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Chapter: Basic & Clinical Pharmacology : Pancreatic Hormones & Antidiabetic Drugs


Thiazolidinediones (Tzds) act to decrease insulin resistance. Tzds are ligands of peroxisome proliferator-activated receptor-gamma (PPAR-f), part of the steroid and thyroid superfamily ofnuclear receptors.


Thiazolidinediones (Tzds) act to decrease insulin resistance. Tzds are ligands of peroxisome proliferator-activated receptor-gamma (PPAR-f), part of the steroid and thyroid superfamily ofnuclear receptors. These PPAR receptors are found in muscle, fat, and liver. PPAR-γ receptors modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduc-tion, and adipocyte and other tissue differentiation. The available Tzds do not have identical clinical effects, and new drug develop-ment will focus on defining PPAR effects and designing ligands that have selective action—much like the selective estrogen recep-tor modulators .

In addition to targeting adipocytes, myocytes, and hepatocytes, Tzds also have significant effects on vascular endothelium, the immune system, the ovaries, and tumor cells. Some of these responses may be independent of the PPAR-γ pathway. The Tzd oncogenic effects are complex and may be both tumorigenic and antitumorigenic.

In persons with diabetes, a major site of Tzd action is adipose tissue, where the drug promotes glucose uptake and utilization and modulates synthesis of lipid hormones or cytokines and other proteins involved in energy regulation. Tzds also regulate adipo-cyte apoptosis and differentiation. Numerous other effects have been documented in animal studies, but applicability to human tissues has yet to be determined.Two thiazolidinediones are currently available: pioglitazone and rosiglitazone (Table 41–8). Their distinct side chains create differences in therapeutic action, metabolism, metabolite profile, and adverse effects. An earlier compound, troglitazone, was with-drawn from the market because of hepatic toxicity thought to be related to its side chain.

Pioglitazone has PPAR-αas well as PPAR-γactivity. It isabsorbed within 2 hours of ingestion; although food may delay uptake, total bioavailability is not affected. Absorption is decreased with concomitant use of bile acid sequestrants. Pioglitazone is metabolized by CYP2C8 and CYP3A4 to active metabolites. The bioavailability of numerous other drugs also degraded by these enzymes may be affected by pioglitazone therapy, including estro-gen-containing oral contraceptives; additional methods of contra-ception are advised. Pioglitazone may be taken once daily; the usual starting dose is 15–30 mg/d, and the maximum is 45 mg/d. A triglyceride-lowering effect is observed with pioglitazone and is more significant than that of rosiglitazone, presumably because of its PPAR-α-binding characteristics. Pioglitazone is approved as a monotherapy and in combination with metformin, sulfonylureas, and insulin for the treatment of type 2 diabetes. The risk of blad-der cancer appears to be cumulatively increased with high doses.

Rosiglitazone is rapidly absorbed and highly protein-bound.It is metabolized in the liver to minimally active metabolites, pre-dominantly by CYP2C8 and to a lesser extent by CYP2C9. It is administered once or twice daily; 2–8 mg is the usual total dose.

Rosiglitazone shares the common Tzd adverse effects but appears to carry more cardiovascular risk than pioglitazone. Concurrent administration of nitrates and insulin putatively enhances the risk of myocardial infarction and is contraindicated; renin-angiotensin system blockers may have a similar risk but are not specifically prohibited. Because of toxicities, the FDA now limits rosiglitazone prescriptions to patients already on treatment with the medica-tion, and to those whose blood sugar cannot be controlled with other antidiabetic medicines and who, after consultation with their provider, do not wish to be on pioglitazone or a pioglitazone-containing drug. For those restricted populations, rosiglitazone isapproved for use in type 2 diabetes as monotherapy, in double combi-nation therapy with a biguanide or sulfonylurea, or in quadruple combination with a biguanide, sulfonylurea, and insulin.

Tzds are considered euglycemics and are efficacious in about 70% of new users. The overall response is similar to that achieved with sulfonylurea and biguanide monotherapy. Individuals experi-encing secondary failure with other oral agents should benefit from the addition (rather than substitution) of a Tzd. Because their mechanism of action involves gene regulation, the Tzds have a slow onset and offset of activity over weeks or even months. Combination therapy with sulfonylureas and insulin can lead to hypoglycemia and may require dosage adjustment.

An adverse effect common to both Tzds is fluid retention, which presents as a mild anemia and peripheral edema, especially when the drugs are used in combination with insulin or insulin secretagogues. Both drugs increase the risk of heart failure. Many users have a dose-related weight gain (average 1–3 kg), which may be fluid related. Rarely, new or worsening macular edema has been reported in association with treatment. Loss of bone mineral den-sity and increased atypical extremity bone fractures in women are described for both compounds, which is postulated to be due to decreased osteoblast formation. Studies are ongoing to determine whether the demineralization and fracture risk is increased in men. Long-term therapy is associated with a drop in triglyceride levels and a slight rise in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol values. These agents should not be used during pregnancy or in the presence of significant liver disease (ALT more than 2.5 times upper limit of normal) or witha concurrent diagnosis of heart failure. Because of the hepatotoxicity observed with troglitazone, a discontinued Tzd, the FDA continues to require monitoring of liver function tests before initiation of Tzd therapy and periodically afterward. To date, hepatotoxicity has not been associated with rosiglitazone or pioglitazone. Anovulatory women may resume ovulation and should be coun-seled on the increased risk of pregnancy.

Thiazolidinediones have benefit in the prevention of type 2 dia-betes. The Diabetes Prevention Trial reported a 75% reduction in diabetes incidence rate when troglitazone was administered to patients with prediabetes. Another study reported that troglitazone therapy significantly decreased the recurrence of diabetes mellitus in high-risk Hispanic women with a history of gestational diabetes.

Although these medications are highly efficacious, the adverse effects of weight gain, congestive heart failure, demineralization and increased bone fracture in women; possible (for rosiglitazone) worsening of cardiovascular status; and unknown oncogenic risk potentially limit their popularity and future use.

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