Controversies of Pioglitazone in the Management of Diabetes Mellitus

Abstract

Type II-diabetes mellitus (T2DM) is a chronic metabolic disorder which is treated with oral hypoglycaemic agents including pioglitazone.The present work is aimed to collect a brief profile of pioglitazone,belonging to the thiazolidinedione class and controversies surroundingits use. Pioglitazone which was marketed in 1999 acts on the nuclearperoxisome proliferator-activated receptor γ PPAR-γ in adipose tissue,skeletal muscles and liver. Pioglitazone is safe, potent, insulin sensitizing
gene activator and regulate blood sugar level when administered orallyalone or combination with sulphonyl ureas or metformin. India is oneof the leading T2DM patients country and most patients are usingpioglitazone because of its efficacy and economy. Even though it is asafe drug for diabetics, it was observed that it causes adverse effectslike hepatotoxicity, cardiac failure, osteoporosis and urinary bladdercancer and hence pioglitazone was suspended in India in June 2013for a brief duration by the Indian government. There are over 30 lakhpeople in India using this drug and there is no strong evidence to showthat the drug has serious life threatening side effects in patients inIndia and also using Pioglitazone is less expensive than other drugs. Byconsidering the safety, efficacy, potency and economy, health ministryof India revoked the earlier suspension on the diabetic patients andhas allowed the manufacture and prescription of Pioglitazone and itsformulation with several conditions. Hence, there is a lot of debate aboutbenefit to risk ratio of this drug. Our study presenting brief informationabout pioglitazone and its controversies for diabetic mellitus in India.

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RRJHCP| Volume 2 | Issue 3 | September 2016
Research & Reviews: Journal of Hospital and Clinical
Pharmacy
Controversies of Pioglitazone in the Management of Diabetes
Mellitus
T Balasubramanian*, M Karthikeyan, Sujith Puthanpurakkal
Department of Pharmacology, Al Shifa College of Pharmacy, Kizhattur, Poonthavanam, Malapuram, Kerala, India
Review Article
ABSTRACT
Type II-diabetes mellitus (T2DM) is a chronic metabolic disorder
which is treated with oral hypoglycaemic agents including pioglitazone.
The present work is aimed to collect a brief prole of pioglitazone,
belonging to the thiazolidinedione class and controversies surrounding
its use. Pioglitazone which was marketed in 1999 acts on the nuclear
peroxisome proliferator-activated receptor γ PPAR-γ in adipose tissue,
skeletal muscles and liver. Pioglitazone is safe, potent, insulin sensitizing
gene activator and regulate blood sugar level when administered orally
alone or combination with sulphonyl ureas or metformin. India is one
of the leading T2DM patients country and most patients are using
pioglitazone because of its efcacy and economy. Even though it is a
safe drug for diabetics, it was observed that it causes adverse effects
like hepatotoxicity, cardiac failure, osteoporosis and urinary bladder
cancer and hence pioglitazone was suspended in India in June 2013
for a brief duration by the Indian government. There are over 30 lakh
people in India using this drug and there is no strong evidence to show
that the drug has serious life threatening side effects in patients in
India and also using Pioglitazone is less expensive than other drugs. By
considering the safety, efcacy, potency and economy, health ministry
of India revoked the earlier suspension on the diabetic patients and
has allowed the manufacture and prescription of Pioglitazone and its
formulation with several conditions. Hence, there is a lot of debate about
benet to risk ratio of this drug. Our study presenting brief information
about pioglitazone and its controversies for diabetic mellitus in India.
Received date: 26/04/2016
Accepted date: 15/06/2016
Published date: 26/06/2016
*For Correspondence
T Balasubramanian, Department of
Pharmacology, Al Shifa College of Pharmacy,
Kizhattur, Poonthavanam, Malapuram district,
Kerala-679322, India, Tel: 9329844585.
E-mail: tbaluanandhi@gmail.com
Keywords: Diabetes mellitus, Pioglitazone,
Urinary bladder cancer, Suspension, Revoking,
Congestive heart failure.
INTRODUCTION
Noninsulin dependent diabetes mellitus (NIDDM) is a range of dysfunctions described by hyperglycemia and resulting from
the inadequate insulin secretion or resistance to insulin action or redundant glucagon secretion [1]. It is a multifaceted serious
illness involving endocrine pancreas with multiple complications and affecting more than 285 million people worldwide and is
considered one of the three leading causes of death in the world [2]. Diabetes mellitus is treated with Sulfonylureas, Biguanides,
Meglitinide, α Glucosidase inhibitors and Thiazolidinediones. Among the oral antidiabetic drugs, Pioglitazone has been widely
used in India to treat Type 2 diabetic patients. Apart from potent anti-hyperglycaemic action by improving insulin sensitivity, it also
has positive effects on lipid metabolism and endothelial function [3]. There are several issues against the pioglitazone therapy
for diabetic patients in India and globally with regard to risk of bladder cancer. Hence, recently pioglitazone was banned in India,
but again ban was revoked for its use with special precautions. So, it is very essential to know about the pioglitazone and its
controversies in India for the management of hyperglycemia and our study discusses a current detailed prole of pioglitazone with
its controversies in clinical practice for Diabetes mellitus Type 2.

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History of thiazolidinediones
Due to Safety problems and improper clinical effectiveness, number of new antidiabetic drugs introduced in the last
decade faces an uncertain future. Targeting insulin resistance and/or hepatic glucose production was rst made possible with
the introduction of Biguanide metformin. Metformin has been available worldwide since 1957 and was introduced into the
U.S. market in 1995 [4]. Subsequently thiazolidinediones were introduced about a decade ago. With the invention of glitazones
(thiazolidinediones), the control of type 2 diabetes mellitus took a giant leap forward as this is the only class of drugs, other than
metformin, to address the main pathophysiological defect in insulin resistance diabetes mellitus. Oral hypoglygemic agent’s
glitazones have desirable properties beyond their blood glucose lowering effects [5]. The glitazones are peroxisome-proliferator-
activated receptors agonists improve glycemic control by increasing insulin sensitivity in fat, liver, and muscle, and may have a
role in β cell protection [6].
Hence, right from the beginning, thiazolidinediones was mired in controversy because of their adverse effect prole due to
which most drugs in this class have gone off the therapeutic armamentarium at some stage or the other. Troglitazone, the rst
molecule of pioglitazone, was launched in the USA in March, 1997 which became an instant success, particularly in the United
States. It reached Europe later that year, only to be withdrawn within weeks on the from the USA market in March 2004 because
of its liver toxicity [7,8]. Subsequently another two pioglitazones namely rosiglitazone and pioglitazone were launched in the USA
in 1999. However, both rosiglitazone and pioglitazone had their own spectrum of adverse effects like weight gain, decrease
in hematocrit values, edema, cardiac failure and possible worsening of diabetic macular edema [9]. Due to their remarkable
oral ant diabetic efcacy, they became popular and were widely used globally in spite of these side effects. Research shown
that rosiglitazone was a potent hypoglycemic drug with the adverse effect of myocardial infarction [10]. But, this coronary artery
disease side effect was never decisively conrmed, the media hype and subsequent studies recommending that there could be
a minor increase in coronary artery disease rates, eventually led to an extreme decline in the use of this drug, ending in it being
banned in several countries including India [11]. In July 2010, the Health Ministry of India ordered Glaxo Smith Kline to suspend
human studies being conducted in 19 sites across India. Subsequently, in October 2010, the Drug Controller General of India
(DCGI) proposed to the Health Ministry to ban rosiglitazone [12]. Other drugs in the class darglitazone and englitazone have
been discontinued from clinical development or withdrawn from the market. This left pioglitazone as the solitary agent in the
thiazolidinedione class to regulate hyperglycemia.
Pioglitazone
Pioglitazone is widely prescribed oral hypoglycaemic thiazolidinediones and selectively stimulates the nuclear peroxisome
proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α [13,14]. PPAR-γ enhances the transcription of the
several insulin-responsive genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the
liver. It tends to increases transcription of glucose transporter-4 (GLUT 4). As a result, pioglitazone reduces insulin resistance in
the liver and peripheral tissues; increases the expense of insulin-dependent glucose, decreases withdrawal of glucose from the
liver and reduces quantity of glucose in the bloodstream. Improved glycemic control results in lowering of circulating HbA1C and
insulin levels in type 2 DM patients. Apart from potent anti-hyperglycemic action by reducing insulin resistance, it also lowers
serum triglyceride level and raises HDL level without much change in LDL level, probably because it acts on PPAR-α as well.
Hence, on one side there is supporting ground of cardio-protective role of pioglitazone [15]. Whereas some studies showed its
adverse effect of urinary bladder cancer. So there is a lot of debate about benet to risk ratio of this drug.
Pharmacokinetics
Pioglitazone is administered as a single daily oral dose, reaches peak concentration in 2 h and attains steady state in 4-7
days. Bound to serum albumin, it is metabolized in the liver by both CYP2C8 and CYP3A4. Most of the drug is excreted into the
bile and eliminated through faeces, while 15-30% is recovered in urine. The half-life of pioglitazone is 5-6 h, while the half-life of
its active metabolites is 16-23 h [16] .
Pioglitazone
Efcacy
The efcacy of pioglitazone is well documented as monotherapy and in combination with both oral antidiabetics and insulin
[17]. Pioglitazone exerts its effect on both fasting and post prandial blood glucose, thus lowering HbA1c by 1.3 to 1.6%, and the
drug is equipotent to biguanide metformin and sulfonylureas.

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Cardiovascular health
Pioglitazone has been reported to have a cardioprotective effect. Pioglitazone signicantly decreased the progression of
Carotid Intima-Media Thickness (CIMT), improvement in cardiovascular risk factors such as diabetes, obesity, and hyperlipidemia
and prevention of arteriosclerosis [18,19].
Nonalcoholic steatohepatitis
Studies show that pioglitazone, a new diabetes medicine, on decreasing insulin resistance and improving hepatic disease
in patients with nonalcoholic steatohepatitis (NASH). NASH is a chronic liver disease with unknown cause that involves fat
accumulation and inammation in the liver, leading to liver cirrhosis in 10 to 15% of patients and signicant liver scarring in
another 30%. It is most often seen in patients with insulin resistance. Pioglitazone decreases insulin resistance and improves
blood lipid levels, so that it may improve liver disease in NASH [20] .
Adverse effects
Pioglitazone can cause uid retention and peripheral edema, congestive heart failure [6], osteoporosis, Weight gain and
urinary bladder cancer [21-23].
Brand names
Pioglitazone is marketed as trademarks Actos (USA, Canada, UK and Germany), Glustin (Europe), Glizone and Pioz (India).
Controversies
A bridge between bladder cancer and pioglitazone rst appeared in preclinical studies in US in 1999 but initial experimental
pharmacological studies suggested that this might be a rat-specic phenomenon [24]. Unfortunately this urinary bladder cancer
has now been reported in human clinical studies also. Piccinni et al. analyzed association between anti-diabetic drugs and
bladder cancer through adverse event recording. They reported 31 cases of bladder cancer in Pioglitazone users with signicant
ROR above 13 [25].
On 9th June, 2011 the French Agency for the Safety of Health Products concluded to withdraw pioglitazone in regards to high
side effect of bladder cancer [26]. The European Medicines Agency (“EMA”) [27] acknowledged in a statement on June 9, 2011 that:
“While review of pioglitazone is ongoing, the Committee for Medicinal Products for Human Use (CHMP) is not recommending any
changes to the use of pioglitazone-containing medicines”. On June 10, 2011 Germany's Federal Institute for Drugs and Medical
Devices also directed doctors not to prescribe the medication until further investigation of the bladder cancer risk had been
conducted [28]. On June 15, 2011 the U.S. FDA announced that pioglitazone use for more than one year may be associated with an
increased risk of bladder cancer, and that the information about this risk will be added to the Warnings and Precautions section
of the label for pioglitazone-containing medicines.
The ministry of health and family welfare of India has suspended the manufacture and sale of pioglitazone under Section
26A of the Drugs and Cosmetics Act, 1940 with immediate effect, through a notication issued on June 18, 2013. The suspension
had caught physicians, patients and pharmaceutical companies by surprise, following which there were hi-decibel protests
and submissions to the Ministry. In a country full of diabetics, the ban came as a shock to both doctors and patients,’ Lacing
its notication with much caution, the Health Ministry said that it was aware that the drug was risky and safer alternatives
were available. Nevertheless, it proceeds to say that the Drugs Technical Advisory Board recommended the revocation of the
suspension of pioglitazone following consultation with diabetes experts, with certain conditions including that the manufacturers
carry warnings on the packing including a box warning in “bold red letters”, product insert and promotional literature. The drug
should not be used as a rst line of therapy to treat diabetes and it also would carry advice for healthcare professionals, the
notication said. Further, it added, that the drug not be given to patients with a history of bladder cancer, be restricted to the
elderly and prescribed after knowing the patients history. Those prescribed with the drug would also be put through six monthly
reviews and under pharmacovigilance watching, the notication added.
Need of pioglitazone in India over its controversies until safe alternative
In June 18, 2013, the Indian government suspended the popular anti-diabetic drug pioglitazone, over safety concerns only to
revoke the suspension on July 31, 2013. While the oral hypoglycemic controversial drug, which has been linked to urinary bladder
cancer, is back on the Indian market with warnings. Though pioglitazone produces urinary bladder cancer in diabetic patients, a
numerous benecial positive characters with pioglitazone will support the need and continuous use of this safe drug in India for
diabetic patients instead of be banned until alternative available. Pioglitazone gures as an acceptable oral anti diabetic drug
in all international guidelines and recommendations. There are complicated and controversial aspects against pioglitazone and
its urinary bladder cancer. Patients with pioglitazone therapy cause urinary bladder cancer after a long treatment only and this
adverse effect are not only by pioglitazone, and may be with other combined drug or genetic variation including various factors.
Hence, PPARγ stimulation not only progress cancer and also inhibits cancer. Dose dependent cumulative cancer by pioglitazone
also not possible in Indian patients because of low dose, i.e., 30 mg/day as a single dose is used unlike other countries 40 mg/day
[29]. The cardiovascular and other complications produced by diabetic mellitus are more lethal than pioglitazone induced cancer.

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India suffers from a growing diabetes epidemic particularly with insulin sensitive Type 2 diabetes mellitus. Insulin resistance is
more common in Asian Indians and hence glitazones have been very popular in India [30,31].
Pioglitazone is grossly overused in India. As per the Monthly Index of Medical Specialities (MIMS) information, pioglitazone
has annual sales of around INR8 billion (£84 million) in India. Annual sales of xed-dose combinations of pioglitazone with
metformin and glimepiride are around INR5 billion. India is predicted to have 101 million people suffering from diabetes by
2030. Pioglitazone is a Rs. 700 crore plus market in India and several companies including USV, Sun Pharma and Ranbaxy
make the medicine. The sales data show that xed-dose combinations of pioglitazone with other anti-diabetics are top-selling
in the country. On the basis of above said background the pioglitazone is a safe drug for diabetic patients in India and should
not be exempted from anti-diabetic therapy in India until safety drug discovery. Awareness and counseling of the patient using
Pioglitazone is very important, which should include information to contact the prescriber in case of excessive weight gain,
swelling feet, breathlessness, or passing of bloody urine [32]. Asymptomatic hematuria should be investigated with urological
investigations promptly. It is important to recognize the benets of pioglitazone and use it judiciously in appropriate patients who
would benet from the use of this drug.
CONCLUSION
Pioglitazone is a safe, and effective, oral anti-diabetic agent who has great potential in the management of diabetes mellitus
Type 2 in India. Diabetic patients treating with pioglitazone should be insisted to report signs and symptoms of bladder cancer
like blood in urine, pain during micturition, supra-pubic and back pain. Clearly more studies are needed, probably focused on the
Indian population. Our study presenting brief information about pioglitazone and its controversies for diabetic mellitus in India.
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