Effect Of Saroglitazar in Reducing Glycemic Parameters and Lipid Parameters Among Non-Alcoholic Steatohepatitis Patients - A Review Article

Abstract

Non-alcoholic steatohepatitis (NASH), a progressives form of non-alcoholic fatty liver disease (NAFLD), is increasingly prevalent due to the global rise in obesity and metabolic syndrome. It represents a significant and growing challenge in modern healthcare. It is a progressive form of NAFLD, characterized by hepatic steatosis accompanied by inflammation and hepatocellular injury, with or without fibrosis. While simple steatosis (fat accumulation) in the liver may remain benign for years, NASH poses a much greater threat due to its potential progression to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). The pathogenesis of NASH is complex and multifactorial, involving an intricate interplay between genetic predisposition, environmental factors, diet, and gut microbiota. Factors such as the presence of diabetes, obesity, and advanced fibrosis at baseline are associated with a higher risk of disease progression. Diabetic dyslipidemia is a major risk factor characterized by atherogenic lipid abnormalities commonly seen in patients with NASH. Notably, NASH-related cirrhosis is now a leading indication for liver transplantation in several countries. Despite its growing prevalence and significant health impact, there is currently no FDA-approved pharmacotherapy specifically for NASH. Saroglitazar, a novel agent with dual peroxisome proliferator-activated receptor (PPAR) activity, has emerged as a promising candidate in addressing this unmet need. In summary, saroglitazar offers a promising therapeutic approach for NASH by targeting critical elements such as lipid dysregulation, insulin resistance, hepatic steatosis, and inflammation.

Keywords

Introduction

The liver comprises lobes and functional units known as lobules^[1]. Hepatocytes, are main parenchymal cells, function like detoxification, protein synthesis, and metabolic regulation^[2,3]. The liver has dual blood supply from the hepatic artery and portal vein, vascular system. The liver is the central organ for metabolism, detoxification, and nutrient storage. It maintains homeostasis by regulating blood glucose, synthesizing proteins, metabolizing lipids, and clearing toxins^[2,3,4]. Hepatocytes, the main functional cells of the liver, are highly sensitive to metabolic changes. When exposed to chronic metabolic stress — such as insulin resistance, oxidative stress, and lipotoxicity — hepatocytes can undergo dysfunction, leading to fat accumulation, inflammation, and fibrosis.^[3,5] Non-alcoholic steatohepatitis (NASH) represents a progressive and potentially severe form of non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, lobular inflammation, hepatocellular ballooning, and varying degrees of fibrosis^[6]. Over the past few decades, the global prevalence of NASH has increased in parallel with the epidemics of obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome^[7]. This trend underscores the deep interconnection between metabolic disturbances and liver health. Importantly, NASH can occur in individuals who consume little or no alcohol, distinguishing it from alcoholic liver disease (ALD). The disease's silent clinical course often delays diagnosis until advanced stages, which can severely limit treatment options^[7,8]. Understanding the complexity of NASH requires an appreciation of normal liver anatomy and function, as well as the multifactorial processes that contribute to the onset and progression of the disease^[9,10]. However, managing NASH remains challenging due to its multifactorial pathogenesis and the limited availability of approved pharmacologic therapies. Current treatment strategies aim to address the underlying metabolic dysfunction, reduce hepatic inflammation and fibrosis, and prevent disease progression^[11,12]. Saroglitazar, approved in India for NASH, is a dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist^[12,13,14]. It modulates lipid metabolism and improves insulin sensitivity and hepatic inflammation. Clinical trials have demonstrated that saroglitazar leads to significant improvements in hepatic and metabolic parameters. Saroglitazar offers a promising therapeutic approach for NASH by targeting critical elements such as lipid dysregulation, insulin resistance, hepatic steatosis, and inflammation. Its dual PPAR-α/γ agonist properties enable a broad-spectrum effect that addresses the complex pathophysiology of the disease^[14,15,16].

PREVALENCE OF NASH

As lifestyles become more sedentary and diets rich in calories and processed foods become widespread, NASH has emerged as a significant global health concerns ^[17,18]. Globally, it is estimated that approximately 25% of the adult population has NAFLD. Among these individuals, a substantial proportion—approximately 20% to 30%—are believed to develop NASH. This suggests that around 3% to 6% of the global adult population may currently suffer from NASH. However, accurate estimation remains challenging due to the asymptomatic nature of early disease stages and the need for invasive liver biopsies for a definitive diagnosis.^[18] The burden of NASH varies considerably by region, reflecting differences in lifestyle, genetic predispositions, socioeconomic status, and healthcare access. In North America, NASH prevalence is notably high. Studies suggest that about 5% of adults in the United States are affected, driven mainly by the obesity and diabetes epidemics^[19,20]. In Europe, the situation mirrors that of North America, with prevalence estimates for NASH ranging from 2% to 5% of the adult population. Kingdom report higher rates, correlating with rising obesity and metabolic syndrome cases. Eastern European nations are also seeing a surge, although data from this region remain less comprehensives^[18,19,20]. The Middle East and North Africa have highest NAFLD and NASH rates globally, were NAFLD prevalence upwards of 30 ^[19,20].Public health surveillance in this region needs strengthening to better understand and address the emerging threat^[20].

ETIOPATHOGENESIS

The major factors contributing to the development of NASH include:

Insulin Resistance: Insulin resistance plays a central role by increasing the delivery of free fatty acids to the liver, stimulating hepatic lipid synthesis, and impairing fat breakdown. This imbalance results in lipid overload within liver cells, promoting oxidative damage and inflammation^[21,22]. Obesity and Metabolic Dysfunction: Excess adipose tissue, particularly around abdominal organs, releases inflammatory cytokines and free fatty acids, which contribute to liver fat accumulation and systemic inflammation. Conditions associated with metabolic syndrome—such as hypertension, dyslipidemia, and type 2 diabetes—further aggravate liver injury^[23]. Genetic Predisposition: Genetic variations, notably in genes like PNPLA3, TM6SF2, and MBOAT7, have been linked to higher risks of developing NASH. These genetic factors influence lipid metabolism, inflammatory responses, and fibrogenesis within the liver^[24,25]. Alterations in Gut Microbiota: Changes in the gut microbial environment can compromise intestinal barrier function, allowing bacterial endotoxins to enter the liver through the portal vein. These promote immune activation and enhance chronic hepatic inflammation^[26]. Lipotoxicity and Oxidative Stress: The accumulation of toxic lipid species induces oxidative stress and mitochondrial dysfunction in hepatocytes. This leads to cell injury, inflammation, and activation of fibrogenic pathways, which drive disease progression^[25,26]. Additional Contributing Factors: Certain endocrine disorders (such as hypothyroidism and polycystic ovary syndrome), use of specific medications (e.g., corticosteroids, tamoxifen), sleep apnea, and even environmental pollutants have been associated with increased risk of NASH^[27]. Dietary and Lifestyle Factors: High consumption of calorie-dense, sugar-rich, and fat-laden foods, coupled with a sedentary lifestyle, significantly increases the likelihood of hepatic fat deposition and metabolic disturbances that set the stage for NASH^[28].

DIAGNOSTIC APPROACH TO NASH

Clinically, NASH often presents silently, with patients either asymptomatic or exhibiting nonspecific symptoms such as fatigue. A history excluding significant alcohol intake and identifying metabolic risk factors (obesity, type 2 diabetes, dyslipidemia) is essential. Physical examination findings are often absent unless advanced liver disease has developed^[29]. Routine laboratory tests provide clues but are not diagnostic. Moderate elevations in ALT and AST are common, AST/ALT ratio get increased in advanced disease. Other useful parameters include lipid profiles, glucose levels, HbA1c, and serum ferritin. Non-invasive fibrosis scoring systems like FIB-4, NAFLD Fibrosis Score (NFS), and APRI help estimate the likelihood of significant fibrosis but cannot confirm NASH^[29,30]. Imaging studies are crucial for detecting hepatic steatosis. Ultrasound is the first-line tool, although its sensitivity diminishes for mild steatosis and it cannot assess inflammation or fibrosis. MRI-PDFF accurately quantifies liver fat, while transient elastography (FibroScan) and magnetic resonance elastography (MRE) assess liver stiffness, providing non-invasive fibrosis assessment^[31].

 Liver biopsy remains the gold standard for diagnosing NASH. These directly visualizes steatosis, inflammation, hepatocyte ballooning, and fibrosis^[32]. Emerging biomarkers, including cytokeratin-18 fragments, microRNAs, and metabolomic profiles, show promise for non-invasive diagnosis but require further validation^[33]. Artificial intelligence-based tools are also under exploration to enhance diagnostic precision by integrating clinical and imaging data^[34]. Current strategies recommend targeted screening of high-risk populations using non-invasive assessments to identify individuals who may need further evaluation by biopsy. As therapeutic options expand, accurate, early diagnosis will be increasingly vital for managing NASH effectively^[35].

SAROGLITAZAR IN NASH

Saroglitazar, a novel agent with dual peroxisome proliferator-activated receptor (PPAR) activity, has emerged as a promising candidate in addressing this unmet need^[36]. Saroglitazar exhibits predominant PPAR-α agonistic effects, along with moderate activation of PPAR-γ. PPAR-α is primarily responsible for enhancing fatty acid oxidation and improving lipid metabolism, leading to reduced triglyceride accumulation within the liver. Meanwhile, PPAR-γ activation enhances insulin sensitivity and suppresses inflammatory responses^[37]. The combined activation of these receptors by saroglitazar directly targets two major pathophysiological factors contributing to NASH: hepatic steatosis and metabolic dysregulation^[37,38]. Clinical trials have demonstrated that saroglitazar leads to significant improvements in hepatic and metabolic parameters. Reductions in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels suggest a decrease in liver inflammation and injury^[39]. Furthermore, imaging techniques such as MRI-PDFF have shown a measurable decline in liver fat content among patients treated with saroglitazar. Its positive effects on lipid profiles, including reductions in triglycerides and LDL cholesterol, and improvements in glycemic control further strengthen its therapeutic profile, particularly in patients who also suffer from type 2 diabetes mellitus or metabolic syndrome^[40].

IMPACT ON GLYCEMIC PARAMETERS

Several clinical trials and real-world studies have demonstrated the beneficial effects of saroglitazar on glycemic control:

Reduction in Fasting Plasma Glucose (FPG) and Postprandial Glucose (PPG): Saroglitazar has shown a consistent reduction in both FPG and PPG levels. This is attributed to its insulin-sensitizing action via PPARγ activation, which enhances glucose uptake in skeletal muscle and adipose tissue. Studies have reported a decrease in FPG by 10-20 mg/dL and a comparable decline in PPG values over 12-24 weeks of therapy.  Improvement in HbA1c: Glycated hemoglobin (HbA1c), a long-term marker of glycemic control, is significantly lowered in patients treated with saroglitazar. Clinical trials have demonstrated a reduction of approximately 0.5–1.0% in HbA1c after 12–24 weeks of treatment, indicating meaningful improvement in glucose homeostasis. Enhancement of Insulin Sensitivity: Saroglitazar improves insulin sensitivity as reflected by reductions in fasting insulin levels and homeostatic model assessment for insulin resistance (HOMA-IR) scores. This dual benefit can delay the progression of insulin resistance and the need for insulin therapy in diabetic patients.

EFFECT ON LIPID PARAMETERS

Significant Triglyceride Reduction: One of the hallmark effects of saroglitazar is its ability to lower serum triglycerides by 40–50% from baseline. This effect is primarily mediated through PPARα activation, which upregulates genes involved in β-oxidation of fatty acids and downregulates apolipoprotein C-III, an inhibitor of lipoprotein lipase. Reduction in Non-HDL and VLDL Cholesterol: Saroglitazar significantly reduces non-HDL-C and very low-density lipoprotein cholesterol (VLDL-C), both of which are atherogenic lipoproteins. These reductions are clinically meaningful for patients at high cardiovascular risk. Increase in HDL Cholesterol: High-density lipoprotein cholesterol (HDL-C), often termed "good cholesterol," is modestly increased by saroglitazar. Elevation in HDL-C is beneficial in reversing atherosclerosis and protecting against cardiovascular events. Minimal Impact on LDL Cholesterol: While the primary action of saroglitazar targets triglycerides, its effect on low-density lipoprotein cholesterol (LDL-C) is variable and often modest. However, in combination with statins, saroglitazar can provide comprehensive lipid control. A fundamental driver of disease progression in NASH is lipotoxicity, where the accumulation of toxic lipid species leads to hepatocyte injury and subsequent inflammation. Through PPAR-α activation, saroglitazar enhances β-oxidation of fatty acids, thereby reducing hepatic lipid overload. Its PPAR-γ-mediated actions improve insulin sensitivity, thereby reducing insulin-driven hepatic lipogenesis and systemic inflammation^[41,42]. This dual mechanism allows saroglitazar to comprehensively address the multifaceted nature of NASH.

ADVANTAGES OVER CONVENTIONAL THERAPIES

Unlike conventional lipid-lowering agents that primarily target one aspect of lipid metabolism, saroglitazar simultaneously improves lipid and glucose profiles. This dual benefit can potentially reduce the overall cardiovascular risk more effectively than single-target therapies^[43,44].

Moreover, saroglitazar’s favorable safety profile, with a low incidence of adverse effects such as edema and weight gain, makes it a viable option for long-term therapy in diabetic patients^[45].

DISCUSSION

Based on these evidences the topic was reviewed:

Double blinded placebo controlled randomized clinical trial were pooled to assess the impact of Saroglitazar 4mg on traditional lipids, VLDL and small dense LDL-C. Treatment with Saroglitazar significantly improved total cholesterol TRG, LDL, VLDL. Saroglitazar has the potential to not only affect liver disease and also reduce cardiovascular risk in patients with NASH. A single centered, non randomized study prospectively enrolled 91 patients attending the outpatient department of a tertiary care centre in New Delhi. Consenting obese [(BMI) greater than 23kg per meter square] patients of NASH aged between 18 and 65yrs. Participants with fatty liver on ultrasound was evaluated. The main findings of the single centre, non randomized study of Saroglitazar in  patients of NASH was well tolerated and was able to produce improvement in Transaminase level. This study confirmed the role of Saroglitazar in NASH patients by decreasing Hepatosteatosis when associated with weight reduction.  A prospective randomised comparative four arm interventional study of efficacy and safety of Saroglitazar and vitamin E in patients with NAFLD/ NASH the sample size included was 175. The study showed that Saroglitazar and vitamin E showed statistically significant reduction of LSM and CAP along with biochemical, glycaemic and lipid parameters.

CONCLUSION

NASH is a progressive liver disease with rising global impact. While lifestyle modification remains the cornerstone of treatment, pharmacological interventions like saroglitazar offer promising adjunctive benefits.The pathogenesis of NASH is complex and multifactorial, the "two-hit" hypothesis was proposed to explain disease progression, where the first hit involved hepatic steatosis and the second involved oxidative stress and inflammation. However, more recent understanding favors a "multiple parallel hits" model, suggesting that various factors simultaneously contribute to liver injury. As therapeutic options expand, accurate, early diagnosis will be increasingly vital for managing NASH effectively. The treatment of non-alcoholic steatohepatitis is evolving rapidly. Lifestyle modification, particularly weight loss, remains the foundation of therapy. Saroglitazar offers a promising therapeutic approach for NASH by targeting critical elements such as lipid dysregulation, insulin resistance, hepatic steatosis, and inflammation. Its dual PPAR-α/γ agonist properties enable a broad-spectrum effect that addresses the complex pathophysiology of the disease. Although further large-scale histological studies are awaited to confirm its role in reversing fibrosis and achieving histological remission of NASH, existing evidence positions saroglitazar as an important potential addition to future NASH treatment strategies.

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