were considered disingenuous due to lack of placebo and small sample size.

A trial confirming that additional ApoB lowering with ezetimibe-statin combination provides extra event reduction, even in aggressively treated patients.

The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial, which studied gemfibrozil in veterans with coronary artery disease, low HDL, and high triglycerides, showing event reduction that could be explained by changes in LDL and HDL particle counts.

A large multi-pronged therapeutic trial from the 1960s that tested various drugs including niacin, thyroid hormone, clofibrate, and estrogen. Niacin failed to reduce mortality in this trial.

A landmark trial demonstrating that PCSK9 inhibitors (Repatha) significantly reduce cardiovascular events in patients with already low LDL-C on statins, even over a short period.

A PCSK9 inhibitor developed by Amgen that demonstrated significant event reduction in the FOURIER trial, even in high-risk patients with already low LDL-C on statins.

A researcher known for his impressive work on the vascular hypothesis of Alzheimer's disease.

A researcher credited with the discovery of the PCSK9 family of proteins.

An enzyme in the cholesterol synthetic pathway that statins inhibit to reduce cholesterol production.

A key protein discovered by Brown and Goldstein, responsible for clearing LDL particles from the blood. Drugs that increase its expression or half-life are effective in lowering atherogenic lipoproteins.

A protein involved in the transfer of triglycerides to ApoB to form VLDL particles in the liver.

A direct precursor to cholesterol in the Bloch pathway, which predominates in the brain. Serum desmosterol levels can serve as a biomarker for brain cholesterol synthesis, and its suppression by statins is a concern for cognitive health in susceptible individuals.

A protein in the gut and on the hepatobiliary surface that enhances the absorption of sterols, including cholesterol. Ezetimibe inhibits this protein.

A multifactorial disease that can be influenced by metabolic and vascular components. The hypothesis is that while statins might reduce vascular components in some, over-suppression of cholesterol synthesis in the brain could increase susceptibility in others.

An esoteric drug that inhibited delta-24 desaturase in the cholesterol synthetic pathway, lowered cholesterol, but was pulled off the market due to side effects like atherosclerosis and cataracts, highlighting the complexity of drug development.

Discussed as a therapy that lowers triglycerides, with EPA having more effect on ApoB and DHA being more potent on C3. Monitoring omega-3 levels is recommended as not everyone can convert EPA to DHA effectively.

A supplement (Vitamin B3) historically used to lower total cholesterol and raise HDL, but its efficacy in reducing clinical events has been problematic in trials, often showing side effects like flushing and worsening insulin resistance, leading to its current limited role in therapy.

A biotechnology company that developed Repatha, a PCSK9 inhibitor, which showed remarkable event reduction in the FOURIER trial.

A pharmaceutical company involved in developing PCSK9 inhibitors.

Pharmaceutical company that developed several products discussed, including ezetimibe, and conducted trials on cholesterol absorption.