Pioglitazone

Article Author:
Gauri Singh
Article Editor:
Ricardo Correa
Updated:
10/14/2019 1:54:09 PM
PubMed Link:
Pioglitazone

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]


References

[1] Olokoba AB,Obateru OA,Olokoba LB, Type 2 diabetes mellitus: a review of current trends. Oman medical journal. 2012 Jul;     [PubMed PMID: 23071876]
[2] Yki-Järvinen H, Thiazolidinediones. The New England journal of medicine. 2004 Sep 9;     [PubMed PMID: 15356308]
[3] 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 PMID: 12809958]
[4] Hauner H, The mode of action of thiazolidinediones. Diabetes/metabolism research and reviews. 2002 Mar-Apr;     [PubMed PMID: 11921433]
[5] 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 PMID: 19236215]
[6] Schwartz AV,Sellmeyer DE, Effect of thiazolidinediones on skeletal health in women with Type 2 diabetes. Expert opinion on drug safety. 2008 Jan;     [PubMed PMID: 18171315]
[7] 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 PMID: 20110009]
[8] 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 PMID: 17896661]
[9] 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 PMID: 29476615]
[10] Scheen AJ, Thiazolidinediones and liver toxicity. Diabetes     [PubMed PMID: 11431595]