Info

VEGF levels i

Vascular permeability

Edema

FIGURE 3 Multi-factorial mechanisms of edema formation with thiazolidinediones.

Weight Gain

In clinical use, treatment with thiazolidinediones is associated with weight gain (9,10). In the 26-week rosiglitazone approval clinical trials, the mean weight gain in patients treated with rosiglitazone monotherapy was 1.2 kg (on 4mg daily) and 3.5 kg (on 8mg daily). When rosiglitazone was combined with metformin, weight gain was blunted at 0.7 kg (on 4mg daily) and 2.3 kg (on 8mg daily). In these studies, there was a mean weight loss of about 1 kg in the placebo and metformin groups. In a longer 52-week glyburide-controlled study, the mean weight gain with 4 and 8 mg of rosiglitazone daily was 1.75 and 2.95 kg, respectively, versus 1.9 kg in glyburide-treated patients (62). Pioglitazone treatment also is accompanied by weight gain in a dose-related manner (10). The mean weight gain in placebo-controlled monotherapy trials ranged from 0.5 to 2.8 kg for pioglitazone-treated patients compared to a weight loss 1.3 to 1.9 kg in placebo-treated patients (these patients remained glycosuric and hence lost weight). In combination with a sulfonylurea, pioglitazone treatment was associated with an increase in weight of 1.9 kg (15 mg) and 2.9 kg (30 mg), versus -0.8 kg for placebo. When pioglitazone was combined with insulin, the mean weight gain was 2.3 and 3.7 kg for 15 and 30 mg of pioglitazone, respectively, and no weight change for placebo. In these studies, combination pioglitazone and metformin therapy resulted in mean weight gain of 1.0 kg versus -1.4 kg for placebo. Thus, both thiazolidinediones are associated with weight gain that occurs in a dose-dependent manner and is highest in combination with insulin and minimal in combination with metformin, which appears to blunt thiazolidinedione-associated weight gain. As already discussed in the section on adipose tissue, the thiazolidinediones preferentially increase fat accumulation in the metabolically beneficial subcutaneous fat depot and reduce fat accumulation in the metabolically harmful intra-abdominal region.

At the present time, it is not clear how much of the thiazolidinedione-induced weight gain is due to adipose tissue accumulation versus fluid retention. In a recent study, when pioglitazone and glipizide were given in doses sufficient to achieve equivalent glycemic control in patients with type 2 diabetes, pioglitazone 45 mg significantly increased total body water by 2.4 L, thus accounting for 75% of the total weight gain 3.1 kg. In addition, pioglitazone therapy tended to decrease visceral and abdominal fat content, BP and systemic vascular resistance (111).

Hypoglycemia

The thiazolidinediones do not stimulate insulin secretion and hence when used as monotherapy, are not expected to cause hypoglycemia. However, mild to moderate hypoglycemia can occur and has been reported during combination therapy with sulfonylureas or insulin (9,10). Hypoglycemia was reported in 1% of placebo-treated patients and 2% of patients receiving pioglitazone in combination with a sulfonylurea. In combination with insulin, hypoglycemia was reported for 5% of placebo-treated patients, 8% for patients treated with pioglitazone 15 mg, and 15% for patients treated with pioglitazone 30 mg.

Anemia

In studies conducted in non-diabetic volunteers, thiazolidinedione treatment is associated with an increase in plasma volume of ~ 6% to 8% (9) and it is to be expected that due to a dilutional effect, there will be decreases in hemoglobin and hematocrit. In U.S. doubleblind studies, anemia was reported in 0.3% to 1.6% of pioglitazone-treated patients and 0% to 1.6% of placebo-treated patients (10). In clinical use so far, there have not been any reports of significant hematologic effects with thiazolidinedione treatment. Of note, there are also reports of thiazolidinedione-treated patients experiencing slight decreases in white blood cell counts possibly related to the increased plasma volume (9,10).

MONITORING REQUIREMENTS/PRECAUTIONS/CONTRAINDICATIONS Liver Function

Troglitazone, the first glitazone marketed in the United States was associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death which lead to its recall from clinical use in March 2000. Hence, until recently, periodic monitoring of liver function tests was mandatory with the use of both pioglitazone and rosiglitazone. However, in all clinical trials with rosiglitazone and pioglitazone, the incidence of hepatotoxicity and ALT elevations is similar to placebo (9,10) and there have only been very rare reports of hepatotoxicity associated with rosiglitazone and pioglitazone (112,113) in sick patients with other confounding factors. In a recent large analysis of data from several large studies of rosiglitazone use, no evidence of hepatotoxic effects was observed in studies that involved 5006 patients taking rosiglitazone as monotherapy or combination therapy for 5508 person-years (114). These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-y agonist class effect. In fact, poorly controlled patients with type 2 diabetes may even have moderate elevations of serum ALT that decrease with improved glycemic control during treatment with rosiglitazone or other antihypergly-cemic agents (114). There are also reports that the thiazolidinediones improve biochemical and histological features in patients with nonalcoholic steatohepatitis (NASH). In a recent proof-of-concept study, the administration of pioglitazone for 6 months, led to significant metabolic and histologic improvement in subjects with NASH (115).

It is currently recommended that liver enzymes be checked prior to the initiation of therapy with rosiglitazone or pioglitazone in all patients and periodically thereafter at the discretion of the clinician (9,10).

Congestive Heart Failure

As already discussed in the section on edema, in a small minority of patients, thiazolidinedione therapy is associated with significant peripheral edema and in some patients possibly precipitation/worsening of CHF due to several putative causes including an increase in plasma volume, increased renal tubular sodium reabsorption, reflex sympathetic activation, alteration of intestinal ion transport, and increased production of VEGF (a potent tissue permeability factor). In two large 26-week clinical trials in the United States with 611 patients with longstanding type 2 diabetes and a high prevalence of pre-existing medical conditions, an increased incidence of heart failure and other cardiovascular events was seen with rosiglitazone in combination with insulin as compared to patients treated with insulin and placebo (9). Patients who experienced heart failure in these studies were on average older, had a longer duration of diabetes and were mostly on the higher 8 mg daily dose of rosiglitazone. In this population however, it was not possible to determine specific risk factors that could be used to identify all patients at risk of heart failure on combination therapy with rosiglitazone and insulin. Of note, heart failure developed in some patients not known to have prior CHF or pre-existing cardiac conditions.

A recent retrospective cohort study compared new users of thiazolidinedione with all other diabetic patients being treated with oral hypoglycemic agents and reported that thiazolidinedione use was associated with an increased risk of incident CHF [hazard ratio (HR) 1.7; P < 0.001] (116). However, this study did not measure or adjust for levels of glycemia, a known risk factor for CHF in diabetes, and also in this study there was the potential for residual confounding by indication/severity of disease. When these factors are adjusted for, thiazolidinedione use does not appear to be associated with increased CHF risk, as demonstrated in the study by Karter et al. who conducted a cohort study of all patients in the Kaiser Permanente Northern California Diabetes Registry with type 2 diabetes who initiated any diabetes pharmacotherapy (n = 23,440) between October 1999 and November 2001. After adjusting for demographic, behavioral and clinical factors, relative to patients initiating sulfonylureas, there were no significant increases in the incidence of hospitalization for CHF in those initiating pioglitazone (HR = 1.28; 95% CI: 0.85-1.92). There was a significantly higher incidence among those initiating insulin (HR = 1.56; 95% CI: 1.00-2.45) and lower incidence among those initiating metformin (HR = 0.70; 95% CI: 0.49-0.99). Thus, this study of patients with type 2 diabetes failed to find evidence that short-term pioglitazone use was associated with an elevated risk of hospitalization for CHF relative to the standard, first-line diabetes therapy (117).

Despite the above, it is prudent that rosiglitazone and pioglitazone be used with caution in patients with pre-existing edema, especially in those who have milder degrees of heart failure (NYHA Class 1 and 2) (9,10,118). In patients with NYHA Class 3 and 4 cardiac status, treatment with rosiglitazone or pioglitazone is not recommended. In all other patients, rosiglitazone or pioglitazone therapy should be initiated with a low dose and patients should be evaluated early for edema (within several weeks) (Fig. 4). If edema does occur, dose reduction may be attempted. In those who develop symptoms of CHF, it may be prudent to discontinue the drug altogether, since in the published case reports of

Clinical decision to use thiazolidinediones (TZDs)

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