CLINICAL DIABETES
VOL. 15 NO. 2 March/April 1997

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F E A T U R E   A R T I C L E

Trogitazone: A New and Unique OralAnti-Diabetic Agent for the Treatment of Type II Diabetes and the Insulin Resistance Syndrome

Steven V. Edelman, MD

Diabetes is a serious disease that can have a significant impact on the health, quality of life, and life expectancy of those afflicted with it. Diabetes also places a large economic burden on the health-care system. Approximately 16 million Americans have diabetes, and only half of them are currently diagnosed.¹ Of the 16 million Americans with diabetes, approximately 90% have the type II variety, representing approximately 6% of the total population.² An additional 22 million Americans have impaired glucose tolerance, which is thought to be a precursor of type II diabetes.³

Type II diabetes is a multi-system disorder that is associated with not only hyperglycemia but also hypertension, central obesity, and accelerated atherosclerosis.⁴ This group of metabolic disorders is known more commonly as Syndrome X, or the insulin resistance syndrome. The insulin resistance syndrome is, in part, responsible for the very high rates of morbidity and mortality seen in patients with type II diabetes, mostly due to coronary artery and cerebral vascular disease.

It has been estimated that the time it takes for a person with type II diabetes to be diagnosed ranges from 4 to 7 years, mainly because a patient will experience few or no symptoms in the early stages of impaired glucose tolerance and type II diabetes.⁵ Type II diabetes should be classified as a "silent killer," just as hypertension is, because of the adverse effects of hyperglycemia, hypertension, dyslipidemia, and hyperinsulinemia that may be present many years before a patient's symptom complex is severe enough to lead to a definitive diagnosis.

In addition, the natural history of type II diabetes changes a patient's response to the various anti-diabetic regimens. As the pancreas undergoes ß-cell exhaustion, the patient's glycemia worsens, and the need for exogenous insulin increases. It has been estimated that approximately 35% of all people with type II diabetes are currently treated with exogenous insulin, and >50% of those who have had diabetes for more than 10 years are on insulin.⁶

There are many difficulties involved in using insulin therapy for obese patients with type II diabetes, and unfortunately, the majority of those patients have less than ideal metabolic control. Patients with insulin resistance usually require very large insulin doses and may experience increased appetite, weight gain, and inconvenience, which are just a few of the problems that frustrate both patients and caregivers.

Troglitazone (marketed by Parke Davis under the name Rezulin™) is in the fourth and newest class of oral antidiabetic agents to be approved by the U.S. Food and Drug Administration (FDA). The first official indication for troglitazone is for insulin-requiring patients with type II diabetes in poor metabolic control (HbA_1C > 8.5%) despite insulin therapy of >30 U/day given in multiple injections. The purpose of this article is to help primary caregivers understand the clinical usefulness of troglitazone in the management of patients with type II diabetes and the insulin resistance syndrome.

Pathophysiology of Impaired Glucose Tolerance and Type II Diabetes
Type II diabetes is known to have a strong genetic component with contributing environmental determinants.^7-12 It is likely that no single genetic defect will emerge to explain type II diabetes; thus, the disease is heterogeneous and possibly multi-genetic and will likely have a complex etiology.

Although the disease is genetically heterogeneous, there appears to be a fairly consistent phenotype once the disease is fully manifested. Most patients with type II diabetes and fasting hyperglycemia are characterized by insulin resistance, impaired insulin secretion, and increased hepatic glucose production.^13-17

Although these three metabolic abnormalities have been well studied and characterized, the etiologic sequence has only recently come into focus. It is clear that the increased hepatic glucose production of type II diabetes is secondary and can be fully reversed with a variety of forms of antidiabetic therapy.^18-20 In addition, increased hepatic glucose production rates do not exist in the impaired glucose tolerant state (IGT).²¹ Further, accumulating evidence argues strongly that insulin resistance precedes the onset of hyperglycemia and is present before defects in insulin secretion can be detected.^{13-16,17,22,23} Thus, evidence from the literature indicates that those individuals who evolve to type II diabetes from IGT begin with insulin resistance.

In addition to the idea that insulin resistance is likely to be a primary inherited feature in most patients with type II diabetes, acquired factors, such as obesity, sedentary lifestyle, and aging, may also contribute to and influence the natural history of type II diabetes. If ß-cell function is normal, this will lead to a compensatory hyperinsulinemia that maintains relatively normal glucose levels for a period of time. A subpopulation of individuals with compensated insulin resistance eventually go on to develop type II diabetes.

During the transition from the compensated state to frank type II diabetes, at least three additional pathophysiological changes can be observed. First, basal hepatic glucose production rates increase, which is a characteristic of essentially all type 11 patients with fasting hyperglycemia.^13-17 Second, insulin resistance usually becomes more severe, which may be due to the degree of genetic load and/or acquired conditions, such as obesity, sedentary lifestyle, and aging.^21,22 The third and most marked change is a fall in ß-cell function and a decline in insulin secretory ability. Whether this decline in insulin secretion is due to pre-programmed genetic abnormalities in ß-cell function or acquired defects, such as glucose toxicity, ß-cell exhaustion, or both, remains to be elucidated. Nevertheless, a marked decrease in ß-cell function accompanies this transition and is felt to be a major contributor leading to the transition from IGT to type II diabetes.

In summary, the proposed etiologic sequence is that insulin resistance (genetic and/or acquired) is manifested initially, leading to increased insulin secretion to maintain the compensated IGT state. In time, the compensation fails and ß-cell function declines, leading to hyperglycemia. The conversion of IGT to type II diabetes can also be influenced by ethnicity, degree of obesity, distribution of body fat, sedentary lifestyle, the aging process, and other concomitant medical conditions. The heterogeneous nature of type II diabetes and its natural history result in varied responses to different anti-diabetic agents through time.

Pathophysiological Basis of Pharmacological Therapy
The treatment strategies that are selected for managing type II diabetes are based on an understanding of the pathophysiology of hyperglycemia and the unique clinical expression of the associated metabolic abnormalities in an individual. As discussed above, type II diabetes is characterized by three basic abnormalities that contribute to the development of hyperglycemia: peripheral insulin resistance, mainly in the skeletal muscle; excessive glucose production by the liver; and impaired insulin secretion by the pancreas. Fasting and postprandial hyperglycemia varies considerably among individuals depending on the extent, severity, and unique expression of each of these metabolic abnormalities. These differences also play a role in the various responses to different classes of oral anti-diabetic agents.

Sulfonylureas work mainly by stimulating the pancreas to secrete insulin.

The higher levels of insulin work to overcome peripheral insulin resistance and suppress hepatic glucose production similar to exogenous insulin therapy. Excessive insulin levels, produced endogenously and/or exogenously, may induce weight gain and hypoglycemia. In addition, excessive insulin levels have been implicated in accelerating atherosclerosis, although a direct causeand-effect relationship has not been established. Some experts feel that sulfonylureas may also lead to premature ß-cell exhaustion by continued stimulation of pancreatic insulin secretion.

Metformin is a biguanide that works mainly by suppressing excessive hepatic glucose production.²⁴ Metformin also has a lesser effect on improving peripheral insulin resistance. Metformin does not cause weight gain and in some cases may lead to a loss of weight. It does not cause hypoglycemia when used alone. Metformin also benefits the lipoprotein profile, in addition to the effects of improved glycemic control on triglyceride levels. The availability of metformin in the United States has made a beneficial impact on the large number of patients with type II diabetes who were in poor glycemic control on maximum doses of sulfonylurea agents and resistant to starting insulin therapy. Metformin is also very effective as monotherapy.

Acarbose is an alpha glucosidase inhibitor, which works by delaying the absorption of carbohydrates in the small intestine and thus improving postprandial glucose values.²⁵ Postprandial elevation in blood glucose values is a serious and commonly overlooked problem in type II diabetes that contributes to poor metabolic control. Acarbose, like metformin, does not cause hypoglycemia or weight gain when used alone.

The thiazolidinediones are the fourth and newest class of anti-diabetic agents to be approved by the FDA for the treatment of type II diabetes.

Troglitazone
Troglitazone is a thiazolidinedione that works mainly by improving peripheral insulin resistance in skeletal muscle without stimulating insulin secretion. Troglitazone also works to a lesser degree by reducing excessive hepatic glucose production. Troglitazone was developed from earlier thiazolidinediones, which were first discovered in the early 1980s. In addition, troglitazone was synthesized with an alpha-tocopherol substitution and has antioxidant properties, as well as being an "insulin sensitizer."²⁶

Troglitazone improves both fasting and postprandial hyperglycemia in obese human subjects with type II diabetes, and this is accompanied by concomitant reductions in fasting and postprandial insulin levels (Figure 1).²⁷ This reduction in hyperglycemia was also associated with a near-normalization of the elevated rates of hepatic glucose production. Furthermore, glucose clamp studies conducted before and after a 12week treatment period of troglitazone have shown a 40 60% improvement in insulin-stimulated glucose uptake.²⁷ Troglitazone therapy was also associated with significant changes in total triglyceride and high-density lipoprotein (HDL) levels (from 261+ 28 to 214 + 18mg/dl and from 38 + 2 to 42 + 2, P< 0.01, respectively).

Troglitazone has been used in hyperinsulinemic nondiabetic subjects with normal and impaired glucose tolerance.c This led to a substantial improvement in insulin resistance demonstrated by a marked reduction in basal and postprandial hyperinsulinemia after oral glucose, as well as mixed-meal challenge studies (Figure 2). Approximately 80% of the patients with impaired glucose tolerance (fasting glucose < 140 mg/dl and 2-hour glucose values between 140 and 199 mg/dl) reverted to normal glucose tolerance after 12 weeks of troglitazone therapy. Troglitazone also significantly lowered the systolic, diastolic, and mean blood pressure (measured by a 24-hour ambulatory blood pressure monitoring device) in these hyperinsulinemic normal and impaired-glucose-tolerant patients. Troglitazone has no effect on insulin secretion and did not cause hypoglycemia in these nondiabetic subjects. These results were confirmed by a larger, multicenter study with a similar design, which in part led to the inclusion of troglitazone therapy as one of the intervention arms of the Diabetes Prevention Program (DPP).²⁹

The DPP is a 6-year, multicenter study sponsored by the National Institutes of Health. It is designed to prevent the development of type II diabetes in individuals with impaired glucose tolerance.³⁰ Eligible subjects will be randomized into one of four intervention arms: l) an intensive lifestyle group, aimed at reducing body weight and maintaining a regular exercise program; 2) troglitazone plus minimal lifestyle changes; 3) metformin plus minimal lifestyle changes; and 4) minimal lifestyle changes alone. This landmark study may give us valuable information about how to prevent type II diabetes and its associated complications in individuals who are risk for developing this serious condition. Further information can be obtained by calling 1-888-JOIN-DPP.

Troglitazone's First Indication
On December 11,1996, an FDA advisory panel voted to approve troglitazone for the treatment of insulin-requiring patients with type II diabetes who have poor glycemic control (HbA_1C > 8.5) who are taking >30 U/day of insulin in multiple injections. The following data were presented to the public at that meeting in Washington, D.C.

The first study presented was a 6month, randomized, placebo-controlled trial preceded by an 8-week stabilization period. The primary endpoint was to reduce the glycosylated hemoglobin A_1C (HbA_1C). Patients were randomized to either 200 or 600 mg of troglitazone or placebo once a day in the morning with breakfast. Inclusion criteria included a fasting C-peptide ( 0.8 mg/ml), insulin requirements > 30 units per day, HbA_1C between 8.0 and 12.0% (normal < 6.1 %), and a fasting blood glucose (FBG) > 140 mg/dl.

The patients treated with 600 mg of troglitazone had a reduction in HbA_1C of ~1.4%, with more than 50% of the subjects achieving an HbA_1C of < 8%. In addition, there was a reduction in FPG of ~48 mg/dl and a concomitant reduction in exogenous insulin requirements of ~40%.

The second study presented was designed to determine the effect of troglitazone on reducing insulin requirements in subjects with type II diabetes, in addition to improving glycemic control. The primary endpoints were to achieve a 15% reduction in fasting capillary glucose (FCG) or an FOG < 140mg/dl (average over 7 consecutive days) and a reduction in exogenous insulin requirements of > 50%. This study was also a 6-month, randomized trial with a 4-week stabilization period using either 200 or 400 mg of troglitazone or placebo once a day in the morning with breakfast. The inclusion criteria were very similar to those in the first study.

The results demonstrate that ~27% of patients treated with 400 mg/day of troglitazone successfully reached the primary endpoint described above, compared with 7% in the placebo group. In addition, 70% of the subjects had a reduction in insulin dose of >50%, with an average reduction of 58%. The average number of injections per day was reduced from 3 to 1 in 41% of the troglitazone-treated group, and ~15% of patients treated with the higher dose of troglitazone were discontinued from insulin therapy altogether.

Effects of Troglitazone on Body Weight and Lipids
A review of all published clinical trials with troglitazone demonstrates no effect on body weight, either increase or decrease ^26-28

Treatment with troglitazone results in an ~20-25% reduction in triglyceride levels and a 6-18% increase in HDL cholesterol levels, with the variation due to protocol design, patient characteristics, and dosage strength. There is a small but consistent rise in low-density lipoprotein (LDL) cholesterol levels (3-10%), but apolipoprotein B levels remain unchanged.

In a similar fashion to gemfibrozil, troglitazone reduces the production of very-low-density lipoproteins (VLDL) in the liver and may improve lipoprotein lipase activity (an insulin-sensitive enzyme), which helps clear the triglyceride-carrying VLDL and chylomicron particles. Clearance of VLDL and chylomicron remnants result in slightly higher HDL and LDL levels, especially in subjects with high pre-treatment triglyceride levels. It is possible that the post-troglitazone-treated LDL particles are less oxidized and not as small and dense as the pre-treatment LDL particles, although further studies are needed to fully understand the effects of troglitazone on these lipoproteins.³¹

Safety Data and Adverse Events
Safety data and adverse events were reported from more than 30 clinical trials and > 74,000 weeks of patient exposure to troglitazone. In summary, there were no differences in the adverse event rates, including serious nonfatal and fatal events, compared to the placebo group.

Hypoglycemia does not occur when troglitazone is used alone. However, in the first protocol described, where the primary goal was to reduce the HbA_1C, 14-23% of patients treated with troglitazone and insulin, compared with 8% of the placebo group, experienced a nonsevere or mild hypoglycemic reaction (patient recall or < 50 mg/dl). One patient had a severe reaction requiring assistance. There were no severe hypoglycemic reactions in the second insulin reduction protocol, and that study had a 5-8% incidence of mild reactions, compared with 4% observed in the placebo group.

A 2-3% reversible reduction in hemoglobin is consistently observed, and this is thought to be due to a 5-7% elevation in plasma volume. Hemoglobin levels did not fall outside of the normal range in any subject.

Cardiac enlargement has been observed in a rodent model using pharmacological doses of troglitazone. In order to address this concern, an ongoing study was initiated more than 2 years ago to assess the effects of 800 mg/day of troglitazone on the human heart.³² All subjects have received 2-D echocardiography and pulse doppler to measure left ventricular mass index, cardiac index, and stroke volume at 6month intervals. To date, there has been no change in left ventricular mass. Moreover, a significant increase in stroke volume and cardiac index has been observed in the troglitazone-treated group. The troglitazone subjects also experienced a decrease in mean arterial pressure and calculated peripheral vascular resistance.

Prescribing Information
Troglitazone is metabolized by the liver and excreted into the bile. The presence of renal insufficiency does not affect the serum levels or metabolism of troglitazone. The recommended dosage range is between 200 and 600 mg/day, with the average dose estimated to be 400 mg/day. Dosing is once per day with breakfast, and titration is not necessary except for improving efficacy.

When prescribing troglitazone to poorly controlled, insulin-requiring patients with type II diabetes, no insulin dose reduction is recommended at the outset. If fasting and/or pre-meal glucose values consistently drop below 120 140 mg/day, the author recommends a ~10-20% reduction in insulin dose in order to reduce the incidence of hypoglycemia.

The primary goal of initiating troglitazone is to reduce the HbA_1C to less than two percentage points above the upper limit of normal for any particular assay (i.e., < 8.0%, normal 4-6%). Secondary benefits include a reduction in insulin requirements, improvements in triglyceride and HDL levels, lack of weight gain, and a reduction in blood pressure. The advantages of troglitazone are shown in Tables 1 and 2.

Summary
Troglitazone is a new and unique oral anti-diabetic agent that works mainly to reduce peripheral insulin resistance, which is one of the main pathophysiological abnormalities of type II diabetes. Troglitazone may have beneficial effects in the impaired glucose tolerant state, as insulin resistance is thought to be the initial defect in the etiologic sequence leading to early hyperinsulinemia and eventual development of frank diabetes. In addition, if insulin resistance is the central link of insulin resistance syndrome, troglitazone may play a pivotal role in treating type II diabetes and its associated cardiovascular conditions.

Troglitazone will have its initial beneficial impact on the large and increasing population of patients with poorly controlled, insulin-requiring type II diabetes. Troglitazone may also be useful in other conditions associated with insulin resistance, such as the polycystic ovary syndrome.³³ Finally, there is great potential for troglitazone as monotherapy and for combined usage with other oral agents, such as metformin, acarbose, and the sulfonylureas.

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Steven V. Edelman, MD, is an associate professor of medicine in the Division of Diabetes and Metabolism and director of the Endocrine Fellowship Training Program at the University of California at San Diego and the San Diego VA Medical Center.
Note of Disclosure: Dr. Edelman is a member of the speakers bureaus for Parke-Davis, Bristol-Myers Squibb, and Bayer Pharmaceuticals. He is a stock shareholder in Warner Lambert, Inc., the parent company of Parke-Davis, and in Bristol-Myers Squibb.

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