Which single‑ingredient supplements have the strongest randomized‑trial evidence for reducing cardiovascular events?
Executive summary
Randomized‑trial evidence is clearest for a small set of single‑ingredient supplements: omega‑3 (n‑3) fatty acids show modest reductions in cardiovascular mortality and coronary events, folic acid lowers stroke risk in some large trials, and coenzyme Q10 (CoQ10) has been linked to reduced all‑cause mortality in pooled analyses [1] [2] [3]. Many other popular vitamins have null or harmful signals in randomized trials, and trial context (dose, population, background diet, primary vs secondary prevention) drives which supplements appear beneficial [4] [5] [1].
1. Omega‑3 fatty acids: the strongest, most consistent trial signal for fewer cardiac events
Meta‑analyses and evidence maps that pooled randomized controlled trials identify n‑3 (omega‑3) fatty acids as reducing cardiovascular mortality, myocardial infarction, and coronary heart disease events with moderate to high quality evidence—effects reported as statistically significant reductions in CVD mortality and MI [1] [6]. Individual trial results vary by dose, formulation, and background fish intake, but the overall randomized‑trial landscape supports a modest cardioprotective effect of n‑3 supplementation [7] [1].
2. Folic acid and B vitamins: stroke prevention in specific settings
Large randomized trials have shown folic acid, often given as part of B‑vitamin regimens, reduces stroke risk in certain populations—most notably the China Stroke Primary Prevention Trial, which randomized >20,000 hypertensive adults and found fewer ischemic strokes with folic acid added to enalapril [3] [8]. Systematic reviews and guideline syntheses similarly identify folate/B‑vitamin stroke reduction as a reproducible RCT finding, although benefits depend on baseline folate status and the form of B12 used [5] [8].
3. Coenzyme Q10 and selected antioxidants: promising signals but narrower evidence
Evidence maps report reductions in all‑cause mortality or improvements in risk factors with CoQ10 and several phytochemical antioxidants (CoQ10, flavanols, catechins, curcumin, quercetin, genistein) across RCTs, though the amount and consistency of trial data vary by compound [1] [2] [6]. Some RCTs and smaller randomized studies suggest blood‑pressure or surrogate improvements with CoQ10 and other agents, but the overall certainty is lower than for omega‑3s and folic acid and requires further large, event‑driven trials [1] [9].
4. Supplements that failed or harmed in randomized trials—sobering counterweights
High‑quality RCT syntheses find no cardiovascular benefit for common single vitamins such as vitamin D, vitamin C, vitamin E, and multivitamins, and identify harms from specific supplements: beta‑carotene was associated with increased all‑cause and cardiovascular mortality in pooled RCTs, and niacin increased all‑cause mortality when added to statin therapy in randomized studies [1] [10] [5]. Major guideline reviews (USPSTF and Cochrane‑level evidence syntheses) therefore conclude routine supplementation for CVD prevention is not supported for most vitamins [4] [11].
5. How to interpret this patchwork: populations, doses, and vested interests matter
Randomized evidence is heterogeneous—benefit signals often appear in trials with specific populations (e.g., low baseline nutrient status, recent MI, or hypertensive cohorts), particular formulations/doses, or adjunctive therapy contexts, and many reported associations derive from meta‑analytic maps rather than single definitive mega‑trials [1] [3] [12]. Industry and commercial interests can skew attention toward individual positive studies, and editorial commentary warns that promising antioxidant signals need consolidation in large outcome trials before altering practice [6]. Guideline bodies therefore urge obtaining nutrients from diet and reserve supplements for clinical indications or clear deficiencies [4] [8].
Bottom line
Randomized‑trial evidence most robustly supports omega‑3 (n‑3) fatty acids for modest reductions in cardiovascular death and coronary events, folic acid for stroke reduction in certain populations, and emergent but less definitive support for CoQ10 and several phytochemicals; conversely, routine use of many single vitamins is unsupported or harmful according to pooled RCTs and guideline reviews [1] [3] [2] [4] [5]. Trial context, baseline nutrient status, and the balance of harms versus modest benefit must guide interpretation, and large, targeted outcome trials remain necessary to convert several promising signals into standard recommendations [6] [1].