Lipids: lowering LDL cholesterol, and the contrast with raising HDL or lowering triglycerides

Statins: across 14 randomized trials and 90,056 people, each 1 mmol/L lower LDL cholesterol cut all-cause death by 12% and major vascular events by 21% over about 5 years, which meant 48 fewer people per 1,000 with a major vascular event among those who already had coronary heart disease (Baigent et al., 2005; PMID 16214597). Across 26 trials and about 170,000 people, more intensive statin regimens cut major vascular events a further 15% against less intensive ones, and all-cause death fell 10% per 1 mmol/L (Baigent et al., 2010; PMID 21067804). In 4S, simvastatin in 4,444 people with coronary heart disease cut deaths from 256 (12%) to 182 (8%), relative risk The risk in one group expressed as a share of the risk in another. It can make a small absolute difference look large. 0.70 (PMID 7968073). Non-statin drugs: ezetimibe (IMPROVE-IT, PMID 26039521), evolocumab (FOURIER, PMID 28304224) and alirocumab (ODYSSEY OUTCOMES, PMID 30403574) each reduced events when added to a statin. Across 49 trials and 312,175 people, the risk reduction per 1 mmol/L was 0.77 for statins and 0.75 for diet, bile acid sequestrants, ileal bypass and ezetimibe, with no difference between them (Silverman et al., 2016; PMID 27673306). Replicated The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away. hard outcomes, several drugs, independent sponsors: A.

Shepherd et al., WOSCOPS (1995; PMID 7566020): pravastatin cut definite coronary events 31% in men with high cholesterol and no previous heart attack. Ridker et al., JUPITER (2008; PMID 18997196): rosuvastatin 20 mg in 17,802 people with LDL below 130 mg per deciliter and raised C-reactive protein halved LDL cholesterol; the primary end point fell (hazard ratio How often an event happened in the treated group compared with the control group over the same period. A ratio of 0.80 means 20 percent fewer events. 0.56) and death from any cause fell (hazard ratio 0.80). Yusuf et al., HOPE-3 (2016; PMID 27040132): 3.7% against 4.8% over a median 5.6 years, which is 11 fewer people per 1,000 (arithmetic on the abstract's percentages). Bohula et al., VESALIUS-CV (2026; PMID 41211925): evolocumab in 12,257 people with atherosclerosis or diabetes but no previous heart attack or stroke; 5-year rate of coronary death, heart attack or ischemic stroke 6.2% against 8.0%, hazard ratio 0.75. Pooled individual data, Mihaylova et al. (2012; PMID 22607822): in people whose 5-year risk was below 10%, each 1 mmol/L lower LDL cholesterol prevented about 11 major vascular events per 1,000 over 5 years; in people without vascular disease all-cause death fell (rate ratio 0.91 per 1 mmol/L). The absolute benefit is about half that seen in people with heart disease: 25 against 48 fewer people with a major vascular event per 1,000 per 1 mmol/L (PMID 16214597). Replicated hard outcomes: A.

Raising HDL cholesterol has been tested in seven large outcome trials of three kinds of drug. Six found no fewer events, and torcetrapib increased deaths (PMID 17984165), even though torcetrapib and evacetrapib also lowered LDL cholesterol by about a quarter to a third. The one CETP inhibitor that reduced events, anacetrapib in REVEAL, Bowman et al. (2017; PMID 28847206), also lowered non-HDL cholesterol by 17 mg per deciliter; major coronary events were 10.8% against 11.8% in 30,449 people. Across trials the CETP inhibitors gave a risk ratio of 1.01 where 0.90 was expected from their LDL lowering alone (Silverman et al., 2016; PMID 27673306). Tested, harm found for torcetrapib, no benefit for the rest: D on Route 2 Human randomized trials have been run and did not show benefit on the stated outcome. One of the two routes to the lowest letter on EBL's scale.. The niacin finding matches EBL's niacin record.

Two trials added a fibrate to statin-era care and found no fewer events, even where triglycerides fell by a quarter (PROMINENT, PMID 36342113; ACCORD Lipid, PMID 20228404). Apolipoprotein B rose 4.8% with pemafibrate. An older meta-analysis of 18 fibrate trials, most not on a statin background, found a 10% reduction in major cardiovascular events (p = 0.048) and 13% in coronary events but no effect on death from any cause or on stroke (Jun et al., 2010; PMID 20462635); that older question is not what this row grades. Tested, no benefit: D on Route 2.

Bhatt et al., REDUCE-IT (2019; PMID 30415628): 8,179 statin-treated people with triglycerides of 135 to 499 mg per deciliter and cardiovascular disease or diabetes with other risk factors; icosapent ethyl 4 g a day cut the primary composite from 22.0% to 17.2% (hazard ratio 0.75) over a median 4.9 years, 48 fewer people per 1,000 (arithmetic on the abstract's percentages), and cardiovascular death from 5.2% to 4.3%. Funded by Amarin, the maker. The placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received. was mineral oil, and in that arm LDL cholesterol rose 10.9% and C-reactive protein and other markers rose over the trial while they changed little on icosapent ethyl; the authors call the effect of this on the trial's result uncertain (Ridker et al., 2022; PMID 35762321). Yokoyama et al., JELIS (2007; PMID 17398308), an open-label Everyone in the trial knows which treatment they are receiving, so expectations can shape the results, especially for symptoms people report themselves. trial of purified EPA 1,800 mg plus a statin in 18,645 Japanese people, found 19% fewer major coronary events. Nicholls et al., STRENGTH (2020; PMID 33190147), 4 g a day of an EPA plus DHA carboxylic acid against corn oil in 13,078 people, was stopped with no benefit (hazard ratio 0.99); it tested a different product. One large positive blinded trial, supported by an open-label trial at a lower dose, with a disputed placebo: B, matching the icosapent ethyl use on EBL's omega-3 record. This is not a triglyceride effect that carries to other triglyceride drugs: fibrates lowered triglycerides without fewer events (row above).