Saroglitazar

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Drug notes

Saroglitazar

Maria Talla1 MBChB, MRCP, Specialty Trainee Saroglitazar

Gerry McKay1 BSc (Hons), FRCP, Consultant Physician Nuclear receptors Miles Fisher1 MD, FRCP, Consultant Physician PPAR-alpha PPAR-gamma 1Glasgow Royal Infirmary, Glasgow UK

Correspondence to: Fibrate-like effects Thiazolidinedione- Dr Maria Talla, Department of Diabetes, like effects Endocrinology & Clinical Pharmacology, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK; email: [email protected] Fatty acid oxidation ↓ triglycerides Adipogenesis, (↓ total cholesterol) lipogenesis ↑ glucose uptake

Lipid lowering Glucose lowering

Figure 1. Saroglitazar has dual PPAR-alpha and PPAR-gamma activity, having effects on lipids and glucose respectively Introduction outlines the pharmacological effect Pioglitazone, a thiazolidinedione, is a of saroglitazar through dual PPAR peroxisome proliferator-activated agonist activity. Saroglitazar activates receptor (PPAR)-gamma agonist that PPAR-alpha, increasing hepatic oxi- improves glycaemic control in type 2 dation of fatty acids and reducing diabetes. A newer class of drugs, formation and secretion of triglycer- known as glitazars, has been devel- ides.1 Fatty acids are diverted from oped with dual PPAR-alpha/gamma skeletal muscle and adipose tissue to agonist activity. They improve dyslipi- the liver, which in turn decreases daemia through a mechanism similar fatty acid synthesis and delivery of to that of fibrates at the PPAR-alpha triglycerides to peripheral tissues. receptor, and improve glycaemic Saroglitazar also increases lipo control in a manner comparable to lysis and elimination of triglycer- the thiazolidinediones at the PPAR- ide-rich particles from plasma by gamma receptor. activating lipoprotein lipase and The first glitazars were effective at reducing the production of apolipo- reducing HbA1c but did not reach protein C-III, an inhibitor of lipo- clinical use because of serious side protein lipase activity. effects of heart failure (aleglitazar, Through modest effects on the muraglitazar) and decreased glomer- PPAR-gamma receptor saroglitazar ular filtration rate (tesaglitazar). regulates the transcription of insu- Saroglitazar is a new glitazar that has lin-responsive genes involved in the been approved in India for the treat- control of glucose production, trans- ment of diabetic dyslipidaemia. port and utilisation. In healthy volunteers, peak Pharmacology plasma levels were attained at 1 hour PPARs are transcription factors that post-dose with the absorption of the belong to the superfamily of nuclear drug being unaffected by food. A receptors. There are three isoforms maximum serum concentration of – alpha, gamma and delta. Figure 1 337.1±91.0ng/ml (mean ± SD) was

Saroglitazar

achieved following a 4mg single with hypertriglyceridaemia not dose of saroglitazar, with a mean controlled with atorvastatin ther- Key points plasma half-life of 2.9±0.9 hours. apy.3 A total of 302 subjects were ● Saroglitazar is highly protein bound randomised to saroglitazar 2mg Glitazars combine clinical features of at approximately 96% in human (n=101), saroglitazar 4mg (n=99), or fibrates and thiazolidinediones to plasma. It is excreted primarily via matching placebo (n=102). There improve lipids and reduce HbA1c ● the hepatobiliary route. The recom- was a four-week run in period where Saroglitazar has been approved for use mended dose is 4mg daily. other anti-dyslipidaemic drugs other in India, and improves lipids with only than atorvastatin 10mg were discon- minor effects on glycaemia ● Trials of efficacy tinued. The primary end-point was Much more safety data are required for The effects on diabetic dyslipid the reduction in serum triglyceride saroglitazar, particularly effects on aemia were studied in two small, level after a 12-week double-blind cardiovascular and renal end-points short phase III trials. treatment period. The Prospective Randomised Saroglitazar 2mg and 4mg signifi- to the start of the study, at the start Efficacy and Safety study of cantly reduced mean triglycerides of the study and at week 24 in the Saroglitazar V (PRESS V) was a by 45.5% and 46.7% respectively at PRESS V trial. During the PRESS VI 26-week, multicentre, randomised, 12 weeks (p<0.001). These reduc- study, patients were monitored for double-blind study to evaluate the tions were statistically significant cardiac events, ECG abnormalities, safety and efficacy of saroglitazar 2mg when compared to baseline and and cardiac function by 2D Echo at and 4mg compared to pioglitazone placebo. Both saroglitazar doses the start of the study, at the end of 45mg in diabetic dyslipidaemia.2 showed a significant increase in 12 weeks and at 24 weeks after the After a two-week run in period to HDL-C compared to placebo. last dose of the study drug. allow lifestyle modification and to There was a statistically significant wash out previous medications that decrease in fasting plasma glucose Discussion affect lipid levels, 122 patients were levels in both the saroglitazar 2mg Saroglitazar is now approved and randomised to saroglitazar 2mg/day and 4mg arms compared to placebo, used in India for use in treatment of (n=41), saroglitazar 4mg/day (n=41), but the decrease in HbA1c was not dyslipidaemia and hypertriglyceri- or pioglitazone 45mg/day (n=40). statistically significant compared to daemia in type 2 diabetes. The evi- The primary end-point of the study placebo (-0.3% and -0.2% for saro dence for its use in terms of efficacy was the change in serum triglyceride glitazar 2mg and 4mg respectively). and safety is limited. It appears to levels after a 24-week treatment produce significant improvements period compared to baseline. Evidence for safety in lipid parameters with only mini- Saroglitazar 2mg and 4mg signifi- In PRESS V saroglitazar did not alter mal, if any, improvement in HbA1c. cantly reduced mean plasma triglyc- body weight, while there was a mean Further larger studies are required eride from baseline by 26.4% and increase of 1.6kg in the pioglitazone to evaluate its safety, efficacy and 45%, respectively, as compared to arm. Seven of 41 patients in the role in managing diabetic dyslipi- 15.5% for pioglitazone after 24 weeks saroglitazar 2mg arm, seven of 41 in daemia, particularly given that all (p<0.001). The maximum effect of the saroglitazar 4mg arm and 11 of the previous drugs in this class have saroglitazar was achieved by week 12 40 patients in the pioglitazone 45mg been withdrawn from development and sustained at week 24. Other lipid arm reported adverse events. Most because of adverse effects. effects were also demonstrated, par- of these events were considered to Both phase III studies of saro ticularly with the 4mg dose (decrease be unrelated to treatment and mild glitazar had short durations of follow in low-density lipoprotein [5%], very in severity. There were no serious up and small numbers of patients, low-density lipoprotein [45.5%], total adverse events reported in either of therefore no meaningful data on cholesterol [7.7%] and apolipo the saroglitazar groups. cardiovascular safety outcome can protein B [10.9%]). Similarly, in PRESS VI both be implied. Long-term cardiovascu- HbA1c levels were slightly reduced doses of saroglitazar were well toler- lar safety studies would be required at 24 weeks in all three treatment ated with similar numbers of to satisfy criteria for licensing in the groups. This was significant when adverse events in all treatment United States or European Union.4 compared to baseline, but with no arms. Most adverse events were not significant difference between saro related to treatment and were mild Declaration of interests glitazar 2mg, saroglitazar 4mg and to moderate in severity. There were Professor Fisher has received hono- pioglitazone 45mg (HbA1c -0.3%, two reports of serious adverse raria for lectures and advisory boards -0.3% and -0.4%, respectively). events during the study, both due to from Takeda, GlaxoSmithKline, The Prospective Randomised chest pain, which were adjudicated AstraZeneca and Roche. Professor Efficacy and Safety study of and considered unrelated to the McKay has received honoraria for Saroglitazar VI (PRESS VI) was a study drug. lectures for AstraZeneca. 16-week, multicentre, prospective, No significant changes in renal randomised, double-blind study to function were reported in either study. References evaluate the safety and efficacy of In terms of cardiovascular safety, References are available in Practical saroglitazar 2mg and 4mg, com- 2D Echo, ECG and ultrasonography Diabetes online at www.practical pared to placebo, in type 2 diabetes were carried out two weeks prior diabetes.com.

Saroglitazar

References 1. Joshi SR. Saroglitazar for the treatment of dyslipid aemia in diabetic patients. Expert Opin Pharmacother 2015;16(4):597–606. 2. Pai V, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared to pio glitazone 45 mg in diabetic dyslipidemia (PRESS V). J Diabetes Sci Technol 2014;8(1):132–41. 3. Jani RH, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). Diabetes Technol Ther 2014;16(2):63–71. 4. Llano A, et al. Drug development and licensing in diabetes. Pract Diabetes 2016;33(2):60–64.