Continuing Education Activity

Pioglitazone is a drug used in the management of type 2 diabetes mellitus. Pioglitazone is the third marketed thiazolidinedione group of oral antidiabetics, the first is troglitazone which is no longer available due to hepatotoxicity, and the second is rosiglitazone, still on the market. This activity reviews the indications, mechanism of action, and contraindications for pioglitazone in managing type 2 diabetes mellitus. This activity highlights the mechanism of action, adverse effect profile, monitoring, and relevant interactions.

Objectives:

• Identify the mechanism of action of pioglitazone.
• Describe the potential adverse effects of pioglitazone.
• Review dosing of pioglitazone.
• Summarize interprofessional team strategies to improve care coordination and communication to use pioglitazone in diabetes mellitus management and improve outcomes while minimizing adverse effects.

Indications

 Pioglitazone is an oral antidiabetic from the thiazolidinedione drug class, FDA approved for treating type 2 diabetes mellitus in adults, as an adjunct to diet and exercise.

Maintaining blood glucose levels as close to normal as possible is the main goal in diabetes management to prevent the complications of type 2 diabetes mellitus. The American Diabetes Association (ADA) guidelines recommend HbA1C less than 7% in most non-pregnant patients, a stricter goal of less than 6.5% in younger patients with long life expectancy, or a less strict HbA1C goal of less than 8% in others with coexisting comorbidities, especially coronary heart disease and hypoglycemia unawareness among others and with limited life expectancy.[1] Pioglitazone can be used in any of the above settings to manage type 2 diabetes mellitus taking into account its beneficial effects, side effects, and contraindications.

Thiazolidinediones (TZDs) target the fundamental problem of insulin resistance in type 2 diabetes mellitus. Thiazolidinediones on the market include pioglitazone and rosiglitazone. Rosiglitazone is not widely available. A meta-analysis by Nissen and Wolski in 2017 suggested an increased risk of myocardial infarction and cardiovascular death with rosiglitazone use.[2] The Food and Drug Administration restricted rosiglitazone sales between 2011 and 2013 with a risk evaluation and medications strategy and then allowed its sale again afterward. No such restriction has ever been placed on pioglitazone. A randomized, double-blind, placebo-controlled clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic-naive patients with type 2 diabetes mellitus demonstrated significant improvements in HbA1c, insulin sensitivity, and lipid profile.[3]

In treatment guidelines, pioglitazone is recommended as third-line or sometimes second-line therapy if first-line and second-line anti-diabetics fail to achieve glycemic control. When a patient demonstrates prominent insulin resistance, a propensity to hypoglycemia, non-alcoholic fatty liver disease or steatohepatitis, or issues with insurance coverage or payment for first- or second-line anti-diabetic agents, pioglitazone should be considered as a viable option.

Mechanism of Action

The mechanism through which TZDs exert their anti-diabetic effect is augmenting insulin sensitivity by acting on muscle, adipose, and liver tissue. TZDs increase peripheral tissue glucose utilization and, to some extent, decrease glucose production in the liver. This action involves activating 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. Some genes are stimulated, and some genes are inhibited. This includes the genes for fatty acid transporter protein, lipoprotein lipase, glucokinase, and the GLUT4 glucose transporter. TZDs help to reduce insulin resistance in muscle, adipose tissue, and liver. Since PPAR-gamma concentrates heavily in adipose tissue, the effect on muscle and liver seems to be via endocrine signaling from adipocytes by adipokines. 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 improve the complications of type 2 diabetes mellitus with better glycemic control.[4]

While rosiglitazone is a PPAR-gamma agonist, pioglitazone is both PPAR-gamma and PPAR-alpha agonist. PPAR-gamma is mainly localized in adipose tissue, pancreatic beta cells, macrophages, vascular endothelium, and the central nervous system. PPAR-alpha is mainly localized in the liver, heart, skeletal muscle, and vascular wall.  These differences may be responsible for different results of rosiglitazone and pioglitazone on lipid levels and cardiovascular outcomes.

Pioglitazone is readily absorbed, and it reaches peak plasma time in 2 to 4 hours. It is more than 99 percent protein bound. Volume of distribution: 0.63 L/kg. Its elimination half-life is between 3 to 7 hours. It is given once a day, and it is considered to exert its pharmacokinetic effects or, in plain terms, to be effective for 24 hours.

Pioglitazone is metabolized in the liver by CYP2C8 and CYP3A4. It has active metabolites, called metabolite II (hydroxy derivative), metabolite III (keto derivative), metabolite IV (active hydroxy derivative). CYP2C8 inducers may decrease the serum concentration of pioglitazone, whereas CYP2C8 inhibitors may increase the serum concentration of pioglitazone. Hyperglycemia-associated or causing- agents like steroids may diminish the therapeutic effect of pioglitazone. When pioglitazone is combined with other oral anti-diabetics, it increases the risk of hypoglycemia, especially with insulin and insulin secretagogues. Consider decreasing the dose of other oral anti-diabetics when starting pioglitazone. If pioglitazone is given together with insulin, the risk of fluid retention, heart failure, and hypoglycemia increases. Consider decreasing insulin dose. If any side effects occur in combination with insulin, the first option is to discontinue pioglitazone or to decrease pioglitazone dose, and the second option to discontinue or decrease insulin.

Other factors that may affect pioglitazone use:

• Concomitant use of pioglitazone and pregabalin may enhance edema.
• The use of aspirin with pioglitazone may increase the hypoglycemic effect of pioglitazone.
• Selective serotonin reuptake inhibitors may enhance the glucose-lowering effect of pioglitazone.
• Use of pioglitazone with a thiazide or thiazide-like diuretics may decrease the glucose-lowering effect of pioglitazone.
• Use of pioglitazone with Topiramate may result in decreased serum concentration of pioglitazone.
• By decreasing insulin resistance, pioglitazone may cause ovulation in premenopausal women with anovulation, especially in polycystic ovarian syndrome. These anovulatory female patients may get pregnant with the resumption of ovulation.

Pioglitazone stimulates PPAR-gamma receptors located in collecting tubules of the kidney. PPAR-gamma pioglitazone interaction induces sodium channel messenger RNA production.  Pioglitazone increases sodium reabsorption from the epithelial sodium channel at the luminal surface of the collecting tubules and causes fluid retention and possibly edema.[5]

Administration

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

Pioglitazone can decrease hemoglobinA1C by 0.5 and 1.4 percent when used as monotherapy. The magnitude of benefit on glycemic control is variable with combination therapy with other antidiabetics, including insulin.

For adults, the dose starts initially at 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.

For 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, the drug's safety and efficacy are unclear.

Adverse Effects

The common adverse effects of pioglitazone are edema, weight gain, macular edema, osteoporosis, and congestive heart failure (CHF). It may cause hypoglycemia when combined with other antidiabetic drugs and decrease hematocrit and hemoglobin levels.[6]

• Weight gain, fluid retention is considered to contribute to weight gain
• A decrease in hemoglobin and hematocrit most likely due to hemodilution
• It is associated with increased bone fracture risk, especially in women, and might be a potential cause of osteoporosis.[7]
• It correlates with an increase in serum low-density lipoprotein cholesterol levels.
• Myocardial infarction, although it is more common in rosiglitazone users than in users of pioglitazone as per a retrospective cohort study conducted to study cardiac adverse effects of both these drugs.[8]
• It has been proven in four real-life registries that the relative risk of CHF with TZDs was 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.[9]
• In December 2016, the FDA conclusion was that using pioglitazone may be associated with an increased risk of bladder cancer.[10]  However, the cause and effect relationship is not clear-cut, and pioglitazone is still on the market.
• Pioglitazone should be discontinued in patients with developed macular edema.

There is a known drug interaction with oral contraceptives (OCPs), as co-administration of a TZD with 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 OCPs.

Pioglitazone and insulin combination increases the risks of edema and heart failure.

Pioglitazone was associated with bladder tumors in male rats. Although some studies showed an increase of bladder cancer in pioglitazone users in the past, a meta-analysis published in 2017 failed to show an increased risk ratio or hazard ratio between pioglitazone use and the risk of bladder malignancy, allowing Filipova et al. to state that there is no link between long-term use of pioglitazone and bladder cancer.[11]

Contraindications

Contraindications to the use of pioglitazone include the following scenarios[12]:

• 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 is a contraindication in the US
• Symptomatic heart failure at any stage (NYHA Class I, II, III, IV) is contraindicated in Canada
• Any evidence of fluid overload
• Active (current) bladder cancer or history of bladder cancer, uninvestigated microscopic hematuria
• History of fracture or at high risk for fracture
• Active liver disease, liver transaminase  levels more than 2.5 times above the upper limit of normal
• Pregnancy
• The Beers Criteria lists pioglitazone as 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 should be obtained prior to starting pioglitazone and periodically thereafter. The frequency of liver function test monitoring should be based on clinical judgment.  Liver function tests may improve with pioglitazone treatment in patients with nonalcoholic fatty liver disease.[13] 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 NYHA Class I and II heart failure. Patients should receive counseling 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 (hematuria), 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 type 2 diabetes mellitus patients on pioglitazone should be aware of the benefits, mechanism of action, dosage, adverse effects,  indications, and contraindications of the drug. This medication requires an interprofessional team due to potential adverse effects and monitoring for therapeutic effectiveness. The team should educate the patient about the possible 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.

A pharmacist should collaborate to verify that there are no drug interactions, that dosing is appropriate, and, as mentioned above, offer patient counseling. A certified diabetes educator nurse is also invaluable. They can help the patient coordinate the administration and monitoring of the diabetes drug regimen and report to the prescriber any issues that may arise. Pioglitazone therapy requires an interprofessional team approach, including clinicians, endocrinologists, nurses, and pharmacists, collaborating across disciplines to achieve optimal patient results. [Level 5]