Efficacy and safety of saroglitazar for the management of dyslipidemia: A systematic review and meta-analysis of interventional studies.

BACKGROUND AND
OBJECTIVE: Saroglitazar is a newer antidiabetic agent approved to manage dyslipidemia. The objective is tevaluate the efficacy and safety profiles of saroglitazar in patients with dyslipidemia.
METHODS: A systematic search was conducted using PubMed, Cochrane Library, Scopus, and Google Scholar from the inception until January 2022. Interventional studies comparing the anti-hyperlipidaemic effect and safety of saroglitazar with or without a control group(s) were included. The efficacy of saroglitazar was assessed concerning its effect on total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL)-cholesterol, triglycerides, fasting plasma glucose, and non-HDL cholesterol. The effects on serum creatinine levels, bodyweight reduction, alanine aminotransferase and aspartate aminotransferase were considered to be safety endpoint.The Cochrane risk of bias assessment tool was used to assess the methodological quality of the included studies.
RESULTS: A total of six studies with 581 adults with a mean age ranging from 40.2 to 62.6 years were included in this study. A significant decrease in low-density lipoprotein cholesterol was observed with saroglitazar 4 mg therapy compared to saroglitazar 2 mg [standardized mean difference (SMD): -0.23 mg/dL, 95% CI: -0.47 to 0.00; p  =  0.05; 2 studies], and control [SMD: -0.36 mg/dL, 95% CI -0.59 to -0.12; p  =  0.0026; 3 studies]. Also, a significant decrease in the total cholesterol was observed with saroglitazar 4 mg therapy compared to saroglitazar 2 mg [SMD - 0.28 mg/dL, 95% CI: - 0.52 to -0.04; p < 0.01; 2 studies], and control [SMD - 0.49 mg/dL, 95% CI: - 0.72 to -0.26; p < 0.0001; 3 studies]. Saroglitazar was not associated with adverse effects such as increase in serum creatinine levels, alanine aminotransferase and aspartate aminotransferase and bodyweight reduction.
CONCLUSION: Saroglitazar appeared to be an effective and safer therapeutic option for improving dyslipidemia in patients. However, comparative studies of saroglitazar with the other pharmacological agents are warranted.

Introduction

According to the atlas of the International Diabetes Federation (IDF), globally, 463 million individuals have diabetes, and it is expected to reach up to 578 million by 2030 and 700 million by 2045 [1]. In India, around 77 million individuals live with type-2 diabetes (T2D) as of 2019, and >4 million people aged between 20–79 years have died from diabetes-related causes [1]. Cardiovascular diseases (CVD) are the primary cause of morbidity and mortality among individuals with T2D [2], where cardiovascular risk tends to be primarily influenced by dyslipidemia [3]. The anti-hyperlipidaemic agents have been studied for decades, and evidence supports their cardiovascular benefit in selected patients with the presence or absence of T2D [4]. Diabetic dyslipidemia is a type of lipoprotein dysfunction characterized by decreased high-density lipoprotein levels, an increase in triglyceride levels, and an increase in low-density lipoprotein (LDL) particles [5]. Approximately around 70% of the patients who have T2D are likely to develop dyslipidemia [6].

Statins, fibrates, cholesterol absorption inhibitors, niacin, bile acid sequestrants, proprotein convertase subtilisin/kexin type-9 (PCSK-9) inhibitors are the available therapeutic options to treat dyslipidemia [5]. However, the use of statins and fibrates is associated with myopathy [7], where niacin is usually not recommended due to the risk of new-onset of diabetes [8], bleeding, and infections [9], and PCSK-9 inhibitors are more expensive and cause injection site reactions. Hence, there is an immense need for newer medications that can potentially target both dyslipidemias as well as T2D [10]. In patients with T2D, peroxisome proliferator-activated receptor alpha (PPAR-α) agonist improves lipid profile, whereas PPAR-γ agonist improves glucose profile [11].

Dual PPAR α/γ agonists have multiple actions, where they act by improving both lipids as well as glucose profiles [12,13]. Saroglitazar [(S)-a-ethoxy-4-{2-[2-methyl-5-(4-methylthio) phenyl)]-1H-pyrrol-1-yl]- ethoxy)-benzenepropanoic acid magnesium salt] is a novel PPAR α/γ agonist synthesized in India by Zydus Cadila (trade name, Lipaglycn), and is approved by the Drug Controller General of India (DCGI) for the treatment of diabetic dyslipidemia and hypertriglyceridemia [14]. Saroglitazar is not associated with weight gain and edema [13], and thus it is considered a safer medication, with fewer adverse effects such as gastritis, asthenia, and pyrexia [15]. There is a lack of pooled evidence on the safety and efficacy of saroglitazar for the treatment of dyslipidemia. With this background, we conducted a systematic review and meta-analysis aimed to examine the efficacy and safety of saroglitazar for managing dyslipidemia.

Methods

The current systematic literature review was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16].

Eligibility criteria for included studies

The research question for our systematic review is "What is the safety and efficacy of saroglitazar for the management of hypercholesterolemia?" The research question was broken down into PICOS (population, intervention, comparison, outcome, and study design) format. Population (P) comprises adult patients with hypercholesterolemia with or without diabetes. Intervention (I) consists of saroglitazar in any of its effective doses. Comparator (C) was any comparator such as different doses, control, or another drug as per the author’s discretion. Outcomes (O) considered were efficacy and safety of Saroglitazar. The effect of saroglitazar on total cholesterol, LDL-cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol, non-HDL cholesterol, and fasting plasma glucose is considered to be efficacy outcomes. While the reduction in Serum Creatinine, Alanine Transaminases, Aspartate Transaminases, and body weight considered to be safety outcomes. In study design (S), we included all types of interventional studies; randomized, and non-randomized trials. Any studies satisfying the above specified PICOS were included in the systematic review. Reviews, observational and descriptive studies, editorials, commentaries, and conference proceedings were excluded.

Data sources and literature search

A comprehensive literature search was performed using PubMed, Scopus, the Cochrane Library, and Google Scholar from the inception to January 2022. The initial search was performed in April 2019 and was updated in January 2022. We employed all the MesH terms and keywords related to "Saroglitazar" and "hypercholesterolemia" obtained from the databases and previously published studies. In addition to this, all the references of the included studies and a snowball search through Google were performed to search for any additional relevant articles. A detailed search strategy for each database is provided in S1 File.

Study selection and data extraction

The titles and abstracts of retrieved studies were screened, followed by the full text under the predefined inclusion and exclusion criteria. The highly irrelevant studies only were excluded during the title/abstract screening. Two independent reviewers performed the title and abstract screening, followed by full-text screening. A well-defined data extraction sheet was employed for the data abstraction, including the information about studies’ characteristics, participants, interventions, comparator, and outcomes. Two independent researchers were involved in study selection and data extraction, disagreements were resolved through consensus or by a discussion with a third reviewer.

Risk of bias and quality assessment

The Cochrane risk of bias assessment tool was used to assess the methodological quality of the included studies [17]. The quality of the included single-arm trials was evaluated by the National Institute of Health (NIH) Checklist. It consists of 12 items that identify the methodological features that are based on existing study design and study-reporting guidelines. Each item carries one point and scores of 0‒4, 4‒8, and 9‒12 were considered poor, fair, and good-quality studies, respectively. Two independent reviewers evaluated the risk of bias and quality of included studies and resolved any disagreements through consensus or by a discussion with a third reviewer.

Data synthesis

The analyses were performed with R software (R version 4.1.2) using a meta-package. Changes in continuous outcomes were calculated for every included study arm by subtracting the value at baseline from the value after the intervention. All the efficacy estimates were expressed as standardized mean difference (SMD) or absolute weighted mean change (MRAW) and 95% confidence interval (CI) from baseline. According to the Cochrane handbook, standard deviations (SD) were calculated from the standard error or 95% CI for a systematic review of interventions [17]. The Higgins I2 statistics and Cochran’s Q test were used to assess the potential statistical heterogeneity among trials. The meta-analysis was conducted using a fixed-effect model (using inverse-variance) or a random-effect model (DerSimonian–Laird method) based on low heterogeneity (<50%) or high heterogeneity (>50%). Due to less number of included studies (<10), it was not feasible to examine the publication bias through a funnel plot, Egger’s and Begg’s test [17].

Results

A total of 272 citations were identified by electronic search of databases, and 18 citations were identified through hand search. Finally, 276 citations were screened after removing 14 duplicates, while 250 studies were excluded during first-pass screening after reviewing the titles and abstracts. Full texts of 26 citations included during the first pass screening were downloaded for the second pass screening. Lastly, 6 articles met our inclusion criteria. PRISMA flowchart for the study selection is described in Fig 1.

Fig 1

PRISMA flow diagram.

Characteristics of the included studies

We included 6 studies (4 randomised controlled trials [12,18-20] and 2 single-arm trials [21,22]. Treatment follow-up of the included studies ranged from 12 weeks [12,18,20,22] to 24 weeks [19,21]. All included studies were carried out in India, where four were multicentre trials [12,18-20] and two were single-center trials [21,22]. The detailed characteristics of included studies are presented in Table 1.

Table 1

Characteristics of included studies and subjects.

Study ID	Reg No	Country (State/Sites)	Study design	Study duration	Number of participants	Lost to follow up	Age (years)Mean (SD)	GenderN (%)
Bhosle D et al., 2018 [21]	CTRI/2016/03/006778	India (Maharashtra)	Prospective, single centre, single arm study	NR	40	0	48.15 (7.53)	Male: 28 (70) Female: 12 (30)
Rastogi A et al. 2020 [18]	CTRI/2015/06/005845	India (Chandigarh and Mumbai)	Prospective, Multi centre, double blinded RCT	12 weeks	Saroglitazar (4mg): 15	2	53.1 (8.8)	Male: 7 (47)Female: 8 (53)
					Placebo: 15	0	54.9 (7.8)	Male: 9 (60)Female: 6 (40)
Pai V et al., 2014 [19]	Phase III/CTRI/2009/091/000527	India (Pune, Chennai, Kolkata, Chandigarh and Bangalore)	Prospective, Multi centre, double blind RCT	24 weeks	Saroglitazor (2mg): 41	4	48.9 (8.98)	Male: 26 (63)Female: 15 (37)
				24 weeks	Saroglitazor (4mg): 41	2	47.3 (9.10)	Male: 25 (61)Female: 16 (39)
				24 weeks	Pioglitazone (45mg): 40	5	49.9.1 (10.98)	Male: 24 (60)Female: 16 (40)
Deshpande A et al., 2016 [20]	Phase II/CTRI/2010/091/000107	India (2 sites)	Prospective, multi-centric, open-label, single arm exploratory study	12 weeks	50	1	40.26 (7.13)	Male: 32 (64) Female: 18 (36)
Ghosh A et al., 2016 [22]	Phase IV/ CTRI/2014/10/005131	India (West Bengal)	Prospective, randomized, open labelled, parallel group phase IV clinical trial	12 weeks	Metformin (1000 mg/day) + Fenofibrate (160 mg/day): 18	0	58.1	NR
					Metformin (1000 mg/day) + Saroglitazar (4 mg/day): 19	1	62.6	NR
Jani RH et al., 2014 [12]	Phase III/CTRI/2009/091/000533	India (29 centres)	Multicenter, prospective, randomized,double-blind, placebo controlled, interventional, Phase III study	12 weeks for efficacy, 24 weeks for efficacy	Saroglitazar (2 mg): 100	6	50.4 (9.01)	Male: 39 (39) Female: 61(61)
					Saroglitazar (4 mg): 99	6	51.2 (8.66)	Male: 43 (43.4) Female: 56 (56.6)
					Placebo: 102	6	49.8(9.95)	Male: 47 (46.1)Female: 55 (53.9)

CTRI: Clinical Trial registry of India; NR: Not reported; RCT: Randomized Controlled Trial; SD: Standard deviation

Treatment and outcome characteristsics

There was a total of 581 participants from six studies, of whom the majority of them were females (302 [52%]). All the studies have included adult participants with a mean age of 40.2 [20] to 62.6 years [22]. Of six included studies, two studies [12,19] have compared the effect of saroglitazar 4mg to saroglitazar 2mg and control. The details about treatment and outcome characteristics of included studies are presented in Table 2.

Table 2

Treatment and outcome characteristics.

Study ID	Inclusion criteria/Diagnosis	Exclusion Criteria	Intervention/Comparator/ Duration of treatment	Endpoint	Efficacy and Safety Outcome observed	Key Conclusion
Bhosle D et al., 2018 [21]	• Pre-diabetes and dyslipidaemia• Age: 20–60 years• Baseline HbA1c 5.7–6.4% and dyslipidemia (Total cholesterol > 200mg/dl, LDL-C > 130 mg/dl, triglycerides > 150 mg/dl and HDL< 40 mg/dl)	• Type I DM, Type II DM, secondary hypertension, bronchial asthma, chronic obstructive pulmonary disease or any other respiratory disorders and any hepatic or renal diseases• On-going medications affecting blood glucose or lipids were excluded	Saroglitazar 4mg once daily/ No comparator/ Int: 24 weeks	EfficacyPrimary outcome: Change in serum triglycerides; Secondary outcome: Changes in other lipid parameters such as HbA1c, serum total cholesterol, serum LDL-C, serum HDL-C and NonHDL-C levelsSafety:RFT, LFT and ECG Changes following treatment	EfficacySignificant reduction in serum triglycerides HbA1c, serum total cholesterol, serum LDL-C, serum HDL-C and Non HDL-C levelsSafety:No serious adverse event	Saroglitazar is safe and effective in prediabetes with dyslipidaemia
Rastogi A et al. 2020 [18]	• Age: 18–65 years• T2DM on stable dose of metformin (≥ 3 months)• BMI > 25 and < 45 kg/m2• FPG ≤ 240 mg/dL, HbA1c ≥ 6.5% (≥ 48 mmol/mol) and ≤ 8.5% (≤ 69 mmol/mol), TG > 150 and < 300 mg/dL, HDL < 50 mg/dL in women and < 40 mg/ dL in men and creatinine clearance > 60 mL/min	• Treatment with glitazones/ glitazars, insulin, steroid and hormone replacement therapies in last 3 months• History of acute or chronic metabolic acidosis, including diabetic ketoacidosis, abnormal thyroid-stimulating hormone, alanine aminotransferase ≥ 2.5 times the upper limit of normal, congestive heart failure and blood pressure > 160/100 mmHg	Saroglitazar 4mg once daily/12 weeks Placebo/	EfficacyPrimary outcome: Change in plasma TG area under the curve (AUC) oral fat tolerance test; Secondary outcomes: Change in AUC of apolipoportein B48 and B100 concentration, TG-AUC, TG, TC, LDL, HDL, FPG, HbA1cSafety: Adverse events	EfficacyReduction in TG-AUC, TG, TC, LDL, HDL, FPG, HbA1cSafety:Incidence of adverse events and severity of Adverse events	Saroglitazar significantly improved postprandial TGs in people with diabetic dyslipidemia
Pai V et al., 2014 [19]	• Age: 18 to 65 years• BMI > 23 kg/m2), hypertriglyceridemia (fasting TG > 200 to 400 mg/dL)• History of T2DM (HbA1c >7% to 9%), and receiving either a sulphonylurea, metformin, or both treatments for at least 3 months.	• Using insulin, glitazone or glitazar, or medications with a lipid-lowering agent in the past 2 weeks• History of cardiac abnormalities, thyroid dysfunction, hepatic dysfunction, gall stones, renal dysfunction, myopathies, active muscle diseases, ketonuria, concurrent serious illness such as severe infections (tuberculosis, HIV), malignancy, alcohol or drug abuse, allergy or intolerance to the study medications, or their excipients and participation in any other clinical trial in past 3 months.	Saroglitazar (2 or 4mg) once daily/ Pioglitazone (45 mg) once daily/ 24 weeks	EfficacyPercentage change in triglyceride form baseline; Secondary endpoint: Change in lipid profile and fasting plasma glucose at week24SafetyAdverse events	EfficacyReduction in TG, TC, LDL, HDL, FPG, HbA1cSafetyIncidence of adverse events and severity of Adverse events	Saroglitazar effective and safe forimproving hypertriglyceridemia in patients with T2DM
Deshpande A et al., 2016 [20]	• Age: 18–65 years• Diagnosis of HIV1 and on HAART for at least 18 months; on stable ART regimen for at least 8 weeks prior to inclusion in the study and ART regimen not expected to change in next 3 months• Patient clinically diagnosed as HIV lipodystrophy (at least 1 moderate or severe lipodystrophy feature identified by doctor and patient, except isolated abdominal obesity)• Triglycerides level >200 to 500 mg/dL; CD4 count of >50/mm3 and patient who had given written informed consent for participation in the trial	• Patients on insulin and/or glitazone/glitazar therapy• Pregnancy and lactation• History of gall stones, cardiac failure, alcohol and/or drug abuse; history of allergy, sensitivity or intolerance to the study drug and its formulation ingredients; active opportunistic infection in last three months• History of malignancy or active neoplasm; any active hormonal disease and/or hormonal treatment that could affect the outcomes of interest such as clinically overt hypo/hyperthyroidism, hypogonadism, hypercortisolism, or treatment with steroids or growth hormone• Haemoglobin below 9 g/dL or total leucocyte count below 1000/mm3 or platelet count below 50,000/mm3; history of myopathies or evidence of active muscle diseases or CPK ≥10 times upper limits of normal (ULN)• History of active liver disease or hepatic dysfunction demonstrated by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥2.5 times of upper limits of normal or bilirubin more than 2 times UNL• Renal dysfunction (serum creatinine >2 mg/dL) and participated in any other clinical trial in past 3 months	Saroglitazar 4 mg Dialy in the morning/ No comparator/ 12 week	EfficacyPrimary outcome: Percent change in triglyceride levels from baseline to Week 6 and Week 12.Secondary efficacy endpoints were assessment of LDL, VLDL, HDL, Non HDL cholesterol, total cholesterol, Apo A1, Apo B, and C-peptide and fasting insulin for HOMA beta and HOMA IR from baseline to week 6 and week 12Safety:Adverse events	EfficacySignificant reduction in TG, VLDL, TC, Increase in HDL, Apo A1,and Apo B, C-peptide, fasting insulin levels, HOMA of beta cell function for C-peptide, HOMA of insulin resistance for C-peptideSafety:AEs was less than 10%. Adverse events from the gastrointestinal disorder system organ class (SOC) (constipation and abdominal pain)	Saroglitazar was effective in changing lipid profile and HIV associated lipodystrophy with minimal side effects
Ghosh A et al., 2016 [22]	• Age: 18–70 years• Newly diagnosed cases of diabetic dyslipidaemia with plasma triglyceride level ≥ 150 mg/dl and HbA1C ≥ 6.5 and ≤8• No use of any hypolipidaemic agent within last six months• Patients were receiving only metformin 1000 mg per day	• Pregnant or lactating woman• Fasting plasma glucose (FPG) > 250mg/dl, post-prandial plasma glucose (PPPG) > 350mg/dl, LDL-C > 130 mg/dl• Co-morbid cardiovascular, renal and psychiatric complications• Co-administration of drugs that were likely to interact with saroglitazar, fenofibrate or metformin and that are likely to alter lipid profile and glycaemic status	Metformin SR 1000 mg/day and saroglitazar 4 mg per day/ Metformin SR 1000 mg/ day and fenofibrate 160 mg per day/12 weeks	EfficacyPrimary outcome: Change in TG at week 12 visit.Secondary outcome: Changes in HbA1C, HDL-C, LDL-C and Total cholesterol (TC) at week 12 and FPG, PPPG at weeks 4, 8, 12 visitsSafetyBody weight and incidence of adverse events	EfficacySignificant decrease in TG and HbA1C levels were observed in group B compared to group A at week 12FPG and PPPG were significantly reduced in group B compared to group A at every intervalInter group analysis did not show any statistically significant change in body weight, LDL-C and HDL-C at week 12	Saroglitazar was better effective than fenofibrate in lipidemic control when combining with metformin
Jani RH et al 2014. [12]	• Age: 18–65 years• T2DM Diagnosis• Previous treatment with a maximum of two oral hypoglycemic Agents• Low-density lipoprotein cholesterol (LDL-C) level >100 mg/dL; TG level >200 and <500 mg/dL; body mass index >23 kg/m2; and treatment with atorvastatin 10mg for at least 4 weeks	• History of greater than 5% weight loss in the preceding 6 months, unstable angina, acute myocardial infarction in the preceding 3 months, heart failure classified as New York Heart Association Class III–IV• Uncontrolled hypertension, clinically significant edema, thyroid disorder, gallstones, impaired liver (aspartate aminotransferase and alanine aminotransferase ‡2.5 times the upper normal limit [UNL] or bilirubin ‡2 times the UNL) o renal (serum creatinine >1.2 mg/dL) function, ketonuria, myopathies or active muscle diseases (creatinine phosphokinase ‡10 times UNL), severe illness such as tuberculosis, human immunodeficiency infection, malignancy, alcohol and/or drug abuse, allergy, sensitivity or intolerance to the study drugs and their formulation ingredients, and participation in any other clinical trial in the preceding 3 months at the time of enrolment• Treatment within 4 weeks of the run-in period with oral antidiabetes drugs from the glitazone (e.g., pioglitazone or rosiglitazone) and glitazar (investigational products) classes, insulin, lipid-modifying therapy (e.g., fenofibrate) other than atorvastatin 10 mg, thyroid-modulating drug, or anti-inflammatory drugs• Pregnant or breast feeding or had initiated hormonal treatment (e.g., hormonal contraceptive, hormone replacement therapy) in the preceding 3 month	Saroglitazar 2 mg/day orSaroglitazar 4 mg/day/ Placebo/ 12 weeks for efficacy and 24 weeks for safety	EfficacyPrimary outcome: Percentage reduction in TGSecondary outcome: Change in lipid profile: apolipoprotein A1, Apo B, HDL-C, non-HDL-C, LDL-C, total cholesterol, and very LDL-CExploratory efficacy outcome: FPGSafetyClinical severity, Haematological variation, LFT, RFT, Other routine test, Myopathy, inflammatory and cardiovascular markersmarkers	A significant reduction of mean plasma triglyceride levels with 2mg and 4mg of saroglitazar compared with placebo.Saroglitazar2 mg significantly decreased the levels of non-HDL-C, very LDL-C, total cholesterol, and fasting plasma glucoseSaroglitazar 4mg significantly reduced LDL-C and apolipoprotein B levelsSafetyNo significant difference in interventional and control arm	This double blind RCT reported a beneficial effect of saroglitazar in improving the hypertriglyceridemia inpatients with T2DM

Apo B: Apolipoprotein B; dL: Decilitre; FPG: Fasting Plasma Glucose; HDL-C: High Density lipoprotein-Cholesterol; LDL-C: Low Density lipoprotein-Cholesterol; mg: Milligram; RCT: Randomized Controlled Trial; SR: Sustained Release; T2DM: Type-2-diabtes mellitus.

Quality assessment

Risk of bias of the included studies was assessed using the Cochrane risk of bias assessment tool. Bias related to randomization was low among three (75%) studies, while it appeared to have a higher level of bias with the remaining one study. Bias related to the allocation concealment was found to be low (n = 3; 75%) and moderate (n = 1; 25%) among the studies, respectively. Information about blinding participants and assessors was mentioned in three studies. As per the NIH checklist, both Bhosle D et al., 2018 and Deshpande A et al., 2016 trials did not report the information related to the masking of patients or investigators and did not report the sufficient details of the group-level interventions and individual-level outcome efforts. But overall, two trials were rated as good quality as per rating of NIH checklist. Detailed information on overall risk of bias in individual studies is provided in in Figs 2 and 3 and S1 Table.

Fig 2

Risk of bias graph.

Review author’s judgements about each risk of bias assessment presented as percentages across all included studies.

Fig 3

Risk of bias summary.

Review author’s judgements about each risk of bias item for each included study.

Efficacy of saroglitazar

Total cholesterol

Two studies [12,19] compared the saroglitazar 4 mg with 2 mg per day, where there were 138 patients each in the saroglitazar 4 mg/day and 2 mg/day groups that resulted in a standardized absolute mean difference (SMD) of -0.28 mg/dL, on total cholesterol (95% CI -0.52 to -0.04), p = 0.01 (Fig 4). This demonstrates a significant decrease in the total cholesterol among the saroglitazar 4 mg/day group compared to saroglitazar 2 mg/day group in patients with diabetes-related hyperlipidaemia (Table 3). There was no statistically significant heterogeneity among included studies (P = 0.29; I2 = 12%). Besides, three studies [12,18,19] compared the saroglitazar 4 mg with control, where there were 148 patients in saroglitazar 4 mg/day group and 144 patients in the control group. The results showed an SMD of -0.49 mg/dL, (95% CI -0.72 to -0.26), P<0.0001 (Fig 5). This demonstrates a significant decrease in the total cholesterol among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.42; I2 = 0%).

Fig 4

Forest plot of comparison of saroglitazar 4mg versus saroglitazar 2mg on total cholesterol (mg/dL).

Table 3

Mean absolute change results of all clinical outcomes measured in diabetes related dyslipidemia.

ClinicalOutcomes	No of studies	Test for heterogeneity			Test of association
		Q	P	I2 (%)	SMD	95% CI	Z	P
Triglycerides (mg/dL)
Saroglitazar 4mg vs Control	4	13.37	<0.01	78	-0.28	-0.84; 0.27	-1.00	0.31
Saroglitazar 4mg vs 2mg	2	2.24	0.13	55	-0.24	-0.64; -0.15	-1.22	0.22
Total Cholesterol (mg/dL)
Saroglitazar 4mg vs Control	3	1.73	0.42	0	-0.49	-0.72; -0.26	-4.12	<0.0001
Saroglitazar 4mg vs 2mg	2	1.14	0.29	12	-0.28	-0.52; -0.04	-2.33	0.01
LDL-C (mg/dL)
Saroglitazar 4mg vs Control	3	0.38	0.83	0	-0.36	-0.59; -0.12	-3.01	0.0026
Saroglitazar 4mg vs 2mg	2	0.59	0.44	0	-0.23	-0.47; -0.00	-1.96	0.05
HDL-C (mg/dL)
Saroglitazar 4mg vs Control	3	6.58	0.04	70	0.24	-0.29; 0.76	0.89	0.37
Saroglitazar 4mg vs 2mg	2	0.24	0.62	0	-0.17	-0.41; 0.07	-1.41	0.15
Non-HDL-C (mg/dL)
Saroglitazar 4mg vs Control	3	15.19	<0.01	87	-0.66	-1.77; 0.45	-1.17	0.24
FPG (mg/dL)
Saroglitazar 4mg vs Control	4	48.03	<0.01	94	-0.22	-1.38; 0.94	-0.36	0.71
Saroglitazar 4mg vs 2mg	2	0.38	0.53	0	-0.07	-0.30; 0.17	-0.57	0.56
Serum Creatinine (mg/dL)
Saroglitazar 4mg vs Control	2	12.29	<0.01	92	0.58	-0.43; 1.59	1.13	0.25
Saroglitazar 4mg vs 2mg	2	0.69	0.40	0	0.45	0.21; 0.69	3.64	0.0003
Alanine Amino transferase (U/L)
Saroglitazar 4mg vs Control	2	0.68	0.41	0	-0.17	-0.51; 0.05	-1.40	0.16
Saroglitazar 4mg vs 2mg	2	1.18	0.27	15	-0.07	-0.31; 0.16	-0.58	0.56
Aspartate Amino transferase (U/L)
Saroglitazar 4mg vs Control	2	0.78	0.38	0	0.05	-0.18; 0.28	0.41	0.68
Saroglitazar 4mg vs 2mg	2	0	0.54	0	-0.06	-0.29; 0.18	-0.47	0.64
Wieght Change (kg)
Saroglitazar 4mg vs Control	2	8.94	<0.01	89	-0.09	-0.92; 0.73	-0.22	0.82
Saroglitazar 4mg vs 2mg	2	0.26	0.61	0	0.27	0.03; 0.51	2.18	0.02

Fig 5

Forest plot of comparison of saroglitazar 4mg versus control on total cholesterol (mg/dL).

LDL-cholesterol

The pooled analysis of two studies[12,19] compared the saroglitazar 4 mg with saroglitazar 2mg, where 138 patients in each group resulted in an SMD of -0.24 mg/dL, (95% CI -0.47 to 0.00), P = 0.05 (Fig 6). This demonstrates a significant decrease in the LDL cholesterol among the Saroglitazar 4 mg/day group compared to saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). There was no statistically significant heterogeneity among included studies (p = 0.44; I2 = 0%). At the same time, three studies compared the saroglitazar 4 mg with control, where there were 148 patients in the saroglitazar 4 mg/day group and 144 patients in the control group[12,18,19]. The results showed an SMD of -0.36 mg/dL, (95% CI -0.59 to -0.12), p = 0.0026 (Fig 7). This demonstrates a significant decrease in the LDL cholesterol among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was detected among included studies (P<0.83; I2 = 0%).

Fig 6

Forest plot of comparison of saroglitazar 4mg versus saroglitazar 2mg on LDL-cholesterol (mg/dL).

Fig 7

Forest plot of comparison of saroglitazar 4mg versus control on LDL-cholesterol (mg/dL).

Triglycerides

The pooled analysis of two studies [12,19] compared the saroglitazar 4 mg with Saroglitazar 2mg, where there were 138 patients in each group, resulting in an SMD of -0.24 mg/dL, (95% CI -0.64 to 0.15), P = 0.22 (Table 3). There was no statistically significant heterogeneity among included studies (P = 0.13; I2 = 55%). This demonstrates a non-significant decrease in the triglycerides among the saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). Besides, four studies compared the saroglitazar 4 mg with control, where there were 167 patients in the saroglitazar 4 mg/day group and 162 patients in the control group [12,18,19,23]. The results showed an SMD of -0.28 mg/dL, (95% CI -0.84 to 0.27), P = 0.31 (Table 3). This demonstrates a decrease in the triglycerides among the saroglitazar 4 mg/day group compared to the control group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P<0.01; I2 = 78%).

HDL-cholesterol

The pooled analysis of two studies [12,19] compared the saroglitazar 4 mg with Saroglitazar 2mg, where there were 138 patients in each group. The results showed an SMD of -0.17 mg/dL, (95% CI -0.41 to 0.07), P = 0.15 (Table 3). This demonstrates a non-significant decrease in the HDL-cholesterol among the Saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.62; I2 = 0%). Besides, three studies [12,18,19] compared the saroglitazar 4 mg/day with control, where there were 148 patients in saroglitazar 4 mg/day group and 144 patients in the control group. The results showed an SMD of 0.24 mg/dL, (95% CI -0.29 to 0.76), P = 0.37 (Table 3). This demonstrates a non-significant decrease in the HDL-cholesterol among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically, significant heterogeneity was observed among included studies (P = 0.04; I2 = 70%).

Fasting plasma glucose

Two studies [12,19] compared the saroglitazar 4 mg with Saroglitazar 2mg, where there were 138 patients in each group. The results showed an SMD of -0.07 mg/dL, (95% CI -0.30 to 0.17), P = 0.56 (Table 3). This demonstrates a non-significant decrease in the fasting plasma glucose among the saroglitazar 4 mg/day group compared to Saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.54; I2 = 0%). Besides, four studies [12,18,19,22] compared the saroglitazar 4 mg with control, where there were 167 patients in saroglitazar 4 mg/day group and 162 patients in the control group. The results showed an SMD of -0.22 mg/dL, (95% CI -1.38 to 0.94), P = 0.71 (Table 3). This demonstrates a non-significant decrease in the fasting plasma glucose among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically, significant heterogeneity was observed among included studies (P = 0.01; I2 = 94%).

Non-HDL cholesterol

Three studies [18,19,22] compared the saroglitazar 4 mg/day with control, where there were 68 patients in the saroglitazar 4 mg/day group and 60 patients in the control group. The results showed a SMD of -0.66 mg/dL, (95% CI -1.77 to 0.45), P = 0.24 (Table 3). It demonstrates a non-significant decrease in the non-HDL cholesterol among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically, significant heterogeneity was observed among included studies (P<0.01; I2 = 87%).

Safety of saroglitazar

Serum creatinine levels

Two studies [12,19] compared the saroglitazar 4 mg with the saroglitazar 2mg, where there were 132 patients in the saroglitazar 4 mg/day group, and 138 patients in the saroglitazar 2 mg/day group. The meta-analysis demonstrated a significant increase (SMD: 0.45 mg/dL; 95% CI 0.21 to 0.69; P = 0.0003) [Fig 8] in the serum creatinine levels among the saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.41; I2 = 0%). Besides, two studies [12,19] compared the saroglitazar 4 mg with control, where there were 132 patients in the saroglitazar 4 mg/day group and 139 patients in the control group. The results showed a SMD of 0.58 mg/dL, (95% CI -0.43 to 1.59), P = 0.25 (Table 3). It demonstrates a non-significant increase in the serum creatinine levels among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically significant heterogeneity was observed among included studies (P<0.01; I2 = 92%).

Fig 8

Forest plot of comparison of saroglitazar 4mg versus saroglitazar 2 mg on serum creatinine (mg/dL).

Bodyweight reduction

Two studies [12,19] compared the saroglitazar 4 mg with saroglitazar 2mg, where there were 132 patients in saroglitazar 4 mg/day group and 138 patients in Saroglitazar 2 mg/day group. The results showed an SMD of 0.27 kg, (95% CI 0.03 to 0.51), P = 0.02 (Table 3). It demonstrates a significant increase in the bodyweight reduction among the saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.61; I2 = 0%). Besides, two studies [12,19] compared the saroglitazar 4 mg with control, where there were 132 patients in the saroglitazar 4 mg/day group and 139 patients in the control group. The results showed an SMD of -0.09 kg, (95% CI -0.92 to 0.73), P = 0.82 (Table 3). It demonstrates a non-significant decrease in the bodyweight reduction among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). Statistically, significant heterogeneity was observed among included studies (P<0.01; I2 = 89%).

Alanine aminotransferase

Two studies [12,19] compared the saroglitazar 4 mg with saroglitazar 2mg, where there were 132 patients in Saroglitazar 4 mg/day group and 138 patients in saroglitazar 2 mg/day group. The results showed an SMD of -0.07 U/L, (95% CI -0.31 to 0.17), P = 0.56 (Table 3) which demonstrates a non-significant decrease in the alanine aminotransferase among the Saroglitazar 4 mg/day group compared to the saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). There was no statistically significant heterogeneity among included studies (P = 0.28; I2 = 15%). Besides, two studies [12,19] compared the saroglitazar 4 mg with control, where there were 132 patients in the saroglitazar 4 mg/day group and 139 patients in the control group. The results showed an SMD of -0.17 U/L, (95% CI -0.41 to 0.07), P = 0.16 (Table 3). This demonstrates a non-significant decrease in the alanine aminotransferase among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.41; I2 = 0%).

Aspartate aminotransferase

Two studies [12,19] compared the saroglitazar 4 mg with saroglitazar 2mg, where there were 132 patients in the saroglitazar 4 mg/day group and 138 patients in Saroglitazar 2 mg/day group. The results showed an SMD of -0.06 U/L, (95% CI -0.30 to 0.18), P = 0.64 (Table 3). This demonstrates a non-significant decrease in the aspartate aminotransferase among the saroglitazar 4 mg/day group compared to saroglitazar 2 mg/day group in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.55; I2 = 0%). Besides, two studies [12,19] compared the Saroglitazar 4 mg with control, where there were 132 patients in Saroglitazar 4 mg/day group and 139 patients in the control group. The results showed an SMD of -0.05 U/L, (95% CI -0.19 to 0.29), P = 0.68 (Table 3). This demonstrates a non-significant decrease in the aspartate aminotransferase among the saroglitazar 4 mg/day group compared to the control in patients with diabetes-related dyslipidemia (Table 3). No statistically significant heterogeneity was observed among included studies (P = 0.318; I2 = 0%). The summary of all clinical outcomes are presented in Table 3.

Discussion

The current systematic review and meta-analysis looked at the efficacy and safety of Saroglitazar among patients with diabetic dyslipidemia with or without diabetes. This study is the first of its kind that attempted to summarise the efficacy and safety profiles of Saroglitazar; the overall results of this study are encouraging with a reduction in fasting plasma glucose, triglycerides, total cholesterol, LDL-cholesterol, serum creatinine, and body weight, along with improved safety outcomes including hepatotoxicity and renal toxicity.

Diabetic dyslipidemia is a condition that is characterized by low concentrations of HDL with elevated triglycerides, LDL, and postprandial lipemia [24]. At the same time, hypertriglyceridemia is also a notable risk factor and is present in almost 50% of the patients with type-2 diabetes, which is often unresponsive to statins [25]. Since higher levels of triglycerides could significantly increase the risk of cardiovascular diseases, triglycerides management has become the chief priority, especially in patients with diabetes [26]. saroglitazar is a dual peroxisome proliferator-activated receptor (PPAR) agonist with predominant PPAR-α and moderate -γ agonism that can optimise both lipid and glycaemic levels.

Among patients with diabetic dyslipidemia who were not responded to the atorvastatin therapy, a phase III study of saroglitazar has shown a significant improvement in triglyceride, LDL cholesterol, non-HDL-C VLDL, total cholesterol, and fasting plasma glucose [12]. The findings of another phase III clinical trial inferred that saroglitazar could be an alternative for patients those experience the common side effects of fibrates and pioglitazone. However, there is a further need for studies of saroglitazar to well-establish its role in the management of diabetes with dyslipidemia [27]. Furthermore, alongside the favourable finding from the existing clinical trials [12,18-22], the results of a post-marketing study had demonstrated a significant reduction in the triglycerides (35.8%), non-HDL-C (23.4%), LDL-C (16.4%), and total cholesterol (19%) including HbA1c, FBG and PPBG levels with the saroglitazar 4 mg in patients with diabetic dyslipidemia [28].

Overall, when compared to control, once-daily dose of saroglitazar ranging from 2 to 4mg for a duration of 12 to 24 weeks has shown a standard mean difference of -0.28, -0.49, -0.36, 0.24, -0.66, 0.58, -0.09, -0.17, and 0.05, on the triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, non-HDL-cholesterol, serum creatinine, body weight, ALT, and AST, respectively. Furthermore, 4mg saroglitazar has predominantly shown better results when compared with the 2mg Saroglitazar, where a standard mean difference of -0.24, -0.28, -0.23, -0.17, 0.45, -0.07, -0.06, and 0.27, on the triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, serum creatinine, body weight, ALT, and AST, respectively.

In addition, 4 mg saroglitazar has shown the potentiality in decreasing glycaemic-related outcome measures such as FPG to a significant extent (SMD of -0.22 and -0.07) when compared to the control and 2 mg saroglitazar [19,21], which might be a result of its PPAR-c agonist activity. As a result, saroglitazar is emerging as a first-line choice for diabetic dyslipidemia with hypertriglyceridemia for its both lipid and glucose-lowering effects. Safety analysis of saroglitazar revealed no serious adverse events, including hepatotoxicity and renal toxicity in any of the clinical trials, which might be due to its non-renal route of excretion.[29] Instead, it showed a reduction in the ALT (absolute weighted mean difference of 13.6), AST (13.9) and serum creatinine levels for saroglitazar 2mg (0.51) [19,21]. All the reported adverse events like dyspepsia, gastritis, pyrexia were mild in severity and ranged from 10% to 17%, which seems to be better compared to the control groups (up to 20%) [19,20].

Besides exhibiting improved outcomes among patients with diabetes, saroglitazar also showed a significant reduction in serum triglyceride and VLDL levels and increased HDL levels in patients with HIV-associated lipodystrophy [20]. Among patients who are unresponsive or contra-indicated to fibrates and statin therapies, saroglitazar has the potential to undertake the cardiovascular risk associated with high triglyceridemia [19]. Also, since saroglitazar has both antidyslipidemic and anti glycemicglycaemic actions, it would have the ability to address the uncertainties in the reduction of macrovascular and microvascular complications. However, as most of these studies are clinical trials with shorter durations, findings on more extensive observational studies using real-world evidence are warranted.

Limitations

There are certain limitations associated with this study that must be considered while interpreting the findings. Firstly, all the studies included in this systematic review and meta-analysis were clinical trials, which usually account for a limited sample size with a minimum duration of the follow-up period, which makes it difficult to assess the long-term safety and efficacy of saroglitazar. Secondly, some of these studies were single-center and single-arm trials without a comparator group. Thirdly, these findings could not be generalizable to all the patients with dyslipidemia, as all the included studies were solely conducted in India. In addition to this, all the included trials had shorter follow-up duration with surrogate outcomes.

Conclusions

The current evidences, suggests saroglitazar to be effective in reducing LDL cholesterol, non-HDL-C, triglycerides, total cholesterol, and fasting plasma glucose among the dyslipidemic patients. Furthermore, it is appeared to be safe in terms of liver enzymes abnormality and body weight. However, studies are needed to compare the effect of saroglitazar with other antihyperlipidemic medications.

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Risk of bias analysis of single arm studies.

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Search strategy for each database.

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26 Oct 2021

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Reviewer #1: In this systematic review with meta-analysis, the authors synthesize the evidence for saroglitazar on surrogate lipid outcomes (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, non-HDL cholesterol) and safety outcomes (glucose, ALT, AST, and weight change). The author state that they use the PICOS framework to answer questions regarding efficacy and safety of saroglitazar, but it is unclear to me if the PICOS questions (and study protocol) were pre-specified prior to conducting the review.

Major comments

1. The study selection criteria could be more clearly explained. It isn’t clear to me if the patients in the eligible trials had to have diabetes or pre-diabetes or if they just needed to be adults > 18 years of age. Please clarify and add the % of patients with diabetes at baseline to your study summary Table 1.

2. A major problem is in the available underlying studies and the comparisons that were tested. Are the authors most interested in the comparative efficacy and safety of saroglitazar to placebo, or direct head-to-head comparisons to other PPAR agonists (e.g. fenofibrate, pioglitazone) or both? To best answer this question I suggest the author’s only include the highest quality evidence for assessing efficacy which would be a randomized clinical trial. Two studies (Bhosle 2018, Deshpande, and Pay 2014 ) should be excluded as they have no comparator (only treat with saroglitazar) so no conclusions can be drawn.

3. Outcomes: Please list your efficacy and safety outcomes in the methods. The most important outcomes (perhaps 3-5) should be the focus of the review. Your most important safety outcomes should also be included in the abstract.

4. Statistical methods: The authors need to specify the actual analytic package used in R software (R studio is the software ‘container’ used to run R and its packages). The authors need to provide more details about the type of meta-analysis method used.

5. Efficacy and effectiveness have different definitions. I believe the authors are assessing the efficacy of saroglitazar in the context of well-controlled trials.

6. I suggest avoiding using the terms statistically significant or non-significant decrease (page 10, line 218 for example) since it does adequately describe the strength and magnitude of the evidence. Some have suggested wording such as “there no evidence of a difference” or “there was evidence of a difference”. Stating there was a non-significant decrease is probably not appropriate since we do not truly know if there was a decrease or if the change is simply due to biological or analytic variability in the test.

7. Discussion: Please add a citation for the statement regarding first-line choice for dyslipidemia (p 17, line 320). The study didn’t assess glycosylated haemoglobin but it is listed as an outcome on line 322. Also the authors state that serum creatine was decreased (line 361) but in fact in was increase in the meta-analysis.

8. Figure 1 PRISMA: The number included in the quantitative analysis is incorrect. This should be the number of studies actually meta-analyzed. Please state the exact number included in the meta-analysis in the figure and the results section.

9. Conclusions: I don’t think the size and the quality of the included studies permits such strong conclusions in the discussion and abstract. The authors should avoid over interpreting their findings and should discuss the many limitations of the available evidence (e.g., small sample sizes, surrogate outcomes, short duration of follow-up etc.).

Minor comments

1. Introduction and abstract: It appears that saroglitazar is only approved for use in India. It would be helpful to put its approval and contemporary use in context. Are there any data on uptake or how it is used when compared with other PPAR agents?

2. Suggest further language editing. Please ensure consistent capitalization with journal guidelines for article title and text (e.g., saroglitazar, dyslipidemia).

3. Table 1, last row, column “Study design” should likely state for safety (for efficacy is repeated). I also suggest that there are different columns for the intervention and the comparator, rather than having this information in the “number of participants” column.

4. Table 2: There are symbols without a footnote (e.g., ‡). This table should be condensed and similar terminology for each study should be used (it appears that the text might be verbatim from the study publication). The authors should include the results (numeric) for the primary study efficacy and safety outcomes and not interpret the findings in the key conclusion column.

5. Figures: Suggest having forest plot labels “Favours saroglitazar” and “Favours placebo” or the other comparator.

Reviewer #2: In this meta-analysis, the authors investigate the efficacy and safety of Saroglitazar in patients with dyslipidaemia. The results indicate that Saroglitazar has beneficial effects on improving dyslipidaemia in patients with type-2 diabetes. This study has practical and clinical value. Overall, the methods seem sound and the conclusions make a significant contribution to the field. However, in my opinion, this paper also has some important issues that need to be addressed by the authors.

First, a more precise description of the methods should be provided (potentially as supplementary material). For instance:

* Can the authors provide more information on the inclusion and exclusion criteria? “The highly irrelevant studies only were excluded during the title/abstract screening.” What are the reasons and rationale for the irrelevance? And more information can be added to the PRISMA flow diagram, i.e., the number of excluded reviews, observational studies, animal studies, etc. should be illustrated separately.

* It is said that “we conducted the systematic review and meta-analysis aimed to examine the effectiveness and safety of Saroglitazar for the management of dyslipidaemia.” How was this effectiveness and safety defined and what was the measurements of them? There should be a description of these aspects in the method section.

* Description of statistical analysis is missing.

As for the result section, the description of each part of the results should be more varied, otherwise it will make the paper less readable. There are also some very obvious errors in the reference citations and tables/figures. For instance:

* “Two studies [20, 21] compared the Saroglitazar 4 mg with Saroglitazar 2mg”, these two studies should be by Pai V et al., 2014 and Jani RH et al., 2014, not by Deshpande A et al., 2016 and Bhosle D et al., 2018. It is important to double check all the reference citations and not to make such mistakes.

* In the table 1, the number of participants in Pai V et al., 2014 should be “Pioglitazon (45mg): 40”, not “Saroglitazor (45mg): 40”. Such mistakes should be avoided.

And the results of the two single-arm studies are not described.

More cautious formulations could be used in several cases. For instance:

* In the discussion (and the conclusion), it is claimed that “The overall results of this study are encouraging with a significant reduction in glycosylated haemoglobin, fasting plasma glucose, triglycerides, total cholesterol, LDL-cholesterol, serum creatinine ". This conclusion seems misleading given the non-significance of the result (and the existence of high heterogeneity; as acknowledged by the authors in the result session).

* It should be clear from the result of the abstract that this study has examined the safety of Saroglitazar.

* Reference citations should be added in some place, e.g., “which might be due to its non-renal route of excretion”.

Finally, it is true that because of the limited number of studies and sample size, this study has significant limitations and the robustness of the conclusions is not sufficient. I suggest to include a paper published recently by Krishnappa, M et al. which included 1155 patients examining the effectiveness of saroglitazar 2mg and 4mg on glycemic control, lipid profile in patients with type 2 diabetes. This study may strengthen the reliability of meta-analysis.

Ref: Krishnappa M, Patil K, Parmar K, Trivedi P, Mody N, Shah C, Faldu K, Maroo S; PRESS XII study group, Parmar D. Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study). Cardiovasc Diabetol. 2020 Jun 19;19(1):93. doi: 10.1186/s12933-020-01073-w. PMID: 32560724; PMCID: PMC7305598.

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Reviewer #1: Yes: Joseph E Blais

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22 Feb 2022

Respected Editor-In-Chief

Thank you for your timely review of our manuscript entitled “Efficacy and safety of Saroglitazar for the management of Dyslipidemia: A systematic review and meta-analysis of interventional studies” [PONE-D-21-19447]. We have gone through all of your valuable comments. Please find the revisions and justifications made based on comment to comment.

Reviewers' comments:

Reviewer #1

In this systematic review with meta-analysis, the authors synthesize the evidence for saroglitazar on surrogate lipid outcomes (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, non-HDL cholesterol) and safety outcomes (glucose, ALT, AST, and weight change). The author state that they use the PICOS framework to answer questions regarding efficacy and safety of saroglitazar, but it is unclear to me if the PICOS questions (and study protocol) were pre-specified prior to conducting the review.

Response#

We have used PICOS framework and it was pre-specified prior to the conduct of the search for the electronic databases. It is well explained in the methods context of the manuscript. Unfortunately, we did not register our protocol with PROSPERO, because of COVID-19, it was a delay.

Major comments

Comment 1#

The study selection criteria could be more clearly explained. It isn’t clear to me if the patients in the eligible trials had to have diabetes or pre-diabetes or if they just needed to be adults > 18 years of age. Please clarify and add the % of patients with diabetes at baseline to your study summary Table 1.

Response#

For the clarity of respected reviewer, we have undertaken a systematic literature review to study the effect of Saroglitazar on the lipid profile irrespective of diabetes. The concern of the reviewer is clarified in the context of the methods section and it is re-written as described below for a better clarity.

“The research question for our systematic review is "What is the safety and efficacy of Saroglitazar for the management of hypercholesterolemia?" The research question was broken down into PICOS (population, intervention, comparison, outcome, and study design) format. Population (P) comprises of adult patients with hypercholesterolemia with or without diabetes. Intervention (I) consists of Saroglitazar in any of its effective dose. Comparator (C) were any comparator such as different doses, placebo or other drug as per author’s discretion. Outcomes (O) considered were efficacy and safety of Saroglitazar. The effect of Saroglitazar on total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol, non-HDL cholesterol, and fasting plasma glucose considered to be efficacy outcomes. While reduction in Serum Creatinine, Alanine Transaminases, Aspartate Transaminases, and body weight considered to be safety outcomes. In study design (S), we included all type of interventional studies; randomised, and non-randomised trials. Any studies satisfying the above specified PICOS were included in the systematic review. Reviews, observational and descriptive studies, editorials, commentaries and conference proceedings were excluded.”

Comment 2#

A major problem is in the available underlying studies and the comparisons that were tested. Are the authors most interested in the comparative efficacy and safety of saroglitazar to placebo, or direct head-to-head comparisons to other PPAR agonists (e.g. fenofibrate, pioglitazone) or both? To best answer this question I suggest the author’s only include the highest quality evidence for assessing efficacy which would be a randomized clinical trial. Two studies (Bhosle 2018, Deshpande, and Pay 2014) should be excluded as they have no comparator (only treat with saroglitazar) so no conclusions can be drawn.

Response#

Firstly, if we are excluding the single arm studies, we will be biased on evidence and our main objective is to provide very first evidence on efficacy and safety of Saroglitazar. Our aim is not to do any comparative efficacy, instead to give an overall picture on efficacy of Saroglitazar.

Secondly, if we consider your request and exclude two studies we may lose bulk in evidence. Moreover, the evidences derived from these studies are useful to compare the efficacy and safety in different disease of the drug. Furthermore, our safety evidence can be used as future research direction to conduct studies on real-world evidence of Saroglitazar.

Comment 3#

Outcomes: Please list your efficacy and safety outcomes in the methods. The most important outcomes (perhaps 3-5) should be the focus of the review. Your most important safety outcomes should also be included in the abstract.

Response

Thanks for highlighting the flaw, we have modified it accordingly.

“Outcomes (O) considered were efficacy and safety of Saroglitazar. The effect of Saroglitazar on total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol, non-HDL cholesterol, and fasting plasma glucose considered to be efficacy outcomes. While reduction in Serum Creatinine, Alanine Transaminases, Aspartate Transaminases, and body weight considered to be safety outcomes.”

We have added following sentence to abstract

“Saroglitazar showed a reduction in liver transaminases and serum creatinine.”

4. Statistical methods: The authors need to specify the actual analytic package used in R software (R studio is the software ‘container’ used to run R and its packages). The authors need to provide more details about the type of meta-analysis method used.

Response#

Please find the addition with respect to the above comment

“All the analyses were performed with R software (R version 4.1.2) using meta-package. Changes in continuous outcomes were calculated for every included study arm by subtracting the value at baseline from the value after intervention. All the efficacy estimates were expressed as standardised mean difference (SMD) or absolute weighted mean change (MRAW) and 95% confidence interval (CI) from baseline. Standard deviations (SD) were calculated from the standard error or 95% CI, according to the Cochrane handbook for systematic review of interventions. The Higgins I2 statistics and Cochran’s Q test were used to assess the potential statistical heterogeneity among trials. The meta-analysis was conducted using a fixed-effect model (using inverse-variance) or a random-effect model (DerSimonian–Laird method) based on low heterogeneity (<50%) or high heterogeneity (>50%). Due to less number of included studies (<10), it was not feasible to examine the publication bias through funnel plot by Egger's and Begg’s test.”

Comment 5#

Efficacy and effectiveness have different definitions. I believe the authors are assessing the efficacy of saroglitazar in the context of well-controlled trials.

Response

Thank for the valuable suggestion, we have replaced word “effectiveness” with “efficacy”

Comment 6#

I suggest avoiding using the terms statistically significant or non-significant decrease (page 10, line 218 for example) since it does adequately describe the strength and magnitude of the evidence. Some have suggested wording such as “there no evidence of a difference” or “there was evidence of a difference”. Stating there was a non-significant decrease is probably not appropriate since we do not truly know if there was a decrease or if the change is simply due to biological or analytic variability in the test.

Response

Thank you for suggestion and we have considered your request and change made in the context is as follow

“This demonstrates decrease in the triglycerides among the Saroglitazar 4 mg/day group compared to the control group in patients with”

Comment 7#

Discussion: Please add a citation for the statement regarding first-line choice for dyslipidemia (p 17, line 320). The study didn’t assess glycosylated haemoglobin but it is listed as an outcome on line 322. Also the authors state that serum creatine was decreased (line 361) but in fact in was increase in the meta-analysis.

Response#

We have modified that sentence as it was bit contradictory, it is not first line of therapy. There is paucity of the literature stating it is first-line of therapy. Thanks for the pick point regarding the glycosylated hemoglobin, we have rectified our sentence.

Serum creatinine levels for Saroglitazar 2mg were decreased. We have elaborated in the results section and have modified the sentence picking up your concern.

In figure 8 we have compared Saroglitazar 4mg vs 2mg, S creatinine was decreased with 2 mg as compared to 4 mg.

Comment 8#

Figure 1 PRISMA: The number included in the quantitative analysis is incorrect. This should be the number of studies actually meta-analyzed. Please state the exact number included in the meta-analysis in the figure and the results section.

Response#

Thank you for your valuable suggestion, we replaced 6 studied with 4 studies in quantitative section of the (updated) PRISMA.

Comment 9#

Conclusions: I don’t think the size and the quality of the included studies permits such strong conclusions in the discussion and abstract. The authors should avoid over interpreting their findings and should discuss the many limitations of the available evidence (e.g., small sample sizes, surrogate outcomes, short duration of follow-up etc.).

Response#

We have made changes as per your suggestion, the limitation section has been updated and changes made as follows

“There are certain limitations associated with this study that must be considered while interpreting the findings. Firstly, all the studies that are included in this systematic review & meta-analysis were clinical trials, which usually account for a limited sample size with a minimum duration of the follow-up period, which makes it difficult to assess the long-term safety and efficacy of Saroglitazar. Secondly, some of these studies were the single centre and single-arm trails without a comparator group. Thirdly, these findings could not be generalizable to all the patients with dyslipidemia, as all the included studies were solely conducted in India. In addition to this all the included trials were having shorter follow up duration with surrogate outcomes.”

Minor comments

Comment 1#

Introduction and abstract: It appears that Saroglitazar is only approved for use in India. It would be helpful to put its approval and contemporary use in context. Are there any data on uptake or how it is used when compared with other PPAR agents?

Response#

We have added information on its approval and contemporary use in India as

“the treatment of diabetic dyslipidemia and hypertriglyceridemia” however, we didn’t get any data on its uptake and its use as compared to other PPAR analogues.

Comment2#

Suggest further language editing. Please ensure consistent capitalization with journal guidelines for article title and text (e.g., saroglitazar, dyslipidemia).

Response#

Our manuscript have undergone for English language proof reading by a native English speaker to avoid any flaws in English. We have modified concerns raised by the author

Comment 3#

Table 1, last row, column “Study design” should likely state for safety (for efficacy is repeated). I also suggest that there are different columns for the intervention and the comparator, rather than having this information in the “number of participants” column.

Response#

Thanks for your keen observation, we have made changes and it is now reflected in the last row of the column, it was typo error. Deleting arms from number of participants column will not be beneficial, as in current representation it gives clear picture of the number of participants over eyes.

Comment 4#

Table 2: There are symbols without a footnote (e.g., ‡). This table should be condensed and similar terminology for each study should be used (it appears that the text might be verbatim from the study publication). The authors should include the results (numeric) for the primary study efficacy and safety outcomes and not interpret the findings in the key conclusion column.

Response#

Table 2 is completely revised as per the reviewers comment

Comment 5#

Figures: Suggest having forest plot labels “Favours saroglitazar” and “Favours placebo” or the other comparator.

Response#

We have modified as suggested by the reviewer

Reviewer #2:

In this meta-analysis, the authors investigate the efficacy and safety of Saroglitazar in patients with dyslipidemia. The results indicate that Saroglitazar has beneficial effects on improving dyslipidemia in patients with type-2 diabetes. This study has practical and clinical value. Overall, the methods seem sound and the conclusions make a significant contribution to the field. However, in my opinion, this paper also has some important issues that need to be addressed by the authors.

First, a more precise description of the methods should be provided (potentially as supplementary material). For instance:

* Can the authors provide more information on the inclusion and exclusion criteria? “The highly irrelevant studies only were excluded during the title/abstract screening.” What are the reasons and rationale for the irrelevance? And more information can be added to the PRISMA flow diagram, i.e., the number of excluded reviews, observational studies, animal studies, etc. should be illustrated separately.

Response: Thank you for the valuable suggestion, we have updated the PRISMA flow diagram as suggested and we have added the information.

Comment#

* It is said that “we conducted the systematic review and meta-analysis aimed to examine the effectiveness and safety of Saroglitazar for the management of dyslipidaemia.” How was this effectiveness and safety defined and what was the measurements of them? There should be a description of these aspects in the method section.

Response#

We wrongly used the term effectiveness considering the comments of reviewer one we have replaced with safety and efficacy. This is further addressed in the PICOS

Comment#

* Description of statistical analysis is missing.

Response#

All the analyses were performed with R software (R version 4.1.2) using meta-package. Changes in continuous outcomes were calculated for every included study arm by subtracting the value at baseline from the value after intervention. All the efficacy estimates were expressed as standardised mean difference (SMD) or absolute weighted mean change (MRAW) and 95% confidence interval (CI) from baseline. Standard deviations (SD) were calculated from the standard error or 95% CI, according to the Cochrane handbook for systematic review of interventions. The Higgins I2 statistics and Cochran’s Q test were used to assess the potential statistical heterogeneity among trials. The meta-analysis was conducted using a fixed-effect model (using inverse-variance) or a random-effect model (DerSimonian–Laird method) based on low heterogeneity (<50%) or high heterogeneity (>50%). Due to less number of included studies (<10), it is not feasible to examine the publication bias through funnel plot by Egger's and Begg’s test.”

Comment#

As for the result section, the description of each part of the results should be more varied, otherwise it will make the paper less readable. There are also some very obvious errors in the reference citations and tables/figures. For instance:

* “Two studies [20, 21] compared the Saroglitazar 4 mg with Saroglitazar 2mg”, these two studies should be by Pai V et al., 2014 and Jani RH et al., 2014, not by Deshpande A et al., 2016 and Bhosle D et al., 2018. It is important to double check all the reference citations and not to make such mistakes.

Response#

We are really very sorry for such a critical error. It has been modified and taken care in the modified manuscript.

Comment#

* In the table 1, the number of participants in Pai V et al., 2014 should be “Pioglitazon (45mg): 40”, not “Saroglitazor (45mg): 40”. Such mistakes should be avoided.

And the results of the two single-arm studies are not described.

Response#

We have made changes and addition as per reviewer comment and it can be seen in the context

Comment#

More cautious formulations could be used in several cases. For instance:

* In the discussion (and the conclusion), it is claimed that “The overall results of this study are encouraging with a significant reduction in fasting plasma glucose, triglycerides, total cholesterol, LDL-cholesterol, serum creatinine ". This conclusion seems misleading given the non-significance of the result (and the existence of high heterogeneity; as acknowledged by the authors in the result session).

Response#

We have modified the whole manuscript as per the actual findings by avoiding these types of claims

Comment#

* It should be clear from the result of the abstract that this study has examined the safety of Saroglitazar.

Response#

Our objective is clearly states that, this study aimed “To evaluate the efficacy and safety profiles of Saroglitazar in patients with dyslipidemia”. However, we couldn’t specify all PICOS in detail in the abstract due to word limits.

Further, we have added the statement with respect to the safety outcome in the abstract as follows:

“Saroglitazar showed a reduction in liver transaminases and serum creatinine” which considered to be safety outcomes in our study.

Comment#

* Reference citations should be added in some place, e.g., “which might be due to its non-renal route of excretion”.

Response#

Thanks for picky point, we have added reference

Comment#

Finally, it is true that because of the limited number of studies and sample size, this study has significant limitations and the robustness of the conclusions is not sufficient. I suggest to include a paper published recently by Krishnappa, M et al. which included 1155 patients examining the effectiveness of saroglitazar 2mg and 4mg on glycemic control, lipid profile in patients with type 2 diabetes. This study may strengthen the reliability of meta-analysis.

Ref: Krishnappa M, Patil K, Parmar K, Trivedi P, Mody N, Shah C, Faldu K, Maroo S; PRESS XII study group, Parmar D. Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study). Cardiovasc Diabetol. 2020 Jun 19;19(1):93. doi: 10.1186/s12933-020-01073-w. PMID: 32560724; PMCID: PMC7305598.

#Response

Thank you for suggesting the reference. However, we couldn’t include this study as per our review criteria. Our inclusion criteria clearly indicates the inclusion of “participants who diagnosed with hypercholesterolemia with or without diabetes”. Unfortunately this study included “population with diabetes with or without hypercholesterolemia”, which is out of our focus.

Submitted filename: Rebutal letter_R1.docx

Click here for additional data file.

15 Mar 2022

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dr Chhabra and colleagues have conducted a systematic review of interventional studies for saroglitazar and included 4 studies in their meta-analysis. I appreciate the authors efforts to respond to the first round of comments and I can see they have made significant revisions to strengthen their manuscript. However, I still have several concerns regarding the methods and presentation of the results. My major concern is about the latest date of the literature search which was performed 22 months ago (May 2020).

1. Have the authors updated their search of the literature? The date of the last search was May 2020 which is not very recent. I will like to see an updated literature search in case recently published studies have been missed.

2. Abstract, results: Total cholesterol and LDL cholesterol, saraglitazar 4 mg vs control does not match the number of studies included in the results in the text and (Figures 5 and 7 only have 3 studies). The sentence (line 67) to the abstract “Saroglitazar showed a reduction in liver transaminases and serum creatinine” is too vague. I suggest you add the same details as the earlier sentences (intervention, comparator, estimate, p value # of studies).

3. P values for estimates should not be dichotomized at 0.05 level. Please include the actual p value for the pooled estimates in the abstract and results.

4. Please add the unit of measurement for lipids (mmol/L) be added to the forest plot figure titles and Table 3.

5. There is a discrepancy between figure 1 tiff file and figure 1 docx file in the number of studies included in meta-analysis.

Language issues:

Abbreviations: Sometimes LDL cholesterol and LDL-cholesterol (recommend not using the dash as this seems to be the norm for most publications).

Line 2, line 51 and others: No need to specifically capitalize saroglitazar and dyslipidemia

Line 431: use and not &

Line 435: misspelled trials as trails.

Throughout the paper the authors should consistently use the term dyslipidemia which, to my understanding, encompasses any problematic concentration of blood lipid measures such as hyperlipidemia, hypertriglyceridemia or low HDL cholesterol.

Reviewer #2: Thank you for the revision. The majority of concerns have been addressed. Before the manuscript is acceptable for publication, I think a few issues need to be revised again.

First, some more useful information should be added to the abstract section. For the method, it is not necessary to state “Two individual reviewers performed an independent review for study selection, data extraction and quality assessment.”. A summary description of the selection of outcomes or the method of data synthesis can be provided. And for the results part, it is not comprehensive to describe only the significant results. All study results should be summarized because you have discussed them in the discussion section.

Secondly, I agree with reviewer 1 that avoiding using the terms statistically significant or non-significant decrease (not only for TG). Except for TC and LDL-C, the P-values for other results are greater than 0.05, we do not know if there was a truly decrease. And in the discussion and conclusion part, “the overall results of this study are encouraging with a reduction in fasting plasma glucose, triglycerides, total cholesterol, LDL-cholesterol,” such concluding statement exaggerates your results, the significance and strength of the evidence do not support such a conclusion. Perhaps you can say that such results (TG, FPG) could be considered suggestive.

Thirdly, I don’t agree the statement that Saroglitazar showed a reduction in liver transaminases, serum creatinine and body weight (abstract line 67 and discussion line 379), as the results for Saroglitazar 4mg vs control were not significant and the results for 4mg vs control and 4mg vs 2mg were reversed for body weight and Aspartate Amino transferase. It can only be said that there is no evidence that Saroglitazar has effects on these safety outcomes. And the SMD for serum creatinine were positive, which is inconsistent with what is stated in the abstract and discussion.

**********

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Reviewer #1: Yes: Joseph Blais

Reviewer #2: Yes: Xin Huang

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4 Apr 2022

Respected Editor-In-Chief

Thank you for your timely review of our manuscript entitled “Efficacy and safety of Saroglitazar for the management of Dyslipidemia: A systematic review and meta-analysis of interventional studies” [PONE-D-21-19447]. We have gone through all of your valuable comments. Please find the revisions and justifications made based on comment to comment in this rebuttal letter and the same has been updated in the revised manuscript (R2) with track changes.

Reviewer #1: Dr Chhabra and colleagues have conducted a systematic review of interventional studies for saroglitazar and included 4 studies in their meta-analysis. I appreciate the authors efforts to respond to the first round of comments and I can see they have made significant revisions to strengthen their manuscript. However, I still have several concerns regarding the methods and presentation of the results. My major concern is about the latest date of the literature search which was performed 22 months ago (May 2020).

Comment 1#

Have the authors updated their search of the literature? The date of the last search was May 2020 which is not very recent. I will like to see an updated literature search in case recently published studies have been missed.

Response#

Yes, we have updated the literature search in January 2022 and we could identify a single new study related to Saroglitazar, unfortunately, that study didn’t meet our inclusion criteria.

We have updated the same in our methodology part which is as follow

“The initial search was performed in April 2019 and was updated in January 2022.”

Comment 2#

Abstract, results: Total cholesterol and LDL cholesterol, saraglitazar 4 mg vs control does not match the number of studies included in the results in the text and (Figures 5 and 7 only have 3 studies).

The sentence (line 67) to the abstract “Saroglitazar showed a reduction in liver transaminases and serum creatinine” is too vague. I suggest you add the same details as the earlier sentences (intervention, comparator, estimate, p value # of studies).

Response#

Thanks for the picky point we have rectified number of studies from 4 to 3

“and control [SMD: −0.36 mmol/L, 95% CI −0.59 to -0.12; p < 0.01; 3 studies].”

“[SMD − 0.49 mmol/L, 95% CI: − 0.72 to -0.26; p < 0.0001; 3 studies].”

Considering you suggestion about the vague sentence we have removed it from the abstract and instead of the there was requirement of the sentence, we kept new sentence as “Saroglitazar was not associated with any serious adverse events.”

Comment 3. P values for estimates should not be dichotomized at 0.05 level. Please include the actual p value for the pooled estimates in the abstract and results.

Response#

Thanks for your suggestion. As you suggested, we have replaced dichotomized P-values to exact P-Values in both abstract and the results section.

Comment 4. Please add the unit of measurement for lipids (mmol/L) be added to the forest plot figure titles and Table 3.

Response#

Thanks for your suggestion. As you suggested, we have added the unit of measurement in the forest plot figure titles, Table 3, abstract, and the text in the results section for each and every included outcome

Comment 5. There is a discrepancy between figure 1 tiff file and figure 1 docx file in the number of studies included in meta-analysis.

Response#

This was happened as we updated Figure 1 during revision and we accidently forgot remove the tiff file submitted during the initial submission. Now we have attached the final figure 1 (R2) and removed the old file from the submission

Comment 6

Language issues:

Abbreviations: Sometimes LDL cholesterol and LDL-cholesterol (recommend not using the dash as this seems to be the norm for most publications).

Response#

Rectified as per your suggestion, Thanks

Comment 7

Line 2, line 51 and others: No need to specifically capitalize saroglitazar and dyslipidemia

Response#

We have considered your suggestion and changes made are in whole context of the manuscript can be seen as track on mode

Comment 8

Line 431: use and not &

Response#

Rectified, thanks for your suggestion

Comment 9

Line 435: misspelled trials as trails.

Response#

Rectified, thanks for your suggestion

Comment 10

Throughout the paper the authors should consistently use the term dyslipidemia which, to my understanding, encompasses any problematic concentration of blood lipid measures such as hyperlipidemia, hypertriglyceridemia or low HDL cholesterol.

Response#

Thanks for the suggestion, we have rectified it

Reviewer #2:

Thank you for the revision. The majority of concerns have been addressed. Before the manuscript is acceptable for publication, I think a few issues need to be revised again.

Comment 1#

First, some more useful information should be added to the abstract section. For the method, it is not necessary to state “Two individual reviewers performed an independent review for study selection, data extraction and quality assessment.”. A summary description of the selection of outcomes or the method of data synthesis can be provided. And for the results part, it is not comprehensive to describe only the significant results. All study results should be summarized because you have discussed them in the discussion section.

Response#

We have considered your suggestion and we have added the outcomes considered and details on quality assessment in the methodology part of the abstract which is as follows:

“The efficacy of saroglitazar was assessed with respect to its effect in total cholesterol, LDL and HDL-cholesterol, triglycerides, fasting plasma glucose, and non-HDL cholesterol. The effects on serum creatinine levels, bodyweight reduction, alanine aminotransferase and aspartate aminotransferase were considered to be safety endpoint. The Cochrane risk of bias assessment tool was used to assess the methodological quality of the included studies”

Comment 2#

Secondly, I agree with reviewer 1 that avoiding using the terms statistically significant or non-significant decrease (not only for TG). Except for TC and LDL-C, the P-values for other results are greater than 0.05, we do not know if there was a truly decrease. And in the discussion and conclusion part, “the overall results of this study are encouraging with a reduction in fasting plasma glucose, triglycerides, total cholesterol, LDL-cholesterol,” such concluding statement exaggerates your results, the significance and strength of the evidence do not support such a conclusion. Perhaps you can say that such results (TG, FPG) could be considered suggestive.

Response#

We have modified such exaggerating results as per the reviewer’s comments

Comment 3#

Thirdly, I don’t agree the statement that Saroglitazar showed a reduction in liver transaminases, serum creatinine and body weight (abstract line 67 and discussion line 379), as the results for Saroglitazar 4mg vs control were not significant and the results for 4mg vs control and 4mg vs 2mg were reversed for body weight and Aspartate Amino transferase. It can only be said that there is no evidence that Saroglitazar has effects on these safety outcomes. And the SMD for serum creatinine were positive, which is inconsistent with what is stated in the abstract and discussion.

Response#

We have carefully gone through the statement and have removed the sentence from the abstract, Thanks for your kind suggestion.

________________________________________

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Joseph Blais

Reviewer #2: Yes: Xin Huang

Submitted filename: Rebuttal letter_R2.docx

Click here for additional data file.

25 Apr 2022

11 May 2022

REBUTTAL LETTER-R4

Respected Editor-In-Chief

Thank you for your timely review of our manuscript entitled “Efficacy and safety of Saroglitazar for the management of Dyslipidemia: A systematic review and meta-analysis of interventional studies” [PONE-D-21-19447]. We have gone through all of your valuable comments. Please find the revisions and justifications made based on comment to comment in this rebuttal letter and the same has been updated in the revised manuscript (R3) with track changes.

Comment 1

Please ensure that you refer to Table 1 in your text as, if accepted, production will need this reference to link the reader to the Table.

Response#

Based on the reviewer comment, we referred Table 1 in the text before the appearance of table.

Comment 2

Please include your tables as part of your main manuscript and remove the individual files.

Response#

Based on the reviewer comment, we included tables as part of the manuscript and removed individual files.

Thanks for reviewing our paper and providing us with the comments to improve further

Submitted filename: Rebuttal letter_R3.docx

Click here for additional data file.

24 May 2022

Efficacy and safety of saroglitazar for the management of dyslipidaemia: A systematic review and meta-analysis of interventional studies

PONE-D-21-19447R3

Dear Dr. Muhammed,

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Jie V Zhao

Section Editor

PLOS ONE

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Reviewers' comments:

9 Jun 2022

PONE-D-21-19447R3

Efficacy and safety of saroglitazar for the management of dyslipidemia: A systematic review and meta-analysis of interventional studies

Dear Dr. Rashid:

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