A claim you hear on longevity podcasts

Is it true HDL-raising drugs don't prevent heart attacks?

Strong consensus for. Of 10 studies that test it, 7 agree, 2 partly agree and 1 disagrees.

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The claim checked: Raising HDL cholesterol with a drug did not prevent heart attacks or strokes Hear it at 1:06:04

What do the studies say?

Strong consensus for

Seven of ten studies found that drugs that raise HDL cholesterol did not cut heart attacks and strokes, or that any benefit followed the drop in LDL or non-HDL cholesterol. One older gemfibrozil trial found fewer coronary events with LDL unchanged, and two were mixed.

Computed from 10 studies that test this point, each judged by two readers, in full. 4 more studies are waiting for a full read and do not count yet.

What was said on the podcast?

“but there was a 35 raising of HDL cholesterol and that did not translate into one less heart attack or stroke so that ended the HDL hypothesis in a way”
John Kastelein, a guest on The Drive · 255 - Latest therapeutics in CVD, APOE's role in Alzheimer's disease, familial hypercholesterolemia · 1:06:04 on YouTube
Seconds before, he says the drug only raised HDL by 30 percent and had no effect on LDL, apoB or non-HDL cholesterol.
Comes up in 2 episodes of the show.
The study behind the claim The retelling matches it

What did the study actually test?

On tape: a weak CETP inhibitor that only raised HDL by about 30 to 35 percent, with no effect on LDL or apoB, and no fewer heart attacks or strokes. The trial matches: HDL rose 31 to 40 percent, LDL barely moved, and the primary end point did not change. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med, 2012. Randomized, double-blind, placebo-controlled trial of dalcetrapib 600 mg daily, stopped for futility at a median of 31 months, 15,871 patients with a recent acute coronary syndrome on evidence-based care including statins.

What was saidWhat the study did
What was given Matches A weak CETP inhibitor that only raised HDL by about 30 to 35 percent Dalcetrapib 600 mg a day; HDL up 31 to 40 percent against 4 to 11 percent on placebo
Compared with Matches No drug Placebo
What was measured Matches Heart attacks and strokes Coronary death, heart attack, ischemic stroke, unstable angina, resuscitated cardiac arrest
Who took part Matches Not stated Patients with a recent acute coronary syndrome

What it found

“Dalcetrapib had no significant effect on the primary end point, which occurred in 8.3% of the patients in the dalcetrapib group and in 8.0% of the patients in the placebo group (hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) (Figure 2).”

PMID 23126252

How the authors extend it

“Despite the finding that dalcetrapib, as compared with placebo, produced a substantial increase in HDL cholesterol levels, it had no significant effect on major cardiovascular outcomes, including the rate of death from coronary heart disease and the rates of myocardial infarction, ischemic stroke, unstable angina, cardiac arrest with resuscitation, and unanticipated coronary revascularization.”

PMID 23126252

F. Hoffmann-La Roche; two analysing authors are Roche employees. Two readers agreed on the label, and the paper was read in full.

The point checked Strong consensus for

Raising HDL cholesterol with a drug, without lowering LDL cholesterol or apoB, does not reduce heart attacks and strokes

Agree 7

pooled analysis · 2014 · landmark

“Attempts to reduce cardiovascular events or mortality by raising high density lipoprotein levels using three dissimilar classes of agents has, when trialled in the statin era, so far been unsuccessful.”

Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ
Who: Patients in randomised controlled trials of niacin (11 trials), fibrates (20 trials) and CETP inhibitors (8 trials: anacetrapib, dalcetrapib, torcetrapib) against control, with or without background statin treatment
PMID 25038074

pooled analysis · 2009 · landmark

“This association was, however, no longer detectable in models adjusted for changes in low density lipoprotein cholesterol (bivariable or multivariable), indicating that the apparent reduction in outcomes was due to the association of changes in high density lipoprotein cholesterol with changes in low density lipoprotein cholesterol.”

Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ
Who: Participants in randomised controlled trials of any lipid modifying drug or diet (statins, fibrates, resins, niacin combinations, n-3 fatty acids, ACAT inhibitors, probucol, glitazones, hormones, torcetrapib, low fat diets/surgery) versus placebo, usual care or less intensive treatment, followed at least six months
PMID 19221140

pooled analysis · 2017

“Moderate‐ to high‐quality evidence suggests that niacin does not reduce mortality, cardiovascular mortality, non‐cardiovascular mortality, the number of fatal or non‐fatal myocardial infarctions, nor the number of fatal or non‐fatal strokes but is associated with side effects.”

Niacin for primary and secondary prevention of cardiovascular events. Cochrane Database Syst Rev
Who: Adults with or at risk of cardiovascular disease in randomised controlled trials of niacin monotherapy or add-on to other therapy (mostly statins) versus placebo/usual care; mean age 33 to 71 years
PMID 28616955

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controlled trial · 2012 · landmark · cited on tape

“Despite the finding that dalcetrapib, as compared with placebo, produced a substantial increase in HDL cholesterol levels, it had no significant effect on major cardiovascular outcomes, including the rate of death from coronary heart disease and the rates of myocardial infarction, ischemic stroke, unstable angina, cardiac arrest with resuscitation, and unanticipated coronary revascularization.”

Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med
Who: 15,871 patients aged 45 or older with a recent acute coronary syndrome on evidence-based care including statins, at 935 sites in 27 countries
PMID 23126252

controlled trial · 2011 · landmark

“Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels.”

Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med
Who: 3,414 patients aged 45 or older with established cardiovascular disease, low HDL cholesterol, elevated triglycerides, on simvastatin (plus ezetimibe if needed) to keep LDL at 40-80 mg/dl; 85% men, 92% white, at 92 centres in the USA and Canada
PMID 22085343

controlled trial · 2017 · landmark · cited on tape

“In particular, the higher mean level of HDL cholesterol in the anacetrapib group (by 43 mg per deciliter) does not appear to have had as large an effect on coronary events as would be anticipated on the basis of observational studies.”

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N Engl J Med
Who: 30,449 adults older than 50 with atherosclerotic vascular disease on intensive atorvastatin; mean age 67, mean LDL 61 mg/dL, mean HDL 40 mg/dL
PMID 28847206

controlled trial · 2022

“In particular, the 43 mg/dL (1.12 mmol/L) increase in HDL cholesterol does not appear to have had an effect on major coronary events as large as would be anticipated from observational epidemiological studies.”

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease. Eur Heart J
Who: 30,449 men and women aged 50 or older with atherosclerotic vascular disease on intensive atorvastatin (mean age 67, 84% male); 26,129 entered post-trial follow-up
PMID 34910136

Partly agree 2

controlled trial · 2017 · landmark

“Treatment with evacetrapib was associated with an increase in the HDL cholesterol level and a reduction in the LDL cholesterol level that were both significant and substantial, but evacetrapib treatment did not have a beneficial effect on cardiovascular outcomes.”

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease. N Engl J Med
Who: 12,092 patients aged 18 or older with high-risk vascular disease (recent acute coronary syndrome, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes with coronary artery disease), more than 96% on statins
PMID 28514624

controlled trial · 2022

“In conclusion, dalcetrapib did not significantly reduce the risk of occurrence of the primary composite endpoint at end of study, with fewer non-fatal myocardial infarctions, and a numerical excess of cardiovascular deaths and resuscitated cardiac arrests.”

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial. Eur Heart J
Who: 6147 patients aged 45 or older with an acute coronary syndrome 1-3 months earlier and the AA genotype at rs1967309 in ADCY9, on guideline LDL management; mean age 62.3, 22.7% women
PMID 35856777

Disagree 1

controlled trial · 1999 · landmark

“Thus, the results of this study suggest that raising HDL cholesterol and lowering triglyceride levels, even without lowering the LDL cholesterol level, reduces major coronary events in patients whose primary lipid abnormality is a low HDL cholesterol level.”

Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med
Who: 2531 men under 74 with coronary heart disease, HDL cholesterol 40 mg/dL or less, LDL cholesterol 140 mg/dL or less and triglycerides 300 mg/dL or less; mean age 64
PMID 10438259

What else was said but not tested?

  • High HDL cholesterol does not protect against heart disease when LDL cholesterol is high (Mendelian randomization)

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