CONTINUING EDUCATION

Wyeth
TRENDS IN PHARMACY AND PHARMACEUTICAL CARE

An ongoing CE program of The University of Florida College of Pharmacy and DRUG TOPICS

The University of Florida College of Pharmacy is accredited by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education. Accredited in every state requiring CE.® ACPE # 012-999-02-175-H01

This lesson is no longer valid for CE credit after 2/28/05.

CREDIT:

This lesson provides two hours of CE credit and requires a passing grade of 70%.*

OBJECTIVES:

Upon completion of this article, the pharmacist should be able to:

• Discuss pharmacology of the thiazolidinediones, including chemistry, mechanism of action, and adverse effects
• Discuss pharmacokinetics of the thiazolidinediones, including absorption, metabolism, excretion, and drug interactions
• Discuss efficacy of the thiazolidinediones
• Recommend nonpharmacologic and pharmacologic approaches to managing diabetes

*To receive credit you must complete the evaluation. Upon successful completion, the University of Florida College of Pharmacy will mail Statements of Credit for written quizzes within 10 working days. Participants completing the program on-line may print a Statement of Credit after successfully completing the program.

GOAL:

To provide pharmacists with a working knowledge of the thiazolidinediones that will help in better managing therapy for diabetes patients

An overview and comparison of the thiazolidinediones

By James R. Taylor, Pharm.D., Clinical Assistant Professor, University of Florida, Department of Pharmacy Practice, Gainesville

Since 1997, three thiazolidinediones have been marketed. During postmarketing experience, troglitazone was associated with severe idiosyncratic hepatocellular injury. It was voluntarily removed from the market in March 2000. Rosiglitazone and pioglitazone remain available. Both are similar in structure, mechanism of action, and pharmacokinetics. There have been a few reports of hepatic dysfunction possibly due to rosiglitazone or pioglitazone. Rosiglitazone and pioglitazone also appear to have fewer drug interactions than were seen with troglitazone. Both agents have similar efficacy in lowering fasting blood glucose and hemoglobin A1c.

Diabetes mellitus (DM) consists of a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Diabetes affects an estimated 16 million people in the United States, with Type 2 diabetes accounting for approximately 90% of these cases. Insulin resistance, dysregulated hepatic glucose production, and impaired insulin secretion characterize Type 2 DM.

Insulin resistance is defined as an impaired metabolic response to either exogenous or endogenous insulin. Operationally, it can be defined as a steady-state plasma glucose level that is higher than would be expected for the existing plasma insulin level. Insulin resistance together with obesity, hypertension, dyslipidemia, glucose intolerance, and Type 2 DM make up what is commonly referred to as the dysmetabolic syndrome or syndrome X. This cluster of cardiovascular risk factors is very common in Type 2 DM and significantly increases the risk of cardiovascular morbidity and mortality.

Defects in insulin action (decreased insulin sensitivity) are the primary cause of insulin resistance, and this commonly results in an inability of insulin to facilitate the intracellular storage and disposal of glucose. The pancreas attempts to compensate for this elevation in plasma glucose by increasing the production of insulin. The result is hyperglycemia and hyperinsulinemia, both of which are toxic to beta-cells in the pancreas. Eventually, this toxic effect leads to beta-cell dysfunction and impaired insulin secretion.

The search for an agent that focused on enhancing insulin sensitivity and reducing insulin resistance without increasing insulin secretion was first publicized in 1982. Ciglitazone was the first of a new class of antidiabetic agents, the thiazolidinediones, to be studied in Type 2 DM. Subsequently, its development was discontinued. However, the development of troglitazone, pioglitazone, englitazone, rosiglitazone, and darglitazone followed. The development of englitazone and darglitazone has been discontinued. Troglitazone (withdrawn from market in March 2000), rosiglitazone, and pioglitazone are the only thiazolidinediones marketed to date. Rosiglitazone was approved in May 1999, and pioglitazone was approved in July 1999. This review serves to provide an overview and comparison of rosiglitazone and pioglitazone (see Table 1). A brief review of managing diabetes is also included.

Pharmacologic comparison

Chemistry: A thiazolidine-2-4-dione ring is common to all agents of this class. The structural differences occur in the side-chain modifications, which potentially influence their pharmacologic profile, and potential for adverse reactions and drug interactions.

Mechanism of action: The thiazolidinediones owe their glucose-lowering effect to their ability to improve insulin resistance. Their effect on glucose is dependent on the presence of insulin. Unlike sulfonylureas, thiazolidinediones do not stimulate the secretion of insulin from beta-cells in the pancreas. These agents simply improve the target cell response to endogenous insulin. Their mechanism of action results from the binding to and activation of a class of nuclear receptors known as the peroxisome proliferator- activated receptors (PPARs).

Three major PPAR subtypes (, , and ) have been identified. Thiazolidinediones primarily act at the PPAR- receptor, resulting in stimulation of DNA transcription and glucose kinase promotor. This enhances the effects of insulin in the liver, adipose tissue, and skeletal muscle. The resultant effect is an increase in insulin-mediated glucose disposal and a decrease in hepatic glucose production. This increase in insulin sensitivity results in an improvement in insulin resistance. These agents do differ in their binding affinity for the PPAR- receptor (rosiglitazone > pioglitazone), and there is a direct relationship between binding affinity and in vivo antidiabetic potency. However, this difference does not appear to be clinically significant.

Adverse effects: The most common adverse effects associated with the thiazolidinediones are headache, nausea, and diarrhea. Other adverse effects common to this class include anemia, edema due to expanded blood volume, and weight gain. There does not appear to be a clinically significant difference among the currently available agents for any of these adverse effects. None of these agents cause hypoglycemia when used as monotherapy, although they do exhibit a synergistic effect on lowering glucose when used in combination with a glucose-lowering agent such as metformin, insulin, or a sulfonylurea.

The primary concern with this class of agents is the potential for hepatotoxicity. Severe idiosyncratic hepatocellular injury was reported during the marketed use of troglitazone. This effect is usually reversible, but cases of liver transplant and death have been reported. In premarketing clinical trials of troglitazone there were two cases of jaundice and increases of serum alanine transaminase (ALT) levels above three times the upper limit of normal (ULN) in 1.9% of the patients. No cases of jaundice were reported with rosiglitazone or pioglitazone during premarketing trials.

Rosiglitazone and pioglitazone did increase ALT to greater than three times ULN in 0.2% and 0.3% of the patients, respectively. However, the results were similar to that in patients receiving placebo. When rosiglitazone and pioglitazone were first made available, the hope was that, based on the premarketing data, these agents would not have the hepatotoxic potential of troglitazone. There have been four recent reports of hepatic dysfunction possibly associated with rosiglitazone. One case involved a 69-year-old male who developed severe hepatotoxicity after receiving 4 mg/day of rosiglitazone for 21 days. The patient began experiencing symptoms of hepatotoxicity (nausea, anorexia, fatigue, abdominal pain) within one week of initiating rosiglitazone. His symptoms progressed and rosiglitazone was discontinued. Five days later the patient was admitted to the hospital with shortness of breath and abdominal pain. The patient's ALT levels rose to greater than three times the ULN one day after hospital admission and subsequently returned to normal. The patient was also receiving verapamil and pravastatin, both of which can cause hepatitis, but he was on these agents for more than one year.

Another case involved a 61-year-old male receiving 4 mg/day of rosiglitazone for two weeks. The patient reported developing anorexia, nausea, vomiting, and abdominal pain eight days after starting rosiglitazone. His baseline ALT five weeks before starting rosiglitazone was normal. Rosiglitazone was discontinued on admission to the hospital. In the hospital, his ALT levels rose above three times the ULN before returning to baseline. The patient was also receiving chronic acetaminophen and had a remote history of alcoholism, although the researchers felt these did not contribute to his hepatocellular injury.

A 58-year-old female with longstanding diabetes experienced elevated liver enzymes after starting rosiglitazone at 4 mg/day. She had no evidence of liver failure. Rosiglitazone was discontinued, and the liver enzymes returned to normal four weeks later.

The fourth report involved a 47-year-old female with Type 2 DM, hypertension, herpes zoster, depression, and diabetic gastroparesis. She experienced an elevation in liver enzymes after starting 4 mg/day of rosiglitazone. Rosiglitazone was discontinued, and the liver enzymes returned to normal within two weeks.

There have also been a few reports implicating pioglitazone as a possible cause of hepatotoxicity. One case involved a 49-year-old male diabetes patient taking 30 mg/day of pioglitazone. He developed significant hepatic dysfunction after six months of pioglitazone therapy. After the drug was discontinued, the patient's liver enzymes returned to normal. Another case involved a patient who developed fulminant hepatic failure while receiving pioglitazone.

It is worth noting that all of these patients recovered after discontinuation of the thiazolidinediones and that there are other possible explanations for their liver dysfunction. Therefore, it is difficult to draw conclusions concerning a causal relationship with the drug. It remains unclear whether hepatotoxicity is a class effect or is related to the unique tocopherol side chain of troglitazone. We now have several years of postmarketing data with the newer agents, and it does appear that the incidence and severity of hepatotoxicity is much less than that seen with troglitazone. Troglitazone was associated with several dozen deaths and liver transplants from severe hepatotoxicity. These have not been reported with rosiglitazone or pioglitazone.

Despite the lack of significant evidence linking rosiglitazone or pioglitazone to liver toxicity, the manufacturers' labeling includes strict monitoring recommendations. Serum ALT levels should be checked at baseline, every two months for the first year of therapy, and periodically thereafter. These agents should not be initiated in patients with a baseline ALT greater than 2.5 times the ULN. Should ALT rise to 1.5 to 2.5 times the ULN while on therapy, patients should be monitored more frequently. The agents should be discontinued if the patient's ALT level rises above three times the ULN while on therapy.

Edema is an adverse event associated with all thiazolidinediones. The potential for mild to moderate peripheral edema with these agents is well documented, especially in patients who have heart failure or use insulin. Edema can also develop in patients who do not have heart failure or use insulin. This usually necessitates discontinuation of the thiazolidinedione. The incidence of edema with either agent is about 4.8%. The fluid retention can lead to or exacerbate heart failure. Patients should be closely monitored for signs and symptoms of heart failure. Patients with New York Heart Association (NYHA) class III or IV heart failure should not receive thiazolidinedione therapy. While there is a warning about the administration of thiazolidinediones with insulin, it is not absolutely contraindicated. According to the package inserts, rosiglitazone is not approved for use with insulin, whereas pioglitazone is approved. One should not take this to assume that pioglitazone is safer than rosiglitazone in combination with insulin. Diuretics are often used to treat the thiazolidinedione-induced edema. Unfortunately, the edema is often resistant to diuretic therapy and discontinuation of the thiazolidinedione is required.

The fluid retention, along with accumulation of fat, is most likely responsible for the weight gain seen with these agents. The average weight gain is about 1 kg when used as monotherapy and 2-3 kg when used in combination with a sulfonylurea or insulin.

Pharmacokinetic comparison

Absorption: After oral administration, peak plasma concentrations of rosiglitazone and pioglitazone are achieved within one hour and two hours, respectively. Administration of rosiglitazone or pioglitazone with food delays the time to peak plasma concentration by approximately two hours but does not significantly affect the extent of absorption (see Table 2).

Metabolism and excretion: The major routes of metabolism for rosiglitazone are N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. Rosiglitazone undergoes renal and hepatic metabolism with approximately 64% of the dose being eliminated in the urine and 23% in the feces. Dosage reduction is required in the presence of hepatic impairment but not renal dysfunction. Rosiglitazone is primarily metabolized by CYP2C8, and to a lesser extent CYP2C9. In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major CYP450 isoenzymes at clinically relevant concentrations, nor does it appear to induce CYP3A4 metabolism.

Pioglitazone is extensively metabolized by hydroxylation and oxidation, and the metabolites partly undergo glucuronide or sulfate conjugation. Most of the dose is most likely eliminated into the bile unchanged or in the feces as metabolites. Approximately 15%-30% of the dose is eliminated in the urine. Pioglitazone is primarily metabolized by the CYP2C8 and CYP3A4 isoenzymes. In vitro data indicate that pioglitazone does not inhibit any of the major CYP450 isoenzymes. In vivo human studies to assess its induction of CYP3A4 have not been performed.

Drug interactions: Troglitazone was known to interact with ethinyl estradiol, reducing its concentration by up to 30%. This had the potential of producing oral contraceptive failure. Coadministration of rosiglitazone with nifedipine or oral contraceptives containing ethinylestradiol and norethindrone did not result in a reduction in plasma concentration of the object drug.

Due to the lack of human studies to assess the effect of pioglitazone on CYP3A4, caution should be taken when combining pioglitazone with any medication that induces or inhibits this isoenzyme. This includes oral contraceptives containing ethinylestradiol and norethindrone, fexofenadine, astemizole, calcium-channel blockers, corticosteroids, cyclosporine, HMG-coenzyme A reductase inhibitors, tacrolimus, erythromycin, ketoconazole, and itraconazole.

Therapeutic comparison

This section serves as an overview and summary of the therapeutic efficacy of the thiazolidinediones. An overview of the therapeutic comparison of these agents is provided in Table 3. To date, there are no published clinical trials offering a direct comparison of the thiazolidinediones.

Table 3 Therapeutic comparison of the available thiazolidinediones
	Rosiglitazone	Pioglitazone
FBG (mg/dl)	31-76	31-68
HbA1c (%)	0.8-1.5	0.9-2.6
Total cholesterol (%)	up to 4	little effect
LDL cholesterol (%)	up to 19	up to 7
HDL cholesterol (%)	up to 19	up to 22
Triglycerides (%)	up to 15	up to 28
FBG = fasting blood glucose; HbA1c = hemoglobin A1c; placebo-controlled, monotherapy studies; FBG and HbA1c values represent difference from placebo (adjusted mean); total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride values represent percent change from baseline

Effects on glycemic control and insulin resistance: Clinical trials have shown that rosiglitazone reduces fasting blood glucose (FBG) by 31-76 mg/dl and Hb_A1c by 0.8%-1.5%. These effects were dose-dependent. In addition, twice-daily dosing was moderately more effective than once-daily dosing when utilizing comparable daily doses.

Pioglitazone has been shown to reduce FBG and Hb_A1c by 31-68 mg/dl and 0.9%-2.6%, respectively. Doses of 15 and 30 mg/day appear to provide similar efficacy in the reduction of FBG and Hb_A1c. Increasing the daily dose to 45 mg does provide additional benefit over the 15- and 30-mg doses. Notably, only one small study showed a reduction of Hb_A1c by 2.6% over placebo. One small study showed that pioglitazone reduces insulin and c-peptide levels in patients with Type 2 DM.

Lipid-lowering effects: All of the thiazolidinediones have a variable effect on lipids. Rosiglitazone has been shown to increase LDL cholesterol by up to 19%, increase HDL by up to 19%, and increase triglycerides by up to 15%.

Pioglitazone has been shown to have the following effects on lipids: increases LDL cholesterol by up to 7%, increases HDL cholesterol by up to 22%, and decreases triglycerides by up to 28%.

Managing diabetes

Managing Type 2 DM can be a significant challenge. Medical nutrition therapy (MNT) is an integral component of the management of diabetes. In Type 1 DM, MNT should focus on coordinating meal planning and insulin injection times. In Type 2 diabetes, the focus is more on weight loss and control of lipids. Less that 10% of patients with diabetes are diet- controlled (i.e., don't require any medication). However, it is unlikely that patients will achieve good glycemic control with medications alone; MNT is vital to successful management of diabetes.

MNT involves numerous recommendations and should be done by a dietitian or someone trained in nutrition. Simply giving a patient a copy of a 2,000-calorie diet and asking him or her to follow it is unlikely to be successful. However, pharmacists should still be familiar with MNT and be able to provide general recommendations to their patients. Making changes in lifestyle is one of the most challenging aspects of managing diabetes. Reinforcement by pharmacists will help improve a patient's compliance and likelihood of success.

Many patients (especially those on insulin) may be taught to count carbohydrates. One serving of carbohydrates is equal to 15 gm of carbohydrates. Patients are generally taught to have three to five servings per meal. Patients taking insulin may be taught to adjust their insulin doses for carbohydrate servings. Generally, the recommendation is one unit of insulin for each carbohydrate serving. This is especially important for patients who are using an insulin pump.

The therapeutic goals of diabetes care include not only striving toward euglycemia but also normal carbohydrate, protein, and fat metabolism. Insulin is a hormone that is essential for the use and storage of these nutrients. Carbohydrates are the body's primary source of energy. Recommendations for fiber intake are the same for persons with diabetes as for the general population. In patients with Type 2 DM, a diet containing 50 gm per day of food fiber, compared with 24 gm per day, has been shown to improve glycemia and lipids. The average dietary fiber intake for adults is 10 to 30 gm per day.

Nutritive (caloric) sweeteners are included in the carbohydrate total for meals. Scientific evidence does not support the widely held belief that sugars should be avoided based on the assumption that sucrose and other sugars are more rapidly digested and absorbed than starch-containing foods, thereby aggravating hyperglycemia.

In the United States, protein intake is between 15% and 20% of the average adult caloric intake. The recommendation is that 10% of calories come from protein. However, there is little evidence that protein intake at the current level increases risk of nephropathy.

Saturated fats raise cholesterol levels and increase risk of macrovascular disease. Polyunsaturated fats lower cholesterol but have a heterogeneous effect on HDL. Monounsaturated fats lower total cholesterol but not HDL. The recommendation is that less than 10% of total daily calories should be derived from saturated and polyunsaturated fats.

The effect of alcohol on glucose is variable and dependent on the amount and relation to food intake. Alcohol blocks gluconeogenesis (release of glucose from liver) and interferes with the counterregulation to insulin-induced hypoglycemia.

Initial therapy in Type 2 DM typically is monotherapy with a sulfonylurea, metformin, meglitinide, a thiazolidinedione, or alpha-glucosidase inhibitor. If a patient appears to be insulin-resistant, metformin or a thiazolidinedione may be the initial choice. In patients who are hypoinsulinemic, a sulfonylurea or meglitinide often is the initial choice.

Due to the increased risk of lactic acidosis, metformin should not be used in those with renal impairment (SCr 1.5 mg/dl or higher in males or 1.4 or higher in females), liver impairment, CHF (requiring pharmacologic therapy), alcohol abuse, or patients undergoing radiographic dye studies. Metformin does not cause weight gain and typically lowers cholesterol. These are all beneficial effects in Type 2 patients.

Thiazolidinediones can cause weight gain and edema. They should not be used in patients with class III or IV heart failure. Liver function tests should be closely monitored (at baseline, every other month for first year, and then periodically), and the drug should be discontinued if ALT increases above three times normal.

The meglitinides are very similar in action to the sulfonylureas in that they stimulate insulin secretion from functioning beta-cells in the pancreas. The stimulation is glucose dependent so that the effect is diminished at low serum glucose concentrations. Theoretically, this would lead to a reduced incidence of hypoglycemia. In practice, the incidence is slightly less, but it's not a significant difference.

Common combinations of oral agents include sulfonylurea plus metformin, thiazolidinedione or alpha-glucosidase inhibitor; thiazolidinedione plus metformin; and a meglitinide plus metformin. Less frequent and/or well-studied combinations are triple-combination therapy, metformin plus alpha-glucosidase inhibitor (lots of gastrointestinal side effects). Triple-combination therapy (typically involving thiazolidinedione plus metformin plus sulfonylurea) is becoming more common as we strive to achieve good glycemic control and because patients often wish to avoid insulin injections.

Rosiglitazone and pioglitazone significantly improve glycemic control when used as monotherapy or in combination therapy. You can expect an average Hb_A1c reduction of 1.5%-2.5% with the thiazolidinediones. This is comparable to the efficacy of other agents for diabetes (see Table 4). They are generally well tolerated and few patients discontinue the drugs due to adverse effects or lack of efficacy. The American Diabetes Association does not recommend one antidiabetic agent over another as monotherapy. Rather, various factors must be considered. These factors include efficacy, adverse effects, drug interactions, contraindications, effects on lipids and weight, complexity of dosing regimen, cost, and duration of diabetes. The thiazolidinediones do offer several advantages over other oral agents. The main advantage is that they directly target the underlying pathophysiology of Type 2 DM. They also offer convenient dosing. Potential disadvantages include cost, monitoring, and weight gain. The effects on lipids are variable but tend to be more beneficial with pioglitazone.

Conclusion

The development of the thiazolidinediones has been an important addition to the choice of oral agents available to treat Type 2 DM. They are all moderately effective at reducing FBG and Hb_A1c and there appears to be no clinically significant difference in efficacy between the agents currently available. They produce variable effects on lipids.

The chemical structures of these agents are similar and any differences do not appear to provide any distinct advantages or disadvantages.

All of these agents have a similar adverse-effect profile, which includes headache, nausea, diarrhea, anemia, edema, and weight gain. To date, the primary difference among these agents is their propensity to cause hepatotoxicity. Troglitazone has been associated with severe idiosyncratic hepatocellular injury, which, in some cases, has resulted in liver transplant and death. Initially, it was thought that rosiglitazone and pioglitazone were completely devoid of these effects. However, recent case reports have implicated them as a possible cause of hepatic dysfunction. Notably, all of these patients recovered after discontinuation of the rosiglitazone, and there were other possible explanations for their liver dysfunction. However, the incidence and severity of hepatic dysfunction are significantly less with the newer agents.

There do not appear to be any clinically significant differences among these agents in relation to their pharmacokinetics. Rosiglitazone does not appear to induce the CYP3A4 isoenzyme, and there are no data on the effects of pioglitazone on CYP3A4.

Since these agents have a similar efficacy and adverse-event profile, the decision of which agent to choose boils down to cost and effects on lipids. Based on costs at the time of this writing, pioglitazone 15 mg once daily is less expensive than rosiglitazone 2 mg twice daily but a little more expensive than rosiglitazone 4 mg once daily. Pioglitazone 45 mg once daily is slightly less expensive than rosiglitazone 4 mg twice daily and more expensive than rosiglitazone 8 mg once daily. The differences in cost are fairly negligible (see Table 5). Pioglitazone tends to have more beneficial effects on LDL cholesterol and triglycerides. As more postmarketing experience is gained with rosiglitazone and pioglitazone, one agent may become the clear choice over the other. To date, no head-to-head clinical trials have been completed.

References available upon request

TEST QUESTIONS

Write your answers on the answer form below (photocopies of the answer form are acceptable) or on a separate sheet of paper. Mark the most appropriate answer.

1. Which of the following thiazolidinediones was removed from the market due to its propensity to cause hepatic failure?

a. Troglitazone 
b. Rosiglitazone
c. Pioglitazone
d. Ciglitazone

2. Type 2 diabetes is characterized by all of the following except:

a. Insulin resistance
b. Dysregulated hepatic glucose production
c. Impaired insulin secretion
d. Hypoinsulinemia

3. Which of the following is not associated with the mechanism of action of the thiazolidinediones?

a. Improved insulin resistance
b. Stimulation of insulin release from the pancreas
c. Decreased hepatic glucose production
d. Increased insulin sensitivity

4. The thiazolidinediones' mechanism of action primarily results from binding to which of the following peroxisome proliferator-activated receptors (PPARs)?

a. PPAR-
b. PPAR-ß
c. PPAR-
d. PPAR-

5. Which of the following is not an adverse effect associated with the thiazolidinediones?

a. Weight loss  
b. Headache    
c. Nausea
d. Diarrhea

6. Regarding hepatotoxicity with the thiazolidinediones, which of the following is true?

a. Rosiglitazone has been shown to cause hepatic failure and death.
b. Pioglitazone has been shown to cause hepatic failure and death.
c. Rosiglitazone is more likely than pioglitazone to cause hepatic dysfunction.
d. Rosiglitazone or pioglitazone may cause hepatic dysfunction, but the incidence and severity is much less than that seen with troglitazone.

7. The current manufacturer recommendations for monitoring ALT with the thiazolidinediones is:

a. Baseline, every month for first year, then periodically
b. Baseline, every other month for first year, then periodically
c. Baseline then once a year
d. Baseline, every other month for first six months, then periodically

8. Thiazolidinedione therapy should be discontinued if the ALT rises above:

a. 1.5 times upper limit of normal
b. 2.0 times upper limit of normal
c. 2.5 times upper limit of normal
d. 3.0 times upper limit of normal

9. Thiazolidinediones can also cause edema. Which of the following is true?

a. The incidence of edema is about 1%.
b. Edema occurs only if a thiazolidinedione is used in combination with insulin.
c. Thiazolidinediones should not be used in patients with NYHA class III or IV heart failure.
d. The edema occurs only in patients with heart failure.

10. Regarding thiazolidinediones, which of the following is true?

a. Rosiglitazone is significantly more expensive than pioglitazone.
b. Pioglitazone is significantly more expensive than rosiglitazone.
c. Either agent may be used with caution in combination with insulin.
d. Neither agent should ever be used in combination with insulin.

11. Weight gain is another adverse effect of the thiazolidinediones. Which of the following is true?

a. Weight gain is usually 2-3 kg when a thiazolidinedione is used as monotherapy.
b. Weight gain is usually 1 kg when a thiazolidinedione is used in combination with a sulfonylurea or insulin.
c. Weight gain is most likely a result of fluid retention and fat accumulation.
d. Weight gain is most likely a result of reducing insulin resistance.

12. Which of the following is consistent with the absorption characteristics of the thiazolidinediones? Peak plasma levels are:

a. Achieved within one or two hours
b. Achieved within 30 minutes
c. Significantly reduced by administration with food
d. Significantly increased by administration with food

13. Which of the following CYP3A4 isoenzymes primarily metabolizes rosiglitazone?

a. CYP3A4     
b. CYP2C8
c. CYP2C9
d. CYP2D6

14. Pioglitazone may potentially interact with all of the following except:

a. Ethinyl estradiol
b. Cyclosporine
c. Ketoconazole
d. Warfarin

15. Rosiglitazone tends to have which of the following effects on cholesterol?

a. Decreased total cholesterol
b. Increased LDL cholesterol
c. Decreased HDL cholesterol
d. Decreased triglycerides

16. Pioglitazone tends to have which of the following effects on cholesterol?

a. Increased total cholesterol
b. Decreased LDL cholesterol
c. Decreased HDL cholesterol
d. Decreased triglycerides

17. Initial monotherapy recommendations in a patient with Type 2 diabetes who is insulin-resistant often includes:

a. Insulin
b. A thiazolidinedione
c. A sulfonylurea
d. An alpha-glucosidase inhibitor

18. Which of the following agents can cause lactic acidosis in a patient with renal impairment?

a. Metformin    
b. Rosiglitazone
c. Pioglitazone
d. Sulfonylurea

19. Which of the following combination therapies is generally not recommended?

a. Metformin plus sulfonylurea
b. A thiazolidinedione plus sulfonylurea
c. Metformin plus a meglitinide
d. Metformin plus an alpha-glucosidase inhibitor

20. Average Hb_A1c reductions with thiazolidinediones are about:

a. 1.5% to 2.5%
b. 0.5% to 1.0%
c. Less than 0.5%
d. More than 3.0%

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