Landmark Human Trials
The trials that built the evidence base longevity medicine actually rests on. Not a ranking, and not a hall of fame, several of these are here because they failed.
Every entry carries two fields side by side: what the trial established, and what it did not. The second is the one that gets dropped in translation, and it is where most longevity marketing lives.
21 trials · last reviewed July 2026
A library of only successful trials would teach you the opposite of how evidence works.
Vitamin D did not prevent cancer. Vitamin E raised prostate-cancer risk. Aspirin did not extend healthy life and caused bleeding. Intensive lifestyle intervention improved every risk factor in diabetes and did not reduce cardiovascular events.
Each of those had strong mechanistic and observational Research that watches what people already do rather than assigning a treatment. It can show that two things travel together, not that one causes the other. support beforehand. That is the point. Every one of them would have been graded highly by a site that reasons from plausibility, and each was overturned by a trial. This is the argument for EBL's first rule, told through the trials that made it necessary.
Each line is one trial's headline result. The dashed line at 1 means no difference between the groups. A dot to the left means the event happened less often on the treatment; to the right, more often. The bar is the range the result could plausibly lie in: a bar that crosses the dashed line means no clear difference.
The words on the right say what the number means. Each number is a ratio comparing the two groups: 0.70 means the event happened about 30 percent less often in the treated group than in the comparison group, and 1.17 means about 17 percent more often. A ratio of 1 means no difference. The two numbers in brackets are the plausible range; when that range includes 1, the trial did not show a clear difference, and the words say so.
Green: fewer events. White: no clear difference. Red: more events. Each number is from the trial's own abstract, linked in its entry below. Two trials reported a percent reduction rather than a ratio; they are shown here as the matching ratio, and their entries say so.
Not plotted, because the result is a change in a measurement rather than a comparison of how often something happened: CALERIE phase 2, FINGER, COSMOS.
Tap any trial to open it. Grouped by domain, oldest first within each.
01
Lyon Diet Heart Study. Mediterranean diet after myocardial infarction
Lancet 1994 · Nutrition
Lyon Diet Heart Study. Mediterranean diet after myocardial infarction
Does an alpha-linolenic-acid-rich Mediterranean diet reduce recurrent events after a first myocardial infarction?
Just over 600 survivors of a first myocardial infarction in France.
Randomized to a Mediterranean-style diet rich in alpha-linolenic acid versus usual post-infarct dietary advice.
Cardiac death and non-fatal myocardial infarction.
A large reduction in recurrent cardiac events in the intervention arm, of a magnitude rarely seen in dietary trials.
That dietary change after myocardial infarction can meaningfully alter recurrence, in a secondary-prevention setting.
The trial was small, unblinded, stopped early, and used a composite intervention including a canola-based margarine, so the effect cannot be attributed to any single component. The effect size How large a difference the treatment made, as distinct from whether the difference could be detected at all. should be read as hypothesis-strengthening rather than precisely estimated.
Early stopping and small sample size both tend to exaggerate effect estimates. Treat the direction as reliable and the magnitude as uncertain.
Included specifically because a striking result from a small early-stopped trial is exactly the shape of evidence that gets over-quoted. The direction held up; the magnitude has never been reproduced.
Directionally supported by PREDIMED in primary prevention. The magnitude has not been 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..
02
SELECT, selenium and vitamin E for prostate cancer prevention
JAMA 2011 · Nutrition
SELECT, selenium and vitamin E for prostate cancer prevention
Do selenium, vitamin E, or both prevent prostate cancer in healthy men?
More than 35,000 men, largely from the United States, Canada and Puerto Rico.
Randomized, placebo-controlled, four-arm factorial.
Incidence of prostate cancer.
Neither agent prevented prostate cancer. Vitamin E was associated with a statistically significant Unlikely to be explained by chance alone at the threshold the study set. It says nothing about whether the difference is large enough to matter. increase in prostate-cancer risk.
Selenium: 1.09 (0.93 to 1.27). The interval is a 99 percent interval.
That a supplement with strong mechanistic and observational support can, when tested rigorously, fail and cause harm.
It does not generalize to all doses, forms, or populations, and it does not speak to dietary intake as opposed to supplementation.
The prior expectation here was positive, built on antioxidant biology and earlier observational data. That is precisely why the harm signal matters.
The clearest single answer on the site to the question of why mechanism is excluded from EBL grades. This is what happens when plausibility is tested.
Consistent with the broader collapse of antioxidant supplementation for cancer prevention across multiple large trials.
03
PREDIMED, Mediterranean diet for primary cardiovascular prevention
N Engl J Med 2018 · Nutrition
PREDIMED, Mediterranean diet for primary cardiovascular prevention
Does a Mediterranean dietary pattern supplemented with extra-virgin olive oil or nuts prevent major cardiovascular events in people at high cardiovascular risk?
Roughly 7,400 adults in Spain at elevated cardiovascular risk but without cardiovascular disease at entry.
Randomized to Mediterranean diet plus extra-virgin olive oil, Mediterranean diet plus mixed nuts, or a control advised to reduce dietary fat.
Composite of myocardial infarction, stroke, and death from cardiovascular causes.
Both Mediterranean arms reduced the composite endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score. relative to the control diet, with the effect driven substantially by a reduction in stroke.
The nuts arm: 0.72 (0.54 to 0.95).
That a whole dietary pattern, not a single nutrient, can reduce hard cardiovascular events in a high-risk population.
It did not test the diet in low-risk or non-Mediterranean populations, did not isolate which components carried the effect, and did not demonstrate an effect on total mortality.
The original 2013 publication was retracted and republished in 2018 after randomization irregularities were found at some sites: a number of participants had been enrolled by household or by clinic rather than individually. The reanalysis, restricted to properly randomized participants, preserved the principal finding. EBL cites the corrected 2018 publication.
This is the strongest dietary-pattern evidence on the site and underpins the A grade on Mediterranean diet plus extra-virgin olive oil. Note what it does not license: no supplement inherits this result because it contains olive polyphenols.
Consistent with observational cohorts and with the earlier Lyon Diet Heart secondary-prevention trial. No equivalently sized replication exists.
04
VITAL, vitamin D3 for cancer and cardiovascular prevention
N Engl J Med 2019 · Nutrition
VITAL, vitamin D3 for cancer and cardiovascular prevention
Does vitamin D3 2000 IU daily prevent invasive cancer or major cardiovascular events in generally healthy adults?
Over 25,000 US adults, men aged 50 and older and women aged 55 and older, not selected for vitamin D deficiency.
Randomized, double-blind Neither the participants nor the people assessing them know who received the real treatment until the trial ends., placebo-controlled, two-by-two factorial with marine omega-3.
Invasive cancer of any type, and a composite of major cardiovascular events.
Neither primary endpoint The one outcome a trial names in advance as its main test. Results on other outcomes carry less weight. was reduced. Vitamin D3 did not lower cancer incidence or major cardiovascular events.
Major cardiovascular events: 0.97 (0.85 to 1.12).
That routine vitamin D supplementation in a largely replete population does not prevent cancer or cardiovascular disease. This is high-quality negative evidence and it is decisive for the question asked.
It did not test treatment of established deficiency, did not address fracture or falls endpoints as primaries, and its participants were mostly vitamin D sufficient at baseline, so it cannot speak to repletion in deficient people.
A trial in replete people cannot answer whether repletion helps deficient people. Both over-reading and dismissing this trial are common errors.
The single most useful trial on the site for explaining why EBL grades by the question a trial actually asked. Vitamin D remains graded for indications where trials support it, and not for cancer prevention.
Consistent with other large vitamin D prevention trials. The advanced-cancer secondary analysis is listed separately in this library on purpose.
05
CALERIE phase 2. Sustained caloric restriction in healthy adults
Lancet Diabetes Endocrinol 2019 · Nutrition
CALERIE phase 2. Sustained caloric restriction in healthy adults
What does two years of sustained moderate caloric restriction do to cardiometabolic risk in healthy non-obese adults?
Around 200 healthy adults without obesity.
Randomized to a target of roughly 25 per cent caloric restriction versus usual diet, for two years.
Exploratory cardiometabolic risk factors, including lipids, blood pressure and insulin sensitivity markers.
Several cardiometabolic risk factors improved in the restricted arm. Achieved restriction was well below the 25 per cent target.
That sustained caloric restriction is achievable in humans for two years and improves risk markers.
It did not test lifespan, healthspan, disease incidence or mortality, and it was not designed or powered to. No human trial has shown that caloric restriction extends life.
This is the trial most often cited as evidence that caloric restriction extends human lifespan. It measured no such thing, and its own endpoints were exploratory.
The reason caloric restriction sits at C rather than higher. The trials are real and the endpoints are surrogate. That gap is the grade.
Secondary analyses of CALERIE biosamples continue to appear, including epigenetic-aging measures. Those are surrogate endpoints A lab value or measurement used in place of the outcome that matters, such as LDL cholesterol standing in for heart attacks. Moving a surrogate does not always move the outcome. and do not change the grade.
06
VITAL secondary analysis. Vitamin D3 and advanced cancer
JAMA Netw Open 2020 · Nutrition
VITAL secondary analysis. Vitamin D3 and advanced cancer
Within VITAL, did vitamin D3 reduce incidence of advanced (metastatic or fatal) cancer?
The same VITAL cohort.
Prespecified secondary analysis of the randomized trial.
Advanced cancer, a secondary endpoint An outcome a trial also measures but did not choose as its main test., with exploratory stratification by body-mass index.
A reduction in advanced cancer was reported, apparently concentrated among participants with normal body-mass index.
A secondary analysis of VITAL.
A hypothesis worth testing prospectively. Nothing more than that.
This is a secondary endpoint in a trial whose primary endpoint was null, with a subgroup interaction. It does not establish that vitamin D reduces advanced cancer, and it does not overturn the primary result.
The hierarchy matters and is the reason this entry exists: primary endpoint, then prespecified secondary, then subgroup. Confidence falls at every step. A null primary with a positive secondary is a common pattern that gets marketed as a positive trial.
Paired deliberately with the VITAL primary entry. Read together, they teach endpoint hierarchy better than any explainer could.
Not confirmed by a trial designed to test it.
07
LIFE, structured physical activity and mobility disability
JAMA 2014 · Exercise & function
LIFE, structured physical activity and mobility disability
Does a structured physical-activity program prevent major mobility disability in sedentary older adults?
Around 1,600 sedentary adults aged 70 to 89 at risk of disability.
Randomized to a structured moderate-intensity walking, strength, flexibility and balance program versus a health-education comparator.
Major mobility disability, defined as loss of the ability to walk 400 metres.
The activity program reduced incident major mobility disability compared with health education.
That a behavioral intervention can preserve a functional capacity that people actually care about, in the population at risk of losing it.
It did not test mortality, and the comparator received attention and education rather than nothing, so the contrast is against active control rather than inactivity.
None material. This is a well-conducted trial with a hard, patient-relevant endpoint.
Arguably the most important trial in this library for EBL's purpose. The endpoint is not a biomarker A measurable sign in the body, such as a blood test value, used to track a condition or the effect of a treatment.: it is whether a person can still walk. Almost nothing sold as a longevity intervention has evidence of this kind.
Supported by the broader exercise and sarcopenia Age-related loss of muscle mass and strength. literature.
08
CHALLENGE. Structured exercise after colon cancer chemotherapy
N Engl J Med 2025 · Exercise & function
CHALLENGE. Structured exercise after colon cancer chemotherapy
Does a structured exercise program started after chemotherapy lengthen survival in people treated for colon cancer?
889 people at 55 centers with resected high-risk stage II or stage III colon cancer who had completed adjuvant chemotherapy within the previous 2 to 6 months.
Phase 3 randomized trial, enrolling 2009 to 2024. A 3-year program of behavioral support and supervised exercise sessions against health-education materials alone. Not blinded, which an exercise trial cannot be.
Disease-free survival (recurrence, a new primary cancer or death) as the primary endpoint; overall survival as a secondary endpoint.
At a median follow-up of 7.9 years, 5-year disease-free survival was 80.3 percent with the program against 73.9 percent with education alone (hazard ratio 0.72, 95% CI 0.55 to 0.94). Eight-year overall survival was 90.3 percent against 83.2 percent (hazard ratio for death 0.63, 95% CI 0.43 to 0.94). Musculoskeletal adverse events were more frequent with the program, 18.5 against 11.5 percent.
Death: 0.63 (0.43 to 0.94).
That a structured exercise program started after adjuvant chemotherapy lengthened disease-free survival in this population, in a randomized trial with a hard clinical endpoint An outcome that matters directly to a person and is counted without judgment, such as death, heart attack, stroke or fracture. as its primary outcome. It was the first phase 3 trial to test exercise against a cancer survival endpoint.
It did not test exercise during chemotherapy, other cancers, advanced disease, or exercise in place of any part of cancer treatment. Overall survival was a secondary endpoint, which the authors describe as consistent with longer survival rather than proven. The control group received written health education, so the comparison is a supported, supervised program against advice, not exercise against no exercise.
One trial. Rule 03 does not count a single trial as replication however large it is, so in colon cancer alone this result does not replicate. The graded record for structured exercise after cancer treatment draws on a 2026 meta-analysis A study that pools the numbers from several trials into one combined estimate. of 21 randomized trials, mostly in breast cancer, that points the same way.
Carried because it changes what kind of evidence exercise has in cancer care: an outcome trial, not an association. It is the plainest case on this site of a lifestyle program reaching a hard endpoint in a randomized trial.
A 2026 meta-analysis of 21 randomized trials found longer overall and disease-free survival with structured exercise across cancer types, at moderate certainty (Tzang et al., Br J Sports Med, 2026; PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 42744658).
09
4S. Simvastatin in established coronary heart disease
Lancet 1994 · Cardiovascular
4S. Simvastatin in established coronary heart disease
Does lowering cholesterol with simvastatin improve survival in patients with established coronary heart disease?
4,444 patients with angina or prior myocardial infarction and elevated cholesterol.
Randomized, double-blind, placebo-controlled.
All-cause mortality.
Simvastatin reduced all-cause mortality and major coronary events.
Major coronary events: 0.66 (0.59 to 0.75).
That lipid lowering with a statin reduces death in secondary prevention. This is the foundation of statin therapy.
It does not transfer to low-risk primary prevention, where absolute benefit is much smaller, nor to people without elevated cholesterol at the time.
Absolute benefit scales with baseline risk. The same relative reduction means something very different in a low-risk 45-year-old.
Why statins carry a high grade in appropriate high-risk populations, and why that grade is population-specific rather than universal.
Extensively replicated. Among the most reproduced findings in cardiovascular medicine.
10
Heart Protection Study. Simvastatin across a broad risk range
Lancet 2002 · Cardiovascular
Heart Protection Study. Simvastatin across a broad risk range
Does simvastatin benefit high-risk adults across a wide range of baseline cholesterol levels?
20,536 high-risk UK adults with coronary disease, other occlusive arterial disease, or diabetes.
Randomized, placebo-controlled.
Major vascular events including myocardial infarction, stroke and revascularisation.
Simvastatin reduced major vascular events by roughly a quarter, with consistent relative benefit across baseline cholesterol levels including those considered normal.
Reported as a 24 percent reduction (19 to 28).
That relative benefit is broadly consistent across baseline lipid levels, so treatment decisions turn on absolute risk The actual chance of an event in a group. A fall from 2 percent to 1 percent is a 1-point absolute reduction, even though it is a 50 percent relative one. rather than on cholesterol alone.
Consistent relative benefit does not mean equal absolute benefit. The number needed to treat varies enormously across the risk spectrum.
This trial is quoted in both directions, to argue for wider treatment and to argue that treatment is over-broad. Both readings depend on conflating relative and absolute effect.
The single best illustration of EBL's second rule: absolute risk before relative-risk headlines.
Consistent with subsequent statin meta-analyses.
11
SPRINT. Intensive versus standard blood-pressure control
N Engl J Med 2015 · Cardiovascular
SPRINT. Intensive versus standard blood-pressure control
Does targeting systolic blood pressure below 120 mmHg beat a target below 140 mmHg in high-risk adults without diabetes?
Over 9,000 adults aged 50 and older at increased cardiovascular risk, excluding diabetes and prior stroke.
Randomized, open-label Everyone in the trial knows which treatment they are receiving, so expectations can shape the results, especially for symptoms people report themselves., to intensive versus standard systolic targets.
Composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure and cardiovascular death.
Intensive control reduced the primary composite and all-cause mortality, at the cost of more treatment-related adverse events including hypotension, syncope, electrolyte abnormality and acute kidney injury.
All-cause mortality: 0.73 (0.60 to 0.90).
That in this specific population, a lower blood-pressure target reduces events and death, with a real and quantified harm trade-off.
It excluded people with diabetes and prior stroke, so it does not generalize to them. Blood pressure was measured by unattended automated protocol, which reads lower than typical office measurement, so the target is not directly transferable to a routine clinic reading.
The measurement-method point is the one most often missed, and it matters for anyone applying the target to their own home or office readings.
The clearest example on the site of benefit and harm both being real and both being quantified. A grade without a harm number is half a grade.
The final report reinforced the cardiovascular and mortality benefit. Guidelines shifted substantially in response.
12
ASPREE. Low-dose aspirin in healthy older adults
N Engl J Med 2018 · Cardiovascular
ASPREE. Low-dose aspirin in healthy older adults
Does daily low-dose aspirin prolong disability-free survival in healthy older adults without cardiovascular disease?
Over 19,000 community-dwelling adults aged 70 and older, or 65 and older in some US minority groups, free of cardiovascular disease, dementia and disability.
Randomized, double-blind, placebo-controlled.
Disability-free survival, a composite of death, dementia and persistent physical disability.
Aspirin did not prolong disability-free survival, and increased major hemorrhage.
Major hemorrhage was more common on aspirin.
That preventive aspirin in healthy older adults does not extend healthy life and carries real bleeding harm. High-quality negative evidence with a clear harm signal.
It does not apply to secondary prevention, where aspirin retains an established role, nor to anyone taking it on specific medical advice.
The distinction between primary and secondary prevention is the whole of it, and it is the distinction most often lost in translation to the public.
Featured prominently because it contradicts a belief many older adults still hold, and because it is the cleanest example on the site of a harm signal in a healthy population.
Aligned with other contemporary primary-prevention aspirin trials. Guidelines were revised.
13
STAREE. Atorvastatin for primary prevention in adults aged 70 and over
N Engl J Med 2026 · Cardiovascular
STAREE. Atorvastatin for primary prevention in adults aged 70 and over
Does atorvastatin 40 mg daily prevent major cardiovascular events, and does it extend disability-free survival, in adults aged 70 and over with no cardiovascular disease, diabetes or dementia?
9,971 community-dwelling adults in Australia aged 70 and over (mean age 74.7, 51.9% women), recruited through general practices, with no history of cardiovascular disease, diabetes or dementia.
Randomized, double-blind, placebo-controlled, with two primary endpoints tested in a prespecified hierarchy. Median follow-up 5.9 years.
Two primary endpoints: a composite of cardiovascular death, nonfatal heart attack or stroke, or coronary revascularization; and a composite of death from any cause, dementia, or persistent physical disability.
Major cardiovascular events occurred in 297 people on atorvastatin and 412 on placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received. (10.9 versus 15.5 per 1,000 person-years; hazard ratio 0.70, 95% CI 0.61 to 0.82). Disability-free survival did not differ: 637 events against 676 (hazard ratio 0.94, 95% CI 0.84 to 1.05, P = 0.25). Serious adverse events were 2.7% in each arm; musculoskeletal, liver-related and diabetes-related events were more common on atorvastatin.
Death, dementia or persistent disability: 0.94 (0.84 to 1.05).
That in adults over 70 without cardiovascular disease, atorvastatin lowered the rate of heart attacks, strokes and related events by about 30 percent over six years. This is the first large placebo-controlled trial built for this age group, which had previously been answered by extrapolating from trials in younger people.
It did not show that the statin kept people alive longer, or free of dementia or disability. People with diabetes, existing cardiovascular disease or dementia were excluded, so the trial does not speak to them.
The 30 percent relative reduction is about 4.6 fewer events per 1,000 people per year (15.5 against 10.9). The disability-free survival result is a null whose confidence interval The range the true effect probably falls in. A wide interval means the estimate is uncertain. runs from a 16 percent reduction to a 5 percent increase, so a small effect in either direction on that endpoint is not excluded.
Pairs with 4S and the Heart Protection Study, which established statins in people already at high risk. STAREE carries the cardiovascular finding to healthy adults over 70, and it is also the clearest case in this library of a drug moving a hard clinical endpoint while leaving the broader healthspan endpoint unchanged. Both halves are the result.
Published October 2026. No independent replication yet. Imaging and cardiac substudies from the same trial are registered and had not reported results as of October 2026.
14
Diabetes Prevention Program. Lifestyle versus metformin
N Engl J Med 2002 · Cardiometabolic
Diabetes Prevention Program. Lifestyle versus metformin
In people at high risk of type 2 diabetes, does intensive lifestyle intervention or metformin prevent progression to diabetes?
Over 3,000 adults with impaired glucose tolerance.
Randomized to intensive lifestyle intervention, metformin, or placebo.
Incidence of type 2 diabetes.
Lifestyle intervention reduced diabetes incidence by roughly 58 per cent and metformin by roughly 31 per cent, both relative to placebo. Lifestyle outperformed metformin.
Reported as a 58 percent reduction (48 to 66). Metformin: 31 percent (17 to 43).
That progression from impaired glucose tolerance to diabetes is preventable, and that a behavioral intervention beat a drug on this endpoint.
Preventing a diagnosis is not the same as preventing the complications that make the diagnosis matter. Long-term follow-up showed continued delay of diabetes, while differences in microvascular outcomes between the randomized groups were less clear.
The gap between delaying a diagnostic threshold and preventing end-organ damage is the central interpretive question, and it is still not fully settled.
Directly relevant to how EBL frames metformin. Real evidence, specific population, specific endpoint. It does not make metformin a longevity drug for people without dysglycemia.
Long-term DPP Outcomes Study follow-up continues to show diabetes delay.
15
Look AHEAD, intensive lifestyle intervention in type 2 diabetes
N Engl J Med 2013 · Cardiometabolic
Look AHEAD, intensive lifestyle intervention in type 2 diabetes
Does intensive lifestyle intervention producing weight loss reduce cardiovascular events in adults with type 2 diabetes?
Over 5,000 overweight or obese adults with type 2 diabetes.
Randomized to intensive lifestyle intervention versus diabetes support and education, with long-term follow-up.
Composite of cardiovascular death, myocardial infarction, stroke and hospitalization for angina.
The intervention produced sustained weight loss and improvements in fitness and multiple risk factors, but did not reduce the primary cardiovascular composite. The trial was stopped for futility on that endpoint.
Stopped early for futility.
That weight loss, improved fitness and better risk-factor numbers do not automatically translate into fewer cardiovascular events.
It does not show that lifestyle intervention is useless. Other benefits were real. It shows that the cardiovascular endpoint did not move.
Background medical therapy improved substantially in both arms during the trial, which plausibly compressed the achievable difference.
The single best counterweight on this site to surrogate-endpoint reasoning. Everything got better except the thing being measured.
Its interpretation remains actively debated. Later obesity-drug outcome trials did move cardiovascular endpoints, which sharpens rather than settles the question.
16
EMPA-REG OUTCOME, empagliflozin in type 2 diabetes with cardiovascular disease
N Engl J Med 2015 · Cardiometabolic
EMPA-REG OUTCOME, empagliflozin in type 2 diabetes with cardiovascular disease
Does empagliflozin reduce cardiovascular events in adults with type 2 diabetes and established cardiovascular disease?
Over 7,000 adults with type 2 diabetes and established cardiovascular disease.
Randomized, double-blind, placebo-controlled, added to standard care.
Composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.
Empagliflozin reduced cardiovascular death, hospitalization for heart failure and all-cause mortality.
The interval is a 95.02 percent interval.
That a glucose-lowering drug can deliver organ and mortality benefit beyond glycemic control, and that the benefit was largest for heart-failure and death endpoints rather than atherothrombotic ones.
It does not establish benefit in people without diabetes or without established cardiovascular disease, and the mechanism of the mortality benefit is still not fully explained.
The pattern of benefit did not match the expected glucose-lowering mechanism, which is itself instructive about mechanistic prediction.
Included because it is the modern template for how a drug earns a longevity-relevant claim: a hard endpoint, in a defined population, on top of standard care.
Replicated across the SGLT2 inhibitor class, and extended into heart failure and chronic kidney disease populations without diabetes.
17
SELECT (semaglutide): obesity treatment and cardiovascular outcomes
N Engl J Med 2023 · Cardiometabolic
SELECT (semaglutide): obesity treatment and cardiovascular outcomes
Does weekly semaglutide reduce major cardiovascular events in people with overweight or obesity and established cardiovascular disease but without diabetes?
Over 17,000 adults with overweight or obesity and established cardiovascular disease, without diabetes.
Randomized, double-blind, placebo-controlled.
Composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.
Semaglutide reduced the primary cardiovascular composite.
That treating obesity pharmacologically reduces hard cardiovascular events, independent of diabetes. This decoupled obesity treatment from weight as an endpoint.
It does not establish benefit in people without established cardiovascular disease, does not resolve what happens on discontinuation, and does not address long-term effects on lean mass or bone.
Not to be confused with the 2011 selenium and vitamin E SELECT trial, which shares the acronym and nothing else.
The most important recent trial linking a metabolic intervention to hard outcomes. Also the clearest contrast with Look AHEAD, where lifestyle-induced weight loss did not move the same endpoint.
Part of a broadening incretin outcome program across heart failure, kidney disease and sleep apnea.
18
FINGER. Multidomain intervention for cognitive decline
Lancet 2015 · Cognition
FINGER. Multidomain intervention for cognitive decline
Can a multidomain lifestyle intervention preserve cognition in at-risk older adults?
Around 1,200 older adults in Finland at elevated dementia risk.
Randomized to two years of combined dietary counselling, exercise, cognitive training and vascular risk monitoring, versus general health advice.
Change in a composite neuropsychological test score.
Cognitive performance was better maintained in the intervention arm.
That a combined, multidomain program can affect cognitive trajectory over two years in an at-risk population.
It did not show prevention of dementia, cannot attribute the effect to any single component, and two years is short relative to dementia timelines.
A composite cognitive test score is a surrogate. It is a reasonable one, but it is not a diagnosis avoided.
The evidential basis for the multi-domain lifestyle protocol on this site, and the reason it is graded on the combination rather than on any ingredient inside it.
Being tested in adapted forms internationally, including US-based multidomain trials.
19
SPRINT-MIND. Intensive blood-pressure control and dementia
JAMA 2019 · Cognition
SPRINT-MIND. Intensive blood-pressure control and dementia
Does intensive blood-pressure control reduce probable dementia?
The SPRINT cohort followed for cognitive outcomes.
Randomized comparison of intensive versus standard systolic targets, with adjudicated cognitive endpoints.
Probable dementia as the primary cognitive endpoint, with mild cognitive impairment as secondary.
Probable dementia was not significantly reduced. Mild cognitive impairment was reduced, as was a composite of mild cognitive impairment plus probable dementia.
Mild cognitive impairment: 0.81 (0.69 to 0.95).
That the same intervention can affect cognitive and cardiovascular outcomes to different degrees, and that intensive control reduces milder cognitive endpoints.
It did not establish dementia prevention. The trial was stopped early for cardiovascular benefit, which reduced accrued dementia cases and left the primary cognitive endpoint underpowered.
Early stopping for benefit on one endpoint can leave another endpoint unanswerable. This is a structural feature of trial design, not an oversight.
Deliberately placed beside SPRINT rather than standing alone. One intervention, two endpoints, two different answers.
Long-term observational follow-up has been reported. No trial designed primarily for the dementia endpoint has replaced it.
20
COSMOS. Multivitamin-mineral supplementation and cognition
Am J Clin Nutr 2024 · Cognition
COSMOS. Multivitamin-mineral supplementation and cognition
Does a daily multivitamin-mineral improve cognitive function in older adults?
Older adults enrolled in the COSMOS parent trial and its cognitive substudies.
Randomized, placebo-controlled, with cognitive testing across separate substudies using different assessment modes.
Episodic memory and global cognition.
A modest benefit in episodic memory, with the pooled substudies also supporting a small benefit in global cognition.
A small, statistically detectable cognitive benefit in this population over the periods studied.
It did not show prevention of dementia or mild cognitive impairment, did not measure functional independence, and the effect sizes are small enough that clinical meaningfulness for an individual is genuinely uncertain.
COSMOS-Mind, COSMOS-Web and COSMOS-Clinic are substudies of one parent trial, not three independent replications. Presenting them as independent confirmation overstates the evidence, and EBL treats them as one evidence cluster.
A useful example of a real but small effect. A detectable difference in a group mean is not a promise of a noticeable difference for one person.
No independent large replication outside the COSMOS program.
21
Women's Health Initiative. Combined estrogen plus progestin
JAMA 2002 · Hormones
Women's Health Initiative. Combined estrogen plus progestin
Does combined menopausal hormone therapy prevent chronic disease in healthy postmenopausal women?
Over 16,000 postmenopausal women aged 50 to 79 with an intact uterus.
Randomized, placebo-controlled, stopped early.
Coronary heart disease as primary benefit endpoint, invasive breast cancer as primary safety endpoint, with a global index.
Combined conjugated equine estrogen plus medroxyprogesterone acetate did not prevent coronary heart disease and increased breast cancer, stroke and venous thromboembolism. The trial was stopped early.
Nominal interval. Stroke 1.41, breast cancer 1.26.
That combined hormone therapy should not be used to prevent chronic disease in this population, using this formulation.
It did not test modern formulations, transdermal routes, or initiation close to menopause in symptomatic younger women. The estrogen-alone arm in women after hysterectomy produced a materially different risk profile, particularly for breast cancer.
This is the most consequentially over-generalized trial in modern medicine. Reducing it to “hormones are bad” misstates what was tested: one formulation, one route, one dose pair, in a population averaging over a decade past menopause. Outcomes differ by formulation, route, hysterectomy status, age and timing.
Carried as much for how it was received as for what it found. The result was valid and its generalization was not, and a generation of clinical decisions followed the generalization.
Extensively reanalyzed by age and time since menopause. Guidance now distinguishes symptom management in appropriately selected women from chronic-disease prevention, which remains unsupported.
What each graded record was checked against.
A grade can describe every paper it cites correctly and still be wrong, because the largest trial on the question is missing. So every trial above, and other large trials, is matched to each graded record it bears on. The record either cites the trial or says in writing why the trial does not change it. If neither is true, the site does not publish.
51 trials · 56 record checks · 45 cited · 11 set aside with a reason
4S. Simvastatin in established coronary heart disease no graded record
Simvastatin reduced all-cause mortality and major coronary events. PMID 7968073 · trial card above
Statins are covered on a medication page, which carries no letter grade.
AIM-HIGH cited on 1
3,414 randomized. Niacin added to statin therapy raised HDL but did not lower cardiovascular events PMID 22085343
AREDS cited on 1, set aside on 1
3,640 randomized. Antioxidants plus zinc slowed progression to advanced age-related macular degeneration in people already at high risk PMID 11594942
- Beta-Carotene (supplemental): AREDS tested beta-carotene only inside an antioxidant combination, on macular degeneration. This record grades beta-carotene alone for cancer prevention.
ASCEND (aspirin arm) cited on 1
15,480 randomized. Aspirin lowered serious vascular events in diabetes, offset by more major bleeding PMID 30146931
Aspirin (low-dose, primary prevention in healthy older adults)
ASCEND (omega-3 arm) cited on 1, set aside on 1
15,480 randomized. 1 g/day omega-3 did not lower serious vascular events in adults with diabetes PMID 30146932
Omega-3. High-dose EPA (icosapent ethyl, 4 g)
- Omega-3 EPA/DHA 2 to 4 g/day (general supplementation): ASCEND tested 1 g/day in adults with diabetes. This protocol grades 2 to 4 g/day; ASCEND is cited on the omega-3 record's post-infarction row.
ASPREE (cardiovascular and bleeding) cited on 1
19,114 randomized. Aspirin did not lower cardiovascular disease and raised major bleeding PMID 30221597
Aspirin (low-dose, primary prevention in healthy older adults)
ASPREE (disability-free survival) cited on 1
19,114 randomized. Aspirin 100 mg/day did not prolong disability-free survival in healthy older adults PMID 30221596 · trial card above
Aspirin (low-dose, primary prevention in healthy older adults)
ATBC cited on 2
29,133 randomized. Beta-carotene raised lung cancer incidence in male smokers; vitamin E did not lower it PMID 8127329
Beta-Carotene (supplemental) · Vitamin E (supplemental alpha-tocopherol)
CALERIE 2 cited on 1
218 randomized. About 12 percent calorie restriction for 2 years improved cardiometabolic risk factors in non-obese adults PMID 31303390 · trial card above
CARET cited on 1
18,314 randomized. Beta-carotene with vitamin A raised lung cancer and death in smokers and asbestos workers; stopped early PMID 8602180
CHALLENGE cited on 1
889 randomized. Structured exercise after colon-cancer chemotherapy improved disease-free survival PMID 40450658 · trial card above
Structured exercise program after treatment for non-metastatic cancer
China Coronary Secondary Prevention Study (Xuezhikang) cited on 1
4,870 randomized. A red yeast rice extract lowered coronary events after heart attack PMID 18549841
COSMOS. Multivitamin-mineral supplementation and cognition no graded record
A modest benefit in episodic memory, with the pooled substudies also supporting a small benefit in global cognition. PMID 38244989 · trial card above
No multivitamin record.
D-Health cited on 1, set aside on 1
21,315 randomized. 60,000 IU monthly for up to 5 years did not lower all-cause mortality in older Australians PMID 35026158
- Vitamin D3 2,000–4,000 IU + K2 MK-7 100 mcg: D-Health's primary endpoint was all-cause mortality, which this protocol does not grade. Its fracture report (PMID 37011645) is already cited here.
D2d cited on 1
2,423 randomized. 4,000 IU/day did not significantly lower progression from prediabetes to diabetes PMID 31173679
DASH-Sodium cited on 2
412 randomized. Lower sodium lowered blood pressure on both the DASH and the control diet PMID 11136953
DASH dietary pattern · Sodium reduction to under 2,300 mg/day
Diabetes Prevention Program cited on 0, set aside on 1
3,234 randomized. Lifestyle change and metformin both lowered progression to diabetes, lifestyle more so PMID 11832527 · trial card above
- Metformin (for longevity): The Diabetes Prevention Program tested metformin in adults with impaired glucose tolerance, a clinical indication this record expressly does not grade. It is cited on the metformin medication page.
DO-HEALTH cited on 1, set aside on 1
2,157 randomized. Vitamin D 2,000 IU, omega-3 1 g or home strength exercise for 3 years did not improve blood pressure, physical performance, fractures or cognition in adults over 70 PMID 33170239
- Omega-3. High-dose EPA (icosapent ethyl, 4 g): DO-HEALTH's omega-3 arm (1 g/day) was tested on blood pressure, physical performance, cognition, nonvertebral fractures and infections. None of these is a use graded on this record, whose rows are cardiovascular events and post-infarction mortality.
EMPA-REG OUTCOME cited on 1
7,020 randomized. Empagliflozin lowered cardiovascular death and all-cause mortality in type 2 diabetes with heart disease PMID 26378978 · trial card above
FINGER cited on 0, set aside on 1
1,260 randomized. A 2-year multidomain lifestyle program improved cognitive test scores in at-risk older adults PMID 25771249 · trial card above
- Multi-domain diet and lifestyle program with supplements (8 weeks, as studied): This record grades one specific 8-week program with two supplements, as studied. FINGER tested a different 2-year program and cannot replicate or refute it.
GAIT cited on 2
1,583 randomized. Glucosamine, chondroitin or both did not reduce knee pain overall versus placebo PMID 16495392
GEM (Ginkgo Evaluation of Memory) cited on 1
3,069 randomized. Ginkgo 240 mg/day did not lower dementia or Alzheimer incidence over a median 6.1 years PMID 19017911
GuidAge cited on 1
2,854 randomized. Ginkgo extract EGb 761 for 5 years did not lower progression to Alzheimer's disease in adults aged 70 and over with memory complaints PMID 22959217
Heart Protection Study. Simvastatin across a broad risk range no graded record
Simvastatin reduced major vascular events by roughly a quarter, with consistent relative benefit across baseline cholesterol levels including those considered normal. PMID 12114036 · trial card above
Statins are covered on a medication page, which carries no letter grade.
HOPE (vitamin E arm) cited on 1
9,541 randomized. 400 IU/day vitamin E for 4.5 years had no effect on cardiovascular outcomes in high-risk patients PMID 10639540
HOPE-2 cited on 1
5,522 randomized. Folic acid, B6 and B12 lowered homocysteine An amino acid in the blood that rises when vitamin B12, folate or B6 are low. but not major vascular events PMID 16531613
HPS2-THRIVE cited on 1
25,673 randomized. Extended-release niacin with laropiprant did not lower major vascular events and raised serious adverse events PMID 25014686
LIFE cited on 0, set aside on 1
1,635 randomized. Structured walking, strength and balance lowered major mobility disability in sedentary older adults PMID 24866862 · trial card above
- Mobility and fall-prevention protocols: LIFE's primary outcome was major mobility disability, not falls. This record grades falls and fall risk.
Look AHEAD, intensive lifestyle intervention in type 2 diabetes no graded record
The intervention produced sustained weight loss and improvements in fitness and multiple risk factors, but did not reduce the primary cardiovascular composite. PMID 23796131 · trial card above
No intensive weight-loss lifestyle record.
Lyon Diet Heart Study. Mediterranean diet after myocardial infarction no graded record
A large reduction in recurrent cardiac events in the intervention arm, of a magnitude rarely seen in dietary trials. PMID 7911176 · trial card above
A Mediterranean-style diet without extra-virgin olive oil, after a heart attack. The Mediterranean protocol grades the olive-oil diet tested in PREDIMED.
NORVIT cited on 1
3,749 randomized. B-vitamin homocysteine lowering after heart attack did not lower recurrent events PMID 16531614
Physicians' Health Study II (vitamins E and C) cited on 1
14,641 randomized. Vitamin E and vitamin C did not lower major cardiovascular events in men PMID 18997197
PREDIMED (2018 republication) cited on 1
7,447 randomized. Mediterranean diet with extra-virgin olive oil or nuts lowered major cardiovascular events PMID 29897866 · trial card above
Q-SYMBIO cited on 2
420 randomized. CoQ10 300 mg/day for 2 years lowered major adverse cardiovascular events in chronic heart failure PMID 25282031
REDUCE-IT cited on 2
8,179 randomized. 4 g/day icosapent ethyl lowered cardiovascular events against a mineral-oil comparator PMID 30415628
Omega-3. High-dose EPA (icosapent ethyl, 4 g) · Omega-3 EPA/DHA 2 to 4 g/day (general supplementation)
SELECT (extended follow-up) cited on 1
35,533 randomized. Vitamin E 400 IU/day raised prostate cancer risk by 17 percent PMID 21990298 · trial card above
SELECT (primary report) cited on 2
35,533 randomized. Selenium and vitamin E, alone or together, did not prevent prostate or other cancers PMID 19066370
Selenium (Selenomethionine) · Vitamin E (supplemental alpha-tocopherol)
SELECT (semaglutide) cited on 1
17,604 randomized. Semaglutide 2.4 mg weekly lowered major cardiovascular events in obesity without diabetes PMID 37952131 · trial card above
SPRINT-MIND. Intensive blood-pressure control and dementia no graded record
Probable dementia was not significantly reduced. PMID 30688979 · trial card above
Blood-pressure targets with prescription drugs; no graded record.
SPRINT. Intensive versus standard blood-pressure control no graded record
Intensive control reduced the primary composite and all-cause mortality, at the cost of more treatment-related adverse events including hypotension, syncope, electrolyte abnormality and acute kidney injury. PMID 26551272 · trial card above
Blood-pressure targets with prescription drugs; no graded record.
SSaSS (salt substitute) cited on 0, set aside on 1
20,995 randomized. A potassium salt substitute lowered stroke, cardiovascular events and death in rural China PMID 34459569
- Sodium reduction to under 2,300 mg/day: SSaSS tested a potassium-enriched salt substitute, which this record's own text excludes as a different intervention with its own trials.
STAREE. Atorvastatin for primary prevention in adults aged 70 and over no graded record
Major cardiovascular events occurred in 297 people on atorvastatin and 412 on placebo (10.9 versus 15.5 per 1,000 person-years; hazard ratio 0.70, 95% CI 0.61 to 0.82). PMID 42670961 · trial card above
Statins are covered on a medication page, which carries no letter grade.
STRENGTH cited on 2
13,078 randomized. 4 g/day omega-3 carboxylic acid did not lower cardiovascular events against corn oil PMID 33190147
Omega-3. High-dose EPA (icosapent ethyl, 4 g) · Omega-3 EPA/DHA 2 to 4 g/day (general supplementation)
ViDA cited on 1
5,110 randomized. 100,000 IU monthly for a median 3.3 years did not lower cardiovascular disease PMID 28384800
VITAL (omega-3 arm) cited on 1, set aside on 1
25,871 randomized. 1 g/day marine omega-3 did not lower major cardiovascular events or cancer PMID 30415637
Omega-3. High-dose EPA (icosapent ethyl, 4 g)
- Omega-3 EPA/DHA 2 to 4 g/day (general supplementation): VITAL tested 1 g/day. This protocol grades 2 to 4 g/day, where the dedicated trials (STRENGTH, OMEMI) are cited; VITAL is cited on the omega-3 record's primary-prevention row.
VITAL (vitamin D arm) cited on 1, set aside on 1
25,871 randomized. 2,000 IU/day for a median 5.3 years did not lower invasive cancer or major cardiovascular events PMID 30415629 · trial card above
- Vitamin D3 2,000–4,000 IU + K2 MK-7 100 mcg: VITAL's endpoints were cancer and major cardiovascular events. This protocol grades bone loss, a surrogate, and its own text says it does not cover those outcomes; VITAL is cited on the vitamin D record's cancer and cardiovascular rows.
VITAL fracture substudy cited on 2
25,871 randomized. 2,000 IU/day did not lower total, nonvertebral or hip fractures in generally healthy adults PMID 35939577
VITAL secondary analysis. Vitamin D3 and advanced cancer no graded record
A reduction in advanced cancer was reported, apparently concentrated among participants with normal body-mass index. PMID 33206192 · trial card above
A secondary analysis of VITAL on advanced or fatal cancer. The vitamin D cancer row grades incidence and says cancer death is not graded.
VITAL-DEP cited on 1
18,353 randomized. 2,000 IU/day for 5 years did not lower depression risk or change mood scores PMID 32749491
VITAL-Rhythm cited on 0, set aside on 1
25,119 randomized. Neither omega-3 nor vitamin D changed incident atrial fibrillation PMID 33724323
- Omega-3. High-dose EPA (icosapent ethyl, 4 g): VITAL-Rhythm found 1 g/day did not change atrial fibrillation. Atrial fibrillation is not a graded use; it is a caution on this record, stated as dose-related and mattering most at the 4 g/day of the cardiovascular trials, which a 1 g/day null is consistent with.
WHI estrogen plus progestin cited on 1
16,608 randomized. Combined hormone therapy raised breast cancer, stroke and clot risk in older postmenopausal women PMID 12117397 · trial card above
Hormone replacement therapy (combined estrogen + progestin, primary prevention)
Educational use only · Not medical advice. Trial summaries are descriptions of published research, not recommendations to start, stop or change any treatment. See EBL's Position.