Are there proven ways to reduce or eliminate NASH?
Executive summary
There are proven ways to improve and in many cases reverse NASH-related liver injury: sustained weight loss through diet, exercise or bariatric surgery improves steatosis, inflammation and—sometimes—fibrosis; and in March 2024 the FDA granted accelerated approval to resmetirom (Rezdiffra) as the first drug for adults with noncirrhotic NASH and moderate–advanced fibrosis (F2–F3), with roughly a quarter of trial patients showing fibrosis improvement on treatment [1] [2] [3]. Multiple investigational drugs and combination approaches are in late-stage testing, but most remain experimental [4] [5].
1. Weight loss is the backbone — and it changes liver histology
Decades of evidence and guideline authors put lifestyle-driven weight loss at the center of NASH care: losing body weight by diet and increased physical activity reduces liver fat, inflammation and can improve fibrosis; large bariatric surgery series report >80% NASH resolution for steatosis and steatohepatitis and substantial fibrosis regression years after surgery (pooled estimates: steatosis improvement ~91.6%, steatohepatitis ~81.3%, fibrosis ~65.5%) [6] [7] [8]. Clinical reviews and expert guidelines therefore treat weight reduction and Mediterranean-style dietary approaches as first-line therapy [5] [9].
2. Exercise matters independent of weight loss
Randomized and observational studies cited in recent reviews show that structured exercise—including high-intensity interval training—can reduce liver fat and improve liver enzymes even without large weight changes; exercise is therefore a distinct, proven therapeutic element alongside dietary restriction [10] [11].
3. Bariatric surgery can “cure” NASH for many patients — but selection and timing matter
Meta-analyses of bariatric cohorts show dramatic histologic improvements and durable fibrosis regression in a majority of patients, establishing that marked, sustained weight loss can reverse NASH pathology in many cases; professional societies record that surgical weight loss is effective but emphasize careful patient selection and note it is not yet universally framed as a standard NASH drug alternative [7] [6].
4. For years, there were no approved drugs — that changed with resmetirom
Until recently, clinicians relied on off‑label use of agents such as pioglitazone or vitamin E in select patients and on lifestyle measures; the FDA’s accelerated approval of resmetirom (Rezdiffra) in March 2024 is the first regulatory green light for a NASH drug for adults with noncirrhotic NASH and fibrosis, with trial data showing about 23–28% of treated patients achieved fibrosis improvement versus ~13–15% on placebo in one-year analyses [1] [2] [3]. Clinical reviews position resmetirom as an option to be used with diet and exercise [1] [3].
5. Many promising drugs are in the “race” but evidence varies
Industry and academic reporting catalog a crowded late‑stage pipeline — PPAR agonists (lanifibranor), FGF21 analogs, GLP‑1 combinations, and other mechanisms — with some phase 2 signals for liver-fat reduction and histological endpoints but mixed results historically and several high‑profile failures (for example, obeticholic acid was rejected by FDA after safety/efficacy concerns) [4] [5] [12]. Reviews stress that MRI-PDFF (≥30% fat reduction) correlates with histologic improvement but that demonstrating long-term clinical benefit (reduced cirrhosis, mortality) requires longer trials [5].
6. Combination strategies and cardiometabolic context are critical
Experts argue any effective NASH treatment must target underlying metabolic drivers (insulin resistance, dyslipidemia, obesity). Early data suggest combining agents (e.g., FGF21 analogs with GLP‑1s) can amplify liver-fat reduction, while cardiometabolic outcomes must be tracked because NASH patients face cardiovascular risks that influence net benefit [13] [6].
7. Limitations, uncertainties and real‑world access
Evidence limitations include reliance on liver biopsy endpoints with reader variability, short durations for many trials relative to slow disease progression, and accelerated approval pathways that require post‑marketing confirmation; resmetirom’s approval rests on a subset of patients showing fibrosis improvement and must be integrated with lifestyle care [5] [1] [3]. Access, cost and long-term safety remain open questions as the field shifts from lifestyle-only management to drug-plus-lifestyle models [14] [15].
8. Practical takeaways for patients and clinicians
Current, proven actions remain: prioritize sustained weight loss through diet and exercise; consider bariatric surgery when appropriate for durable, large-weight-loss candidates; and for adults with biopsy‑confirmed noncirrhotic NASH and F2–F3 fibrosis, resmetirom is an FDA‑approved pharmacologic option to use alongside lifestyle measures—while other drugs are promising but investigational [8] [7] [1] [2].
Limitations of this briefing: sources emphasize evolving science and regulatory updates; long‑term outcome data and broader post‑approval experience for new drugs are still emerging and vary between reports [5] [4].