THIAZOLIDINEDIONES

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CURRENT THERAPIES FOR DIABETES

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THIAZOLIDINEDIONES Robert R. Henry, MD, FRCP(C)

Type I1 diabetes is associated with three basic pathophysiologic abnormalities: impaired insulin secretion, excessive hepatic glucose production, and insulin resistance in skeletal muscle, liver, and adipose tissue.’ The pharmacologic agents available for the treatment of type I1 diabetes have focused primarily on delaying gastrointestinal glucose absorption (alpha-glucosidase inhibitors), increasing insulin availability (sulfonylureas, insulin), or suppressing excessive hepatic glucose production (biguanides). Treatment modalities have not acted mechanistically to impact directly on the underlying pathology of insulin resistance. After its synthesis in 1982,47it was discovered that the thiazolidinedione derivative ciglitazone could reduce insulin resistance in obese and diabetic animals.’0 Following extensive testing of numerous hindered phenolic compounds, several other agents were developed, including pioglitazone, englitazone, troglitazone, and BRL 49653 (Fig. 1). These compounds are orally active and chemically and functionally unrelated to the other oral antidiabetic agents, including sulfonylureas, biguanides, and alpha-glucosidase inhibitors. Clinical development of most of these compounds has not progressed because of their unacceptable side effect profile. A thiazolidine-2-4-dione structure is common to all agents of this class, but they differ in side-chain modifications which influence their pharmacologic actions and potential for adverse effects. Unlike the other thiazolidinediones, troglitazone was designed to contain an alpha-tocopherol moiety to combine potent lipid peroxide inhibition with hypolipidemic and

This research was supported by funds from the Medical Research Service, the Department of Veterans Affairs and Veterans Affairs Medical Center, San Diego; and grant M01 RR-00827 from the General Clinical Research Branch, Division of Research Resources, National Institutes of Health.

From the Division of Endocrinology and Metabolism, University of California; and the Section of Endocrinology and Metabolism, Veterans Affairs Medical Center, San Diego, California ~

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ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA

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Englitazone Figure 1. Structures of several insulin-sensitizing thiazolidinediones. (From Saltiel AR,

Olefsky JM: Thiazolidinediones in the treatment of insulin resistance in Type II diabetes. Diabetes 431661-1 669, 1996; with permission.)

insulin-sensitizing properties.", s8 Because troglitazone is the only thiazolidinedione to have undergone extensive testing in humans, it is the focus of this review. PHARMACOKINETICS AND METABOLISM

In healthy human subjects, troglitazone is rapidly absorbed following single oral administration, reaching a maximum plasma concentration (CmaJwithin 2

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to 3 hours and having a half-life of approximately 9 hours.43The maximum plasma concentration and area under the 24-hour curve for troglitazone increases in a dose-dependent fashion over a range of 200 to 600 mg/day. Steadystate plasma concentrations are reached within 3 to 5 days following daily administration. The extent of absorption is increased by 30% to 85% and slightly delayed in duration by food intake. Based on its absorption characteristics and metabolism, troglitazone should be given once daily, preferably in the morning with food. The volume of distribution for troglitazone ranges from 10.5 to 26.5 L/kg body weight, and it is more than 99% bound to serum albumin.45There are three major metabolites-a sulfate conjugate (metabolite l), a glucuronide conjugate (metabolite 2),,and an active quinone metabolite (metabolite 3).2', Of these, metabolite 2 is present in negligible amounts in plasma, whereas metabolite 1 achieves steady-state levels six to seven times those of troglitazone and metabolite 3. There is no tendency for troglitazone or its metabolites to accumulate, and it is cleared and metabolized in the liver with excretion into bile and feces. Urinary excretion is negligible (-3%) and primarily in the form of metabolite 2. The mean plasma elimination half-life of troglitazone, based on its accumulation ratio, ranges from 16 to 34 hours. Troglitazone may inhibit some of the p450 enzymes and theoretically could alter plasma levels of drugs metabolized by these enzymes. To date, there are no known drug interactions, although coadministration of cholestyramine or terfenadine can reduce troglitazone absorption by as much as 70%. In addition, coadministration of troglitazone with oral contraceptives containing ethinyl estradiol and norethindrone reduces the plasma concentration of both by approximately 30% and could lead to loss of contraceptive effect. MECHANISMS OF ACTION

The insulin resistance syndrome or syndrome X is characterized by a constellation of abnormalities including obesity, glucose intolerance or type I1 diabetes, dyslipidemia, hypertension, and accelerated vascular disea~e.~" The common or unifying feature of this syndrome is the presence of insulin resistance and compensatory hyperinsulinemia. Although it remains to be determined whether insulin resistance or hyperinsulinemia are causally linked to the development of any or all of these associated disorders, considerable evidence supports such a role. In keeping with this possibility, troglitazone has been shown to have multiple therapeutic effects on the insulin resistance syndrome, including actions on hepatic glucose metabolism and peripheral insulin action as well as reductions of lipid levels, lipid peroxidation, and systemic blood pressure. Although troglitazone does not have direct effects on pancreatic insulin secretion, it seems to exert an insulin-sparing action, restoring the pancreatic response to external stimuli. The molecular mechanism by which troglitazone exerts its cellular effects through activation of the peroxisome proliferator-activated receptors has just begun to be elucidated. Hepatic Effects

In rats, troglitazone enhances hepatic sensitivity to the suppressive effects of insulin on hepatic glucose output.Z6,53 In diabetic mice and starved rats, troglitazone suppresses hepatic gluconeogenesis, perhaps, by the inhibition of long-chain fatty acid oxidati~n.~,14, 16, 31 The hepatic effects of troglitazone may

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also involve regulation of gene expression.z8In Hep G2 cells, troglitazone rapidly stimulates hepatic glucokinase gene transcription directly and enhances the insulin-induced stimulation of glucokinase transcription. To date, few studies have assessed the effects of troglitazone on hepatic glucose production in humans. In a study of type I1 diabetic^,^^ 11 patients (six men and five women) were treated with troglitazone, 200 mg twice daily for 6 to 12 weeks. The characteristics of the group were as follows: mean age, 58.8 years; weight, 93.7 k 5.6 kg; body mass index (BMI), 32.3 ? 1.1 kg/M2, and duration of diabetes, 5.5 +- 1.1years. Basal hepatic glucose output was measured by tritiated [3H]-3-glucoseturnover prior to and at the completion of the treatment period. Basal hepatic glucose output was significantly elevated in the diabetic subjects in comparison with a nondiabetic control population. Response to troglitazone was defined by any fall in the fasting plasma glucose level. Of the 11 patients studied, there were three nonresponders whose fasting plasma glucose rose slightly or remained unchanged after troglitazone treatment. Although the absolute rates of hepatic glucose output were not provided, the basal rate decreased in the total group and even more so in the responders (Fig. 2). Interestingly, no decrease in hepatic glucose output occurred in the three nonresponders. Highly significant correlations were present in the relationship between the level of fasting plasma glucose and the basal rate of hepatic glucose output before and during treatment with troglitazone. Thus, the reduction of

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Figure 2. Hepatic glucose production rates. Bars represent mean ? SE hepatic glucose production rates before (open bars) and during (cross-hatched bars) troglitazone treatment in total group and responders. Solid bar, mean t SE basal hepatic glucose production rate in 17 weight-matched nondiabetic control subjects for comparison. Differences between pretreatment and during treatment with troglitazone results were P < 0.01 (responders) and P < 0.05 (total). Individual data are given in left-hand bars for responders ( 0 ) and nonresponders ( 0 ) . (From Suter SL,Nolan JJ, Wallace P,et al: Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 15:193-203, 1992; with permission.)

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fasting plasma glucose levels was highly dependent on the hepatic glucose response to troglitazone treatment. In a randomized double-blind study of 18 nondiabetic obese subjects (15 men and three women), nine of whom had impaired glucose tolerance by World Health Organization (WHO) criteria, troglitazone, 200 mg twice daily, was compared with placebo over 12 weeks.33Twelve subjects (nine men and three women) were treated with -troglitazone and six (all men) with placebo. Basal hepatic glucose output was measured by tritiated [3H]-3-glucoseturnover prior to and at the completion of the treatment period. As might be expected, basal hepatic glucose output was not elevated in the nondiabetic group and did not change in either study group following treatment. Peripheral Insulin Effects

Initial studies of troglitazone demonstrated an improvement of insulin sensitivity and hyperinsulinemia when administered chronically to insulin-resistant animals.13 In contrast to the effects of prolonged troglitazone administration, several studies have demonstrated that troglitazone also has acute effects that are both insulin-mimetic and insulin-sensitizing in nature.", 2h At the cellular level, troglitazone has been shown to prevent and reverse hyperglycemia-induced insulin resistance in rat-1 fibroblasts and NIH3T3 cells.22,23, 29 In isolated ' rat ventricular cardiomyocytes, troglitazone induces dose-dependent increases of 2-deoxyglucose uptake in parallel with increased expression of GLUTl and GLUT4 protein and a twofold increase of GLUT4 redistribution to the plasma membrane.2In L6 muscle cells, administration of the active quinone metabolite 3 had both acute and chronic effects to increase glucose transport, most notably in the absence of insulim6 This effect of metabolite 3 was dose-dependent and associated with increases in both GLUTl and GLUT4 transporter proteins. In 3T3-Ll adipocytes, troglitazone stimulates basal glucose transport and increases GLUTl transporter expression.5" Based on the previously described animal and cell culture studies, troglitazone demonstrates both an acute (minutes-to-hours) and chronic (days-to-weeks) onset of action consistent with more than one distinct mechanism of action. The relatively slow and progressive increase in activity over time is consistent with a transcriptional action of the thiazolidinediones. Although the exact mechanism of action remains to be determined, it is known that troglitazone is a ligand and can activate specific nuclear receptors termed peroxisome prolifevator-activator This family of nuclear receptors is comprised of three subreceptors (PPARS).~~ types designated PPARa, PPARy, and PPARS (also known as WARP, FAAR, OR NUC-1).27Evidence to date indicates that these receptors may be important regulators of lipid homeostasis, adipocyte differentiation, and insulin actionz7,42 A close relationship has been shown to exist between the potency of various thiazolidinediones to stimulate PPARy and their antidiabetic Thiazolidinediones have been shown to stimulate GLUTl and GLUT4 gene expression2,h and to reduce ob gene, tumor necrosis factor alpha (TNFa), and hepatic glucokinase expression through activation of PPARy.8,37,4y It is likely that the expression of numerous other genes will be found to be affected by thiazolidinediones and to contribute to the insulin-sensitizing and lipid-lowering actions of these compounds. It seems that troglitazone and other thiazolidinediones act, at least in part, by binding with PPARy to enhance the expression of a number of genes encoding proteins involved in glucose and lipid m e t a b ~ l i s m . ~ ~ Several studies have directly assessed the in vivo effects of troglitazone on

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peripheral insulin action in patients with type I1 diabetes and those at high risk for the disease.” 9, 33, 4H Both the euglycemic clamp and the frequently sampled intravenous glucose tolerance test (FSIGT) have been used in a limited number of studies to quantitate changes of insulin sensitivity. Several additional studies have used less direct methods to assess the effects of troglitazone on insulin resistance, including the insulin tolerance test and the intravenous or oral glucose tolerance test. The first report to quantitate the peripheral action of troglitazone in type I1 diabetes in the United States evaluated the effect of 200 mg given twice daily over a period of 6 to 12 weeks in 11 patients (six men, five All of the patients had a fasting plasma glucose level of more than 150 mg/dL, a mean age of 58.8 years, weight of 93.7 +- 5.6 kg, BMI of 32.3 k 1.1 kg/M2, and a diabetes duration of 5.5 +- 1.1 years. Mean fasting plasma glucose fell by 18% (-40 mg/dL) from 225 to 185 mg/dL. Of the 11 patients, eight responded with a reduction in fasting plasma glucose and three did not. All of the patients underwent either a 120 or 300 mU/M2/minute euglycemic clamp before and after treatment to assess changes in peripheral insulin action. Despite the modest decrease in fasting glucose, there was a 59% increase in peripheral glucose disposal during the 120 mU/m2/minute clamp and a 31% increase during the 300 mU/m2/minute clamp in the group as a whole after troglitazone treatment (Fig. 3). Following separation into troglitazone-treatment responders (n = 8) versus nonresponders ( n = 3), the responders demonstrated a 76% and 38% increase and the nonresponders a 25% and 18Y0 increase during the 120 mU/ m2/minute and 300 mU/m*/minute clamps, respectively. In keeping with this improved insulin action, the postprandial glucose excursions during a 7-hour meal tolerance test measured by the total and incremental (above basal) area under the curves were significantly reduced, as were postprandial and incremental insulin levels. Basal and mean postprandial free fatty acid kvels were also significantly lower following troglitazone treatment. Peripheral insulin action has been evaluated in eight Japanese patients with type I1 diabetes treated in a double-blind fashion with 400 mg/day of troglitazone for 12 weeks; a control group of six patients with type I1 diabetes received placebo treatment? In contrast to the study performed in the United States,’H the Japanese diabetic population tended to be leaner (BMI, -22 kg/m2), less hyperglycemic (fasting glucose, 160 to 180 mg/dL), and to have less peripheral hyperinsulinemia (fasting insulin, <10 versus 30 pU/mL). Fasting plasma glucose decreased by 15.4% in the troglitazone-treated group, with no change in and 20Y0, the placebo group. Peripheral glucose disposal increased by 51%, respectively, during a multistep hyperinsulinemic euglycemic clamp (8.0, 21.6, and 72.1 pmol/kg/minute insulin infusion) performed before and after troglitazone treatment. Basal and clamp free fatty acid levels during the 8.0 pmol/kg/ minute insulin infusion clamp were also lower following troglitazone administration in comparison with before treatment or with placebo. Despite the remarkable difference in the characteristics of the two diabetic populations, both glycemia and insulin action improved similarly in both studies. In another set of studies by the same group of investigators, the action of insulin was indirectly evaluated using the intravenous glucose tolerance test (IVGTT) (0.3 g of glucose/kg body weight) in lean Japanese patients with type I1 diabetes?’, 3y The patients had unsatisfactory glucose control on diet or sulfonylurea therapy which was continued during treatment with 400 mg/ day of troglitazone for 8 weeks. In the initial report,38the main effect was a reduction of basal glucose and insulin levels with no effect on incremental (above basal) glucose or insulin levels. The K-value or disappearance constant derived from

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SE glucose disposal rates Figure 3. Glucose-clamp studies. Bars represent mean before (open bars) and during troglitazone treatment (cross-hatched bars) during 120 mu/ M %nin-’ insulin-infusion studies (left side) and 300 mU/M Vmin insulin infusion studies (right side). Differences between pre- and post-troglitazone results were P < 0.01 at each insulin dose. Mean 2 S E steady state glucose and insulin values before and during troglitazone treatment were 90 i 1 versus 95 & 2 mM and 448 k 29 versus 359 t 25 pM for the 120 mU/M-*/min- infusion and 92 ? 1 versus 92 k 1 mM and 2220 ? 170 versus 1865 -+ 86 pM for the 300 mU/M-*/min~ insulin infusion, respectively. Individual data represent responders ( 0 ) and nonresponders ( 0 ) . (From Suter SL, Nolan JJ, Wallace P, et al: Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 15:193-203, 1992; with permission.)

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the IVGTT was unchanged (0.43 to 0.41) following troglitazone administration. In the follow-up study, plasma glucose levels at 2, 3, 4, 6, 8, 10, 15, 20, and 30 minutes of the IVGTT were significantly reduced after troglitazone but not at later time points (45, 60, 90, 120, and 180 minutes). Fasting plasma glucose improved in eight patients and was unchanged or increased in two after troglitazone. Fasting insulin was reduced in 3 of 10 patients, and only the insulin level at 15 minutes of the IVGTT was significantly reduced. The area under the curve for glucose during the IVGTT was significantly less (from 40.7 k 5.5 to 34.9 ? 6.2 mmol/L/hour), as was the area for insulin (from 158.5 2 67.4 to 123.0 k 55.3 pmol/L/hour). Troglitazone has been reported to be effective in type IA glycogen storage disease complicated by diabetes mellitus.5*Six months 3 f therapy with 400 mg/ day troglitazone was associated with improved glucose tolerance and increased secretion of c-peptide following a 75-g oral glucose load and a decreased HbA,,. The metabolic clearance rate of glucose determined by a hyperinsulinemic euglycemic glucose clamp was also increased after treatment, consistent with improved insulin action. There have been two reports of troglitazone treatment for Werner’s 56 In one case report, a patient was treated with troglitazone, 200 mg twice daily for 4 weeks in whom glibenclamide was not effective.5”Before

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troglitazone treatment, the fasting glucose and insulin levels were elevated at 139 mg/dL and 14.4 pU/mL, respectively. During a 75-g oral glucose load, plasma glucose rose to 330 mg/dL and insulin to 116.5 pLJ/mL at 120 minutes. As expected with the presence of insulin resistance, plasma glucose decreased only 29% at 30 minutes after an insulin loading test (0.15 U/kg intravenously). Consistent with improved peripheral insulin sensitivity, the glucose disposal rate during a stepped three-infusion dose (0.5, 3.0, and 10 mU/kg/minute) hyperinsulinemic euglycemic clamp was improved from 0.01, 2.7, and 6.0 mg/ kg/minute before to 2.7, 4.4, and 9.3 mg/kg/minute after troglitazone. The maximal glucose disposal rate increased by 53% but remained 65% below that of control subjects. In the other report by the same group of investigators,”’ the effects of troglitazone were reported in two additional patients with Werner’s syndrome. There was an 8-week run-in period on a controlled diet, but previous treatment was otherwise unchanged. The troglitazone treatment period was 4 weeks as an inpatient, with pIasma glucose measured seven times a day at 730, 10, and 11:30 AM, and 2, 5:30, 8, and 10 PM weekly at 8-, 4-, and 1-week intervals before and 2 and 4 weeks after treatment. A stepped hyperinsulinemic euglycemic clamp was performed at insulin infusion rates of 20, 120, and 400 mU/M2/minute before and 4 weeks after treatment. All plasma glucose measures were markedly lower after troglitazone treatment, with a corresponding improvement of insulin sensitivity. The mean glucose disposal rate was increased by troglitazone treatment from 0.01 ? 0.00, 2.58 ? 0.11, and 5.61 ? 0.37 mg/kg/minute to 2.53 ? 0.12,4.20 k 0.13, and 9.20 ? 0.13 mg/kg/minute, respectively, in one patient and from 0.01 +- 0.00, 2.83 ? 0.63, and 5.42 -+ 0.68 mg/kg/minute to 1.59 t 0.32, 5.70 t 0.66, and 11.84 t 0.82 mg/kg/minute, respectively, in the other. The dose-response curve following treatment was shifted up and to the left, consistent with improved insulin sensitivity and responsiveness. Changes of peripheral insulin action have been evaluated in nbndiabetic obese patients with insulin resistance. In the initial US study by Nolan and colleagues,3” 18 subjects (15 men, three women), nine of whom had impaired glucose tolerance, were randomized in a double-blind fashion to placebo ( n = 6) or troglitazone, 200 mg twice daily (n = 12) for 12 weeks. Fasting glucose levels fell minimally from 99 k 4 to 95 2 4 mg/dL, but fasting insulin decreased 48% from 18 2 8 to 10 t 4 pU/mL after troglitazone. The mean 2-hour glucose following a 75-g oral glucose tolerance test decreased from 146 k 25 to 126 ? 17 mg/dL, and the incremental area under the glucose curve decreased by 25% (Fig. 4). All but one of the seven subjects with impaired glucose tolerance reverted to normal glucose tolerance. In this subgroup with impaired glucose tolerance, there was a mean decrease of the 2-hour plasma glucose from 164 _t 14 to 131 +- 19 mg/dL and a 36% reduction of incremental glucose area under the curve during the oral glucose tolerance test. Troglitazone therapy decreased the incremental insulin area under the curve by 40% in all 12 subjects and by 48% in the seven subjects with impaired glucose tolerance. Following a standard meal tolerance test, incremental glucose area under the curve were reduced by 24% and 41%, respectively. The incremental glucose area under the curve was reduced 40% in the impaired glucose tolerance group after troglitazone. Peripheral glucose disposal also increased poststudy by 22% (from 4.7 t 1.7 to 6.0 ? 1.7 mg/kg/minute) during the 40 mU/mz/minute hyperinsulinemic glucose clamp and by 10% (from 9.0 t 1.8 to 9.9 ? 1.3 mg/kg/minute) during the 300 mU/m2/minute insulin infusion clamp. The clamp-derived insulin sensitivity index increased 75% from 1.6 to 2.8 in all 12 subjects and by more than twofold in the impaired glucose tolerance subgroup after troglitazone (Fig. 5). The

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Figure 4. Mean +- SE fasting triglyceride levels (mg/dL) over time of study. Levels were significantly lower in the troglitazone group (small square) than the placebo group (large circle) after 3 weeks ( P < 0.01) and remained lower throughout the study. (From Antonucci T, Whitcomb R, McLain R, et al: Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care 20:188-193, 1997; with permission.)

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Figure 5. Values are means k SE. Results show the values for the insulin-sensitivity index as calculated from values measured in the basal state and during the studies with the euglycemic-hyperinsulinemic clamp in which insulin was infused at a rate of 40 mU/Mz/min. (From Nolan JJ, Ludvik B, Beerdsen P, et al: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 331:1188-1193, 1994; with permission.)

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insulin-sensitivity index (S,) derived from the FSIGT more than doubled (from and 10 of 12 subjects had improved values. 0.7 +- 0.6 to 1.6 t 0.9 X In a study by Dunaif and co-workers; 21 massively obese women with polycystic ovary syndrome, eight of whom also fulfilled WHO criteria for impaired glucose tolerance, were randomized in a double-blind fashion to receive either 200 mg (10 women) or 400 mg (11 women) of troglitazone for 3 months. Baseline and treatment effects were compared with those in 12 ageand weight-matched ovulatory controls. Fasting insulin as well as 2-hour glucose and insulin levels during baseline glucose tolerance testing were significantly increased in the women with polycystic ovary syndrome. Following treatment of the entire troglitazone group, fasting and 2-hour insulin but not glucose levels during the glucose tolerance test were significantly decreased. Similarly, the integrated insulin, but not the glucose response to the glucose load, was significantly decreased after treatment. The S, determined during the modified FSIGT test increased significantly in both the 200-mg and 400-mg troglitazone treatment groups and in all but three subjects. The glucose effectiveness (S,) was unaffected by troglitazone treatment. The disposition index [the product of insulin sensitivity (S,) and the acute insulin response to glucose (AIR,)] also increased at the 400-mg troglitazone dose. Glucose tolerance was normalized in five of the eight women but became impaired in three of the troglitazone-treated subjects. Obese women with impaired glucose tolerance and a history of gestational diabetes mellitus had improved whole-body insulin sensitivity following treatment with either 200 mg (12 women) or 400 mg (13 women) of troglitazone for 12 weeks3 The Sr increased in a dose-dependent fashion, with a mean increase of 88 +- 22% above baseIine in the 400-mg treatment group. Twelve of the thirteen subjects in the 400-mg group had an increased S, compared with baseline. As in the previous study of patients with polycystic ovary syndrome, s, was unchanged in both treatment groups. Consistent with improved insulin sensitivity, fasting plasma insulin levels were significantly reduced by 20 2 9% in the 400-mg group. AIthough insulin sensitivity improved, plasma glucose levels, both fasting and following oral and intravenous glucose challenge, changed minimally in both troglitazone-treatment groups. Studies in insulin-resistant subjects, including those with impaired glucose tolerance, polycystic ovary disease, previous gestational diabetes, and type 11 diabetes, demonstrate that insulin action can be substantially improved following troglitazone treatment. The extent of improvement in insulin action can be impressive, but it is not necessarily accompanied by corresponding improvements in glucose tolerance. Pancreatic Insulin SynthesidSecretion

Numerous studies have demonstrated reduced circulating insulin levels following treatment with troglitazone and no direct stimulatory effects on insulin secretion. However, troglitazone does seem to exert effects on insulin synthesis and islet insulin content and may restore the responsiveness of the desensitized islet to stimulation in severely diabetic animals.'*,I R In humans, troglitazone use has led to reductions in the elevated proinsulin and proinsulin/insulin ratio present in type I1 diabetic patients.2u Cardiovascular, Lipid, and Antioxidant Effects

Troglitazone lowers levels of several lipids, including triglycerides and free fatty acids. High-density lipoprotein (HDL) cholesterol is increased in most

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circumstances. The reduction in triglyceride levels seems to result from several mechanisms, including reduced free fatty acid substrate availability, decreased hepatic triglyceride synthesis, and enhanced peripheral clearance.I3Troglitazone use has been associated with increases in low-density lipoprotein (LDL) cholesterol of approximately 10% but no change in apolipoprotein B levels. The LDL particles are larger, more buoyant, and less prone to oxidative modification. In addition to changes in particle size, troglitazone is exogenously incorporated into LDL particles and, through its radical scavenging antioxidant properties, protects LDL from oxidative modification.32It remains to be determined whether the ability to protect LDL from oxidative modification will have beneficial effects on the development of atherosclerosis. The appearance of cardiac abnormalities in animals during the use of large pharmacologic doses of troglitazone and other thiazolidinediones has raised concern that detrimental effects on cardiac size or function could occur in humans treated with troglitazone. However, in diabetic rats, troglitazone treatment partially restores cardiac function and seems to be cardioprotective for postischemic damage.*6Troglitazone has been shown to be a potent inhibitor of vascular smooth muscle cell growth and intimal hyperplasia in rats with experimental arterial injury.25Because vascular smooth muscle cell proliferation precedes the formation of organized atherosclerotic plaques, such evidence supports the possibility that troglitazone may delay or prevent the development of atherosclerosis rather than foster its development. To address the effects of troglitazone on the human heart, an ongoing multicenter study over 2 years in duration has evaluated changes in cardiac mass and function in type I1 diabetic patients treated with trog1ita~one.l~ A total of 154 patients with type I1 diabetes were initially randomized to treatment with either the sulfonylurea glyburide, titrated to achieve glycemic control, or to 800 mg/day of troglitazone. All of the patients underwent two-dimensional echocardiography and pulse Doppler study to measure left ventricular mass index, cardiac index, and stroke volume index every 3 months. To date, theri, has been no difference from baseline or from glyburide-treated patients in left ventricular mass index. However, a significant increase in stroke volume and cardiac index as well as a decrease in mean arterial pressure and calculated peripheral vascular resistance have occurred in troglitazone-treated patients in comparison with glyburide-treated patients, changes that are not gender-specific. Therefore, type I1 diabetic patients treated with troglitazone for more than 2 years have not shown any increase in cardiac mass or impairment of cardiac function. In fact, these patients seem to have benefited from enhanced cardiac output and stroke volume, possibly secondary to decreases in mean arterial pressure and peripheral vascular resistance. These effects could be caused by a direct effect of troglitazone on cardiac myocytes and vascular smooth muscle or, indirectly, by metabolic changes. Considerable evidence suggests that hyperinsulinemia may be a major contributor to the development of hypertension in the insulin resistance syndrome. Because thiazolidinediones reduce insulin resistance and hyperinsulinemia in obesity, impaired glucose tolerance, and type I1 diabetes, they also have the potential for therapeutic value in hypertension. In rats, pioglitazone reduces blood pressure to an extent not explained by changes in whole-body insulin ~ensitivity.~ In vascular smooth muscle, pioglitazone has direct vascular effects mediated, at least in part, by the blockade of calcium uptake by vascular smooth muscle. In obese insulin-resistant hypertensive rats, troglitazone treatment results in dose-dependent decreases of systolic blood pressure in concert with increased urinary sodium excretion and creatinine clearance.59The effect of troglitazone, 200 mg twice daily for 8 weeks, on blood pressure has been

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evaluated in 18 Japanese outpatients (nine male, nine female) with hypertension and mild d i a b e t e ~ ?The ~ , ~criterion ~ for entry into the study was a fasting glucose level of 130 mg/dL or greater and less than 300 mg/dL with or without sulfonylurea treatment. Following troglitazone treatment, both systolic and diastolic blood pressure decreased significantly from 164 ? 3/94 2 2 mm Hg to 146 t 3/82 2 3 mm Hg (an 11.0% and 12.8% decrease) at 8 weeks with no change in pulse rate. Fasting plasma glucose decreased from 159 -+ 10 to 144 2 14 mg/dL (9.4%) at 8 weeks. Fasting insulin levels decreased but not significantly from 9.1 2 1.2 to 6.3 ? 0.8 kU/mL, and plasma renin activity was unchanged. A significant correlation was found between the decrease in blood pressure and the decrease in serum insulin (r = 0.59) at the end of study. Thus, troglitazone therapy has been shown to have beneficial effects on both glucose metabolism and blood pressure in hypertensive type I1 diabetic patients. The other study examining the effect of troglitazone in obese nondiabetic subjects does not provide any insight into the possible mechanisms of its blood pressure-lowering Day-long blood pressure monitoring, performed before and during 12 weeks of treatment with 200 mg of troglitazone twice daily demonstrated significant reductions in both systolic (130 ? 11 to 125 -+ 10 mm Hg) and diastolic blood pressure (81 2 8 to 77 2 7 rrun Hg). As in the diabetic subjects described previously, the effects on blood pressure were modest, although the nondiabetic subjects were not hypertensive before troglitazone treatment. THERAPEUTIC EFFICACY

Troglitazone alters glucose metabolism by exerting effects primarily on insulin action with no direct influence on insulin secretion. It has greatest benefit when given in conditions associated with insulin resistance, such as type I1 diabetes, obesity, polycystic ovary disease, and impaired glucose tderance. In addition to’ its insulin-enhancing and glucose-lowering properties, troglitazone has the potential to reduce various lipid parameters and blood pressure and to exert antioxidant effects. Use of troglitazone to treat obese women with polycystic ovary disease has resulted in improved insulin sensitivity accompanied by significant decreases in testosterone, dehydroepiandrosterone sulfate, estradiol, and estrone.’ The decreases in testosterone levels correlate Significantly with decreases in the integrated insulin responses during an oral glucose load. These data indicate that elevated testosterone levels in polycystic ovary disease are related to insulin resistance and can be reduced toward normal by the insulin-sensitizing agent troglitazone. A dose of 400 mg daily was generally more effective than the 200mg dose and was also associated with significant decreases in androstenedione and luteinizing hormone (LH) values and increases in sex hormone-binding globulin levels. Thus, insulin-sensitizing agents such as troglitazone, probably by reducing hyperinsulinemia, attenuate the augmented steroidogenesis and LH release in polycystic ovary syndrome and seem to have therapeutic value. In contrast to the benefits of improving insulin action and reducing circulating hyperinsulinemia in polycystic ovary disease, the ability of troglitazone to improve insulin action has shown to be less efficacious in improving glucose tolerance in obese women with impaired glucose tolerance and a history of gestational diabetes3 Such individuals are at high risk of progressing to &pe I1 diabetes and may be unable to have an improvement in glucose tolerance because of the severity of the associated pancreatic beta cell defect. Even though peripheral insulin resistance is reduced, the pancreas of such individuals may be unable to sustain a sufficient hyperinsulinemic response to improve glucose tolerance.

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Table 1. CHANGE IN DIAGNOSTIC CLASSIFICATION FROM NORMAL TO IMPAIRED

GLUCOSE TOLERANCE Study Group

Number

Normal Glucose Tolerance

Impaired Glucose Tolerance

24 24

15 (62) 6 (25)

0.008

18 (75)

21 20

10 (48) 16 (80)

11 (52) 4 (20)

0.016

P Value

Week 6

Placebo Troglitazone Week 12

Placebo Troglitazone

9 (38)

Percentages are in parentheses. For normal glucose tolerance, fasting and 2-hour serum glucose (during a 75 g OGTT) are < 140 mg/dL ( 7.i 8 mmol/L). Adapted fromAntonucci T, Whitcomb R, McLain R, et al: Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care 2O:l88-193,1997;with permission.

When troglitazone was used in obese subjects with impaired glucose tolerance alone, 400 mg given daily for 12 weeks resulted in significant reductions in glucose, insulin, and C-peptide responses following a 75-g oral glucose load.' By 12 weeks of treatment, 80% (16 of 20) of patients treated with troglitazone had normalized glucose tolerance in comparison with 48% (10 of 21) of those receiving placebo (Table 1). By 3 weeks of treatment, triglyceride levels were lower in the troglitazone-treated group and remained so throughout the study (see Fig. 4). Other lipid parameters, blood pressure, and glycemic parameters, including fructosamine and glycosylated hemoglobin, remained unchanged. Similar responses in individuals with impaired glucose tolerance have been reported by Nolan and c o - w o r k e r ~ . ~ ~ Most clinical trials using troglitazone have been conducted in type I1 diabetic patients who have not achieved satisfactory glycemic control on diet alone or when treated with sulfonylureas. In several studies, sulfonylureas have been continued following the addition of troglitazone. At doses ranging from 200 to 800 mg daily, troglitazone has significantly greater effects on reducing fasting and postprandial plasma glucose and glycosylated hemoglobin when added to sulfonylurea failures or compared with placebo. In general, studies of type I1 diabetes conducted in Japan have included nonobese subjects with a BMI of less than 27 kg/M2, whereas most studies outside of Japan have been conducted in more obese individuals (> 30 kg/M2). Beneficial effects have occurred in both populations, although efficacy may be greater in the more obese subjects. In a study of 792 type I1 diabetic subjects, equivalent effects on glycemia and insulinemia were achieved by troglitazone doses of 400 to 800 mg given daily over a 12-week period.54In a contrasting study, the multicenter European Troglitazone Study Group reported the results of troglitazone therapy in 330 mildly obese (BMI, 28 to 29 kg/M2) type I1 diabetic patient^.^^ These patients were previously treated with diet alone or other oral hypoglycemic agents that were discontinued 3 to 4 weeks prior to study initiation. Troglitazone doses were 200, 400, 600, or 800 mg once daily, or 200 or 400 mg twice daily for 12 weeks. After 12 weeks, the mean HbA1, was significantly lower in the troglitazone-treated group (7.0% to 7.4%) in comparison with the placebo-treated group (8.0%). Interestingly, all of the doses of troglitazone were equally effective in regards to glycemic reductions. Troglitazone treatment was associated with a reduction of fasting plasma insulin of 12% to 26% in comparison with placebo, improved insulin sensitivity, and no change in weight. At the highest troglita-

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zone doses of 600 and 800 mg/day, serum triglycerides and free fatty acids were significantly lower and HDL cholesterol higher. LDL cholesterol levels increased 10% to 15% at the 400 and 600 mg doses only. The incidence of adverse events was similar to that with placebo, although there was a tendency toward reduced neutrophil counts at the highest troglitazone doses. In a large study of lean type I1 diabetic patients from Japan failing to achieve adequate glycemic control on diet therapy alone, troglitazone, 400 mg daily for 12 weeks, was compared with placebo.” Fasting plasma glucose in the troglitazone-treated group fell approximately 13% (from 182 2 28 to 158 2 34 mg/dL) and HbA,, from 8.6 -+ 1.5% to 8.1 2 1.7%compared with no significant change in the placebo group. Nearly 50% of the troglitazone-treated patients had a fasting plasma glucose reduction of more than 20% or a HbA,, reduction of more than 1%. Baseline BMI and HbA,, were higher in this group of responders. Serum triglycerides also fell significantly by approximately 20%, and the reduction was best in those patients with high triglyceride levels. There was a slight but significant weight gain of 1.3 pounds. The lower response in this group of subjects most likely reflects differences of patient characteristics and the fact that this population was not very insulin-resistant. No changes occurred in total or HDL cholesterol or blood pressure, and there were no serious adverse events. No information is yet available directly comparing the efficacy of troglitazone with that of other antidiabetic agents such as sulfonylureas, biguanides, or alpha-glucosidase inhibitors. When troglitazone is given as monotherapy or combined with sulfonylureas in individuals with type I1 diabetes, the mean reduction in fasting plasma glucose is approximately 40 mg/dL or 20% with a range of 15 to 60 mg/dL. In addition to changes in fasting plasma glucose, troglitazone therapy has resulted in the mean reductions of HbA,, of 1%,fasting serum insulin of 30%, and serum triglycerides of 40 mg/dL or 20% of the initial value. In several studies of type I1 diabetes, HDL was reported to increase by as much as 10%.39,48 Changes in total and LDL cholesterol have been variable, with 48 Modest reductions increases of as much as 10% reported in several in both systolic and diastolic blood pressure of 5% to 10% have been reported in hypertensive diabetic patients35,36 and in normotensive obese and impaired glucose-tolerant subjects.33Increases in weight have not usually occurred with troglitazone therapy, but most studies have been of short duration, usually 3 months or less. The data have been compiled primarily from studies using troglitazone doses of 200 or 400 mg daily. Most studies indicate that a daily dose of 400 mg of troglitazone is more efficacious than 200 mg. However, whether 600-mg or 800-mg monotherapy results in better glycemic or lipid responses than lower doses remains to be determined as current data are conflicting. An intriguing aspect of troglitazone therapy is the fact that some patients fail to respond to primary or initial therapy. Depending on how a therapeutic response is defined, a substantial number of type I1 diabetic patients do not have a significant glycemic reduction with troglitazone. Overall, 20% to 30% of type I1 diabetic patients have unchanged glycemic parameters when troglitazone is provided as monotherapy or added to sulfonylurea treatment failures. As yet, no common metabolic variables have been identified to indicate which patients are likely to be nonresponders. In most studies, the best responders have been diabetic patients who are more obese and severely insulin-resistant yet still have sufficient pancreatic reserve to mount a hyperinsulinemic response. Even in responders, however, the time course of onset of action can be variable, generally requiring 1to 4 weeks of therapy for initial plasma glucose-and insulin-lowering

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effects,34,48 with maximal responses after 6 to 8 weeks. No studies describe how frequently secondary failure to troglitazone occurs or in whom it is most likely to develop. Recently, two multicenter studies have evaluated the effects of troglitazone in insulin-treated type I1 diabetic patients.*' These double-blind placebo-controlled trials were conducted in the United States over 6-month intervals. In the first study, 350 insulin-treated type I1 diabetic patients with mean HbAI, of 9.5% were randomized to receive either placebo or troglitazone, 200 mg or 600 mg daily. The insulin dose was reduced only if two consecutive fasting glucose values were 100 mg/dL or less. In both the 200-mg and 600-mg dose regimens, there was a significant reduction in HbAI, in comparison with baseline and placebo after 6 months. In the 600-mg treatment group, the reduction in HbA,, was 1.41% from baseline and 1.29% in comparison with placebo (Fig. 6). HbA,, of less than 8?0 occurred in 30% of patients treated with 200 mg of troglitazone daily and in 57% of patients treated with 600 mg. Despite this improved glycemia, the exogenous insulin dose of 70 to 75 units of insulin per day was reduced by 15% (- 10 units) in the 200-mg treatment group and by 42% (-30 units) in the 600-mg treatment group (Fig. 7) at the end of 6 months. In the second study, 222 type I1 diabetic patients receiving 30 to 150 units of insulin per day were evaluated to determine whether the addition of 200 or 400 mg of troglitazone daily would improve glucose control and reduce insulin requirements in comparison with placebo.41When glycemic control was either maintained or improved, the insulin dose decreased by 41% in the 200-mg

a, C P,

m

5C m

2

Figure 6. Mean change from baseline (YO)in HbA,, levels at weeks 10/12 and 24/26 in insulin-treated type II diabetic patients on placebo or 200 mg or 600 mg of troglitazone. Dark bar = placebo; light bar = 200 mg; medium bar = 600 mg. 'P< 0,0001 compared to placebo. Means were adjusted for baseline and investigator center. (From Rezulin (troglitazone) Package Insert. Warner-Lambert Company, 1997; with permission.)

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a t rn a m m E

.P

c

c m

a 3 -0 a c 0) 2

a a

Figure 7. Mean change from baseline of exogenous insulin dose at weeks 10112 and 24/ 26 in insulin-treated type I I diabetic patients on placebo or 200 mg or 600 mg of troglitazone. Dark bar = placebo; light bar = 200 mg; medium bar = 600 mg. * P < 0.0001 compared to placebo. Means were adjusted for baseline and investigator center. (From Rezulin (troglitazone) Package Insert. Warner-Lambert Company, 1997; with permission.) *

treatment group and by 58% in the 400-mg treatment group in comparison with a 14% reduction with placebo. In 51% of patients receiving 200 mg and 70% treated with 400 mg of troglitazone, the exogenous insulin dose was reduced by more than 50%. Discontinuation of insulin was possible in 7% of patients receiving 200 mg and in 15% of patients receiving 400 mg of troglitazone daily in comparison with 1.5% receiving placebo. With the 400-mg dose, 41% of patients were able to decrease the frequency of insulin injections from three to one per day. As would be expected from the mechanism of action of troglitazone, improvements in glycemia were possible with lower exogenous doses of insulin. Based on these results, the initial indication for troglitazone is type I1 diabetes with inadequate glycemic control (HbA,, > 8.5%) despite multiple insulin injections of more than 30 units per day. Troglitazone should be used in insulin-treated type I1 diabetic patients who are unable to achieve acceptable glycemic control with diet, exercise, and insulin therapy. In many cases, acceptable glycemic control may be achieved and the exogenous insulin dose reduced as well. PRECAUTIONS, SAFETY DATA, AND ADVERSE EFFECTS

The experience to date with troglitazone indicates that it is well-tolerated with a favorable side effect profile. In clinical studies, most adverse events have

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been minor and rapidly reversible with drug discontin~ation.~’ In controlled trials, the overall incidence and types of adverse events are similar to placebotreated patients. Most adverse events are somatic complaints occurring in less than 10% of patients. Patient withdrawal from clinical trials is similar to that with placebo, being approximately 5%. Several laboratory abnormalities have been noted with increased frequency in troglitazone-treated patients, including small reversible reductions in hemoglobin, hematocrit, and neutrophil counts but within the normal range. These reductions occurred within the first 4 to 8 weeks of therapy and remained stable for up to 2 years of treatment. The reductions in hematologic parameters may be related, in part, to the dilutional effect of a 6% to 8% increase in plasma volume that is observed in troglitazonetreated patients. Reductions in hemoglobin to below the normal range occur in approximately 5% of troglitazone- and placebo-treated patients. Cardiac enlargement has been observed in rodents exposed to more than ten times the therapeutic dose of troglitazone in humans. However, exposure of patients with type I1 diabetes to 600 to 800 mg daily for 2 years has not been associated with an increase in left ventricular mass or a decrease in cardiac output. In controlled clinical trials, cardiac events were not increased, although patients with New York Heart Association Class 111 or IV disease were not studied and should be treated cautiously with troglitazone. Liver function abnormalities, including increases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) occur more frequently in troglitazone-treated patients in comparison with those receiving placebo. In controlled trials, reversible elevations in AST or ALT greater than three times the upper limit of normal occurred in 2.2% of troglitazone-treated patients and 0.6”/0 of placebo-treated patients. Of 2510 patients enrolled in troglitazone clinical trials in the United States, 20 patients had treatment discontinued because of liver function abnormalities. All of the abnormalities were reversible, including two cases of jaundice considered on the basis of liver biopsy to be caused by an idiosyncratic drug reaction. Troglitazone does not stimulate pancreatic insulin secretion or lead to hypoglycemia when used alone. However, when troglitazone is combined with insulin or other antidiabetic medications, hypoglycemia may occur and necessitate a reduction in these agents. When troglitazone was used in combination with insulin in the US clinical trials, hypoglycemia occurred more frequently than in the placebo group. Reactions were mild, with severe hypoglycemic reaction requiring assistance, occurring in 1%or less of troglitazone-treated patients. Because troglitazone is metabolized in the liver and excreted primarily in bile, the elimination of troglitazone and metabolites 1 and 3 from plasma does not correlate with creatinine clearance. Therefore, the dose of troglitazone does not need to be adjusted in patients with renal insufficiency. In hepatic insufficiency, the plasma concentrations of troglitazone and metabolites 1 and 3 are increased by 300% to 400% when compared with those in healthy subjects without hepatic disease. Although no adverse effects occurred in patients with hepatic dysfunction, troglitazone should be used cautiously in such patients. There is insufficient information as to whether troglitazone can be used in pregnant women. Currently, it should not be used to treat hyperglycemia during pregnancy. Similarly, troglitazone should not be administered to breast-feeding women as it may be secreted into human milk. Because troglitazone use in anovulatory premenopausal women with insulin resistance has been associated with the resumption of menses, ovulation may occur, leading to increased potential for pregnancy. Troglitazone should not be used in the pediatric population until more information on safety and efficacy is available. Troglitazone has

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been studied in the elderly population and has the same efficacy and safety as in nonelderly diabetic patients.

INDICATIONS AND APPROPRIATE CLINICAL USE

Clinical studies have demonstrated that troglitazone has efficacy in the treatment of insulin resistance in patients with type I1 diabetes, impaired glucose tolerance, polycystic ovary disease, and women with previous gestational diabetes. Sufficient information is available from clinical trials to warrant its use in insulin-requiring type I1 diabetic patients. Ongoing clinical trials will provide additional information on its efficacy in these conditions and as monotherapy or in combination with other antidiabetic agents for the treatment of type I1 diabetes. The recommended dosage is 200 to 600 mg daily, with the usual dose being 400 mg once daily with meals. When used in insulin-treated type I1 diabetic patients, troglitazone should be started at 200 mg at the usual dose of insulin. Self-monitoring of capillary blood glucose is essential to assess efficacy and for safety. If the glycemic response is inadequate, the dose should be advanced by 200-mg increments every 2 to 4 weeks to a maximum of 600 mg daily. The insulin dose should be decreased by 10% to 25% based on glucose monitoring when the fasting glucose level is consistently below 120 mg/dL. Ultimately, the goal should be to use troglitazone to achieve glycemia as nearnormal as possible at the lowest exogenous insulin dose.

SUMMARY

The thiazolidinediones are a unique class of compounds that exert direct effects on the mechanisms of insulin resistance and result in improved insulin action and reduced hyperinsulinemia. Troglitazone is the first of these compounds to be approved for use in humans and has the potential not only to reduce glycemia and insulin requirements in type I1 diabetes but to improve other components of the insulin resistance syndrome including dyslipidemia, hypertension, and accelerated cardiovascular disease. Such compounds also hold promise for the prevention of type I1 diabetes and for the treatment of other insulin-resistant states including polycystic ovary disease. In addition to the novel mechanism of action through binding and activation of PPARs, troglitazone has other unique advantages, including once-a-day administration, a low incidence of minor side effects, no known drug interactions, hepatic metabolism and secretion, and potent antioxidant properties. Thiazolidinedione compounds such as troglitazone provide an important additional resource for the health care provider in the management of type I1 diabetes and other components of the insulin resistance syndrome.

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25. Law RE, Meehan WP, Xi X-P, et al: Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest 98:1897-1905, 1996 26. Lee M-K, Olefsky JM: Acute effects of troglitazone on in vivo insulin action in normal rats. Metabolism 44:1166-1169, 1995 27. Lemberger T, Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: A nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol 12~335-363,1996 28. Li WW, Leff T Regulation of hepatic glucokinase gene transcription by troglitazone. Diabetes 44 (suppl 1):46A, 1995 29. Maegawa H, Ide R, Hasegawa M, et al: Thiazolidine derivatives ameliorate high glucose-induced insulin resistance via the normalization of protein-tyrosine phosphatase activities. J Biol Chem 270:7724-7730, 1995 30. Mimura K, Umeda F, Hiramatsu S, et al: Effects of a new oral hypoglycaemic agent (CS-045)on metabolic abnormalities and insulin resistance in type 2 diabetes. Diabet Med 11:685-691, 1994 31. Murano K, Inoue Y, Emoto M, et al: CS-045, a new oral antidiabetic agent, stimulates fructose-2,6-bisphosphate production in rat hepatocytes. Eur J Pharmacol 254:257262, 1995 32. Noguchi N, Sakai H, Kato Y, et al: Inhibition of oxidation of low density lipoprotein by troglitazone. Atherosclerosis 123:227-234, 1996 33. Nolan JJ, Ludvik B, Beerdsen P, et al: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 331:1188-1193,1994 34. Norris R, Valiquett T, Balagtas C: Comparison of troglitazone (CI991) dosing regimens and placebo in the treatment of patients with NIDDM. Diabetes 42(suppl 1):59A, 1993 35. Ogihara T,Rakugi H, Ikegami H, et a1 Antihypertensive effect of CS-045(troglitazone), a new oral insulin action enhancer, in hypertensive patients with non-insulin-dependent diabetes mellitus. Rinsho Iyaku 10:1657-1669, 1994 36. Ogihara T, Rakugi H, Ikegami H, et al: Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am J Hypertens 8:316-320, 1995 37. Ohsumi J, Sakakibara S, Yamaguchi J, et al: Troglitazone prevents the inhibitory effects of inflammatory cytokines on insulin-induced adipocyte differentiation in 3T3-Ll cells. Endocrinology 135:279-282, 1994 38. Onuma T, Tsutsui M, Goto T, et al: Effect of CS-045 on glucose tolerance in patients with NIDDM. Prog Med 10:3207-3211, 1990 39. Onuma T, Tsutsui M, Goto T, et al: The effect of a new oral hypoglycemic drug, CS-045, on glucose tolerance and serum lipids in nonobese Japanese patients with non-insulin-dependent diabetes mellitus: A pilot study. Curr Ther Res 55:416421,1994 40. Reaven G: Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988 41. Rezulin (Troglitazone) Package Insert. Warner-Lambert Company, Morris Plains, NJ, 1997 42. Saltiel AR, Olefsky JM: Thiazolidinediones in the treatment of insulin resistance in type I1 diabetes. Diabetes 45:1661-1669, 1996 43. Shibata H,Nii S, Kobayashi M, et a1 Phase I study of a new hypoglycemic agent CS045 in healthy volunteers: Safety and pharmacokinetics in single administration. Rinsho Iyaku 9:1503-1518, 1993 44. Shibata H, Nii S, Kobayashi M, et al: Phase I study of a new hypoglycemic agent CS045 in healthy volunteers: Safety and pharmacokinetics in repeated administration. Rinsho Iyaku 9:1519-1537, 1993 45. Shibukawa A, Sawada T, Nakao C, et al: High-performance frontal analysis for the study of protein binding of troglitazone (CS-045) in albumin solution and in human plasma. J Chromatogr A 697337-343, 1995 46. Shirnabukuro M, Higa S, Shinzato T, et al: Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats. Metabolism 45:1168-1173, 1996 47. Sohda T, Mizuno K, Imamiya E, et al: Studies on antidiabetic agents. 11. Synthesis of 5-[4-(l-methylcyclohexylmethylmethoxy)benzyl]thiozolidine-2,4-dione(ADD-3878) and its derivatives. Chem Pharm Bull 30:3580-3585, 1982 48. Suter SL, Nolan JJ, Wallace P, et al: Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 15:193-203, 1992

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49. Szalkowski D, White-Carrington S, Berger J, et al: Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulinstimulated glucose uptake, and gene expression in 3T3-Ll cells. Endocrinology 136:1474-1481, 1995 50. Tafuri SR: Troglitazone enhances differentiation, basal glucose uptake, and GLUT4 protein levels in 3T3-Ll adipocytes. Endocrinology 137:47064712, 1996 51. Takino H, Okuno S, Uotani S, et al: Increased insulin responsiveness after CS-045 treatment in diabetes associated with Werner’s syndrome. Diabetes Res Clin Pract 24~167-172, 1994 52. Tanigawa K, Ohguni S, Kato Y: Effect of CS-045 in a case of type IA glycogen storage disease complicated by diabetes mellitus. Tonyobyo 37:301-306, 1994 53. Tominaga M, Igarashi M, Daimon M, et al: Thiazolidinediones (AD-4833 and CS-045) improve hepatic insulin resistance in streptozotocin-induced diabetic rats. Endocrine J 40:343-349, 1993 54. Valiquett TR, Balagtas CC, Whitcomb RW, et al: Troglitazone dose-response study in patients with noninsulin-dependent diabetes. [abstract]. Clin Res 42:400A, 1994 55. Willson TM, Cobb JE, Cowan DJ, et al: The structure-activity relationship between peroxisome proliferator-activated receptor y agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem 39665-668, 1996 56. Yano M, Okuno S, Uotani S, et al: The effect of a new oral antihyperglycemic drug (CS-045) on insulin resistance in Werner’s syndrome. Int Congr Series Excerpta Med 997357-360,1992 57. Yoshioka T, Aizawa Y , Fujita T, el al: Studies on hindered phenols and analogues. V. Synthesis, identification, and antidiabetic activity of the glucuronide of CS-045. Chem Pharm Bull 39:2124-2125, 1991 58. Yoshioka T, Fujita T, Kanai T, et a1 Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation. J Med Chem 32:421428, 1989 59. Yoshioka S, Nishino H, Shiraki T, et al: Antihypertensive effects of CS-045 treatment in obese Zucker rats. Metabolism 42:75-80, 1993

Address reprint requests to Robert R. Henry, MD, FRCP(C) Chief, Section of Endocrinology and Metabolism Veterans Affairs Medical Center (IIIG) 3350 La Jolla Village Drive San Diego, CA 92161