Which randomized controlled trials compare ketogenic diets to other diets for long‑term reversal of NAFLD/MAFLD?
Executive summary
Randomized controlled trials directly testing ketogenic diets (KD or very‑low‑carbohydrate ketogenic diets, VLCKD) against other dietary strategies specifically for long‑term reversal of NAFLD/MAFLD are limited: a small number of RCTs compare VLCKD/KD to calorie‑restricted, low‑fat, Mediterranean or intermittent‑fasting regimens with liver fat or surrogate hepatic outcomes, but most are short to intermediate duration and underpowered for long‑term histologic “reversal” end points [1] [2] [3].
1. The handful of RCTs that exist: names, comparators, and what they measured
Notable randomized trials include Kirk et al., which randomized NAFLD patients to a VLCKD versus a low‑calorie control diet and found similar weight loss and decreases in intrahepatic triglyceride content from baseline but no between‑group difference at study end (reported in a review summarizing the trial) [1]; Holmer et al. conducted a randomized trial comparing intermittent calorie restriction to a low‑carbohydrate high‑fat diet in NAFLD patients over 12 weeks and is cited as a recent RCT addressing dietary strategies for NAFLD [1] [4]; and a randomized clinical trial in obese adults from Malaga compared a calorie‑restricted KD against a Mediterranean control (and other time‑restricted/fasting arms) for three months, showing KD was effective for short‑term weight loss though the trial focused on obesity rather than liver histology [5]. A 2025 randomized trial by Chirapongsathorn et al. is listed as examining KD effects on MASLD progression, indicating newer RCT evidence is emerging [6].
2. Short vs long term: most RCTs are short/intermediate and use surrogate outcomes
Many KD studies report rapid reductions in liver fat within days to weeks (for example, a 6‑day KD study showed marked liver‑fat decreases and metabolic changes) but these are acute physiological observations rather than long‑term reversal trials [2]. Reviews and umbrella analyses repeatedly emphasize that available randomized trials are often small, of brief duration, and frequently measure intrahepatic lipid content, liver enzymes, or imaging surrogates rather than long‑term histologic resolution of steatohepatitis or fibrosis that would constitute definitive “reversal” [3] [7].
3. What the aggregate evidence and meta‑analyses say — plus limitations
Meta‑analyses and umbrella reviews note that low‑carbohydrate and ketogenic approaches reduce intrahepatic lipid and produce greater long‑term weight loss compared with low‑fat diets in some pooled trials, but they caution heterogeneity, small sample sizes, surrogate outcomes, and limited long‑term histologic data [8] [7] [9]. Systematic reviews explicitly call for larger, longer RCTs focused on NAFLD/MAFLD endpoints because current trials either prioritize weight loss or are not powered to show regression of fibrosis or sustained disease remission [3] [7].
4. Balanced interpretation and hidden agendas in reporting
Enthusiastic reviews argue KD has plausible mechanisms (reduced inflammation, improved insulin sensitivity, altered hepatic mitochondrial flux) and potential to benefit NAFLD/MAFLD, and some RCTs support short‑term reductions in liver fat [10] [2]. Skeptical voices and methodological reviews point out that trials often compare different caloric prescriptions, prioritize weight loss as the mediator rather than macronutrient composition per se, and sometimes receive attention from advocates of low‑carb diets—creating a narrative bias toward KD benefits despite limited long‑term hepatic outcome data [3] [9]. Industry or specialty enthusiasm is not directly documented in the provided sources; however, calls for more rigorous RCTs and the recent emergence of new trials (e.g., Chirapongsathorn et al.) illustrate both scientific interest and the present evidence gap [6] [3].
5. Bottom line for the question asked: which RCTs compare KD to other diets for long‑term reversal?
Trials that directly compare KD/VLCKD to other diets in patients with NAFLD/MAFLD include Kirk et al. (VLCKD vs low‑calorie control), Holmer et al. (low‑carb high‑fat vs intermittent calorie restriction/SoC over 12 weeks), and several calorie‑restricted KD versus Mediterranean or low‑fat trials in obese populations that report short‑term hepatic or metabolic outcomes [1] [5] [4]. However, none of the cited RCTs reliably demonstrate long‑term histologic reversal of NAFLD/MAFLD over months-to-years, and systematic reviews emphasize that long‑term, liver‑histology–focused RCTs remain scarce [1] [3] [7]. Readers should interpret current RCT data as suggestive that KD can rapidly reduce liver fat and support weight loss, while recognizing that definitive long‑term reversal evidence from large RCTs is still lacking [2] [8].