Background
Cardiovascular diseases (CVDs) have emerged as the leading cause of morbidity and mortality worldwide with 80% of the disease burden occurring in low and middle-income countries [
1]. Type 2 diabetes mellitus (T2DM) and dyslipidemia are now established risk factors of CVDs [
1,
2]. With the rising prevalence of T2DM and dyslipidemia, CVDs have emerged as major public health threats worldwide [
3‐
5]. Dyslipidemia in T2DM, also known as diabetic dyslipidemia, is characterised by high levels of triglyceride (TG) and small-dense low-density lipoprotein cholesterol (sd-LDL-C), low levels of high-density lipoprotein cholesterol (HDL-C), and increased insulin resistance, all of which increase the risk of CVDs [
6]. Despite the success of statins in achieving the guideline recommended LDL-C goals, patients with dyslipidemia remain at a high residual risk of developing CVDs and this risk is further increased in T2DM patients [
7‐
9]. Therefore, treatments targeting high TG, high non-HDL-C, and low HDL-C could be more effective in reducing the residual risk for future CVDs [
7‐
9].
In recent years, dual peroxisome proliferator activated receptor (PPAR) α/γ agonists have attracted global attention as promising new treatment options for diabetic dyslipidemia due to a unique mechanism of action in improving lipid and glucose profile simultaneously [
9,
10]. PPAR-α agonist action improves lipid profile, whereas PPAR-γ agonist action improves glucose profile in patients with diabetic dyslipidemia [
9,
10]. Many dual PPAR α/γ agonists were developed but failed during preclinical stage or the clinical development stage due to lack of efficacy or safety issues [
9,
10]. Saroglitazar, developed by Zydus Cadila, is a novel dual PPAR α/γ agonist (predominant PPAR-α and moderate PPAR-γ actions), aiming to improve lipid and glucose profiles without significant weight gain and edema (common in PPAR-γ agonists such as thiazolidinediones) [
9].
Preclinical studies and Phase-1 & Phase-2 clinical trials demonstrated favourable effects of Saroglitazar on lipid and glycemic parameters [
9,
11,
12]. In a Phase-3 clinical trial (PRESS V) in patients with diabetic dyslipidemia, Saroglitazar 2 mg and 4 mg significantly reduced TG from baseline to week-24 by 26% and 45%, respectively [
11]. In another Phase-3 clinical trial (PRESS VI) in patients with diabetic dyslipidemia not controlled with Atorvastatin 10 mg, Saroglitazar 2 mg and 4 mg significantly reduced TG from baseline to week-12 by 45%. [
12]. In both Phase-3 clinical trials, Saroglitazar also improved other lipid parameters and glucose parameters [
9,
11,
12].
Following successful clinical trials, Saroglitazar was granted marketing authorization in India in 2013 and is indicated for the management of diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin alone [
9]. Since 2013, clinicians/clinical researchers have studied the effects of Saroglitazar in real world clinical settings in India. This review was done to summarize the effects of Saroglitazar in patients with diabetic dyslipidemia in real world clinical studies conducted in India after marketing authorization.
Discussion
Fibrates have been prescribed as lipid modifying agents for more than four decades; however, they have low potency and limited selectivity for PPAR-α [
31‐
33]. Moreover, Fibrates have been associated with increased risk of myopathy, cholelithiasis, venous thrombosis, decline in renal function, and elevated transaminase concentrations [
33]. Pemafibrate, a new novel selective PPAR-α modulator with high potency, could emerge as a more effective and safe alternative to Fibrates for management of dyslipidemia [
34].
Thiazolidinediones, structural analogs of Fibrates, reduce insulin resistance and improve blood glucose levels through PPAR-γ agonist action [
31‐
33]. However, thiazolidinediones have been associated with weight gain and peripheral edema [
32,
33]. Moreover, Rosiglitazone was also associated with increased risk of myocardial infarction and has been withdrawn from Europe [
33]. There has been a global concern over Pioglitazone use due to possibility of increased risk of heart failure and bladder cancer [
33,
35].
Clinical evidences from Bezafibrate (a pan—PPAR [α, β/δ, γ] activator) studies supported the concept of a pan-PPAR/dual-PPAR therapeutic approach for diabetic dyslipidemia [
31,
32]. In the past two decades, Glitazars, dual PPAR α/γ agonists, have attracted global attention due to unique lipid and glycemic modifying actions [
9,
33,
36]. Many Glitazars such as Muraglitazar, Ragaglitazar, Tesaglitazar, Naveglitazar, Farglitazar, Aleglitazar were developed but failed during preclinical stage or the clinical development stage due to lack of efficacy or safety issues [
9,
36‐
38]. Clinical development of Muraglitazar was discontinued due to cardiovascular AEs such as myocardial infarction, stroke, heart failure [
9]. Clinical development of Aleglitazar was discontinued due to AEs such as heart failure, gastrointestinal bleeding, and renal dysfunction [
9,
38].
Saroglitazar is the first and only dual PPAR α/γ agonist (Glitazars) to be approved as well as prescribed in clinical practice, anywhere in the world [
9,
33]. Following marketing authorization in India (2013), Saroglitazar was also granted marketing authorization in Mexico (2017). This is the first review to summarize the effects of Saroglitazar in patients with diabetic dyslipidemia in real world clinical studies conducted after its marketing approval in India in 2013. In this review, we reviewed 18 articles including 5 published manuscripts and 13 abstracts. In total, 5824 patients with diabetic dyslipidemia received Saroglitazar 4 mg for durations ranging from 12 weeks to 58 weeks in the selected studies.
Kaul et al. [
21] was the first study to examine the effects of Saroglitazar on non-HDL-C as the primary endpoint and sd-LDL-C as a secondary endpoint in 104 patients with diabetic dyslipidemia. The authors observed significant decrease in non-HDL-C (baseline: 142.3 ± 59.3 mg/dL to week-24: 109.9 ± 45.5 mg/dL), sd-LDL-C (baseline: 32.5 ± 11.3 mg/dL to week-24: 25.9 ± 11.8 mg/dL), HbA1c (baseline: 8.1 ± 1.7 (%) to week-24: 6.9 ± 0.7 (%)), and significant increase in HDL-C (baseline: 37.3 ± 18.4 mg/dL to week-24: 43.4 ± 15.6 mg/dL) in the per-protocol population [
21]. Shetty et al. [
13] was the largest observational study of Saroglitazar in 2804 patients with diabetic dyslipidemia. The authors observed significant decrease in TG (baseline: 312.3 ± 122.7 mg/dL to week-12: 188.7 ± 61.4 mg/dL), non-HDL-C (baseline: 201.8 ± 64.1 mg/dL to week-12: 149.4 ± 41.0 mg/dL), HbA1c (baseline: 8.3 ± 1.3 (%) to week-12: 7.4 ± 0.9 (%)), and significant increase in HDL-C (baseline: 38.8 ± 8.7 mg/dL to week-12: 41.0 ± 7.1 mg/dL) [
13].
Joshi et al. [
15] conducted a postmarketing surveillance study of Saroglitazar in 18 T2DM patients with severe hypertriglyceridemia (baseline TG ≥ 1000 mg/dL). The authors observed significant decrease in TG (baseline: 1265.9 ± 394.3 mg/dL to week-12: 402.0 ± 221.8 mg/dL), non-HDL-C (baseline: 320.8 ± 172.8 mg/dL to week-12: 176.4 ± 62.9 mg/dL), and HbA1c (baseline: 8.9 ± 1.7 (%) to week-12: 7.8 ± 0.9 (%)) [
15]. Chatterjee et al. [
30] conducted a 58 weeks observation study of Saroglitazar in 158 patients with diabetic dyslipidemia (baseline TG ≥ 150 mg/dL). The authors found significant reduction in TG (baseline: 319.9 ± 178.8 mg/dL to week-58: 174.0 ± 113.6 mg/dL), non-HDL-C (baseline: 140.1 ± 55.4 mg/dL to week-58: 104.5 ± 49.7 mg/dL), and HbA1c (baseline: 7.9 ± 1.5 (%) to week-58: 7.3 ± 1.4 (%)) [
30].
Three studies included NAFLD patients with diabetic dyslipidemia [
17,
18,
22]. Joshi et al. [
18] conducted a single centre, single arm, prospective, open label study in 221 patients with diabetic dyslipidemia also diagnosed for NAFLD by transient elastography (FibroScan™). The authors found that Saroglitazar significantly reduced TG (baseline: 321.0 mg/dL to week-24: 129.0 mg/dL) and ALT (baseline: 89.0 IU/L to week-24: 21.0 IU/L) and improved fatty liver (evaluated by transient elastography (FibroScan™)) in 39% (86/221) patients [
18]. Similarly, Saboo et al. [
17] observed that Saroglitazar significantly decreased TG (baseline: 259.3 ± 37.9 mg/dL to week-24: 151.5 ± 53.6 mg/dL) and ALT (baseline: 64.1 ± 6.2 IU/L to week-24: 28.7 ± 3.2 IU/L) in 31 NAFLD patients with diabetic dyslipidemia. Goyal et al. [
22] also found that Saroglitazar significantly decreased TG (baseline: 334.7 ± 74.0 mg/dL to week-24: 158.5 ± 46.0 mg/dL) and ALT (baseline: 98.0 ± 32.0 IU/L to week-24: 34.0 ± 14.0 IU/L) in 84 patients with diabetic dyslipidemia (78.5% of these 84 patients were diagnosed for NAFLD by transient elastography (FibroScan™)).
One excluded study, STOP-D, was a prospective, single centre, single arm study in 40 patients with pre-diabetes (baseline HbA1c: 5.7-6.4%) and dyslipidemia (TG > 150 mg/dL, total cholesterol > 200 mg/dL, LDL-C > 130 mg/dL and HDL-C < 40 mg/dL) [
39]. The authors found that Saroglitazar significantly reduced TG (baseline: 348.0 ± 86.9 mg/dL to week-24: 216.4 ± 72.3 mg/dL) and HbA1c (baseline: 6.3 ± 0.2% to week-24: 5.5 ± 0.3%) [
39].
In Phase-3 clinical trials, most frequently reported AEs (≥ 2% of patients) with Saroglitazar 4 mg use were asthenia, gastritis, dizziness, tremors in the PRESS V study and were gastritis and pain in the PRESS VI study [
11,
12]. In real world clinical studies, Kaul et al. [
21] reported hypoglycemia after first dosing to be Saroglitazar related AE.
In all included studies, Saroglitazar favourably modulates lipid and glycemic parameters without significant AEs in patients with diabetic dyslipidemia [
13‐
30]. Saroglitazar 4 mg effectively reduced lipid parameters—TG, TC, LDL-C and non-HDL-C, glycemic parameter—HbA1c, and effectively increased lipid parameter—HDL-C in patients with diabetic dyslipidemia [
13‐
30]. Saroglitazar has a potential to address the residual cardiovascular risk associated with high non-HDL-C, high TG, and low HDL-C in patients with diabetic dyslipidemia [
7,
8]. The Emerging Risk Factors Collaboration, in a study of more than 300,000 people without initial vascular disease from 68 long-term prospective studies, found that non HDL-C was the strong predictor for coronary heart disease (CHD) (50% increased risk) and ischemic stroke (12% increased risk) [
2]. Toth et al. conducted an observational administrative claims analyses of statin-treated patients aged ≥ 45 years with high residual cardiovascular risk [
40]. In a multivariate analysis, patients with TG (200-499 mg/dL) (n = 13,411), compared to patients with TG (< 150 mg/dL) and HDL-C (> 40 mg/dL) (n = 32,506), was associated with 35% increased risk of composite major cardiovascular events, 35% increased risk of nonfatal myocardial infarction, and 27% increased risk of nonfatal stroke [
40]. The Emerging Risk Factors Collaboration also found that HDL-C was associated with 22% decreased risk of CHD [
2].
Saroglitazar was also found effective in lowering ALT [
17,
18,
22] and improving fatty liver (evaluated by sonographic (FibroScan™) investigation) in NAFLD patients with diabetic dyslipidemia [
18]. These results are also supported by a preclinical study conducted by Jain et al. [
41]. In experimental non-alcoholic steatohepatitis (NASH) model (animal model of mice with choline-deficient high-fat diet-induced NASH), the authors found that Saroglitazar reduced ALT, hepatic steatosis, inflammation, ballooning, and prevented fibrosis development [
41]. At present, there are no medications approved for NAFLD/NASH [
42]. Saroglitazar could become a promising treatment option for NAFLD/NASH [
17,
18,
22]. However, the efficacy and safety of Saroglitazar in patients with NAFLD/NASH must be examined in RCTs. At present, several RCTs are going on in the USA (ClinicalTrials.gov Identifier: NCT03061721) and India (CTRI/2015/10/006236) to study the effects of Saroglitazar in patients with NAFLD/NASH.
There are strength and weakness of all selected studies in this review. There is a possibility of under-reporting of AEs due to lost to follow-up in studies based on real-world clinical settings [
21,
30]. Moreover, there are 13 abstracts out of 18 selected studies and we cannot critically review these studies due to limited information available in the abstracts. However, these abstracts were presented at the top global annual scientific congress such as the scientific sessions of the American Diabetes Association, the annual scientific congress of the American Association of Clinical Endocrinologists, and the Annual Conference of Asian Pacific Association for the Study of the Liver. Moreover, all the selected studies included patients from the real-world clinical settings that certainly improves the generalizability of the study results of all selected studies [
21,
30]. Additionally, the study results from Chatterjee et al.dyslipidemia [
30] supports long-term effectiveness and safety of 58 weeks for Saroglitazar in patients with diabetic dyslipidemia.
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