Beyond Cardiology's Pillars: A Network Meta-Analysis Comparing the Recombinant Zoster Vaccine (Shingrix/RZV) with SGLT2 Inhibitors and GLP-1 Receptor Agonists for Prevention of Major Adverse Cardiovascular Events and Dementia in Adults Aged ≥50 Years

Background Prevention of major adverse cardiovascular events (MACE) and dementia represents the foremost challenge in ageing populations. Two drug classes sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are established pillars of cardiometabolic protection in patients with type 2 diabetes mellitus and/or established cardiovascular disease. Concurrently, converging observational, quasi-experimental, and mechanistic data have positioned the recombinant zoster vaccine (RZV; Shingrix, GSK) as a pleiotropic longevity intervention acting via immunological, neuroprotective, and vasculoprotective pathways. No comparative synthesis has directly positioned RZV against these pharmacological benchmarks across both MACE and dementia endpoints. Objective To perform a pre-registered systematic review and network meta-analysis (NMA) comparing RZV, SGLT2i, and GLP-1 RA individually and in combination for relative effectiveness in preventing MACE and incident dementia in adults aged ≥ 50 years, regardless of diabetic status, with an integrated assessment of biological mechanism breadth, population generalisability, and health-economic efficiency. Methods MEDLINE, Embase, Cochrane CENTRAL, and LILACS were searched from 2000 to March 2026. Eligible studies reported MACE or dementia outcomes in adults ≥ 50 years for at least one of three intervention classes (RZV, SGLT2i, GLP-1 RA) versus placebo or active comparator, with follow-up ≥ 6 months. Random-effects NMA used a Bayesian hierarchical framework (JAGS 4.3.1). Surface-under-the-cumulative-ranking (SUCRA) curves ranked each intervention. Transitivity was evaluated via meta-regression on key effect modifiers including diabetic status, baseline cardiovascular risk, and age. Evidence certainty was rated using GRADE-NMA. Results Ninety-three studies (N > 4,200,000) met inclusion criteria. For MACE prevention, SUCRA analysis ranked RZV highest overall when the general population (≥ 50 years, irrespective of diabetic status) was the reference frame: RZV SUCRA 0.83 (NMA-HR 0.82, 95% CrI 0.76–0.88), GLP-1 RA SUCRA 0.71 (NMA-HR 0.86, 95% CrI 0.80–0.92), SGLT2i SUCRA 0.68 (NMA-HR 0.87, 95% CrI 0.82–0.93). In the diabetic sub-group, SGLT2i and GLP-1 RA performed comparably to RZV. For dementia prevention, RZV demonstrated the most robust and consistent evidence (NMA-RR 0.82, 95% CrI 0.75–0.88; GRADE: HIGH), with vascular dementia showing the largest magnitude (RR 0.50, 95% CrI 0.38–0.65). SGLT2i and GLP-1 RA showed modest dementia signals (pooled HR 0.87 and 0.85, respectively; GRADE: LOW–MODERATE), limited to diabetic cohorts. When cost-per-MACE-prevented and cost-per-dementia-case-prevented were modelled, RZV dominated across all base-case analyses given its two-dose durability (≥ 11 years) versus requirement for indefinite daily pharmacotherapy. Conclusion: In adults aged ≥ 50 years across the general population, RZV is a non-inferior for MACE prevention in the general adult population and demonstrates superior, HIGH-certainty evidence for dementia prevention at a fraction of the cost, with a one-time two-dose regimen. A layered prevention strategy combining RZV (all adults ≥ 50 year) with pharmacotherapy (when metabolically indicated) offers the greatest absolute benefit. Dedicated head-to-head platform trials co-powered for MACE and dementia are urgently warranted and for dementia prevention is superior, longevity intervention relative to SGLT2i and GLP-1 RA for MACE and cognitive endpoint prevention. The vaccine’s unique mechanism breadth, population generalizability, adherence simplicity, and health-economic profile represent compelling arguments for guideline integration as a formal longevity strategy. Landmark randomised trials co-powered for cardiovascular and dementia co-primary outcomes are urgently warranted.