Table of Contents

2016 Month : December Volume : 2 Issue : 2 Page : 16-19

A NOVEL DUAL PPAR- ALPHA/GAMA AGONIST, SAROGLITAZAR FOR THE TREATMENT OF DIABETIC DYSLIPIDAEMIA AND HYPERTRIGLYCERIDAEMIA.

Tushar B. Chudiwal1, Momin Mohd. Abdul Mujeeb2

1Associate Professor, Department of Pharmacology, Revera Institute of Medical Sciences and Research, Vikramgadh, Thane.
2Associate Professor, Department of Pharmacology, Grant Government Medical College, Mumbai.

Corresponding Author:
Dr. Tushar B. Chudiwal,
GB19, Pride Enigma,
Phase III, Sutgirni Chowk,
Garkheda-431005, Aurangabad.
E-mail: tusharchudiwal@gmail.com

ABSTRACT

BACKGROUND

Cardiovascular Disease (CVD) has become the leading cause of death. Diabetes and dyslipidaemia are commonly associated modifiable risk factors for cardiovascular diseases. Majority of patients with diabetes also suffer from dyslipidaemia (diabetic dyslipidaemia). Diabetic dyslipidaemia is more atherogenic as it is commonly associated with high Triglyceride (TG) levels, high proportion of small dense low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol (HDL-C) level (atherogenic dyslipidaemia). Currently used pharmacotherapies for the management of diabetes and dyslipidaemia like thiazolidinediones (PPAR-γ agonist; for insulin resistance) and fibrates (PPAR-α agonist; for hypertriglyceridaemia) have many limitations and side effects. Saroglitazar, a dual PPAR-α/γ agonists, is an emerging therapeutic option with its dual benefit on glycaemic and lipid parameters. Saroglitazar, a dual PPAR-α/γ agonist, is a potential therapeutic option for the management of diabetic dyslipidaemia. It has dual benefit of significant improvement in glycaemic parameters (glycated haemoglobin and fasting blood glucose) and significant improvement in dyslipidaemia (TGs, apolipoprotein B, non-HDL-C). The results of Phase III clinical trials indicate that saroglitazar is devoid of conventional side effects of fibrates and pioglitazone.

KEYWORDS

Diabetes, Dyslipidaemia, PPAR, Saroglitazar, Triglycerides.

How to cite this article

Chudiwal TB, Mujeeb MMA. A novel dual PPAR-α/γ agonist, saroglitazar for the treatment of diabetic dyslipidaemia and hypertriglyceridaemia. Journal of Evolution of Research in Medical Pharmacology 2016; Vol. 2, Issue 2, July-December 2016; Page:16-19

BACKGROUND

Cardiovascular Disease (CVD) has become the leading cause of death and loss of disability-adjusted life years.[1] Although in recent past decades age-adjusted cardiovascular death rates have declined in several developed countries, rates of CVD have grown up greatly in low- and middle-income countries.[2,3] as about 80% of the CVD burden now occurring in these countries. INTERHEART study suggested nine modifiable risk factors (abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, decreased consumption of fruits and vegetables, alcohol consumption and lack of physical activity) accounted for most of the risk of Myocardial Infarction (MI) worldwide in both sexes and at all ages.[3] In INTERHEART study, after multivariate analysis, current smoking and abnormal lipid levels (dyslipidaemia) were found to be the two strongest risk factors accounting for MI followed by history of diabetes, hypertension and psychosocial factors.[3]

Dyslipidaemia is a primary and major risk factor for Coronary Artery Disease (CAD) and may even be a prerequisite for CAD occurring before other major risk factors come into play. Increasing evidence also points to insulin resistance, which results in increased levels of plasma triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C) and a decreased concentration of high-density lipoprotein cholesterol (HDL-C)  as an important risk factor for peripheral vascular disease, stroke and CAD.[4,5]

Current therapy for the management of hypertriglyceridaemia is lifestyle therapy and pharmacotherapy with fibrates, niacin, omega-3 fatty acids or combination of these drugs with statins.[6] Three different receptor subtypes, PPAR-α, PPAR-γ and PPAR-β/δ have been identified.

PPAR-α is found in the liver, kidney, heart and muscle and is implicated in the uptake and oxidation of fatty acids and lipoprotein metabolism. PPAR-β/δ is expressed in most cell types and plays an important role in lipid metabolism and cell differentiation and growth. PPAR-γ is mainly expressed in adipose tissue with lower expression detected in a wide range of differing tissues like spleen, intestine, pancreas, colon, kidney, skeletal muscle and macrophages.[7]

When activated by the ligand, PPARs form heterodimers with another nuclear receptor named retinoid X-receptor. Subsequent conformational changes in the receptor lead to dissociation of co-repressors and recruitment of co-activators. This process ultimately results in upregulation or downregulation of various genes involved in metabolic pathways. PPAR-α activation causes upregulation of genes involved in lipid metabolism including Fatty Acid Transporter Protein (FATP), acyl-coenzyme (CoA) synthase, carnitine palmitoyl transferase I and II, Lipoprotein Lipase (LPL) and downregulation of apoprotein CIII.[8] On the other hand, PPAR-γ activation leads to upregulation of numerous genes involved in glucose and lipid metabolism including activating protein 2, phosphoenolpyruvate carboxykinase, acyl-CoA synthase, LPL, FATP-1 and CD36, adiponectin and so on.[9,10]

Each PPAR agonist activates or represses a unique set of co-activators and co-repressors in a tissue-specific manner.[11] This property of differential regulation of genes by different PPAR agonist is responsible for unique pharmacodynamics and safety profile of each PPAR agonist. It also explains why some PPAR agonists are unsafe, whereas others are efficacious and safe.

Chemistry

The chemical name for saroglitazar is benzenepropanoic acid, a-ethoxy-4-[2-[2-methyl-5-[4-(methylthio)phenyl]-1H-pyrrol-1-yl]ethoxy]-, magnesium salt (2:1), (aS) - with the structural formula shown in Box 1. Structure activity relationship studies have indicated that most PPAR agonists have a lipophilic heterocyclic tail and acidic side chain with aromatic center in-between.[12] Saroglitazar has a-alkoxy carboxylic group at acidic side chain and pyrrole as core heterocycle with phenyl ring as aromatic center. The a-ethoxy carboxylic acid group forms the H-bond with various amino acids of PPAR-α and PPAR-γ receptors and activates these receptors with higher potency for PPAR-α, Saroglitazar.

 

Pharmacokinetics

Pharmacokinetic properties of saroglitazar were evaluated in Phase I, prospective, randomised, double-blind, placebo-controlled, single-center study.Saroglitazar was rapidly well.

 

Parameter

Saroglitazar 4 mg

Cmax (ng/mL)

337.07±90.99

Tmax (h)

0.71±0.25

AUC last (ng.h/mL)

806.40±160.4

AUC¥ (ng.h/mL)

855.96±172.53

T1/2 (h)

2.93±0.87

Table 1. Pharmacokinetic Parameters (Means ± Standard Deviations) of Saroglitazar Following a Single Oral Dose of Saroglitazar 4 mg in Healthy Subjects

 

Data taken from.

AUC: Area under the plasma concentration - time curve; AUC¥: AUC from time zero to infinity; AUC last: AUC from time zero to the time of the last measurable concentration; Cmax: Maximum plasma concentration; T1/2: Elimination or terminal half-life; Tmax: Time to reach Cmax.

 

Absorbed across all doses in single-dose pharmacokinetic study. The median time to reach maximum concentration (Tmax) was found to be < 1 h (range: 0.63 - 1 h) under fasting conditions across the doses studied (0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 mg). The maximum plasma concentration (Cmax) ranged from 3.98 to 7461 ng/mL across the dose range. The AUC increased in a dose-related manner. The average terminal half-life of saroglitazar was 5.6 h. Saroglitazar was not eliminated by the renal route. Single-dose pharmacokinetic properties of saroglitazar 4 mg is given in Table 1.

 

Clinical Efficacy Studies

PRESS V Study

PRESS V study was a multicenter, prospective, randomised, double-blind, active control, interventional, Phase III study conducted in India. The major efficacy parameters are highlighted in Table 2.

 

PRESS VI Study

PRESS VI study was a multicenter, prospective, randomised, double-blind, placebo control, interventional, Phase III study conducted in India. The major efficacy parameters are highlighted in Table 3.

 

 

Saroglitazar

2 mg/day;

n = 37

Saroglitazar

4 mg/day;

 n = 39

Pioglitazone

45 mg/day; n = 33

Serum Triglycerides

Baseline (mean ± SD) [mg/dL]

253.9±68.44

257.0±52.39

265.0±61.66

Absolute change (LSM ± SD) [mg/dL]

-78.2±81.98z

-115.4±68.11*,z

-33.3±162.41

Percentage change (LSM ± SD)

-26.4±31.57z

-45.0±24.78*,z

-15.5±54.40

Low-Density Lipoprotein Cholesterol

Baseline (mean ± SD) [mg/dL]

134.8±42.56

130.8±38.83

116.6±29.25

Absolute change (LSM ± SD) [mg/dL]

3.6±40.07

-12.0±39.38*,z

3.5±23.17z

Percentage change (LSM ± SD)

12.2±52.64

-5.0±30.36

4.8±22.58

Fasting Plasma Glucose

Baseline (mean ± SD) [mg/dL]

143.9±42.35

152.7±65.99

138.2±31.94

Absolute change (LSM ± SD) [mg/dL]

-11.3±50.11

-22.6±66.30z

-21.8±46.24

Percentage change (LSM ± SD)

-1.5±39.42

-8.3±31.91

-12.8±30.06

Glycated Haemoglobin (%)

Baseline (mean ± SD)

8.1±0.86

7.9±0.58

8.2±0.75

Absolute change (LSM ± SD)

-0.3±0.83z

-0.3±0.60z

-0.4±0.72z

Table 2. PRESS V Study: Change from Baseline in Efficacy Variables at Week 24 (Modified Intention-to-Treat Population, Last Observation Carried Forward Method)

 

Data taken from.

Note: *indicates significant as compared to pioglitazone. zSignificant compared to baseline.

LSM: Least Square Mean; SD: Standard Deviation.

 

 

Saroglitazar

2 mg/day;

 n = 86

Saroglitazar

4 mg/day;

 n = 86

Placebo;

n = 94

Serum Triglycerides (mg/dL)

Baseline (mean ± SD)

273.3±78.58

287.3±85.94

286.6±78.92

Mean ± SE difference from baseline

-132.7±8.30*,z

-139.5±8.29*,z

-78.0±7.93z

LSM ± SE percentage change from baseline

-45.5±3.03*

-46.7±3.02*

-24.9±2.89

Non-High-Density Lipoprotein Cholesterol (mg/dL)

Mean ± SE difference from baseline

-51.4±3.59*,z

-57.7±3.58*,z

-38.6±3.43z

LSM ± SE percentage change from baseline

-29.2± 2.25*

-32.5± 2.25*

-20.1±2.15

Apolipoprotein B (mg/dL)

Mean ± SE difference from baseline

-29.9±2.11z

-34.3±2.09*,z

-25.6±2.00z

LSM ± SE percentage change from baseline

-27.4±2.17

-32.0±2.15*

-22.9±2.06

Fasting Plasma Glucose (mg/dL)

Baseline (mean ± SD)

179.6±71.23

176.3±71.58

184.1±68.27

Mean ± SE difference from baseline

-23.6±7.92*,z

-25.4±7.92*,z

-2.0+7.58

Table 3. PRESS VI Study: Change from Baseline in Efficacy Variables at Week 12 (Intention-to-Treat Population)

 

Data taken from.

*Significant as compared to Placebo. zSignificant compared to baseline.

LSM: Least square mean; SD: Standard deviation; SE: Standard error.

 

Safety and Tolerability

In both PRESS V and PRESS VI studies, there were no significant changes observed from baseline and between the treatment arms in any of the safety laboratory findings. Saroglitazar 2 and 4 mg once daily (q.d.) did not result in significant change from baseline in safety laboratory parameters that is haemoglobin, blood cells count, blood indices, thyroid stimulating hormone, liver enzymes (Alkaline Phosphatase [ALP], Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST]) and renal function (creatinine, blood urea nitrogen) in 24 weeks PRESS V trial.Similarly, in PRESS VI trial, 12-week treatment with saroglitazar 2 and 4 mg q.d. did not result in significant change from baseline in safety laboratory parameters (haemoglobin, liver enzymes, renal function and creatinine phosphokinase).

 

 

Saroglitazar

2 mg

(n = 41)

Saroglitazar

4 mg

(n = 41)

Pioglitazone

45 mg

(n = 40)

Adverse Event

Number of Patients (%)

Asthenia

1 (2.4)

3 (7.3)

1 (2.5)

Gastritis

0 (0.0)

2 (4.9)

2 (5.0)

Chest discomfort

1 (2.4)

1 (2.4)

1 (2.5)

Peripheral oedema

1 (2.4)

0 (0.0)

2 (5.0)

Dizziness

1 (2.4)

1 (2.4)

1 (2.5)

Tremors

1 (2.4)

1 (2.4)

1 (2.5)

Table 4. PRESS V Study: Commonly

Reported Adverse Events

 

Data taken from.

There was mean increase of 1.6 kg bodyweight in pioglitazone arm and no significant change in bodyweight in saroglitazar arms in PRESS V study. The most commonly observed adverse events in PRESS V study are shown in Table 4. The most frequently reported adverse events in PRESS VI study are shown in Table 5. In both Phase III clinical trials, most of the reported adverse events were not related to treatment and were mild-to-moderate in intensity.

 

Ongoing Clinical Trial of Saroglitazar

PRESS X trial (CTRI registration no.: CTRI/2013/06/ 003754) [44]: PRESS X is an ongoing multicentric, prospective, randomised, Phase IV clinical study to evaluate the safety and efficacy of saroglitazar (2 or 4 mg/day) as compared to fenofibrate (160 mg/day) in patients with dyslipidaemia (targeted sample size is 1010). Primary outcome of this study is percentage change in TG levels from baseline at 6, 12 and 24 weeks of followup.

PRESS IX trial (CTRI registration no.: CTRI/2014/08/ 004885): This is an ongoing prospective, multicenter, double-blind, randomised, Phase III study to evaluate the safety and efficacy of saroglitazar 4 mg versus placebo in the treatment of HIV-associated lipodystrophy. Subjects clinically diagnosed as HIV lipodystrophy with confirmed diagnosis of HIV 1 and on highly active Antiretroviral Therapy (ART) for at least 18 months on stable ART regimen for at least 8 weeks will be enrolled. At least 104 patients will be enrolled in saroglitazar 4 mg and 52 patients in placebo group. The primary end point of the study is percentage reduction of visceral adipose tissue at week 52 from baseline.

 

DISCUSSION

More than 70% of patients with T2DM die of cardiovascular causes. Dyslipidaemia is one of the most common comorbid conditions in patients suffering from diabetes. Insulin resistance and T2DM are associated with several changes in lipids and lipoproteins. Insulin-resistant subjects have higher total VLDL TGs and lower HDL-C than subjects with high insulin sensitivity. Elevated levels of TG-rich lipoproteins, either in the fasting or postprandial state are characteristic findings in patients with T2DM (VLDL-C, metabolites of VLDL-C, chylomicron remnants). Low HDL-C often associated with high levels of total and VLDL TGs is another characteristic lipid abnormality in patients with T2DM [48]. Current management of dyslipidaemia in diabetes is cornered around LDL-C reduction by statin therapy. However, residual risk as discussed above, is the major challenge we are facing. Proper blood glucose and comprehensive dyslipidaemia management is the cornerstone for prevention of cardiovascular events in diabetic population.

 

PPAR-γ Agonist and T2DM

Thiazolidinediones (TZDs) are synthetic exogenous agonists of PPAR-γ and are used in the treatment of T2DM. Currently, two TZDs, rosiglitazone and pioglitazone are available, although rosiglitazone is being withdrawn from the market in Europe and its use is restricted in the US, due to concerns about the increase in prevalence of MI. The proactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events) studied > 5000 patients with diabetes.

 

 

 

Saroglitazar

2 mg

(n = 100)

Saroglitazar

4 mg

(n = 99)

Placebo

(n = 102)

Adverse Event

Number of Patients (%)

Dyspepsia

2 (2.0)

0 (0.0)

0 (0.0)

Gastritis

1 (1.0)

4 (4.0)

1 (1.0)

Chest pain

0 (0.0)

1 (1.0)

2 (2.0)

Pain

0 (0.0)

2 (2.0)

1 (1.0)

Pyrexia

3 (3.0)

1 (1.0)

0 (0.0)

Table 5. PRESS VI Study: Commonly

Reported Adverse Events

 

Data taken from.

 

At high risk for macrovascular complications, and reported that treatment with pioglitazone produced a non-significant reduced risk for coronary and peripheral vascular events. For a secondary end point a composite of death, MI or stroke, a statistically significant benefit was observed. However, pioglitazone was associated with significant increase in the risk of heart failure compared to placebo therapy.

 

PPAR-α Agonist and Dyslipidaemia

Fibrates are agonist of PPAR-α and are used for the treatment of high TGs. ACCORD and FIELD trial showed that fenofibrate (with or without statin therapy) does not reduce the primary end point of cardiovascular events significantly. It is important to note that the baseline median TG levels in these two trials were 162 and 155 mg/dL, respectively. In sub-group analysis of various fibrates, trials have suggested significant cardiovascular risk reduction in patient population with baseline TGs level of ‡ 204 mg/dL. A subgroup analysis of FIELD study (in patients population with TGs ‡ 204 mg/dL and low HDL) suggested significant 27% risk reduction (95% CI 9 - 42, p = 0.005; number needed to treat = 23) with TG lowering therapy in primary end point of cardiovascular events. A meta-analysis of five large fibrate trials (HHS, VA HIT, BIP, FIELD and ACCORD studies) indicated that fibrate therapy significantly reduces cardiovascular events by 35% (95% CI, 22 - 46) in patient population with TGs levels ‡ 204 mg/dL and low HDL levels. A very recently published study of 34 years followup involving 75,725 participants from Copenhagen City Heart Study (CCHS) and Copenhagen General Population Study (CGPS) has shed light on the role of non-fasting TG levels as a risk factor for CVD. Results of the study have shown that those with non-fasting TG levels £ 90 mg/dL have ~ 60% risk reduction in ischaemic heart disease as compared to those with non-fasting TG levels ‡ 350 mg/dL.

PPAR-α and PPAR-γ agonists are useful for the comprehensive management of dyslipidaemia and diabetes. But, currently available PPAR-α and PPAR-γ agonists have many limitations and side effects, limiting their clinical utility. Hence, there is a need for safe PPAR-α and PPAR-γ agonist.

 

Dual PPAR-α/γ

Dual agonists simultaneously stimulate PPAR-α and PPAR-γ receptors with varying potencies at each site for treatment of T2DM, insulin resistance and dyslipidaemia. Glitazar is a class of agents having dual PPAR-α and PPAR-γ agonistic activity. Several dual PPAR-α and PPAR-γ agonists have been clinically developed; however, none have progressed beyond Phase III development due to various reasons like lack of efficacy or safety and compound specific.

Saroglitazar is a strong PPAR-α with moderate PPAR-γ action. Currently, saroglitazar is the only approved glitazar available in India for the treatment of diabetic dyslipidaemia.

 

CONCLUSION

Saroglitazar, a dual PPAR-α/γ agonist, is a potential therapeutic option for the management of diabetic dyslipidaemia. It has dual benefit of significant improvement in glycaemic parameters (glycated haemoglobin and fasting blood glucose) and significant improvement in dyslipidaemia (TGs, apolipoprotein B, non-HDL-C). Future clinical trials of saroglitazar will further establish its place in the management of diabetes, dyslipidaemia and associated cardiovascular risk.

 

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