Metabolic Health

Metabolic health is glucose, lipids, body composition, and the liver — the cardiometabolic axis that drives most preventable death. It is also the corner of this database with the strongest evidence and the largest effect sizes, because the endpoints here (LDL cholesterol, HbA1c, body weight, cardiovascular events) are measurable and have been tested in some of the biggest outcome trials in medicine. When you see an A-tier score in this category, it usually rests on hard event data, not surrogate markers.

What actually has the evidence

Statins (rosuvastatin, atorvastatin) are the reference standard: decades of outcome trials and the Cholesterol Treatment Trialists meta-analyses show roughly a 20–25% drop in major vascular events per ~1 mmol/L of LDL lowering. PCSK9 inhibitors stack on top — evolocumab (FOURIER, 2017) and alirocumab (ODYSSEY OUTCOMES, 2018) lowered LDL further and cut events in already-treated patients; inclisiran does it with a twice-yearly injection. For high triglycerides on a statin, icosapent ethyl (REDUCE-IT, 2018) reduced cardiovascular events by about 25%.

The GLP-1 / GIP drugs changed the weight-loss conversation. Semaglutide produced roughly 15% average weight loss in STEP-1 (2021) and, more importantly, cut major cardiovascular events by about 20% in people with established heart disease and no diabetes in SELECT (2023). Tirzepatide (a dual GLP-1/GIP agonist) reached roughly 21% weight loss in SURMOUNT-1 (2022). These score well on both evidence and benefit — the open question is durability after stopping.

The investigational frontier

Retatrutide, a triple GLP-1/GIP/glucagon agonist, hit roughly 24% weight loss at 48 weeks in its Phase 2 trial (2023); the Phase 3 TRIUMPH programme is ongoing, so it stays investigational here. Lp(a)-lowering RNA therapies (pelacarsen, olpasiran) are the first drugs aimed at a genetic risk factor that diet and statins barely touch — the pelacarsen Lp(a)HORIZON cardiovascular outcomes readout is expected in 2026, which is the event that would move its tier. Resmetirom (Rezdiffra) became the first FDA-approved drug for MASH (fatty liver) in 2024.

Evidence and safety gaps

Berberine is marketed as "nature’s Ozempic." Small trials report modest improvements in glucose and lipids, with effect estimates substantially below those reported for GLP-1 drugs. Trials of rapid weight-loss interventions also report some loss of lean mass, with resistance training and adequate protein studied as modifiers. DNP appears here because reported rapid fat loss coexists with fatal hyperthermia and documented deaths; its separate Benefit and Safety axes make that divergence visible.