Saturday, January 23, 2016

Saroglitazar | Antidiabetic Drug | Dual PPAR Inhibitor | Treatment of Diabetic Dyslipidemia | Glitazar

Saroglitazar [(2S)-2-Ethoxy-3-[4-(2-{2-methyl-5-[4-(methylsulfanyl)phenyl]-1H-pyrrol-1-yl}ethoxy)phenyl]propanoic acid] is a novel class of anti-diabetic drug, which target both α and γ Peroxisome Proliferator Activated Receptors (PPAR) isoforms. This new class of dual PPAR agonists, termed as glitazar, which bind to both α and γ PPAR isoforms, are currently under active investigation for treatment of a larger subset of the symptoms of the metabolic syndrome [1].

Saroglitazar: Dual PPAR Inhibitor for T2DM Patients

In February 2013, Saroglitazar became the first glitazar that has been approved by any FDA for clinical use. Saroglitazar is marketed under the trade name Lipaglyn and developed by Zydus Cadila. Saroglitazar (2 and 4 mg q.d.) is currently approved in India by Drug Controller General of India (DCGI ) for the management of diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy. Lipaglyn provides the option of a once-daily oral therapy for the patients suffering from diabetic dyslipidemia.
Saroglitazar has another first attached to it. It is the first indigenously developed NCE by any Indian company; in this case Zydus Cadila.
Lipaglyn is indicated 4 mg (or 2 mg where such a need arise) oral dose once daily. 

Saroglitazar Synthesis

WO2003009841A1: Industrial Process


1H NMR (Estimated) for Saroglitazar

Experimental: 1H NMR: 1.14 (3H, t, J = 6.9Hz); 2.37 (3H, s); 2.48 (3H, s); 2.92-3.06 (2H, m); 3.32-3.42 (1H, m); 3.57-3.64 (1H, m); 3.9 (2H, t, J=6.36 Hz); 4.0 (1H, dd); 4.28(2H, t, J = 6.2 Hz); 5.9 (1H, d, J = 3.3 Hz); 6.08 (1H, d, J = 3.38 Hz); 6.6 (2H, d, J = 8.5Hz); 7.1(2H, d, J = 8.5Hz); 7.26 (2H, d, J = 8.4Hz); 7.3 (2H, d, J = 8.34Hz)


The results from various clinical trials do not cite any serious adverse events for Saroglitazar. A small number of incidence reported are dyspepsia, gastritis, pyrexia, pain and chest pain. Their occurrence is nearly as those reported for placebo in the study.

None of the study reports any of the sideeffects commonly associated with PPAR inhibitors such as edema, weight gain, myopathies or derangement of liver and/or kidney functions.

Saroglitazar controversy:

Zydus Cadila says that's its antidiabetic pill is free from side-effects. One expects Saroglitazar to exhibits few (if not all) of the side-effects that occur with other members of glitazar family. I agree that in Saroglitazar case these side-effects may not be life threatening as in other marketed antidiabetic drugs such as pioglitazone, etc; but a pill with no side-effect is "hard to swallow" pill.

Lancet in one of its publication has cited three antidiabetic launched in India that have a used a very "un-scientific" technique to do so. Saroglitazar is the only NCE here, the other two being Hydroxychloroquine (already used as for rheumatoid arthritis treatment) and Berberine (a herbal preparation). Lancet cites that these drugs or preparations have been launched without any extensive clinical trials. The clinical trials done are with small sample size; and/or of very short time frame. In simple words, Lancet feels that these drugs have been "pushed" down the Indian throats. Though the originator companies have strongly refuted this publication; but the question still stay ..... how can be there no AEs? Any foreign particle (including drug molecules) trigger a wide range of receptors, some have an instantaneous reaction (or visualization); other are like slow poison, waiting for a time period to strike. Lack of time-based knowledge of effects is pretty dangerous and west knows it best; as they have launched pain-killers that killed people via heart-attacks [3].

1. Agrawal, R. The first approved agent in the Glitazar's Class: Saroglitazar. Curr Drug Targets 2014, 15(2), 151-155.
2. Lohray, B. B.; et. al. Novel pyrroles having hypolipidemic hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them and their use in medicine. WO2003009841A1
3. Luthra, A.; et. al. The marketing of unproven drugs for diabetes and dyslipidaemia in India. The Lancet Diabetes and Endocrinology 2015, 3(10), 758-760.