Therapeutic insights into Saroglitazar: a dual PPAR- α/γ agonist targeting diabetic dyslipidaemia and NAFLD

Priyanka Pinto, Lavanya K*, Dr. Manjari Sharma

Department of Pharmacy Practice, PESU Institute of Pharmacy, PES University, Bangalore, Karnataka.

*Correspondence: lavanyak91410@gmail.com

DOI: https://doi.org/10.71431/IJRPAS.2025.41202

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disorder ranging from simple steatosis (more than 5% of hepatocyte fat accumulation) to non-alcoholic steatohepatitis (NASH) (hepatic inflammation with or without fibrosis) to fibrosis, cirrhosis, progressing to end-stage liver disease and eventually hepatocellular carcinoma. It has emerged as a global health problem [1]. NAFLD, which affects over 25% of the world's population, is related to metabolic illnesses, particularly type 2 diabetes mellitus (T2DM) [2]. When compared to normal people, individuals with type II diabetes mellitus (DM) have an increased risk of developing cardiovascular complications [3-5]. Among various contributing factors, diabetic dyslipidemia, manifested by atherogenic lipid abnormalities and chronic low-grade inflammation, is the leading cause of atherosclerosis-related morbidity and mortality, as well as diminished quality of life [6]. These metabolic changes are due to insulin resistance, which causes oxidative stress and pro-inflammatory cytokine release (e.g., TNF-α, IL-6, MCP-1). Persistent cytokine activation impairs endothelial function and reduces nitric oxide bioavailability, thereby boosting adhesion molecules, leading to atherosclerosis acceleration [7]. In these patients, cardiovascular disease (CVD) is increased significantly due to the influence of LDL-C cholesterol; despite statin therapy effectively lowering LDL-C, a significant residual cardiovascular risk persists, emphasizing the need for agents that target both metabolic derangements and vascular inflammation. Saroglitazar is one such agent that was approved in India for the management of diabetic dyslipidemia since 2013 [8-10]. Saroglitazar addresses this need through its dual PPAR-α/γ agonist action, which not only ameliorates lipid abnormalities but also improves insulin sensitivity and reduces inflammation, thereby targeting key pathways underlying NAFLD/NASH and cardiovascular risk in these patients [11]. Earlier dual PPAR agonists like muraglitazar, tesaglitazar, and aleglitazar were discontinued due to safety concerns such as weight gain, fluid retention, cardiac events, or renal toxicity despite their favorable metabolic effects. The advent of Saroglitazar overcomes the safety limitations encountered with earlier glitazars by selectively balancing PPAR-α and PPAR-γ activation [8]. In the evolving healthcare setting, genetic factors are identified as important contributors to the development and progression of a certain type of disease. Therefore, addressing such factors using a precision medicine approach is crucial.

METHODS

To identify appropriate studies, a comprehensive literature search was conducted using PubMed, Embase, Clinicaltrials.gov, and Google Scholar using “Saroglitazar,” “PPAR agonist,” “diabetic dyslipidemia,” " NAFLD/NASH," “anti-inflammatory,” “endothelial dysfunction,” and “cardiovascular risk” individually and in combination. Articles published between January 2001 and October 2025 were considered, with more emphasis on recently published ones (2015-2025). It included preclinical investigations, human clinical trials (randomized or observational), and review articles on the efficacy, safety, or mechanism-based insights of Saroglitazar in diabetic dyslipidemia or NAFLD/NASH available in English, excluding case reports, editorials without original data, and conference abstracts. Also, studies unrelated to dyslipidemia, diabetes, or cardiovascular outcomes were excluded.

REGULATORY APPROVALS

Saroglitazar was first approved by the drug controller general of India in 2013 as an antidiabetic agent in patients with diabetic dyslipidemia and hypertriglyceridemia that could not be taken under control by traditional statin therapy [12]. It was later approved as an adjunct to metformin in January 2020 and thereafter, since March 2020, has been available as a treatment option for patients with non-cirrhotic non-alcoholic steatohepatitis (NASH) [13] and, since December 2020, for non-alcoholic fatty liver disease (NAFLD), making it the world’s first approved drug especially for NASH/NAFLD [14].

Although it has not received marketing approval as of November 2025 in the United States and Europe, in July 2021, the European Medicines Agency granted orphan drug designation to it for the treatment of primary biliary cholangitis (PBC) [15]. Similarly, the FDA has granted it both Orphan Drug and Fast Track designations for the treatment of primary biliary cholangitis, reflecting its therapeutic promise in rare cholestatic liver diseases and highlighting its potential beyond metabolic and hepatic disorders [16].

MECHANISM OF ACTION OF SAROGLITAZAR: DUAL PPAR- α/γ AGONISM

Saroglitazar acts majorly as a PPARα (peroxisome proliferator-activated receptor) with moderate PPARγ activity, making it a dual PPAR-α/γ agonist; therefore, it provides the synergistic benefit of lipid modulation and glycemic control along with improved insulin sensitization [17, 18]. As a PPARα agonist, it increases the activity of lipoprotein lipase, which in turn hydrolyzes triglycerides (TG) packed into chylomicrons and VLDL in the bloodstream, leading to the generation of free fatty acids (FFA), thereby enhancing the hepatic absorption of more fatty acids than usual, along with elevated hepatic fatty acid breakdown. It also lowers VLDL and TG production and secretion, together with enhanced synthesis of Apo AI and Apo AII, which increases HDL-C. It also inhibits the expression of Apo CIII and therefore facilitates TG clearance [19, 20]. As a PPARγ agonist, it primarily promotes the uptake of fatty acids by subcutaneous adipose tissue instead of visceral adipose tissue by promoting adipocyte differentiation. This reduction in circulating fatty acids decreases accumulation of lipids in pancreatic beta cells, thereby improving beta cell function and insulin secretion in response to rising blood glucose, hence decreasing glucose levels in blood through GLUT4-induced glucose uptake in the liver [20, 21]. It also contributes to improved insulin sensitivity in peripheral tissues and the reduction in glycosylated hemoglobin (HbA1c) levels in the blood [22].

Pharmacokinetically, Saroglitazar magnesium is efficiently absorbed orally and is primarily metabolized in the liver. Its minimal renal excretion supports effective hepatic targeting, optimizing its efficacy in correcting dyslipidemia and insulin resistance [14]. Therefore, through its dual mechanism of action, it shows superiority to agents targeting only one pathway.

Saroglitazar in NAFLD/NASH

Saroglitazar is presently emerging as a potential treatment for NAFLD/NASH, especially in patients with dyslipidemia and type 2 diabetes [13]. Apart from its effect on lipid parameters and insulin sensitivity, it also revealed significant dose-dependent reductions in liver fat content, along with improvements in hepatic enzymes, especially ALT and AST. Evidence from a meta-analysis by Das S et al., which showed a mean reduction in ALT as 26.01 U/L and AST as 19.68 U/L after supplementary therapy with 4 mg Saroglitazar, and a study by Padole P et al., support these observations [23, 24]. This interaction occurs through its dual PPAR α/γ action, which tackles the underlying pathophysiological mechanisms of NAFLD/NASH, which lowers hepatic damage and subsequent reductions in ALT and AST levels [25]. It is also well tolerated, with minimum adverse effects reported so far when compared to gastrointestinal disorders with liraglutide, edema, fractures, and weight gain with pioglitazone [26-28], and also pruritus with obeticholic acid [29]. Therefore, Saroglitazar is the emerging efficacious and safe drug for treating NAFLD/NASH.

ONGOING CLINICAL TRIALS / INVESTIGATIONAL APPLICATIONS

Primary biliary cholangitis (PBC)

The EPICS-III Phase 2b/3 Trial (NCT05133336) was conducted from April 1, 2022, and the study was completed in May 2025. It is a double-blinded, multicentric, placebo-controlled, randomized phase 2b/3 study that evaluates the safety and efficacy of Saroglitazar magnesium in patients with PBC, and the study results are not yet submitted [30]. Another multicentric, phase 3 open-label extension trial that evaluates the safety and effectiveness of Saroglitazar in patients with PBC (NCT06427395) is ongoing from July 2024, with expected completion in 2027 [31].

Non-alcoholic steatohepatitis (NASH)/ Non-alcoholic fatty liver disease (NAFLD)

A study of Saroglitazar magnesium for the treatment of non-alcoholic steatohepatitis with fibrosis (NASH) (NCT05011305), which started in 2021 and is estimated to be completed in 2025, is a Phase 2b, multicenter, double-blind, prospective, randomized, placebo-controlled trial that investigates its efficacy and safety [32]. Another study, which evaluates the efficacy and safety of Saroglitazar 4 mg in people with NAFLD associated with comorbidities (NCT05872269), is a phase 4, open-label, non-randomized, single-arm, multicenter trial that began in 2023 and is expected to be completed in 2025 [33].

A detailed summary of major metabolic drug classes and their effects on lipid parameters, glycemic control, inflammation, cardiovascular outcomes, and safety is shown in Table 1.

Table 1: Overview of Drug Classes Targeting Metabolic Pathways Relevant to NAFLD and NASH

Compared to other agents such as statins, fibrates, thiazolidinediones, SGLT2 inhibitors, and PCSK9 inhibitors, Saroglitazar is distinguished as the only approved dual PPAR-α/γ agonist that simultaneously improves lipid, glycemic, and inflammatory parameters. Its balanced receptor activation profile makes Saroglitazar a promising treatment option for individuals with diabetic dyslipidemia and NAFLD/NASH. Although its safety profile is favorable, robust clinical trials to prove its long term cardiovascular effects are still needed.

BIOMARKER OVERVIEW:

linking inflammation and atherosclerosis in diabetic dyslipidemia

Diabetes is a chronic systemic inflammation marked by sustained elevated levels of inflammatory markers in individuals with the condition [79]. Inflammation plays a significant role in the development of atherosclerosis, with inflammatory markers such as high-sensitivity CRP, interleukin-6 (IL-6), lipoprotein associated phospholipase A2 (Lp-PLA2), and leukocyte counts being strongly linked to cardiovascular disease (CVD) [80, 81].

 Studies have examined the connection between these inflammatory markers and their correlation with coronary atherosclerosis, especially in relation to diabetic dyslipidemia, where inflammation accelerates vascular damage [82]. CRP is produced and secreted by hepatocytes, an acute-phase protein with a molecular weight of 115 kDa; production is stimulated by pro-inflammatory cytokines such as IL-6, IL-1, and TNF-α [83].

It acts as a hallmark of the acute-phase response and a strong predictor of cardiovascular events secondary to atherosclerosis [84]. Increased CRP levels were observed in both type 2 DM and prediabetic states. Importantly, CRP is now considered not only as an inflammatory marker but also as a promising therapeutic target in managing metabolic and cardiovascular diseases [85].

Among several pro-inflammatory cytokines, interleukin-6 is elevated two- to threefold higher in type 2 DM, where it directly contributes to insulin resistance [86]. IL-6-induced upregulation of adhesion molecules promotes the initiation, formation, and instability of atherosclerotic plaques, thereby increasing cardiovascular risk in diabetic dyslipidemia [87]. Lipoprotein-associated phospholipase A2 (Lp-PLA2), also called platelet-activating factor acetyl hydrolase [88], is an enzyme mainly carried on LDL that increases with obesity, heightening the risk of cardiovascular disease (CVD) [89].

In the blood, approximately 80% of Lp-PLA₂ is attached to LDL particles, while around 20% is attached to HDL under normal conditions. However, in type 2 diabetes, this distribution becomes altered, with a greater portion bound to LDL (atherogenic) and a small fraction to HDL (protective). This balance is disturbed, shifting the balance toward an atherogenic profile and increasing the cardiovascular risk [90].

White blood cells (WBCs) are elevated in patients with type 2 diabetes and are associated with macro- and microvascular complications, reflecting cardiovascular risk and representing a potential intervention target in diabetic dyslipidemia [91]. Diabetic dyslipidemia is marked not only by elevated hs-CRP but also low levels of adiponectin. Adiponectin, produced by adipose tissue, plays a central role in regulating blood sugar, lipids, and inflammation. Low levels increase the risk of atherosclerosis in diabetes [92, 93]. Hs-CRP and adiponectin exhibit an inverse relationship. Compared to healthy individuals, those with metabolic syndrome are characterized by lower adiponectin and higher hs-CRP levels [94], with reduced adiponectin concentrations contributing to adverse lipid alterations such as reduced HDL-C and elevated triglycerides [95]. Consequently, hypoadiponectinemia in T2DM integrates pathways of inflammation, dyslipidemia, and cardiovascular risk [96].

Anti-inflammatory and Endothelial Protective Effects of Saroglitazar

In multiple preclinical animal studies (NASH and cardiotoxicity models), Saroglitazar has shown promising effects beyond lipid-glycemic control. It has been shown to improve the functioning of endothelium and reduce pro-inflammatory molecules. Akbari et al. investigated the effects of Saroglitazar on inflammatory mediators and metabolic effects in an animal model of non-alcoholic steatohepatitis (NASH). The study reported that dual PPAR-α/γ activation significantly decreased hepatic pro-inflammatory cytokines such as TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1), while increasing serum adiponectin levels compared to controls through suppression of NF-kB-mediated inflammatory signaling. Hence, Saroglitazar exhibits anti-inflammatory and adiponectin-enhancing properties that may contribute to lowering cardiovascular risk in patients with type 2 diabetes and diabetic dyslipidemia [97]. Similarly, Rasheed et al. [18] investigated that Saroglitazar significantly reduced cardiac injury markers (CK-MB, LDH, and troponin I) and inflammatory mediators, including CRP, TNF-α, and IL-1β, in rats compared to the control group. Saroglitazar also improved antioxidant status; based on these findings, it exhibits anti-inflammatory and cardioprotective effects. In human clinical trials, Gawrieh S et al. [13] investigated and found that Saroglitazar showed significant improvements in lipid profile, glycemic control, and adiponectin levels. These findings support the anti-inflammatory, antioxidant, and cardiometabolic benefits of Saroglitazar.

In diabetic dyslipidemia, the combined effects of insulin resistance, hyperglycemia, abnormal triglycerides, lipoprotein profiles, and impaired HDL function collectively lead to endothelial injury by enhanced oxidative stress, inflammation, and nitric oxide (NO) dysregulation that altogether promote vascular dysfunction and thrombosis leading to atherosclerosis [98, 99]. In real-world human studies of Saroglitazar in diabetic dyslipidemia, improvements have been reported in lipid and glycemic markers; however, dedicated human studies assessing endothelial function are lacking. Although direct evidence is unavailable, its metabolic and anti-inflammatory properties may indirectly contribute to improved vascular health [100, 101].

DUAL PPAR- α/γ AGONISTS: DISTINCTIVE EFFICACY AND SAFETY PROFILE

An overview of dual PPAR-α/γ agonists, including their efficacy, safety concerns, metabolic effects, and regulatory outcomes, is presented in Table 2.

Table 2: Dual PPAR-α/γ agonists: distinctive efficacy and safety profile.

Saroglitazar is the only dual PPAR-α/γ agonist developed to address both efficacy and safety limitations encountered with earlier glitazars such as Muraglitazar, Tesaglitazar, and Aleglitazar, where these drugs exhibit strong or balanced PPAR-γ activation leading to weight gain, fluid retention, cardiac events, or renal toxicity despite their favorable metabolic effects. By selectively predominant PPAR-α activation while preserving only moderate PPAR-γ activity, Saroglitazar achieves therapeutic balance in lipid and glucose metabolism with reduced risk of γ-associated side effects.

ROLE OF GENETIC VARIANTS IN NAFLD

Individuals with NAFLD, even when sharing similar metabolic risk factors, exhibit differences in the disease susceptibility, severity and its progression. These differences are partly related to their molecular and genetic variations besides other factors. These variations in turn influence lipid metabolism, insulin sensitivity, hepatic fat accumulation, inflammatory response, and occasionally the therapeutic response to drugs as well [106, 107]. Numerous single nucleotide polymorphisms (SNPs) contributing to the development and progression of NAFLD are found in various genomic studies. Identifying and studying these variations gives way for the pharmacogenomic basis of individualized therapy.

 The most commonly replicated modulator of NAFLD pathogenesis is the PNPLA3 gene (patatin-like phospholipase domain-containing protein 3), which is also called adiponectin. This gene functions by hydrolyzing triglycerides and retinyl esters such as palmitate within the hepatocytes; however, variation in this gene (gene variant rs738409), by cytosine to guanine substitution resulting in codon change at position 148 (isoleucine to methionine), leads to triglyceride and retinyl ester accumulation, increasing the severity of the disease [108, 109]. Studies have also revealed the association between PNPLA3 and serum ALT elevation [110, 111].

TM6SF2 is another gene associated with NAFLD. TM6SF2 (Transmembrane 6 superfamily member 2). This gene functions by loading triglycerides into apolipoprotein B100 and helps in VLDL secretion from the liver cells, whereas this function is disrupted by its variant rs58542926. This variation is caused by guanine to adenine substitution at position 499 on the DNA sequence, causing amino acids at position 167 to change from glutamate to lysine. This altogether increases liver triglycerides and reduces circulating lipoproteins. Thus, increasing NAFLD risk but reducing the risk of cardiovascular diseases [112, 113].

Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), also known as LPIAT1, is also a gene involved in NAFLD. It has an important role in membrane phosphatidyl chain remodeling called “Lands’ cycle.” Within the cycle, it helps in adding arachidonic acid to lysophosphatidylinositol (lyso-PI) and forming phosphatidylinositol (PI) with arachidonic acid. Its variant rs641738 is formed by substitution of cytosine with thymine at the 3′ untranslated region of the gene, and it does not code for any protein. This variant decreases the levels of phosphatidylinositol (PI) with arachidonic acid inside the hepatocytes and within the circulation, which increases hepatic fat and risk of fibrosis without inflammation, including higher levels of ALT [114-116].

Similarly, GCKR (glucokinase regulatory gene), which is a regulator of the glucose-metabolizing enzyme glucokinase found in the liver and beta cells of islets, has variants that are associated with increased risk of NAFLD. GCKR maintains lipid and glucose homeostasis by regulating de novo lipogenesis and glucose influx. The variant rs1260326, obtained by replacement of proline with leucine at position 446, alters this function. It makes GCKR less responsive to fructose 6-phosphate during glycolysis, leading to more glucose influx and more malonyl-CoA, and also inhibits fatty acid oxidation, leading to greater hepatic fat accumulation [117, 118]. SOD2 is another enzyme that protects hepatocytes from reactive oxygen species (ROS). The rs4880 variant of this gene increases inflammation and predisposes to NASH [119].

SAROGLITAZAR AS A PRECISION MEDICINE APPROACH IN MAFLD

The shift from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) is linked to overall metabolic dysfunction rather than a liver-specific disorder with at least one cardiometabolic risk factor, which includes insulin resistance, dyslipidemia, obesity, inflammation, and endothelial dysfunction. Therefore, managing MAFLD necessitates a precision medicine approach that personalizes therapy based on individual metabolic profiles [120,121]. Some reports also suggest that the cost of managing adverse drug reactions outweighs the cost of actual medication, which necessitates personalized therapy [122].

In this case, Saroglitazar, due to its dual PPAR-α/γ agonism, directly regulates a number of inflammatory and metabolic processes that are dysregulated in people with high-risk NAFLD genotypes and can be an emerging model for precision pharmacotherapy. Through PPAR-α agonism, it causes fatty acid β-oxidation in mitochondria, and within the peroxisomes, it transcriptionally activates lipid-metabolizing genes [123]. This might overcome increased triglyceride buildup in the carriers of PNPLA3, TM6SF2, and GCKR variants, and also through PPAR-γ agonism, it improves insulin sensitization [124] and thereby prevents overexpression of ChREBP (carbohydrate response element binding protein) and SREBP-1c (sterol regulatory element-binding protein-1c), which are elevated in de novo lipogenesis [125,126] promoted by GCKR polymorphism. Hence, Saroglitazar has the potential to act on pathways that are affected by NAFLD genetic variants.

LIMITATIONS OF EXISTING EVIDENCE AND FUTURE RESEARCH PERSPECTIVES ON SAROGLITAZAR

Despite Saroglitazar's potential benefits, as shown in preclinical studies and short-term clinical trials, significant gaps persist. Firstly, due to the absence of large-scale, long-term cardiovascular outcome trials that confirm whether its biomarker effects minimize serious cardiovascular outcomes [127, 128]. Secondly, while initial changes in liver enzymes and hepatic fat are beneficial [129], these benefits may not directly correlate to histological healing of NASH and also do not provide a guarantee of long-term protection against cirrhosis and hepatic malignancies [130]. Moreover, it is approved only in India; global regulatory approval is withheld due to a lack of large-scale, multinational trials, including a lack of enrollment, which restricts generalizability [131]. Although its moderate PPAR-γ activity minimizes undesirable adverse effects compared to earlier dual agonists, theoretical risks of fluid retention or weight gain still remain [19]. Mild elevations in serum creatinine have also been reported, reflecting the need for renal monitoring, and the long-term influence on kidney function has not yet been clearly established [132].

Therefore, further large and long-term prospective studies, including post-marketing surveillance, are necessary to assess the long-term safety and efficacy of Saroglitazar [18, 133]. Preliminary studies indicate that combining Saroglitazar with statins or fibrates yields additional improvements in lipid parameters and glycemic indices [134]. Future investigations should also evaluate Saroglitazar in combination with SGLT-2 inhibitors to determine synergistic advantages in reducing inflammation and cardiometabolic risk [135].

CONCLUSION

Saroglitazar, being a dual PPAR-α/γ agonist, is currently emerging as a novel, promising treatment approach that targets dyslipidemia, insulin resistance, and inflammation concurrently, with beneficial outcomes in diabetic dyslipidemia and NAFLD/NASH. The drug shows beneficial effects on triglycerides, liver enzymes, HDL-C, and inflammatory biomarkers such as hs-CRP, TNF-α, and IL-6, and also its safety profile looks more favorable than prior dual agonists; its dual receptor activation reduces adverse effects, including edema and weight gain, which are seen with previous glitazars. Despite its favorable outcomes in short-duration, real world studies, the absence of large, long-duration cardiovascular outcome trials and restricted global regulatory approval creates way for careful interpretation. Well-designed multicenter trials are needed to evaluate its cardiovascular effects, renal consequences, and long-term significance, which may eventually establish saroglitazar as a therapeutic option.

ACKNOWLEDGEMENT: The authors have no acknowledgements to declare.

FUNDING: None

CONFLICT OF INTEREST: Authors declare  no conflict of interest

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