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NewsletterOctober 2002 Newsletter New anti-diabetic agents: Thiazolidinediones KW Tim Park, MD Beth Israel Deaconess Medical Center Boston, MA Insulin resistance, characterized by reduced responsiveness to normal circulating levels of insulin, is a common defect of almost all patients with type II diabetes mellitus. Thiazolidinediones (TZDs), also known as glitazones, are a new class of oral antidiabetic agents that increase insulin sensitivity to increase glucose uptake by adipocytes and decrease glucose output by hepatocytes. Troglitazone was the first TZD introduced in the United States in 1997. Although only minor elevation in liver enzymes was noted in 1.9 % of patients on troglitazone in clinical trials, delayed severe and unpredictable hepatotoxicity was reported after post-marketing use in more than 600,000 patients in the U.S. (1). Following reports of 61 deaths from hepatic failure and 7 liver transplants associated with the drug, it was withdrawn in March 2000 (2). Troglitazone has now been replaced by more potent agents, rosiglitazone and pioglitazone, which have thus far not been associated with similar hepatotoxicity. TZDs have been shown to be effective in lowering Hb A1c and fasting blood glucose either as a monotherapy or in combination with metformin, sulfonylurea, or insulin. TZDs tend to lower HbA1c by 0.5 - 1.5 % in a dose-related manner (3). This effect is seen in both drug-naive patients previously treated with diet alone and in patients who have previously been treated with standard antidiabetic regimen and presumably have more advanced stages of the disease. In a multicenter study of 200 type II diabetics resistant to sulfonylurea and metformin, Yale et al. showed that troglitazone 400 mg/d effectively lowered Hb A1c by 1.4 % and might be an alternative to insulin (4). This study was conducted before troglitazone was withdrawn, but still showed the potential use of TZDs. In addition, Buch et al. showed that in massively obese patients with type II diabetes who were on large doses of insulin, addition of rosiglitazone to the treatment regimen led to a reduction in median insulin dose from 204 u/day to 159 u/day and a fall in Hb A1c from 8.1 % to 6.7 % (5). Although the precise mechanism of action of TZDs is not known, they may owe their antidiabetic action to activation of nuclear peroxisome proliferator activated receptor ã (PPAR-ã) (6,7). PPARg is a nuclear hormone receptor, expressed predominantly in adipocytes and involved in adipogenesis and control of glucose and lipid metabolism. Physiologically, PPARg is activated by the fatty acid 9,13-hydroxy octadecadienoic acid. Impairment of PPARg may be involved not only in insulin resistance, but also in obesity, dyslipidemia, and inflammation. Because of their activation of PPARg, TZDs have been investigated for possible effect on lipid metabolism and obesity as well as glucose control and for possible role as a superdrug to treat the metabolic syndrome encompassing both hyperglycemia and dyslipidemia and reduce the cardiovascular risk. In a multicenter study in Japan, Nakamura et al. showed that a 12-week treatment with troglitazone led to not only a reduction in Hb A1c, but also a decrease in triglycerides, a decrease in systolic hypertension, and a shift in fat distribution from visceral fat to subcutaneous fat (8). Visceral fat is associated with cardiovascular morbidity. In addition, Brunzell reported that rosiglitazone increases high density lipoprotein (HDL) cholesterol, especially HDL2, maintains the HDL:LDL ratio, and decreases circulating free fatty acids (9). The reduction in fatty acids may be due to enhanced insulin-mediated suppression of fatty acid release and contributes to glucose control (10). Unlike troglitazone, rosiglitazone and pioglitazone have not been associated with significant hepatic impairment. However, even with troglitazone, the onset of hepatic damage was typically delayed and occurred between the third and seventh month of usage (1) and long-term experience with the newer TZDs is lacking. It is therefore recommended that these drugs should be avoided in patients with preexisting liver disease or alcohol abuse. With troglitazone, factors associated with increased liver enzymes were age, concurrent insulin use, and concurrent therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase (i.e., statins used to lower cholesterol) (11); whether these may be risk factors for liver damage with other TZDs remains to be seen. Another class side effect of TZDs is fluid retention (12,13). As a result, the patient may experience edema, weight gain, mild dilutional anemia, and possible exacerbation of congestive heart failure. Heart failure, either past or current, is considered a contraindication to using TZDs and patients with limited cardiac reserve who are on TZDs should be monitored closely for their fluid status. References:
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