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Saroglitazar for non-obese metabolic-dysfunction associated steatotic liver disease (MASLD): An open-label randomised controlled trial
For correspondence: Dr Arka De, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India e-mail: arkascore@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Bhagat N, De A, Duseja A, Ganesh CP, Kumar M, Mehta M, et al. Saroglitazar for non-obese NAFLD/MASLD: An open-label randomised controlled trial. Indian J Med Res. 2026;163:477-85. doi: 10.25259/IJMR_2953_2025
Abstract
Background and objectives
Nearly one-third of individuals with metabolic dysfunction–associated steatotic liver disease (MASLD)/non-alcoholic fatty liver disease (NAFLD) are non-obese, yet evidence for pharmacotherapy in this subgroup remains limited. This study assessed the safety and effectiveness of saroglitazar among non-obese individuals with MASLD/NAFLD.
Methods
In this open-label randomised controlled trial (RCT), non-obese [body mass index (BMI) <25 kg/m2] adults with NAFLD/MASLD and raised alanine aminotransferase levels (ALT >50 U/L) were allocated in a 1:1 ratio to either saroglitazar (4 mg/day) combined with lifestyle modification (Group A) or lifestyle intervention alone (Group B) for a period of six months. The trial was registered with clinical trial registry (CTRI/2022/09/046081). The primary outcome was the change in controlled attenuation parameter (CAP). Secondary outcomes included changes in anthropometric measures, insulin resistance, glycaemic indices, lipid profile, ALT, fibroscan–aspartate aminotransferase (FAST) score, hepatic steatosis index (HSI), non-invasive fibrosis markers [liver stiffness measurement (LSM), fibrosis-4 (FIB-4), aspartate aminotransferase to platelet ratio index (APRI),], and adverse events.
Results
Sixty-six participants (33 per group) completed the study. Both groups showed significant reductions in CAP; however, the median change in CAP did not differ between the two groups [24 dB/m (9–48.8) vs. 14 dB/m (−4.5 to 50); P=0.52]. Alterations in BMI and waist circumference were similar between groups. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) [0.68 (0.14–1.69) vs. −0.51 (−1.12 to 0.44); P=0.03], triglycerides [34 (−1.5 to 76.8) vs. −10 (−28.5 to 20.5) mg/dL; P=0.006], and ALT (43.7±36.7 vs. 28.1±21.5 U/L; P=0.04) were significantly improved in the saroglitazar group. Changes in HSI, FAST score, APRI, FIB-4, and liver stiffness were similar between groups. No serious adverse events were observed.
Interpretation and conclusions
In non-obese NAFLD/MASLD patients, the combination of saroglitazar with lifestyle changes over a period of six months improved insulin resistance, triglycerides, and ALT but did not confer additional benefit over lifestyle intervention alone for non-invasive hepatic steatosis or liver fibrosis markers.
Keywords
Insulin resistance
MASLD
NAFLD
Non-obese NAFLD
Saroglitazar
Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), represents one of the leading causes of chronic liver disease worldwide, affecting nearly one-third of the global population.1 In India, prevalence rates range from 9 to 53%, reflecting marked geographic and urban–rural heterogeneity.2 Although obesity is a major risk factor, approximately one-third of patients with NAFLD/MASLD are non-obese, indicating that factors beyond excess body weight contribute to hepatic steatosis.3
Non-obese patients with NAFLD/MASLD generally exhibit a comparatively favourable metabolic risk profile, with lower prevalence of diabetes, hypertension, and metabolic syndrome than obese patients. However, accumulating evidence indicates that this apparent metabolic advantage does not translate into a more benign liver disease course. Evidence from extensive cohort and population-level investigations demonstrates that the burden of significant and advanced fibrosis among non-obese individuals with NAFLD/MASLD is comparable to—and in certain contexts exceeds—that of obese counterparts.4-6 In the NASH-CO study, individuals with a lean phenotype exhibited increased rates of advanced fibrosis and heightened susceptibility to liver-related complications, chronic kidney disease, and death.7 Similarly, a meta-analysis by Ha et al8 demonstrated that overall and cardiovascular mortality did not differ between lean and non-lean NAFLD/MASLD individuals, although lean patients experienced a substantially increased rate of liver-related mortality.8 Data from India further support these findings, with lean MASLD patients demonstrating histological and clinical severity comparable to those of obese individuals.9,10 Collectively, these observations underscore that body mass index alone is an unreliable predictor of disease severity and progression.
Management of non-obese NAFLD/MASLD poses a clinical challenge, as weight reduction—the cornerstone of therapy in obese patients—may be limited by already normal body weight. Although lifestyle modification remains first-line therapy, its long-term efficacy in non-obese individuals is variable, and pharmacotherapeutic options for this subgroup remain poorly defined. Agents recommended by expert guidelines, such as vitamin E and pioglitazone,11-13 have not been specifically evaluated in non-obese patients, and several newer agents in advanced clinical trials have excluded patients with normal body mass index (BMI).
Saroglitazar, a dual peroxisome proliferator–activated receptor (PPAR)-α/γ agonist, has received regulatory approval in India for the treatment of NAFLD/MASLD based on its favourable effects on insulin resistance, hepatic inflammation, and dyslipidaemia. Goyal et al14 reported significant improvements in liver enzymes, liver stiffness, controlled attenuation parameter, and metabolic indices; however, the absence of a lifestyle-only comparator and predominance of obese patients limited attribution of benefit to saroglitazar alone.14 In a small phase-2 randomised controlled trial (RCT), Siddiqui et al15 demonstrated biochemical and histological improvements with saroglitazar, but the study was underpowered for fibrosis outcomes and did not stratify patients by body mass index.15 The only large randomised controlled trial (EVIDENCES IV), systematically excluded patients with normal BMI, leaving a critical evidence gap for non-obese NAFLD/MASLD.16
We conducted an open-label RCT to evaluate the efficacy and safety of saroglitazar in non-obese patients with NAFLD/MASLD, comparing saroglitazar plus lifestyle intervention with lifestyle intervention alone over six months using non-invasive hepatic and metabolic endpoints.
Methods
Study design and ethical approval
This prospective, open-label, RCT was conducted at the department of Hepatology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India between October 2022 and December 2023. The Institutional Ethics Committee granted approval, and the trial was prospectively registered with the Clinical Trials Registry–India (CTRI/2022/09/046081). The research conformed to the principles of the Declaration of Helsinki and was reported in alignment with consolidated standards of reporting trials guidelines ( Figure).
Study population
Adults aged ≥18 yr with body mass index (BMI) <25 kg/m2 with NAFLD/MASLD, and alanine aminotransferase (ALT) >50 U/L were eligible. NAFLD/MASLD was diagnosed based on imaging or histology after exclusion of secondary causes of steatosis. Participants consuming >20 g/day of alcohol were excluded. Screening included viral hepatitis markers, autoimmune hepatitis profile, celiac serology, and tests for Wilson disease and haemochromatosis.
Hepatic steatosis on ultrasonography was defined by increased hepatic echogenicity relative to the renal cortex and graded as mild, moderate, or severe. A controlled attenuation parameter (CAP) value >248 dB/m on FibroScan or compatible histology was also considered diagnostic. Exclusion criteria included cirrhosis [liver stiffness measurement (LSM)>13.6 kPa], hepatocellular carcinoma or other malignancy, pregnancy or lactation, use of vitamin E or pioglitazone, severe comorbid illness precluding protocol adherence, and refusal to consent.
Randomisation and interventions
Eligible participants were randomised in a 1:1 fashion based on a computer-generated list created by an independent statistician. Allocation concealment was achieved through the use of sequentially numbered, opaque, sealed envelopes. Group A received saroglitazar 4 mg once daily plus lifestyle intervention, while Group B received lifestyle intervention alone for six months.
Participants on stable background medications for diabetes, hypertension, or dyslipidemia (unchanged dose for >6 wk) were allowed to continue therapy. Drugs known to significantly affect body weight were not permitted.
Lifestyle intervention
All participants were advised to undertake moderate-intensity aerobic exercise for 30–45 min on at least five days per wk. Each participant received an individualised dietary plan from a qualified dietitian who was blinded to treatment allocation. Dietary advice followed American Dietetic Association recommendations, emphasising increased intake of fruits and vegetables, moderate complex carbohydrates, restriction of saturated fats, and low–glycaemic index foods, with portion sizes tailored to energy requirements.
Dietary counselling was provided at baseline and reinforced at six-weekly intervals. Dietary adherence was assessed using food record diaries and 24-h dietary recall over three consecutive days, with average caloric and protein intake calculated. Dietary plans were modified and counselling reinforced where required.
Monitoring and follow up
Baseline demographic and clinical data, including metabolic comorbidities, were recorded. Anthropometric measurements included BMI and waist circumference, measured by a trained investigator blinded to treatment allocation. Central obesity was defined as a waist circumference >90 cm in men and >80 cm in women.11 This anthropometric assessment was done by a trained fellow who was blinded from the allocated routes and was not involved in the management of the patient.
Laboratory assessments included complete blood counts, liver function tests, renal function tests, lipid profile, fasting glucose, HbA1c, and fasting insulin. FibroScan (Echosens, Paris) measurements for CAP and liver stiffness were performed by a trained technician blinded to allocation. Steatosis severity was categorised as follows: absent (S0: <248 dB/m), mild (S1: 248–<268 dB/m), moderate (S2: 268–<280 dB/m), and severe (S3: ≥280 dB/m).17 To minimise observer variability, CAP was assessed using vibration-controlled transient elastography with ≥10 valid measurements, a success rate >80%, and an interquartile range/median <20%. Assessments were performed at baseline and six months, while laboratory parameters were repeated at baseline, three months, and six months. homeostasis model assessment-estimated insulin resistance (HOMA-IR), hepatic steatosis index (HSI), fibroscan–aspartate aminotransferase (FAST) score, fibrosis-4 (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI) were calculated using standard formulae. Medication adherence was assessed at each visit using pill counts and patient self-report. All adverse events were monitored and graded based on the common terminology criteria for adverse events (CTCAE), version 5.0.
Outcomes
The primary outcome assessed was the six-month change in hepatic steatosis, quantified using CAP. Secondary outcomes included variations in BMI, waist circumference, HOMA-IR, glycaemic measures, lipid parameters, ALT, HSI, FAST score, and non-invasive fibrosis indices (LSM, APRI, and FIB-4), in addition to adverse events.
As the study was conducted in a non-obese, predominantly non-diabetic population and validated CAP responder thresholds for such cohorts were unavailable at the time of study design, CAP change was analysed as a continuous variable, and no categorical CAP endpoint was prespecified. A ≥30 dB/m reduction in CAP was explored post hoc as a clinically meaningful change, based on prior biopsy-validated and reproducibility studies.17,18 We acknowledge that this outcome was not prespecified at trial registration.
Sample size calculation
Sample size estimation was based on a randomised phase-II trial16 in which saroglitazar 4 mg produced a numerical reduction in CAP of −25.4±55.6 dB/m compared with a 4.5±56.6 dB/m increase in the placebo group. Using this observed effect size, with an alpha error of 0.05 and 80% power, 33 participants per group were required. Allowing for a 10% attrition rate, 36 participants were planned per group.
Statistical analysis
Statistical analyses were carried out using GraphPad Prism (v9.5.1). Normality of the data was examined with the D’Agostino–Pearson test. Depending on the distribution, continuous variables are presented as mean with standard deviation or as median with interquartile range, whereas categorical data are shown as percentages. Comparisons between study groups employed either the unpaired t-test or the Mann–Whitney U test. Within-group changes were evaluated using paired t-tests or the Wilcoxon signed-rank test. Proportional differences were examined using chi-square or Fisher’s exact testing. Significance was defined at a two-sided P value of 0.05 or below.
Results
Study population
A total of 72 non-obese patients (BMI <25 kg/m2) with NAFLD/MASLD were enrolled and randomised equally to receive saroglitazar plus lifestyle intervention (Group A) or lifestyle intervention alone (Group B). Three participants in each group were lost to follow up within the first week, prior to initiation of the allocated intervention. Consequently, 33 patients in each group were included in the modified intention-to-treat analysis. All 66 participants completed the six-month follow-up period ( Figure).
Baseline characteristics
Baseline demographic, anthropometric, biochemical, and non-invasive hepatic parameters were comparable between the two groups ( Table I). The median age was 34.5 years, and 77% of participants were male. Median BMI was similar in Group A and Group B [24.03 (22.73–24.71) vs. 24.15 (22.97–24.73) kg/m2; P=0.84]. Approximately 60% of participants in both groups had central obesity as per Indian cut-offs. The prevalence of diabetes, hypertension, and dyslipidemia did not differ significantly between groups. Baseline ALT, CAP, HSI, FAST score, APRI, FIB-4, and liver stiffness measurements were also comparable. Intra and intergroup comparisons between various parameters were listed in Table II and Table III, respectively.
| Parameters |
Group A (n=33) Saroglitazar 4 mg once/day with lifestyle interventions |
Group B (n=33) Lifestyle interventions alone |
P value |
|---|---|---|---|
| Age (yr) | 34.5 (28.5 to 43.2) | 34.5 (27 to 39.7) | 0.306 |
| Gender | |||
|
Male Female |
25 (77.78%) 8 (22.22%) |
25 (77.78%) 8 (22.22%) |
0.999 |
| BMI (kg/m2) | 24.03 (22.73 to 24.71) | 24.15 (22.97 to 24.73) | 0.839 |
| Abdominal circumference (cm) | 90.9±4.76 | 89.0±5.07 | 0.104 |
|
Centrally obese Male Female |
21 (63.6%) 13 (52%) 8 (100%) |
20 (60.6%) 12 (48%) 8 (100%) |
0.799 0.804 0.999 |
| Dyslipidemia | 17 (51.5%) | 15 (45.5%) | 0.622 |
| Type 2 diabetes mellitus | 3 (9.1%) | 2 (6.1%) | 0.643 |
| Hypertension | 2 (6.1%) | 0 | 0.151 |
| Aspartate aminotransferase [AST] (U/L) | 39 (25.2 to 61) | 34 (24.2 to 46.7) | 0.104 |
| Alanine aminotransferase [ALT] (U/L) | 61 (56 to 98.5) | 61 (57.5 to 73) | 0.114 |
| HbA1c (%) | 5.5 (5.02 to 5.7) | 5.4 (5.2 to 5.65) | 0.520 |
| Fasting Blood Sugar [FBS] (mg/dl) | 92.5 (86.5 to 98.5) | 90 (88 to 97) | 0.319 |
| Total cholesterol (mg/dl) | 175.5 (155.3 to 204.8) | 185 (163.5 to 193.5) | 0.478 |
| Triglyceride (mg/dl) | 133 (109 to 226.3) | 106 (86 to 156.5) | 0.210 |
| High-density lipoprotein [HDL] (mg/dl) | 44.41±11.68 | 45.15±9.92 | 0.786 |
| Low-density lipoprotein [LDL] (mg/dl) | 111.5 (92 to 134.3) | 113 (98 to 129.5) | 0.631 |
| Homeostasis model Assessment of insulin resistance [HOMA IR] | 2.06 (1.97 to 3.45) | 2.32 (1.49 to 2.93) | 0.795 |
|
Controlled attenuation parameter [CAP] (dB/m) S1 (248 to <268 dB/m) S2 (268 to <280 dB/m) S3 (≥280 dB/m) |
295.5 (267.5 to 325.3) 8 (24.3%) 5 (15.1%) 20 (60.6%) |
275 (258.5 to 329) 10 (30.3%) 7 (21.2%) 16 (48.5%) |
0.513 0.606 |
| Hepatic steatosis index [HSI] | 40.7 (35.3 to 45.1) | 41.1 (38.5 to 46.4) | 0.288 |
| FibroScan-AST [FAST] Score | 0.33±0.21 | 0.25±0.18 | 0.109 |
| AST-to-platelet ratio index [APRI] | 0.47 (0.32 to 0.72) | 0.36 (0.24 to 0.49) | 0.105 |
| FibroScan-AST Score [FIB4] | 0.84 (0.44 to 1.3) | 0.60 (0.43 to 0.73) | 0.223 |
| Liver stiffness measurement [LSM] (kPa) | 5.7 (4.62 to 6.95) | 5.75 (4.62 to 6.5) | 0.692 |
Values are expressed as mean±standard deviation, median (interquartile range), or number (%). BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; CAP, controlled attenuation parameter; HSI, hepatic steatosis index; FAST, fibroScan-AST Score; APRI, AST-to-platelet ratio index; FIB-4, fibrosis-4 index; LSM, liver stiffness measurement
| Parameters | Group A (n=33) | Group B (n=33) | ||||
|---|---|---|---|---|---|---|
| Baseline (n=33) | 6 months follow-up (n=33) | P value | Baseline (n=33) | 6 months follow-up (n=33) | P value | |
| BMI (kg/m2) | 24.0 (22.73 to 24.71) | 23.1 (22.26 to 24.48) | 0.001 | 24.1 (22.97 to 24.73) | 23.6 (22.56 to 24.44) | 0.009 |
| Abdominal circumference (cm) | 90.9±4.76 | 90.38±5.20 | 0.001 | 89.03±5.07 | 88.79±4.72 | 0.572 |
| ALT (U/L) | 61 (56 to 98.5) | 32 (20 to 54.75) | 0.001 | 61 (57.5 to 73) | 37 (23 to 47) | 0.001 |
| HbA1c (%) | 5.5 (5.02 to 5.7) | 5.4 (4.82 to 5.57) | 0.005 | 5.4 (5.2 to 5.65) | 5.3 (5.0 to 5.65) | 0.075 |
| Total cholesterol (mg/dl) | 180.2±40.1 | 165.5±32.1 | 0.038 | 186.7±32.5 | 179.3±29.1 | 0.176 |
| Triglyceride (mg/dl) | 133 (109 to 226.3) | 94.5 (74 to 153.5) | 0.004 | 106 (86 to 156.5) | 122 (78.5 to 155.5) | 0.777 |
| HDL (mg/dl) | 42.5 (35.3 to 50.7) | 48 (42 to 56) | 0.022 | 44 (38.2 to 51.7) | 45 (40 to 52) | 0.306 |
| LDL (mg/dl) | 111.5 (92 to 134.3) | 92 (80 to 114.8) | 0.005 | 113 (98 to 129.5) | 107 (87 to 135) | 0.302 |
| HOMA IR | 2.06 (1.97 to 3.45) | 1.45 (1.01 to 1.93) | 0.017 | 2.32 (1.49 to 2.93) | 2.64 (1.50 to 3.37) | 0.813 |
| CAP (dB/m) | 295.5 (267.5 to 325.3) | 267.2 ± 49.2 | 0.001 | 275 (258.5 to 329) | 267.7 ± 42.97 | 0.001 |
| HIS | 40.7 (35.3 to 45.1) | 32.7 (30 to 33.9) | 0.001 | 41.1 (38.5 to 46.4) | 33.9 (31.5 to 37.6) | 0.001 |
| FAST score | 0.27 (0.17 to 0.45) | 0.18 (0.11 to 0.27) | 0.001 | 0.20 (0.09 to 0.38) | 0.16 (0.08 to 0.24) | 0.013 |
| APRI | 0.47 (0.32 to 0.72) | 0.39 (0.33 to 0.50) | 0.018 | 0.36 (0.24 to 0.49) | 0.35 (0.19 to 0.48) | 0.211 |
| FIB4 | 0.84 (0.44 to 1.3) | 0.92 (0.64 to 1.52) | 0.483 | 0.60 (0.43 to 0.73) | 0.85 (0.52 to 1.02) | 0.284 |
| LSM (kPa) | 5.7 (4.62 to 6.95) | 4.9 (4.1 to 5.5) | 0.001 | 5.75 (4.62 to 6.5) | 5.6 (4.5 to 6.0) | 0.368 |
Values are expressed as mean±standard deviation or median (interquartile range). P values represent within-group comparisons between baseline and 6-month follow up.
| Parameters |
Group A (n=33) Saroglitazar 4 mg once/day with lifestyle interventions |
Group B (n=33) Lifestyle interventions alone |
P value |
|---|---|---|---|
| ΔBMI (kg/m2) | 0.47±0.75 | 0.28±0.59 | 0.272 |
| Δ% body weight change | 1.50 (0 to 4.46) | 1.24 (0 to 1.84) | 0.259 |
| Patients with weight loss >3% | 13 (39.3%) | 10 (28.6%) | 0.346 |
| ΔAbdominal circumference(cm) | 0.69±1.21 | 0.51±2.45 | 0.704 |
| ΔALT (U/L) | 43.7±36.7 | 28.12±21.5 | 0.042 |
| Patients with ALT improvement >17 | 29 (89.8%) | 22 (66.7%) | 0.043 |
| ΔHOMA IR | 0.68 (0.14 to 1.69) | -0.51 (-1.12 to 0.44) | 0.034 |
| ΔHbA1c (%) | 0.15 (0.02 to 0.37) | 0.1 (-0.1 to 0.35) | 0.303 |
| Δtotal Cholesterol (mg/dl) | 15 (-5.75 to 38) | 4 (-16.5 to 30) | 0.399 |
| ΔTriglyceride (mg/dl) | 34 (-1.5 to 76.75) | -10 (-28.5 to 20.5) | 0.006 |
| ΔHDL(mg/dl) | -3.8 (-11 to 1.75) | -1.0 (-3.5 to 2.5) | 0.535 |
| ΔLDL(mg/dl) | 10.5 (-2.75 to 39.75) | 7 (-13.5 to 28.5) | 0.167 |
| ΔCAP (dB/m) | 24 (9 to 48.75) | 14 (-4.5 to 50) | 0.516 |
| Patients with improvement of CAP ≥30 dB/m | 16 (48.5%) | 14(42.4%) | 0.62 |
| Patients with resolution of steatosis(CAP <248dB/m) | 9 (27.3%) | 9 (27.3%) | 0.999 |
| Patients with improvement of steatosis by ≥1 grade | 20 (60.6%) | 15 (45.5%) | 0.217 |
| ΔHSI | 8.53±7.94 | 8.35±8.18 | 0.929 |
| ΔFAST Score | 0.09 (0 to 0.18) | 0.04 (-0.01 to 0.11) | 0.291 |
| ΔAPRI | 0.07 (-0.04 to 0.28) | 0.01 (-0.05 to 0.12) | 0.106 |
| ΔFIB4 | -0.14 (0.51 to 0.14) | -0.15 (-0.31 to 0.04) | 0.951 |
| ΔLSM (kPa) | 0.65 (0.2 to 1.1) | 0.2 (-0.5 to 1) | 0.102 |
Values are expressed as mean±standard deviation, median (interquartile range), or number (%). Δ indicates change from baseline to 6-month follow up. P values represent between-group comparisons
Primary outcome
Both groups demonstrated a significant reduction in CAP at six months compared with baseline. However, the median change in CAP (ΔCAP) did not differ significantly between Group A and Group B [24 dB/m (9 to 48.75) vs. 14 dB/m (−4.5 to 50), P=0.52] ( Table III).
The proportion of patients achieving resolution of steatosis (CAP <248 dB/m) was identical in both groups (27.3% each; P=0.99). Similarly, patients with ≥1 grade improvement in steatosis between both groups did not differ significantly (60.6% vs. 45.5%; P=0.22).
Secondary outcomes
Anthropometric parameters
Both groups showed modest but significant reductions in BMI at six months; however, the between-group difference in ΔBMI was not significant (0.47±0.75 vs. 0.28±0.59 kg/m2; P=0.27). Percentage weight loss and the proportion of patients achieving >3% weight reduction was also comparable between groups ( Table III). Changes in abdominal circumference were similar between Group A and Group B (P=0.70).
Metabolic parameters
Improvement in insulin resistance was significantly greater in Group A. The median ΔHOMA-IR was +0.68 (0.14 to 1.69) in Group A compared with −0.51 (−1.12 to 0.44) in Group B (P=0.03).
Triglyceride reduction was also significantly greater in Group A [Δ 34 mg/dL (−1.5 to 76.75) vs. −10 mg/dL (−28.5 to 20.5); P=0.006]. Changes in total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and HbA1c did not differ significantly between groups ( Table III).
Biochemical and non-invasive liver disease assessment parameters
Serum ALT levels declined significantly in both groups; however, the reduction was greater in Group A (ΔALT 43.7±36.7 U/L vs. 28.1±21.5 U/L; P=0.04). A higher proportion of patients in Group A achieved an ALT reduction >17 U/L (89.8% vs. 66.7%; P=0.04).
Both groups demonstrated significant improvements in HSI and FAST scores at six months, but between-group differences in ΔHSI and ΔFAST were not significant. No significant between-group differences were observed for changes in APRI, FIB-4, or liver stiffness measurements. Using a post hoc exploratory threshold of a ≥30 dB/m reduction in CAP, 16 of 33 patients (48.5%) in the saroglitazar group and 14 of 33 patients (42.4%) in the lifestyle-only group achieved a clinically meaningful improvement, with no significant between-group difference (P=0.62) ( Table III).
Adverse events
Saroglitazar was generally well tolerated. No grade 3 or 4 adverse events, or treatment discontinuations were reported. All adverse events were mild (CTCAE grade 1–2). These included nausea (12% vs. 6%), abdominal pain (6% vs. 3%), and cough with diarrhoea (3% vs. 0%) (Table IV). The incidence of weight gain was comparable between Group A and Group B (15% vs. 6%; P=0.23).
| Adverse event |
Group A (n=33) Saroglitazar 4 mg once/day with lifestyle interventions |
Group B (n=33) Lifestyle interventions alone |
|---|---|---|
| Nausea | 4 (12) | 2 (6) |
| Abdominal pain | 2 (6) | 1 (3) |
| Cough with diarrhoea | 1 (3) | 0 |
| Weight gain | 5 (15) | 2 (6) |
| Grade 3–4 adverse events | 0 | 0 |
| Serious adverse events | 0 | 0 |
| Treatment discontinuation due to AEs | 0 | 0 |
Values are expressed as a number (%). All adverse events were mild to moderate (CTCAE grade 1–2). CTCAE, common terminology criteria for adverse events
Discussion
In this open-label RCT involving non-obese patients with NAFLD/MASLD, the addition of saroglitazar (PPAR-α/γ agonist)19,20 to lifestyle intervention resulted in significant improvements in insulin resistance, triglyceride levels, and ALT compared with lifestyle intervention alone. However, saroglitazar did not demonstrate superiority over lifestyle modification with respect to the primary endpoint of change in CAP or other non-invasive markers of hepatic steatosis, steatohepatitis, and fibrosis over a six-month period. it suggests that lifestyle-related factors, including modest weight loss, may have been major contributors to steatosis improvement in this non-obese cohort. These findings suggest that while saroglitazar confers metabolic and biochemical benefits, these do not translate into additional improvement in hepatic surrogate endpoints beyond that achieved with optimised lifestyle measures in non-obese individuals, at least in the short-term.
Several Indian and international studies have reported improvements in non-invasive markers of hepatic steatosis, steatohepatitis, and early fibrosis (grades 1–3) with saroglitazar; however, most were single-arm studies lacking comparison with lifestyle intervention alone.14-16,21-25 An important observation of this study was that more than 3% weight reduction occurred in one-third of participants, a threshold associated with meaningful improvement in hepatic steatosis in lean individuals.26 This likely explains the comparable reductions in CAP, HSI, FAST score, and fibrosis indices across both groups, underscoring the potency of lifestyle intervention even in non-obese NAFLD/MASLD. The dissociation observed between metabolic improvement and hepatic surrogate response may reflect the relatively short duration of therapy, early disease stage, or limitations in the sensitivity of non-invasive markers to detect incremental treatment effects in this phenotype.
This study has certain limitations that warrant consideration. It was a relatively small, open-label RCT and was not powered to detect modest between-group differences, particularly for fibrosis assessment. CAP was selected as a pragmatic, liver-specific surrogate of hepatic steatosis. Concerns regarding operator dependence were addressed through strict FibroScan quality criteria (≥10 valid measurements, success rate >80%, IQR/median <20%). Moreover, all our patients were non-obese, predominantly non-diabetic, a population, in which CAP has been shown to have less variability and high correlation with histologic accuracy. However, it remains less sensitive than histology or MRI-based techniques for detecting small incremental changes. Insulin resistance, a clinically relevant and mechanistically important outcome for saroglitazar, improved significantly, but was evaluated as a secondary endpoint, and the study was not powered for this. In addition, the six-month follow-up period, low baseline liver stiffness values, early disease stage, and limited burden of metabolic comorbidities in this non-obese cohort may have constrained the ability to demonstrate changes in fibrosis-related indices. The absence of histological assessment or magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) further limits definitive inference regarding structural hepatic changes, and therefore, the findings should be interpreted as exploratory.
Despite these limitations, this study addresses an important evidence gap by specifically evaluating saroglitazar in non-obese NAFLD/MASLD using a lifestyle-only comparator arm. These results emphasise the central role of lifestyle modification in non-obese NAFLD/MASLD and suggest that future trials should be larger, adequately powered, blinded, and of longer duration, with more sensitive and clinically meaningful primary endpoints to better define the role of pharmacotherapy in this increasingly recognised phenotype.
Declaration
This study was presented as an oral/poster presentation at the INASL 2023 Annual Conference, and the abstract was published in the Journal of Clinical and Experimental Hepatology (Supplement of conference abstracts). doi: 10.1016/j.jceh.2023.07.183
Author contributions
NB: Patient recruitment, data analysis, manuscript writing; ARD: Conceptualisation, patient recruitment, data curation, data analysis, manuscript writing; AD: Conceptualisation, patient recruitment, data curation and critical revision; GC: Data collection; MK: investigation; MM: Investigation; ST: Patient recruitment and critical revision; NS: Investigation; VS: Patient recruitment and critical revision.
Financial support and sponsorship
The study was partially funded by Society for Study of Liver Disease (SSLD) (SSLD/1/2022).
Conflicts of Interest
None.
Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation
The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.
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