Effect of Addition of Saroglitazar to Lifestyle Modifications in Patients with Nonalcoholic Fatty Liver Disease: A Prospective Observational Study

Abstract

Objective:

Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder with significant health implications. This study aims to evaluate the effect of adding Saroglitazar to lifestyle modifications in improving NAFLD-related parameters compared to lifestyle modifications alone.

Methodology:

A prospective observational study was conducted at the Outpatient Department of Gastroenterology, M. S. Ramaiah Hospitals, including patients diagnosed with NAFLD. Patients were divided into two groups: Group 1 received lifestyle modification counseling, and Group 2 received Saroglitazar 4 mg OD in addition to lifestyle modification counseling for 12 weeks. Liver function tests and ultrasonographic findings were assessed at baseline and after 12 weeks.

Results:

A statistically significant improvement (P = 0.02) in alanine transaminase (ALT) levels was observed within the treatment Group 2, along with a trend of improvement in aspartate transaminase (AST) levels (P = 0.07). However, no significant difference in AST and ALT levels was found between the groups. Ultrasonographic improvements were noted in few patients receiving Saroglitazar, and the drug was well tolerated, with minor adverse events such as nausea and fatigue.

Conclusions:

The addition of Saroglitazar to lifestyle modifications showed a beneficial effect in improving NAFLD-related parameters over 12 weeks compared to lifestyle modifications alone.

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver conditions, ranging from simple steatosis, characterized by fat accumulation without inflammation, to nonalcoholic steatohepatitis (NASH), which involves liver inflammation and damage.[1] If left untreated, NASH can lead to cirrhosis, liver failure, and hepatocellular carcinoma. The global prevalence of NAFLD is rising alongside increasing obesity and diabetes rates, affecting approximately 32% of the adult population. The estimated annual incidence is 46.9 cases per 1000 person-years, with males being significantly more affected than females.[2]

NAFLD management consists of nonpharmacological and pharmacological approaches. Lifestyle modifications, including dietary interventions and regular physical activity, play a central role in preventing and treating the disease. Studies suggest that the Mediterranean diet improves liver health beyond simple weight loss benefits. A weight reduction of 3%–5% can lead to improvements in NAFLD, while a loss of 7%–10% is necessary for resolving steatohepatitis and fibrosis.[3] Despite these strategies, long-term adherence to lifestyle modifications remains a challenge, necessitating the exploration of pharmacological treatments. Several drugs have been studied for NAFLD treatment, including metformin, thiazolidinediones, sodium glucose transporters-2 inhibitors, and Vitamin E.[3]

In addition, peroxisome proliferator-activated receptors (PPARs) have gained attention due to their role in regulating metabolism, inflammation, and cellular function. PPARs exist in three isoforms – PPARα, PPARβ/δ, and PPARγ – each influencing different metabolic pathways.[4] Glitazars, dual PPARα and PPARγ agonists, were explored for NAFLD treatment due to their ability to target dyslipidemia and insulin resistance. Saroglitazar, a novel glitazar with a predominant PPARα effect and moderate PPARγ activation, has shown promise in improving lipid metabolism and insulin sensitivity without significant side effects, making it a potential candidate for NAFLD management.[4]

Despite promising initial results, there is limited research on the safety and efficacy of Saroglitazar in the Indian population. Therefore, this study was undertaken to evaluate the safety and effectiveness of Saroglitazar in NAFLD patients, particularly in comparison to lifestyle modifications alone.

METHODOLOGY

This was a prospective observational study conducted from August 2022 to June 2024 at M. S. Ramaiah Hospitals, focusing on NAFLD patients diagnosed according to the American Association for the Study of Liver Diseases[5] 2018 criteria. The primary aim was to evaluate the efficacy and safety of Saroglitazar in NAFLD patients compared to lifestyle modifications alone. The study was approved by the M. S. Ramaiah Medical College’s Ethics Committee (MSRMC/EC/PG-3/07-2022).

Inclusion criteria

• Patients aged ≥18 years with NAFLD

• Willing to provide informed consent

• Confirmed hepatic steatosis by imaging or histology

• No significant alcohol consumption (males: <210 g/week or 21 drinks/week and females: <140 g/week or 14 drinks/week)

• No competing etiologies for hepatic steatosis or coexisting chronic liver diseases.

Exclusion criteria

• History of excess alcohol consumption

• Positive hepatitis B surface antigen or anti-hepatitis C virus

• Recent use of metformin, pioglitazone, or statins

• Severe cardiac, renal, or malignant diseases

• Use of herbal medications for NAFLD

• Pregnant and lactating women.

Study procedure

This prospective observational study was conducted on NAFLD patients visiting the Department of Gastroenterology, Ramaiah Hospitals. Written informed consent was taken from all the patients who were willing to participate in the study. All the relevant data including the demographic profile, preexisting diseases, drugs received by the patient, and the relevant available investigation reports such as liver function tests (LFTs) and ultrasonography (USG) findings were collected during the initial visit. Patients were divided into two groups based on the treatment advised by the treating gastroenterologist:

• Group 1: Lifestyle modifications alone

• Group 2: Saroglitazar 4 mg OD along with lifestyle modifications [Figure 1].

Figure 1.

Study flowchart

Lifestyle modifications included low-calorie diet (750 kcal less than required), protein intake (1–1.5 g/kg body weight), and 200 min of exercise per week.

The efficacy of the treatment was assessed based on the change in LFTs (alanine transaminase [ALT] and aspartate transaminase [AST]) from the baseline to end of week 12 of treatment between the two groups. The safety of the treatment was assessed by analyzing the treatment emergent adverse effects (TEAEs) to Saroglitazar, and causality assessment was done using Naranjo’s scale.[6]

Sample size estimation

Based on a study done by Goyal et al.,[4] Saroglitazar was expected to reduce ALT levels from 94 IU to 39 IU over 24 weeks. With 80% power and a 95% confidence level, a minimum of 31 subjects per group (total 62 patients) was required.

Statistical analysis

Descriptive statistics were used for ALT and AST levels (mean ± standard deviation). Paired t-test was used to compare baseline and week 12 values within groups. Independent t-test was used to compare changes between the two groups. All statistical analyses were conducted using IBM SPSS version 29.0 (IBM Corporation; Armonk, New York, USA).

RESULTS AND DISCUSSION

The study population consisted of 39 (62.90%) males and 23 (37.10%) females, which was similar to previous studies by Roy et al. (70% of males and 30% of females)[7] and Riazi et al., who reported a higher NAFLD incidence in males (70.8 cases per 1000 person-years) compared to females (26.9 cases per 1000 person-years).[2] The mean age of study subjects was 49.06 ± 11.81 years, consistent with the findings by Choudhari et al. (49.1 ± 11.09 years)[8] and Jaiswal et al. (46.8 ± 20 years).[9]

Baseline AST and ALT values were higher in Group 2 when compared to Group 1. There was a statistically significant difference in AST and ALT values between the two groups as mentioned in Table 1. At the end of 12 weeks, there was an increase in AST and ALT levels in Group 1 (P = 0.061), while there was a decrease in AST levels in Group 2 (P = 0.074) as shown in Figures 2 and 3, respectively.

Table 1.

Baseline characteristics of the study subjects

Characteristics	Group 1, (n=31) mean±SD	Group 2, (n=31) mean±SD	P
Age (years)	54±10.74	47.69±12.14	0.034*
AST (IU)	20.9±07.40	26.29±09.23	0.014*
ALT (IU)	21.52±11.88	30.19±15.46	0.016*
ALP (IU)	77.65±26.51	87.07±32.85	0.224
GGT (IU)	35.33±42.47	28.30±15.35	0.778

*P<0.05 – Statistically significant. SD=Standard deviation, AST=Aspartate transaminase, ALT=Alanine transaminase, ALP=Alkaline phosphatase, GGT=Gamma-glutamyl transferase

Figure 2.

Graphical representation of pre- and posttreatment liver function test levels in Group 1. P value: aspartate transaminase – 0.061, alanine transaminase – 0.151, alkaline phosphatase – 0.14, gamma-glutamyl transferase – 0.944. AST: Aspartate transaminase, ALT: Alanine transaminase, ALP: Alkaline phosphatase, GGT: Gamma-glutamyl transferase

Figure 3.

Graphical representation of pre and post treatment liver function test levels in Group 2. P value: aspartate transaminase – 0.074, alanine transaminase – 0.02*, alkaline phosphatase – 0.18, gamma-glutamyl transferase – 0.69 (*P < 0.05 significant). AST: Aspartate transaminase, ALT: Alanine transaminase, ALP: Alkaline phosphatase, GGT: Gamma-glutamyl transferase

AST levels decreased in Group 2, but were not statistically significant (P = 0.074). A study by Rajesh et al. showed a similar nonsignificant AST reduction (P = 0.07),[1] whereas ALT levels showed a statistically significant decrease (P = 0.02) in Group 2 at the end of week 12 as shown in Figure 3, consistent with the findings by Rajesh et al.,[1] Roy et al.,[7] and Jaiswal et al.[9]

We compared the change in LFT values at the end of 12 weeks between the groups. There was no statistically significant difference observed for AST, ALT, and gamma-glutamyl transferase values. Only alkaline phosphatase levels showed a statistically significant decrease at the end of week 12 as shown in Table 2.

Table 2.

Comparison of LFT values between groups at the end of week 12

Parameter (IU)	Group 1, mean±SD	Group 2, mean±SD	P
AST	23.68±9.61	23.06±9.98	0.806
ALT	23.58±15.76	25.19±14.83	0.680
ALP	90.7±31.60	72.23±29.57	0.022*
GGT	35.17±40.29	27.23±17.35	0.319

*P<0.05 – Statistically significant. LFT=Liver function test, SD=Standard deviation, AST=Aspartate transaminase, ALT=Alanine transaminase, ALP=Alkaline phosphatase, GGT=Gamma-glutamyl transferase

Ultrasonography findings

In Group 1, the baseline USG findings were of Grade 1 fatty liver for majority (80.64%) of the patients, whereas in the treatment group, the baseline USG findings were of Grade 2 fatty liver for majority (77.41%) of the patients. At the end of 12 weeks, only few patients had posttreatment USG findings. In Group 2, four patients showed resolving findings and one patient had the same findings as at baseline. In Group 1, one patient showed disease progression, two patients had unchanged findings, and one patient demonstrated resolving features. Posttreatment, ultrasonographic improvements were observed in the Saroglitazar group, consistent with a study done by Rajesh et al.[1]

Treatment emergent adverse events

Most patients tolerated the drug, but few patients (n = 2) experienced fatigue and nausea, but none required treatment discontinuation. TEAEs were classified as possible according to Naranjo’s scale. Previous studies done by Goyal et al.[4] and Padole et al.[10] also showed similar findings.

CONCLUSIONS

In the present study, we observed that the overall effect of addition of Saroglitazar to lifestyle modifications was better in improving NAFLD-related parameters compared to lifestyle modifications alone over a period of 12 weeks. The limitations of our study are as follows: there was a statistically significant difference observed in few of the baseline characteristics (age and AST and ALT levels) as this was an observational study. Adherence to lifestyle modifications was not strictly monitored and long-term benefits and risks of Saroglitazar were not assessed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.