Protocols by Charles Sieg

Heart and metabolism

Cardiovascular disease, explained

How cardiovascular disease starts, what actually causes it, what lowers the risk, and where the evidence stands as of November 2026.

Overall evidence Strong44 sourcesReviewed November 5, 2026

The causal chain for LDL and ApoB, blood pressure, smoking, and diabetes rests on genetic studies and many large randomized trials; the inflammation and omega-3 evidence is narrower, and two 2026 drug trials, one aimed at Lp(a) and one at inflammation, missed their main goals, according to company press releases.

The short version

  • Cardiovascular disease is the leading cause of death in the United States: the CDC counted 919,032 cardiovascular deaths in 2023, about 1 in 3 deaths1, and the American Heart Association ranks heart disease alone first, at 22% of deaths2.
  • It is mostly atherosclerosis: fatty plaque building in the artery wall over decades, with heart attacks and many strokes arriving when a clot forms on a plaque3.
  • The best-proven causes are LDL and other ApoB particles4,5, high blood pressure6,7, smoking8, and diabetes9. Lp(a) is a causal risk factor too10, but in September 2026 Novartis announced that a large trial of pelacarsen, a drug that lowers it, missed its main goal11.
  • The risk reducers with the strongest evidence are lowering LDL (statins are the proof, and PCSK9 antibodies, ezetimibe, and bempedoic acid each have outcome trials too)12,13,14,15, lowering blood pressure7, not smoking8, and being fit16.
  • Two things I would not lean on: alcohol, because a large genetic study found no protection against heart attack17, and a high CRP number treated as a target, because the ZEUS trial lowered CRP without cutting cardiovascular events, according to the company's 2026 press release18.

How it starts and progresses

Atherosclerosis is fibrofatty lesions forming in the artery wall. LDL is probably required for them to form, and hypertension, smoking, and diabetes are established accelerants3.

The part that matters most is the particle count. Every atherogenic particle (LDL, VLDL, chylomicron remnants, and Lp(a)) carries exactly one ApoB molecule, so an ApoB blood test is a particle count5. Cholesterol gets into the artery wall only inside those particles, and the number that get in depends mainly on how many are in the blood5. Smaller particles are trapped more easily because they bind to the wall, while larger ones leave more cholesterol each time5.

Time matters as much as level. Across more than 200 studies covering over 2 million people, the link between LDL exposure and cardiovascular events was dose-dependent and log-linear, and it grew stronger with longer exposure4. That is why a moderately high number that sits there for decades is not harmless.

The ending is mostly thrombotic: clots forming on plaque cause most heart attacks and many strokes3.

Why it's the leading cause of death

  • CDC: 919,032 cardiovascular deaths in 2023, about 1 in 3 deaths, one every 34 seconds. Coronary heart disease alone killed 371,506 people in 20221.
  • The American Heart Association's 2026 statistics update ranks heart disease first among US causes of death, at 22% of deaths, and counts about 125.9 million US adults (47.3%) with high blood pressure2. That update has since had a correction published, so check the corrected report before quoting its exact counts19.

What causes it, and the best evidence

ApoB and LDL

Strong The European Atherosclerosis Society consensus concluded that LDL causes atherosclerotic cardiovascular disease, based on genetic studies, cohorts, Mendelian randomization, and randomized trials covering more than 2 million participants and over 150,000 cardiovascular events4. ApoB tracks the particle count that drives this, and the authors of the ApoB review argue it is a better risk marker than LDL-C or non-HDL-C5. They are advocates for the test, so I read that as a strong argument and not a settled guideline. The 2026 US guideline is more measured. In the ACC's summary, ApoB may be used to assess leftover risk once LDL-C and non-HDL-C goals are met, in people with cardiovascular-kidney-metabolic syndrome, type 2 diabetes, high triglycerides, or known cardiovascular disease, and in those groups it may be a more accurate risk marker than LDL-C20.

Lp(a)

Strong that it adds risk, Mixed on lowering it with a drug. The 2022 European consensus found Lp(a) to be a causal, continuous risk factor for cardiovascular disease and aortic valve stenosis, even when LDL is very low, and recommended measuring it at least once in adults10. The 2026 US guideline agrees: measure it at least once in adulthood, and because lifestyle barely moves it, repeat tests are generally not needed20.

What changed is the drug side. On September 4, 2026, Novartis announced topline results from Lp(a)HORIZON, an outcomes trial of pelacarsen in 8,323 people with elevated Lp(a) and established cardiovascular disease. The drug lowered Lp(a) but did not meet the primary endpoint, a composite of cardiovascular death, heart attack, stroke, and urgent coronary revascularization11. That is a company press release, not yet peer-reviewed, with no effect sizes; Novartis says the full data will be presented at an upcoming medical congress11. Amgen's outcomes trial of olpasiran has 7,297 people enrolled, and its registry record (last updated October 27, 2026) estimates primary completion on March 31, 202821. So in the sources I could check as of November 2026, no drug aimed at Lp(a) has shown fewer cardiovascular events, and Novartis's own release says elevated Lp(a) has no approved targeted treatment11. High Lp(a) still means managing the other risk factors harder10.

Blood pressure

Strong In SPRINT, 9,361 adults at increased risk were randomized to a systolic target under 120 or under 140 mm Hg. The tighter target cut the primary outcome from 2.19% to 1.65% a year (HR 0.75, 95% CI 0.64 to 0.89) and all-cause death (HR 0.73) over a median 3.26 years6. It also caused more low blood pressure, fainting, electrolyte problems, and acute kidney injury6. The Ettehad meta-analysis of 123 trials and 613,815 people found that every 10 mm Hg drop in systolic pressure cut major cardiovascular events by 20% (RR 0.80), stroke by 27%, and all-cause mortality by 13%7.

The 2025 AHA/ACC guideline replaced the 2017 version22. According to the ACC's announcement, the categories did not change (normal under 120/80, stage 1 at 130 to 139 or 80 to 89, stage 2 at 140 or higher or 90 or higher), the treatment goal for adults with high blood pressure is under 130/80 mm Hg, PREVENT estimates 10- and 30-year risk in ages 30 to 79, and a urine albumin-to-creatinine ratio is now recommended for everyone with high blood pressure23. Home monitoring is on Body, fitness, and imaging tests.

Smoking

Strong In a US cohort of more than 200,000 adults, current smokers had about three times the all-cause death rate of never smokers and lost more than 10 years of life. Quitting between 25 and 34 regained about 10 years, and quitting before 40 erased about 90% of the excess risk8. That study measures all deaths, not heart deaths alone. Smoking is an established driver of atherosclerosis in its own right3.

Insulin resistance and diabetes

Strong for diabetes, Moderate for insulin alone. Across 102 prospective studies and 698,782 people, diabetes roughly doubled coronary heart disease risk (HR 2.00) and raised ischemic stroke risk (HR 2.27)9. Fasting glucose showed no significant added risk between 3.90 and 5.59 mmol/L, then climbed above that9. In people without diabetes, a meta-analysis of 65 studies linked the highest HOMA-IR to a 64% higher risk of coronary heart disease (RR 1.64), but fasting insulin on its own was not significant (RR 1.12, 95% CI 0.92 to 1.37)24. These are observational numbers.

Controlling blood sugar and avoiding diabetes is its own topic, with its own page: see Blood sugar.

Inflammation

Mixed CANTOS gave an antibody that blocks inflammation, canakinumab, to 10,061 heart attack survivors with hsCRP of at least 2 mg/L. It did not lower LDL, yet the 150 mg dose cut the primary endpoint (HR 0.85, 95% CI 0.74 to 0.98) over a median 3.7 years, with more fatal infections and no drop in all-cause death25. COLCOT gave 0.5 mg of colchicine a day to 4,745 people within 30 days of a heart attack and cut the primary endpoint from 7.1% to 5.5% (HR 0.77, 95% CI 0.61 to 0.96) over a median 22.6 months. The gain came from fewer strokes and urgent angina hospitalizations, not from fewer deaths or heart attacks, and serious pneumonia was more common (0.9% versus 0.4%)26.

Then a miss. On July 31, 2026, Novo Nordisk announced that ZEUS, which enrolled over 6,300 people with cardiovascular disease, chronic kidney disease, and hsCRP of 2 mg/L or higher, found no reduction in major cardiovascular events with the IL-6 antibody ziltivekimab (HR 0.99, 95% CI 0.88 to 1.11), even though it lowered IL-6 and hsCRP; serious infections were more frequent18. That is also a company press release, not yet peer-reviewed. So inflammation matters in some settings, but I would not treat a CRP number as a target on its own.

Alcohol

Moderate The idea that a drink a day protects the heart did not hold up in a large genetic study from China. The China Kadoorie Biobank followed 512,715 adults for about 10 years. Men who reported about 100 g of alcohol a week had lower risks than nondrinkers or heavier drinkers, the familiar U-shaped curve, but genetically predicted intake told a different story: per 280 g a week, it was linked to more intracerebral hemorrhage (RR 1.58, 95% CI 1.36 to 1.84) and ischemic stroke (RR 1.27, 95% CI 1.13 to 1.43), and to no protection against heart attack (RR 0.96, 95% CI 0.78 to 1.18)17. The genetic analysis was in men, because only 2% of the women drank in most weeks, and like the rest of the study it is observational, not a trial17. The 2025 blood pressure guideline says the ideal is no alcohol, and for those who drink, no more than 2 drinks a day for men and 1 for women23.

What lowers the risk

Statins

Strong The Cholesterol Treatment Trialists' meta-analysis pooled 26 randomized trials. Each 1.0 mmol/L (about 39 mg/dL) of LDL lowered cut major vascular events by 22% (RR 0.78, 95% CI 0.76 to 0.80) and all-cause mortality by 10%12. More intensive statin therapy beat less intensive therapy, lowering major vascular events by another 15%12. Cancer incidence did not change (RR 1.00)12. The abstract does not report muscle or liver side effects, so this is the benefit side of the ledger only.

Beyond statins

Strong for lowering LDL by other routes, too. The trials below are the ones with outcomes, and the doses are what the trials used, not advice.

  • Ezetimibe. IMPROVE-IT added ezetimibe 10 mg to simvastatin 40 mg in 18,144 people after an acute coronary syndrome. Over a median 6 years, average LDL-C was 53.7 versus 69.5 mg/dL and the 7-year event rate was 32.7% versus 34.7% (HR 0.936, 95% CI 0.89 to 0.99), a modest 2.0-point difference. Merck funded it14.
  • PCSK9 antibodies. FOURIER gave evolocumab to 27,564 patients with cardiovascular disease already on statins. LDL-C fell 59% more than with placebo, to a median 30 mg/dL, and the primary endpoint was 9.8% versus 11.3% (HR 0.85, 95% CI 0.79 to 0.92) over a median 2.2 years13. ODYSSEY OUTCOMES gave alirocumab to 18,924 people after an acute coronary syndrome: 9.5% versus 11.1% (HR 0.85, 95% CI 0.78 to 0.93), with all-cause death 3.5% versus 4.1% over a median 2.8 years27. Amgen funded FOURIER and Sanofi and Regeneron funded ODYSSEY, and both trials were in people who already had disease13,27.
  • Bempedoic acid. CLEAR Outcomes randomized 13,970 statin-intolerant patients and found 11.7% versus 13.3% on the primary endpoint (HR 0.87, 95% CI 0.79 to 0.96) over a median 40.6 months, with more gout (3.1% versus 2.1%) and gallstones (2.2% versus 1.2%); Esperion Therapeutics funded it15. The 2026 guideline elevates it to a first-line nonstatin option on that evidence, according to an ACC expert analysis28.
  • An oral PCSK9 inhibitor. On July 17, 2026, the FDA approved Lipfendra (enlicitide), a once-daily tablet and the first oral PCSK9 inhibitor, as an adjunct to diet and exercise to lower LDL-C in adults with high cholesterol, including heterozygous familial hypercholesterolemia. In its two trials, 3,207 adults already on the most statin they could tolerate, LDL-C fell an average of 56% and 59% versus placebo at week 24. The approval rests on that LDL-C change; the FDA's announcement mentions no outcomes data, so whether it prevents heart attacks is unproven as of November 202629.
  • Inclisiran. The ACC's March 2026 summary of the guideline says it is still being studied to see whether its LDL-C lowering means fewer cardiac events20, and I found no reported outcome results as of November 2026. The ORION-4 registry record, last updated May 1, 2026, lists 16,124 people enrolled, a status of active but not recruiting, and an estimated primary completion of October 202630.

Blood pressure treatment

Strong See the numbers above: each 10 mm Hg lower systolic pressure meant fewer events across 123 trials7.

A weight-loss drug with outcomes

Moderate SELECT randomized 17,604 adults aged 45 or older with cardiovascular disease, a BMI of 27 or higher, and no diabetes to the trial dose of semaglutide, 2.4 mg weekly, or placebo. Over a mean 39.8 months, cardiovascular death, heart attack, or stroke occurred in 6.5% versus 8.0% (HR 0.80, 95% CI 0.72 to 0.90), and 16.6% versus 8.2% stopped treatment because of adverse events. Novo Nordisk funded it31. It tested one drug in people who already had heart disease, so it does not tell me what any other drug does for the heart, including retatrutide, which I take and which has its own page.

Fitness

Moderate In 122,007 adults who did treadmill tests, elite fitness versus low fitness carried an all-cause mortality hazard ratio of 0.20. For comparison, smoking was 1.41 and diabetes 1.4016. This is observational and from one clinic, so fitter people may simply be healthier to start with. It still stacks up with the rest of the risk-factor picture.

Omega-3s

Mixed REDUCE-IT gave 8,179 statin-treated patients with high triglycerides 4 g a day of a purified EPA drug (icosapent ethyl) or placebo. The primary endpoint was 17.2% versus 22.0% (HR 0.75, 95% CI 0.68 to 0.83) over a median 4.9 years, with more hospitalizations for atrial fibrillation (3.1% versus 2.1%) and a nonsignificant rise in serious bleeding (2.7% versus 2.1%)32. STRENGTH tested 4 g a day of an EPA and DHA product against corn oil in 13,078 high-risk patients and found nothing (12.0% versus 12.2%, HR 0.99), and it was stopped early33. The products differ, and so do the comparators, so the trials do not cleanly contradict each other. They also do not tell me what a fish oil capsule does.

The Omega-3 Index is red blood cell EPA plus DHA. Harris and von Schacky proposed it as a risk marker: 8% or higher was linked to the most protection and 4% or lower to the least34. That is observational and does not prove that raising the number lowers risk. The American Heart Association advisory recommends one to two seafood meals a week35.

Rhonda Patrick on the omega-3 index

Rhonda Patrick interviewed Bill Harris, co-inventor of the Omega-3 Index, on her FoundMyFitness podcast. The episode covers using red blood cell omega-3 as a measure of long-term status, plant versus marine sources, genetic variants that change how much a person needs, and whether the index predicts life expectancy36. This is a conversation, not a trial, and it does not mean she endorses anything on this site.

Where the 2026 guideline sets the bar

Moderate (a guideline is consensus, not a trial). The 2026 multisociety dyslipidemia guideline retires and replaces the 2018 cholesterol guideline37. In the ACC's summary, LDL-C and non-HDL-C goals are back: LDL-C under 100 mg/dL for borderline or intermediate risk, under 70 for high risk, and under 55 for very-high-risk people with established disease20. For very-high-risk disease the non-HDL-C goal is under 85 mg/dL28. These numbers come from the ACC's pages, not the full guideline, and the guideline's PubMed record links two later items in Circulation (June 23 and September 8, 2026) that I could not read, so the current text is the one to check before quoting a number37.

Estimating your own risk

PREVENT and Life's Essential 8

Moderate The AHA's PREVENT equations were built and tested in 6,612,004 adults aged 30 to 79 from 25 derivation and 21 validation data sets, with 211,515 cardiovascular events38. Both new guidelines use PREVENT for 10- and 30-year risk20,23. Life's Essential 8 is the AHA's cardiovascular health score: eight metrics, each scored from 0 to 10039. These are tools for estimating average risk, not a diagnosis.

Coronary calcium and CT angiography

Moderate A coronary artery calcium (CAC) score counts calcified plaque on a CT scan. In 6,722 people, scores of 101 to 300 carried 7.73 times the coronary event risk of a score of 0, and scores above 300 carried 9.67 times40. The 2026 guideline recommends selective CAC scans for men over 40 and women over 45 at borderline or intermediate risk, and says any calcium supports an LDL-C goal under 100 mg/dL, with lower targets at higher scores20. CT angiography is a different test for a different group. In SCOT-HEART, 4,146 people with stable chest pain were randomized to CT angiography plus standard care or standard care alone, and over a median 4.8 years, death from coronary heart disease or nonfatal heart attack at 5 years was 2.3% versus 3.9% (HR 0.59, 95% CI 0.41 to 0.84)41. It says nothing about screening people with no symptoms. Both scans get more detail on Body, fitness, and imaging tests.

Sauna, in one line

In a Finnish cohort of 2,315 men followed a median 20.7 years, four to seven sauna sessions a week was linked to a sudden cardiac death HR of 0.37 versus one session (95% CI 0.18 to 0.75)42. That is observational. Sauna has the full story.

How I use it

I follow a keto diet, and keto can push LDL up in some people43,44. I also take retatrutide. I have no numbers or results from my own bloodwork to put here yet.

Cautions

  • This is not medical advice. Several of the drugs and tests above are decisions for a doctor who knows your history.
  • Everything here is population evidence. It describes what happens on average, not what will happen to one person.
  • Aggressive blood pressure targets caused more fainting and kidney injury in SPRINT6.
  • Omega-3 drugs raised atrial fibrillation hospitalizations in REDUCE-IT32.
  • Two 2026 results (Lp(a)HORIZON and ZEUS) are topline company press releases that have not been peer-reviewed; the full data may change how they read11,18.
  • A keto diet can raise LDL; Keto has the data43,44.

Tests worth knowing

The blood tests I think are worth understanding, with what each measures and the cutoffs a source backs, are on Lab tests worth knowing. Blood pressure, coronary calcium, DEXA, VO2 max, and spirometry are on Body, fitness, and imaging tests.

References

  1. Centers for Disease Control and Prevention. Heart Disease Facts. Centers for Disease Control and Prevention, October 24, 2024.ArticleRead

    What it found: CDC page reporting 919,032 cardiovascular disease deaths in 2023 (about 1 in 3 US deaths, one every 34 seconds) and 371,506 coronary heart disease deaths in 2022; heart disease is the leading cause of death for men, women, and most racial and ethnic groups.

    Limits: A public-health summary page; its date was displayed as October 24, 2024 but was not labeled as a last-reviewed date, and CDC and AHA counts differ slightly because they define the category differently.

  2. American Heart Association. Heart disease, stroke deaths down, yet still kill more in US than any other cause. EurekAlert! (American Heart Association news release), January 21, 2026.ArticleRead

    What it found: News release on the 2026 AHA statistics update (2023 data): heart disease is the leading US cause of death at 22% of deaths; cardiovascular deaths were 915,973 (down from 941,652 in 2022) and coronary heart disease deaths 349,470; about 125.9 million US adults (47.3%) have high blood pressure.

    Limits: A press release summarizing the full report, not the report itself, and the report was later corrected.

  3. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nature Reviews Disease Primers. 2019;5(1):56.ReviewPubMed 31420554 · DOI

    What it found: Primer on atherosclerosis: fibrofatty lesions form in the artery wall and probably require LDL; hypertension, smoking, and diabetes are established risk factors, inflammation and clonal hematopoiesis are emerging ones, and thrombotic complications cause most heart attacks and many strokes.

    Limits: A review article that summarizes the field and gives no new data.

  4. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. European Heart Journal. 2017;38(32):2459-2472.Position standPubMed 28444290 · DOI

    What it found: Consensus review of genetic studies, more than 200 prospective cohorts, Mendelian randomization studies, and randomized trials covering more than 2 million participants, over 20 million person-years, and over 150,000 cardiovascular events. It found a consistent, dose-dependent, log-linear link between LDL exposure and cardiovascular risk that grows with the duration of exposure, and concluded that LDL causes atherosclerotic cardiovascular disease.

    Limits: A consensus review of other studies, not a new trial; it rests on the quality of the underlying genetic, cohort, and trial data.

  5. Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, et al. Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review. JAMA Cardiology. 2019;4(12):1287-1295.ReviewPubMed 31642874 · DOI

    What it found: Narrative review arguing that every atherogenic particle (VLDL, LDL, chylomicron remnant, Lp(a)) carries one apoB molecule, so plasma apoB counts the particles; cholesterol enters the artery wall only inside apoB particles, and the number entering depends mainly on how many are in the blood. The authors conclude that apoB is a better marker of atherogenic risk than LDL-C or non-HDL-C.

    Limits: A narrative review by authors who advocate apoB testing, not a systematic review or a trial.

  6. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. The New England Journal of Medicine. 2015;373(22):2103-2116.Randomized trialPubMed 26551272 · DOI

    What it found: SPRINT randomized 9,361 adults without diabetes, with systolic pressure of 130 mm Hg or higher and increased cardiovascular risk, to a systolic target under 120 or under 140 mm Hg. Over a median 3.26 years (stopped early), the primary composite outcome was 1.65% versus 2.19% per year (HR 0.75, 95% CI 0.64 to 0.89) and all-cause death HR was 0.73 (0.60 to 0.90).

    Limits: Excluded people with diabetes and prior stroke, was stopped early, and the intensive arm had more hypotension, syncope, electrolyte abnormalities, and acute kidney injury.

  7. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet (London, England). 2016;387(10022):957-967.Meta-analysisPubMed 26724178 · DOI

    What it found: Meta-analysis of 123 trials with 613,815 participants. Each 10 mm Hg lower systolic pressure cut major cardiovascular events (RR 0.80, 95% CI 0.77 to 0.83), coronary heart disease (0.83), stroke (0.73), heart failure (0.72), and all-cause mortality (0.87, 0.84 to 0.91).

    Limits: Pools trials of drug treatment, so it shows what lowering pressure with medication does, not what diet or exercise alone would do.

  8. Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, et al. 21st-century hazards of smoking and benefits of cessation in the United States. The New England Journal of Medicine. 2013;368(4):341-350.Cohort studyPubMed 23343063 · DOI

    What it found: Survey-linked cohort of 113,752 women and 88,496 men aged 25 or older. Current smokers had about three times the all-cause death rate of never smokers (HR about 3.0 for women, 2.8 for men) and lost more than 10 years of life; quitting at 25 to 34 regained about 10 years and quitting before age 40 removed about 90% of the excess risk.

    Limits: Self-reported smoking in a national survey, and the outcome is all-cause mortality, not heart disease specifically.

  9. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet (London, England). 2010;375(9733):2215-2222.Meta-analysisPubMed 20609967 · DOI

    What it found: Collaborative analysis of 102 prospective studies (698,782 people, 52,765 vascular outcomes). Diabetes roughly doubled coronary heart disease risk (HR 2.00, 95% CI 1.83 to 2.19) and raised ischemic stroke risk (2.27); fasting glucose showed no significant link to risk between 3.90 and 5.59 mmol/L but risk rose above that.

    Limits: Observational; it tracks diabetes and glucose as risk markers and cannot separate their effect from related factors like weight and blood pressure.

  10. Kronenberg F, Mora S, Stroes ESG, Ference BA, Arsenault BJ, Berglund L, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. European Heart Journal. 2022;43(39):3925-3946.Position standPubMed 36036785 · DOI

    What it found: European Atherosclerosis Society consensus statement concluding that Lp(a) is a causal, continuous risk factor for cardiovascular disease and aortic valve stenosis across ethnic groups, including at very low LDL cholesterol. It recommends at least one Lp(a) measurement in every adult and early, intensive management of other risk factors when Lp(a) is high.

    Limits: A consensus statement, not a trial; the abstract notes that Lp(a)-specific drugs still need outcome trials to confirm clinical benefit.

  11. Novartis. Novartis announces Lp(a)HORIZON Phase III topline results for pelacarsen in patients with elevated Lp(a) and established cardiovascular disease (CVD). Novartis media release, September 4, 2026.ArticleRead

    What it found: Company press release, not peer-reviewed. The trial of 8,323 patients with elevated Lp(a) and established cardiovascular disease did not meet its primary endpoint (cardiovascular death, nonfatal heart attack, nonfatal stroke, or urgent coronary revascularization requiring hospitalization); pelacarsen lowered Lp(a) but this did not translate into fewer cardiovascular events in the overall population (Lp(a) of 70 mg/dL or higher).

    Limits: A topline statement with no effect sizes, safety data, or dose; full results are promised at an unnamed medical congress.

  12. Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet (London, England). 2010;376(9753):1670-1681.Meta-analysisPubMed 21067804 · DOI

    What it found: Individual-patient meta-analysis of 26 statin trials (39,612 people in 5 trials of more versus less intensive therapy, 129,526 in 21 trials of statin versus control). Each 1.0 mmol/L LDL reduction cut major vascular events by 22% (RR 0.78, 95% CI 0.76 to 0.80) and all-cause mortality by 10% (RR 0.90), with no effect on cancer incidence (RR 1.00).

    Limits: The abstract reports mortality and cancer outcomes but not muscle or liver side effects, and the trials were mostly in people already at elevated risk.

  13. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England Journal of Medicine. 2017;376(18):1713-1722.Randomized trialPubMed 28304224 · DOI

    What it found: FOURIER randomized 27,564 patients with atherosclerotic cardiovascular disease and LDL-C of 70 mg/dL or higher on statins to the PCSK9 antibody evolocumab or placebo for a median 2.2 years. LDL-C fell 59% more with evolocumab (to a median 30 mg/dL), and the primary endpoint was 9.8% versus 11.3% (HR 0.85, 95% CI 0.79 to 0.92).

    Limits: A median 2.2 years is short for a lifelong exposure, the patients already had cardiovascular disease, and Amgen funded the trial.

  14. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England Journal of Medicine. 2015;372(25):2387-2397.Randomized trialPubMed 26039521 · DOI

    What it found: IMPROVE-IT randomized 18,144 patients hospitalized for an acute coronary syndrome to simvastatin 40 mg plus ezetimibe 10 mg or simvastatin plus placebo for a median 6 years. Time-weighted LDL-C was 53.7 versus 69.5 mg/dL, and the 7-year primary endpoint rate was 32.7% versus 34.7% (HR 0.936, 95% CI 0.89 to 0.99).

    Limits: The benefit was modest (2.0 percentage points over 7 years), it came from people after an acute coronary syndrome on simvastatin 40 mg, and Merck funded the trial.

  15. Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. The New England Journal of Medicine. 2023;388(15):1353-1364.Randomized trialPubMed 36876740 · DOI

    What it found: CLEAR Outcomes randomized 13,970 statin-intolerant patients to bempedoic acid or placebo for a median 40.6 months. LDL-C fell 29.2 mg/dL more than on placebo, and the four-part primary endpoint was 11.7% versus 13.3% (HR 0.87, 95% CI 0.79 to 0.96); gout was 3.1% versus 2.1% and cholelithiasis 2.2% versus 1.2%.

    Limits: Statin-intolerant people with or at high risk for cardiovascular disease only, so the result does not show what bempedoic acid adds on top of a full statin dose, and Esperion Therapeutics funded it.

  16. Mandsager K, Harb S, Cremer P, Phelan D, Nissen SE, Jaber W. Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing. JAMA Network Open. 2018;1(6):e183605.Cohort studyPubMed 30646252 · DOI

    What it found: Retrospective cohort of 122,007 adults (mean age 53.4) referred for treadmill testing at one Cleveland clinic from 1991 to 2014, followed a median of 8.4 years with 13,637 deaths. Elite fitness versus low fitness carried an adjusted mortality hazard ratio of 0.20 (95% CI 0.16 to 0.24), and elite versus high fitness 0.77 (0.63 to 0.95); low fitness was comparable to or worse than coronary artery disease (HR 1.29), smoking (1.41), or diabetes (1.40).

    Limits: Retrospective, single-center, and observational, in people referred for treadmill testing, so it shows association rather than proof that raising fitness lowers death risk.

  17. Millwood IY, Walters RG, Mei XW, Guo Y, Yang L, Bian Z, et al. Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China. Lancet (London, England). 2019;393(10183):1831-1842.Cohort studyPubMed 30955975 · DOI

    What it found: A prospective study of 512,715 Chinese adults followed for about 10 years, with genotype-based (Mendelian randomization) analysis in men. Per 280 g/week of alcohol, genetically predicted intake was linked to intracerebral hemorrhage (RR 1.58, 95% CI 1.36 to 1.84) and ischemic stroke (RR 1.27, 95% CI 1.13 to 1.43) but not to heart attack (RR 0.96, 95% CI 0.78 to 1.18).

    Limits: Chinese men were the genetic analysis group (only 2% of women drank most weeks), and the genotype method measures lifelong intake differences, not the effect of a person cutting back.

  18. Novo Nordisk. Novo Nordisk provides update on the ZEUS phase 3 trial in people with ASCVD, CKD and inflammation. BioSpace (Novo Nordisk company announcement), July 31, 2026.ArticleRead

    What it found: Company press release, not peer-reviewed. ZEUS enrolled over 6,300 people with atherosclerotic cardiovascular disease, chronic kidney disease, and hsCRP of 2 mg/L or higher; once-monthly ziltivekimab 15 mg lowered IL-6 and hsCRP but did not reduce major adverse cardiovascular events (HR 0.99, 95% CI 0.88 to 1.11), and serious infections were more frequent.

    Limits: A topline statement; the full data are still to be presented, and it tested one IL-6 antibody in people with kidney disease.

  19. Palaniappan LP, Allen NB, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, et al. 2026 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation. 2026;153(9):e275-e906.ReviewPubMed 41562125 · DOI

    What it found: The American Heart Association's annual statistical report on heart disease, stroke, and cardiovascular risk factors, with new chapters on cardiovascular-kidney-metabolic syndrome and tobacco and nicotine. The PubMed abstract gives no figures; the headline numbers used on this site come from the AHA news release.

    Limits: The abstract carries no statistics, and a correction to the report was later published in Circulation 154(5), so figures should be checked against the corrected text.

  20. American College of Cardiology. ACC, AHA Release New Clinical Guideline For Managing Dyslipidemia. American College of Cardiology (Journal Scan), March 13, 2026.ArticleRead

    What it found: ACC summary of the 2026 dyslipidemia guideline: LDL-C goals of under 100 mg/dL for borderline or intermediate risk, under 70 for high risk, and under 55 for very-high-risk ASCVD; ApoB may help assess residual risk once LDL-C and non-HDL-C goals are met; Lp(a) should be measured at least once in adulthood, with repeat testing generally not needed; selective coronary calcium scans for men over 40 and women over 45 at borderline or intermediate risk; PREVENT-ASCVD replaces the Pooled Cohort Equations for 10- and 30-year risk in ages 30 to 79; inclisiran is still being studied for outcomes.

    Limits: A summary page, not the guideline; it gives no numeric thresholds for non-HDL-C, ApoB, Lp(a), or calcium scores.

  21. ClinicalTrials.gov, U.S. National Library of Medicine. A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Olpasiran on Major Cardiovascular Events in Participants With Atherosclerotic Cardiovascular Disease and Elevated Lipoprotein(a). ClinicalTrials.gov, October 27, 2026.Regulatory noticeRead

    What it found: Registry record (last update posted October 27, 2026): Amgen's olpasiran outcomes trial, 7,297 enrolled, status active but not recruiting, primary completion estimated March 31, 2028.

    Limits: A registry entry, not a result; the estimated date can move.

  22. Writing Committee Members, Jones DW, Ferdinand KC, Taler SJ, Johnson HM, Shimbo D, et al. 2025 AHA/ACC/AANP/AAPA/ABC/ACCP/ACPM/AGS/AMA/ASPC/NMA/PCNA/SGIM Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2025;152(11):e114-e218.GuidelinePubMed 40811497 · DOI

    What it found: The guideline that replaces the 2017 ACC/AHA high blood pressure guideline, built on a literature search from December 2023 to June 2024 and designed as a living document; published online in August 2025.

    Limits: I read the PubMed record and the ACC press release, not the full guideline, so the thresholds I quote come from the press release.

  23. American College of Cardiology. New High Blood Pressure Guideline Emphasizes Prevention, Early Treatment to Reduce CVD Risk. American College of Cardiology (press release), August 14, 2025.ArticleRead

    What it found: ACC release on the 2025 guideline: categories unchanged from 2017 (normal under 120/80, elevated 120 to 129, stage 1 130 to 139 or 80 to 89, stage 2 140 or higher or 90 or higher), a goal of under 130/80 mm Hg, PREVENT for 10- and 30-year risk in ages 30 to 79, urine albumin-to-creatinine ratio for everyone with high blood pressure, sodium under 2,300 mg a day, alcohol ideally none (if any, no more than 2 drinks a day for men and 1 for women), and 75 to 150 minutes a week of exercise.

    Limits: A press release summarizing the guideline, so I did not see the class of recommendation or level of evidence for each point.

  24. Gast KB, Tjeerdema N, Stijnen T, Smit JWA, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS One. 2012;7(12):e52036.Meta-analysisPubMed 23300589 · DOI

    What it found: Meta-analysis of 65 studies (516,325 participants without diabetes). Highest versus lowest HOMA-IR carried a coronary heart disease RR of 1.64 (95% CI 1.35 to 2.00); fasting insulin alone gave RR 1.12 (0.92 to 1.37), which was not significant.

    Limits: Pooled observational studies, so the numbers are associations, and the fasting-insulin result had a confidence interval that crossed 1.

  25. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. The New England Journal of Medicine. 2017;377(12):1119-1131.Randomized trialPubMed 28845751 · DOI

    What it found: CANTOS randomized 10,061 patients with a prior heart attack and hsCRP of at least 2 mg/L to canakinumab (50, 150, or 300 mg every 3 months) or placebo for a median 3.7 years. Canakinumab did not lower LDL; the 150 mg dose cut the primary endpoint (HR 0.85, 95% CI 0.74 to 0.98) and the 300 mg dose gave HR 0.86 (0.75 to 0.99), while the 50 mg dose was not significant (0.93).

    Limits: Tested a drug in people who had already had a heart attack, with more fatal infections on canakinumab and no drop in all-cause mortality; it does not show that lowering CRP by other means helps.

  26. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. The New England Journal of Medicine. 2019;381(26):2497-2505.Randomized trialPubMed 31733140 · DOI

    What it found: COLCOT randomized 4,745 patients within 30 days after a heart attack to colchicine 0.5 mg once daily or placebo for a median 22.6 months. The primary endpoint was 5.5% versus 7.1% (HR 0.77, 95% CI 0.61 to 0.96); serious pneumonia was 0.9% versus 0.4%.

    Limits: Only people who had just had a heart attack were enrolled, and the benefit was driven by stroke and urgent angina hospitalization, not by cardiovascular death or heart attack itself.

  27. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. The New England Journal of Medicine. 2018;379(22):2097-2107.Randomized trialPubMed 30403574 · DOI

    What it found: ODYSSEY OUTCOMES randomized 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier to the PCSK9 antibody alirocumab or placebo every 2 weeks for a median 2.8 years. The primary endpoint occurred in 9.5% versus 11.1% (HR 0.85, 95% CI 0.78 to 0.93) and all-cause death in 3.5% versus 4.1% (HR 0.85, 95% CI 0.73 to 0.98); injection-site reactions were 3.8% versus 2.1%.

    Limits: Only people with a recent acute coronary syndrome and persistently high LDL-C, apolipoprotein B, or non-HDL-C on statins were enrolled, so it does not speak to primary prevention.

  28. Abuhalimeh BJ, Alhmouz M, Behrooz L. Implications of the 2026 ACC/AHA/Multisociety Dyslipidemia Guideline for Lipid Management in Vascular Disease. American College of Cardiology (Expert Analysis), June 16, 2026.ArticleRead

    What it found: ACC expert analysis of the 2026 guideline: LDL-C under 55 mg/dL and non-HDL-C under 85 mg/dL for very-high-risk ASCVD, LDL-C under 70 mg/dL for ASCVD not classed as very high risk, PCSK9 inhibitors lowering LDL-C by about 60% versus 15 to 20% for ezetimibe, and bempedoic acid elevated to a first-line nonstatin option on the strength of CLEAR Outcomes.

    Limits: An expert commentary on vascular disease; it gives no numeric thresholds for Lp(a) or ApoB.

  29. U.S. Food and Drug Administration. FDA Approves First Oral PCSK9 Inhibitor to Lower LDL Cholesterol in Adults with High Cholesterol. U.S. Food and Drug Administration (press announcement), July 17, 2026.Regulatory noticeRead

    What it found: FDA announcement that Lipfendra (enlicitide), a once-daily oral tablet and the first oral PCSK9 inhibitor, approved for Merck Sharp & Dohme LLC, is an adjunct to diet and exercise to lower LDL-C in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia; in two trials of 3,207 adults on maximally tolerated statins, LDL-C fell an average of 56% and 59% versus placebo at week 24, the trials' primary endpoint.

    Limits: The page mentions no cardiovascular outcomes data; it says nothing about whether the drug prevents heart attacks or strokes.

  30. ClinicalTrials.gov, U.S. National Library of Medicine. A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease. ClinicalTrials.gov, May 1, 2026.Regulatory noticeRead

    What it found: Registry record (last update posted May 1, 2026): a double-blind, placebo-controlled outcomes trial of inclisiran in people with atherosclerotic cardiovascular disease, 16,124 enrolled, status active but not recruiting, primary completion estimated October 2026, sponsored by the University of Oxford with TIMI and Novartis.

    Limits: A registry entry, not a result; the record did not state whether results are posted, and I found no reported outcome data as of November 2026.

  31. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England Journal of Medicine. 2023;389(24):2221-2232.Randomized trialPubMed 37952131 · DOI

    What it found: SELECT randomized 17,604 adults aged 45 or older with cardiovascular disease, a BMI of 27 or higher, and no diabetes to once-weekly semaglutide 2.4 mg or placebo for a mean follow-up of 39.8 months. The primary composite (cardiovascular death, nonfatal heart attack, or nonfatal stroke) was 6.5% versus 8.0% (HR 0.80, 95% CI 0.72 to 0.90), and 16.6% versus 8.2% stopped the drug or placebo because of adverse events.

    Limits: Only people who already had cardiovascular disease were enrolled, the trial was of semaglutide, so it cannot be applied to other weight-loss drugs, and Novo Nordisk funded it.

  32. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England Journal of Medicine. 2019;380(1):11-22.Randomized trialPubMed 30415628 · DOI

    What it found: REDUCE-IT randomized 8,179 statin-treated patients with elevated triglycerides (135 to 499 mg/dL) to 2 g of icosapent ethyl twice daily or placebo for a median 4.9 years. The primary composite endpoint was 17.2% versus 22.0% (HR 0.75, 95% CI 0.68 to 0.83); hospitalization for atrial fibrillation was 3.1% versus 2.1% and serious bleeding 2.7% versus 2.1%.

    Limits: Tested a purified prescription EPA drug at 4 g a day in people with high triglycerides on statins, so it does not tell us what over-the-counter fish oil or diet would do.

  33. Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020;324(22):2268-2280.Randomized trialPubMed 33190147 · DOI

    What it found: STRENGTH randomized 13,078 high-risk patients on statins to 4 g a day of omega-3 carboxylic acids (EPA and DHA) or corn oil. The primary composite outcome occurred in 12.0% versus 12.2% (HR 0.99, 95% CI 0.90 to 1.09); the trial was stopped early for low probability of benefit, and GI side effects were more common on omega-3 (24.7% versus 14.7%).

    Limits: Used a different omega-3 product than REDUCE-IT and a corn oil comparator, so the two trials cannot be cleanly compared.

  34. Harris WS, Von Schacky C. The Omega-3 Index: a new risk factor for death from coronary heart disease?. Preventive Medicine. 2004;39(1):212-220.ReviewPubMed 15208005 · DOI

    What it found: Review that proposes red blood cell EPA plus DHA (the Omega-3 Index) as a graded, modifiable risk factor for death from coronary heart disease: an index of 8% or higher was associated with the greatest cardioprotection and 4% or lower with the least.

    Limits: A 2004 proposal built on observational data and older trials; it does not show that raising the index causes lower risk.

  35. Rimm EB, Appel LJ, Chiuve SE, Djoussé L, Engler MB, Kris-Etherton PM, et al. Seafood Long-Chain n-3 Polyunsaturated Fatty Acids and Cardiovascular Disease: A Science Advisory From the American Heart Association. Circulation. 2018;138(1):e35-e47.Position standPubMed 29773586 · DOI

    What it found: AHA science advisory recommending one to two seafood meals a week to reduce the risk of heart failure, coronary heart disease, ischemic stroke, and sudden cardiac death, with the largest benefit when seafood replaces less healthy foods.

    Limits: An expert advisory that relies largely on observational studies, and its abstract does not name specific fish or give supplement advice.

  36. Patrick R. #068 Dr. Bill Harris on the Omega-3 Index: Increasing Omega-3 to Promote Longevity & Transform Health. FoundMyFitness, September 10, 2021.PodcastListen

    What it found: Podcast interview with Bill Harris, co-inventor of the Omega-3 Index: red blood cell omega-3 as a measure of long-term status, plant versus marine sources, genetic variants that change omega-3 needs, whether the index predicts life expectancy, and omega-3 metabolites that resolve inflammation.

    Limits: A podcast conversation, not a study; the episode description gives no numeric index ranges.

  37. Writing Committee Members, Blumenthal RS, Morris PB, Gaudino M, Johnson HM, Anderson TS, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2026;153(17):e1154-e1276.GuidelinePubMed 41824552 · DOI

    What it found: The multisociety guideline that retires and replaces the 2018 AHA/ACC blood cholesterol guideline, covering evaluation, management, and monitoring of high cholesterol, hypertriglyceridemia, and elevated lipoprotein(a); published online in March 2026.

    Limits: I read the PubMed record and the ACC summaries, not the full guideline, so the numbers I quote come from the ACC pages; the PubMed record also links two later items in Circulation (June 23 and September 8, 2026) that I could not read.

  38. Khan SS, Matsushita K, Sang Y, Ballew SH, Grams ME, Surapaneni A, et al. Development and Validation of the American Heart Association's PREVENT Equations. Circulation. 2024;149(6):430-449.Cohort studyPubMed 37947085 · DOI

    What it found: The PREVENT risk equations were derived in 3,281,919 participants from 25 data sets and validated in 3,330,085 from 21 data sets (6,612,004 adults aged 30 to 79 in all, with 211,515 incident cardiovascular events). C-statistics were 0.794 in women and 0.757 in men.

    Limits: A risk-prediction model: it estimates average risk for groups of people and says nothing about how a given person's plaque is behaving.

  39. Lloyd-Jones DM, Allen NB, Anderson CAM, Black T, Brewer LC, Foraker RE, et al. Life's Essential 8: Updating and Enhancing the American Heart Association's Construct of Cardiovascular Health: A Presidential Advisory From the American Heart Association. Circulation. 2022;146(5):e18-e43.Position standPubMed 35766027 · DOI

    What it found: A presidential advisory that updates the cardiovascular health score the American Heart Association defined in 2010 from 7 metrics to 8, with each metric scored from 0 to 100.

    Limits: A scoring framework, not a trial; the abstract does not say how much risk any score change removes.

  40. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. The New England Journal of Medicine. 2008;358(13):1336-1345.Cohort studyPubMed 18367736 · DOI

    What it found: MESA cohort of 6,722 people without clinical cardiovascular disease followed a median 3.8 years (162 coronary events). Compared with a calcium score of 0, scores of 101 to 300 raised adjusted coronary event risk 7.73-fold and scores above 300 raised it 9.67-fold, and adding the score to standard risk factors improved prediction.

    Limits: Short follow-up with few events, and the abstract does not show that screening with calcium scores leads to better outcomes.

  41. SCOT-HEART Investigators, Newby DE, Adamson PD, Berry C, Boon NA, Dweck MR, et al. Coronary CT Angiography and 5-Year Risk of Myocardial Infarction. The New England Journal of Medicine. 2018;379(10):924-933.Randomized trialPubMed 30145934 · DOI

    What it found: SCOT-HEART randomized 4,146 patients with stable chest pain to standard care plus coronary CT angiography or standard care alone, with a median follow-up of 4.8 years. Death from coronary heart disease or nonfatal heart attack at 5 years was 2.3% versus 3.9% (HR 0.59, 95% CI 0.41 to 0.84), with no difference in invasive angiography (HR 1.00) or revascularization (HR 1.07).

    Limits: Patients had stable chest pain, so the result does not apply to screening people with no symptoms.

  42. Laukkanen T, Khan H, Zaccardi F, Laukkanen JA. Association between sauna bathing and fatal cardiovascular and all-cause mortality events. JAMA Internal Medicine. 2015;175(4):542-548.Cohort studyPubMed 25705824 · DOI

    What it found: Prospective cohort of 2,315 men aged 42 to 60 in eastern Finland, followed a median of 20.7 years, with 929 deaths. Compared with one sauna session a week, 4 to 7 sessions a week had an adjusted sudden cardiac death hazard ratio of 0.37 (95% CI 0.18 to 0.75), and sessions longer than 19 minutes versus under 11 minutes gave 0.48 (0.31 to 0.75); crude all-cause deaths were 49.1%, 37.8%, and 30.8% at 1, 2 to 3, and 4 to 7 sessions a week.

    Limits: Observational, men only, with sauna habits recorded at baseline, so it cannot show that sauna caused the lower risk (fitter or healthier men may sauna more often).

  43. Retterstøl K, Svendsen M, Narverud I, Holven KB. Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: A randomized controlled study. Atherosclerosis. 2018;279:52-61.Randomized trialPubMed 30408717 · DOI

    What it found: Randomized trial in which 30 healthy, normal-weight young adults (15 per group) ate under 20 g of carbohydrate a day or their usual diet for 3 weeks. LDL-C rose from 2.2 to 3.1 mmol/L on the diet while controls stayed at 2.5 (+44% versus controls, individual changes 5% to 107%), and ApoB rose significantly.

    Limits: Thirty completers (9 people dropped out) over 3 weeks, so it shows the direction of change, not what happens over years.

  44. Budoff M, Manubolu VS, Kinninger A, Norwitz NG, Feldman D, Wood TR, et al. Carbohydrate Restriction-Induced Elevations in LDL-Cholesterol and Atherosclerosis: The KETO Trial. JACC: Advances. 2024;3(8):101109.Cohort studyPubMed 39372369 · DOI

    What it found: Eighty people on a ketogenic diet for a mean 4.7 years with LDL-C of 190 mg/dL or higher (mean 272), HDL-C of 60 or higher, and triglycerides of 80 or lower were matched 1:1 to controls with mean LDL-C of 123 mg/dL. Coronary calcium was median 0 versus 1 (P=0.520), total plaque score was not different (P=0.357), and LDL-C did not track with plaque in either group.

    Limits: Eighty matched pairs selected for a high-HDL, low-triglyceride profile, one time point, controls drawn from a different cohort, and plaque is not the same as heart attacks, so it cannot show long-term safety or apply to people with other lipid profiles.