Across 29 randomised trials and 218,657 adults without a prior coronary event, benefit in primary prevention tracked statin intensity. At low-to-moderate ASCVD risk, high-intensity statins cut 3-point MACE (HR 0.53) more than moderate-intensity ones (HR 0.76). At high risk, evolocumab plus statin (HR 0.59), bempedoic acid (HR 0.64) and high-intensity statin (HR 0.80) all beat no therapy, while EPA and fibrates showed no benefit over a statin comparator.
The practical message is reassuringly conventional: the cheapest, best-studied drug class does most of the work, and how aggressively it lowers LDL matters more than which agent is chosen. That fits the long-standing Cholesterol Treatment Trialists' evidence that each unit of LDL reduction yields a proportional drop in events. The failure of EPA and fibrates to add value on top of statins also matches earlier trial disappointments, though fibrates did reduce 4-point MACE in lower-risk groups. Bempedoic acid emerges as a credible alternative for statin-intolerant patients, and evolocumab's add-on benefit is real but comes with cost and access barriers.
The caveats are substantial. Certainty was low or very low for 23 of 27 comparisons, no network contained a closed loop so consistency could not be tested, and heterogeneity was moderate (I² 59-62%). Indirect comparisons across trials spanning 1984-2026 mix very different populations and background care. Trials of newer agents often enrolled patients already near secondary-prevention risk, so the primary-prevention label is imperfect. This is confirmatory rather than paradigm-shifting; anyone weighing therapy should discuss their personal ASCVD risk with a clinician.