Side Effects

Both rosiglitazone and pioglitazone have now been in clinical use worldwide with several million patients treated with these drugs. The vast majority of these patients have tolerated these agents well and have shown clinical improvement in their glycemic status (9,10). Overall in these studies, the types of adverse experiences reported with rosiglitazone and pioglitazone were similar to placebo, except for hypoglycemia and edema. Importantly, the incidence of withdrawals from clinical trials due to an adverse event other than hyperglycemia was similar for patients receiving placebo or a thiazolidinedione.

Edema

In clinical trials and post-marketing surveillance, both pioglitazone and rosiglitazone have been associated with an increased incidence of edema which varied from about 3.0% to 7.5% with the thiazolidinediones compared with 1.0% to 2.5% with placebo or other oral antidiabetic therapy (9,10). The highest incidence of edema has been reported when thiazolidinediones are used in combination with insulin. In clinical studies, patients treated with insulin plus pioglitazone or insulin plus rosiglitazone have an incidence of edema of 15.3% and 14.7%, respectively (compared with 7.0% and 5.4% in the insulin-only groups). Of clinical concern, in a very small minority of patients, the thiazolidinediones lead to significant peripheral edema and in some patients possibly precipitation/worsening of CHF (87,108).

It is still not clear by what precise mechanism(s) the thiazolidinediones cause edema or whether the edema is related to decompensation of cardiac function (108). In studies in non-diabetic volunteers, the thiazolidinediones increase plasma volume by about 6% to 7% (10). As PPAR-y is predominantly expressed in the renal medullary collecting ducts, a critical site for fluid reabsorption, activation of PPAR-y in the distal nephron may serve as the primary mechanism responsible for thiazolidinedione-induced fluid retention. In rodent models, thiazolidinedione-induced weight gain and edema was blocked by the collecting duct-specific diuretic amiloride. In addition, thiazolidinedione-induced fluid retention was prevented by deletion of PPAR-y from the collecting duct, using a specific mouse model (109,110).

Whether it is an increase in plasma volume that leads to edema or other causes such as increased renal tubular sodium reabsorption, or even reflex sympathetic activation, alteration of intestinal ion transport, or increased production of VEGF (a potent tissue permeability factor) is not clear at present (Fig. 3). Studies into the pathophysiology of edema associated with thiazolidinediones are ongoing, since it is important to elucidate the mechanism(s) responsible for the causation of edema in patients with type 2 diabetes treated with thiazolidinediones, and even more important to determine if it is possible to identify those patients susceptible to development of edema and CHF. Knowledge of the mechanisms of edema formation could lead to effective preventative or therapeutic modalities. There are anecdotal reports of improvement in thiazolidinedione-associated edema with diuretics.

Thiazolidinediones f

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