Pioglitazone


Article Author:
Gauri Singh


Article Editor:
Ricardo Correa


Editors In Chief:
Dustin Constant
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/28/2019 10:15:52 AM

Indications

Pioglitazone is an oral hypoglycemic drug from the thiazolidinedione drug class, FDA approved for the treatment of diabetes mellitus type 2 (DM-2) in adults, as an adjunct to diet and exercise.

DM is a chronic metabolic illness with prevalence trends steadily rising worldwide. It is predicted that the prevalence of DM (especially DM-2) will increase in the next two decades, more so in developing nations within the adult population aged between 45 and 64 years.[1] The need to maintain blood glucose levels is critical to prevent the progression of this disease and its complications. The American Diabetes Association (ADA) has a set goal of HbA1C less than 7% in most non-pregnant patients, a stricter goal of less than 6.5% in some patient groups, or a less strict one of less than 8% in others, based on subjective patient characteristics.

Thiazolidinediones (TZDs) are the first drugs to address the fundamental problem of insulin resistance in type 2 DM patients; the class includes pioglitazone and rosiglitazone. (The FDA restricted the use of rosiglitazone due to increased cardiovascular events reported with it).[2] A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with DM-2 demonstrated immense improvements in HbA(1c), insulin sensitivity, and lipid profile.[3]

Mechanism of Action

The mechanism through which TZDs exert their anti-diabetic effect is augmenting insulin sensitivity. This action involves the activation of a nuclear receptor, the gamma isoform of peroxisome proliferator-activated receptor (PPAR-gamma ). The activation of this nuclear receptor, in turn, alters the gene transcription of several genes involved in glucose and lipid metabolism, along with energy balance. These genes include those for fatty acid transporter protein, lipoprotein lipase, glucokinase, and the GLUT4 glucose transporter. TZDs help to reduce insulin resistance in muscle, liver, and adipose tissues. Since PPAR-gamma iconcentrates heavily in adipose tissue, the effect on muscle and liver seems to be to via endocrine signaling from adipocytes. The exact mechanism of action of TZDs is still not entirely clear, but they have been proven to potentially improve the insulin resistance syndrome and the complications of DM-2.[4]

Administration

Pioglitazone is taken orally, with or without food. Can be taken as monotherapy, but is usually used as an addition to metformin/sulfonylurea or insulin therapy.

For adults, dose starts initially with 15 mg or 30 mg orally once daily. For those who respond inadequately, dose increments of 15 mg of the drug are appropriate as needed. The maximum permissible dose is 45 mg/day by mouth every day.

Adults who do not have symptomatic heart disease, but possess any risk factors for congestive heart failure, or those belonging to NYHA Class I or II heart failure category, the recommended dose is no more than 15 mg orally once daily.

Maximum dose:

  • Adults - 45 mg/day orally
  • Elderly - 45 mg/day orally
  • For adolescents and children, drug safety and efficacy is unclear

Adverse Effects

The common adverse effects of pioglitazone are edema, weight gain, macular edema, and congestive heart failure (CHF). It may cause hypoglycemia when combined with other antidiabetic drugs as well as decrease hematocrit and hemoglobin levels.[5]

  • It is associated with increased bone fracture risk, especially in women and therefore, may be a potential cause for osteoporosis.[6]
  • It correlates with an increase in serum low-density lipoprotein cholesterol levels.
  • Myocardial Infarction, although it is more common in users of rosiglitazone than in users of pioglitazone as per a retrospective cohort study conducted to study cardiac adverse effects of both these drugs.[7]
  • It has been proved in four real-life registries, that the relative risk of CHF with TZDs resulted between 1.06 and 1.76 (between 1.10 and 1.44 if combined with insulin) in comparison to treatment without TZDs. Such a relatively high CHF risk merits acknowledgment along with the potential benefits of TZDs in the management of type 2 diabetes. The odds ratio of intraclass correlation was 1.43 (pioglitazone vs. placebo) in diabetic patients with high cardiovascular risk in the PROactive trial.[8]
  • In December 2016, the FDA conclusion was that using pioglitazone may be associated with an increased risk of bladder cancer.[9]These findings were based on an extensive review after many such warnings came to light.

There is a known drug interaction with oral contraceptives (OCPs), as co-administration of a TZD with an OCPs containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception. Therefore, ensure extra caution regarding contraception in patients receiving pioglitazone and an OCPs.

Contraindications

Contraindications to the use of pioglitazone include the following scenarios:

  • Patients with a known hypersensitivity to pioglitazone or any of its components.
  • Diabetic ketoacidosis or type 1 diabetes, since pioglitazone is active only in the presence of insulin.
  • Hypoglycemia, therefore, regular blood sugar monitoring is imperative. 
  • Initiation of therapy in patients with established New York Heart Association (NYHA) Class III or IV heart failure.
  • Symptomatic heart failure patients.
  • The Beers Criteria lists pioglitazone to be a potentially inappropriate medication (PIM) for the geriatric population with heart or kidney failure.

Monitoring

  • Pioglitazone is known to derange liver function. Therefore,  liver function tests will be necessary before the start of therapy, every two months for the first year, and periodically after that.[10] Advise patients to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine.
  • Pioglitazone should be used carefully in patients with or without pre-existing heart failure. Patients should receive counsel to look out for signs like shortness of breath, rapid weight gain, and/or edema (peripheral or pulmonary) after drug initiation and dose changes. 
  • Assess and maintain bone health in accordance with current standards, especially in female patients.
  • Patients are encouraged to report any warning signs of bladder cancer like red colored urine (haematuria), increased urge or frequency of urination, weight loss, etc.

Toxicity

There is no known antidote for pioglitazone overdose; the only treatment in such cases is supportive management.

Enhancing Healthcare Team Outcomes

Healthcare workers in all capacities dealing with DM-2 patients on pioglitazone should be aware of the dosage and adverse effects of the drug. They should educate the patient about the potential side effects, and the importance of considering the drug to be an adjunct to lifestyle and dietary changes. Patients should be aware of regular monitoring with blood glucose, HbA1C, and liver function tests, and encouraged to inform doctors of any signs of heart failure or dermatologic reactions. Pioglitazone therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Pioglitazone - Questions

Take a quiz of the questions on this article.

Take Quiz
A 65-year-old patient with diabetes mellitus develops orthopnea, dyspnea on exertion, and lower extremity edema for two weeks. His previous visit with the cardiologist two months ago was normal. He is on multiple medications for blood pressure and blood sugar control. Which of the following medications is the most likely cause of the patient's symptoms?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 67-year-old non-smoker, non-alcoholic male patient visits the office with his wife complaining of dark urine and abdominal pain since a week. His wife has noticed him being more tired than usual for a month. His medical history includes diabetes mellitus type II and hypothyroidism. His current medications include thyroxine, pioglitazone, and metformin. On examination, his vitals and system review are within normal limits, except for a yellow sclera. Lab reports demonstrate deranged liver function tests. If the cause of the patient's symptoms is drug-induced, what is the mechanism of action of the potentially responsible drug being used by the patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 70-year-old, unconscious male patient is rushed to the emergency after collapsing at work. His emergency contact confirms his medical history that includes diabetes mellitus type 2 and hypertension but is unaware of the medications he is on. While primary assessment and management are being done, a drug pack in his bag with a worn out label reads that it acts on PPAR-gamma nuclear receptors. Which of the following is a common indication for using this class of drugs in such a patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 47-year-old woman with a history of type 2 diabetes mellitus and hypertension undergoes a minor fall at home, resulting in a fracture of her right radius. Which of the following medications could potentially cause such a fracture?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 35-year-old female presents to the office for nausea and vomiting for two weeks. She further reveals two months of amenorrhoea. Her menses are usually regular, every 28-30 days, lasting four days with moderate flow. She is sexually active with her boyfriend, with inconsistent condom and diaphragm use. Her medical history includes hypothyroidism, diabetes mellitus type 2, and a tubectomy performed five years ago for pelvic inflammatory disease. Regular medications include thyroxine, pioglitazone, rabeprazole, oral contraceptive pills. A urinary beta-HCG test is positive. Which of the following is most likely responsible for the patient's ineffective contraception?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Pioglitazone - References

References

Olokoba AB,Obateru OA,Olokoba LB, Type 2 diabetes mellitus: a review of current trends. Oman medical journal. 2012 Jul;     [PubMed]
Yki-Järvinen H, Thiazolidinediones. The New England journal of medicine. 2004 Sep 9;     [PubMed]
Hauner H, The mode of action of thiazolidinediones. Diabetes/metabolism research and reviews. 2002 Mar-Apr;     [PubMed]
Herz M,Johns D,Reviriego J,Grossman LD,Godin C,Duran S,Hawkins F,Lochnan H,Escobar-Jiménez F,Hardin PA,Konkoy CS,Tan MH, A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus. Clinical therapeutics. 2003 Apr;     [PubMed]
Rizos CV,Elisaf MS,Mikhailidis DP,Liberopoulos EN, How safe is the use of thiazolidinediones in clinical practice? Expert opinion on drug safety. 2009 Jan;     [PubMed]
Schwartz AV,Sellmeyer DE, Effect of thiazolidinediones on skeletal health in women with Type 2 diabetes. Expert opinion on drug safety. 2008 Jan;     [PubMed]
Ziyadeh N,McAfee AT,Koro C,Landon J,Arnold Chan K, The thiazolidinediones rosiglitazone and pioglitazone and the risk of coronary heart disease: a retrospective cohort study using a US health insurance database. Clinical therapeutics. 2009 Nov;     [PubMed]
De Flines J,Scheen AJ, [Glitazones and congestive heart failure: update on PROactive, ADOPT, DREAM and RECORD clinical trials]. Revue medicale suisse. 2007 Aug 29;     [PubMed]
Scheen AJ, Thiazolidinediones and liver toxicity. Diabetes     [PubMed]
Tang H,Shi W,Fu S,Wang T,Zhai S,Song Y,Han J, Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer medicine. 2018 Apr;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Surgery-Podiatry Cert Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Surgery-Podiatry Cert Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Surgery-Podiatry Cert Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Surgery-Podiatry Cert Medicine. When it is time for the Surgery-Podiatry Cert Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Surgery-Podiatry Cert Medicine.