reviewed by Vass Vassiliou

Yang et al. (2025) recently examined follow-up data from 6,409 individuals aged ≥75 years without cardiovascular disease (CVD), using the US population-based NHANES III cohort. The study is of particular importance as it addresses an underrepresented population-group in most lipid-lowering randomized controlled trials (RCTs), i.e., older adults. [1] The investigators observed that among older adult participants, 1,227 used lipid-lowering drugs. Over a median 6.5-year follow-up, use of these medications was associated with 26% lower all-cause mortality (HR 95% CI 0.67–0.81) and 36% lower cardiovascular mortality (HR 95% CI 0.54–0.76), with an average survival advantage of 1.6 years. The study’s findings are consistent with previous randomized controlled trials conducted in younger populations, which demonstrated that lipid-lowering therapy significantly reduces both all-cause and cardiovascular mortality. These findings have been integrated into the clinical guidelines of all major cardiovascular societies. [2-5]

Randomized controlled trials remain the cornerstone of evidence-based medicine, yet their external validity is often limited by the demographic composition of enrolled participants. Lipid-lowering therapies have been extensively studied in RCTs, but older adults, who carry the highest burden of atherosclerotic CVD, are frequently underrepresented. Several structural factors contribute to this gap. Most RCTs employ restrictive eligibility criteria, excluding patients with multimorbidity, polypharmacy, or frailty, all highly prevalent among individuals aged 70 years and older. Recruitment practices also tend to favor younger, healthier participants due to perceived safety concerns and anticipated adherence challenges. Furthermore, logistical barriers, including mobility limitations, cognitive impairment, and transportation difficulties, limit trial participation among the elderly.

The implications of this underrepresentation are significant and related to daily clinical practice. While subgroup analyses from large statin trials suggest that lipid-lowering therapies retain cardiovascular benefit in older adults, evidence is less robust for newer agents such as PCSK9 inhibitors and inclisiran, particularly regarding safety in the context of polypharmacy and frailty. As a result, clinicians face uncertainty when translating RCT evidence to real-world elderly populations, which may contribute to therapeutic inertia or suboptimal dosing. Addressing this evidence gap requires intentional trial design strategies. Broadening inclusion criteria, employing pragmatic and decentralized trial designs, and integrating real-world data from registries or electronic health records can improve representativeness. Adaptive trial methodologies and patient-centered approaches can also reduce participation barriers among older adults. Ensuring the inclusion of older adults in RCTs is essential not only for scientific validity but also for equitable cardiovascular care.

With the rapid aging of populations worldwide and the rising prevalence of CVD among older adults, robust evidence in this demographic has become increasingly critical. However, despite carrying the highest absolute risk for CVD events, elderly individuals remain markedly underrepresented in RCTs. This lack of representation limits the generalizability of existing trial evidence to those most affected by the disease. Generating high-quality data in this population-group is therefore essential to optimize treatment strategies, tailor therapeutic decisions to the unique physiological and clinical characteristics of aging patients and ultimately improve health outcomes. Strengthening the evidence base for older adults will not only help reduce morbidity and mortality but also support healthcare systems in addressing the growing burden of CVD in aging societies.