Extrapancreatic Effects Of Sulfonylureas And Meglitinides

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Sulfonylureas cause a moderate improvement in the lipid profile due to improvement of lipid metabolism by increased levels of insulin and lowered level of glucose, which is considered an indirect effect.

Large randomized trials, such as the UKPDS, usually showed a weight gain of 2 to 4 kg with longer acting sulfonylureas, e.g., glibenclamide and chlorpropamide. This weight gain can be avoided by dietary advice if patients are compliant. Indeed, no weight gain was observed in smaller studies with glipizide, glimepride, and the shorter acting substances (20). Weight gain is apparently related to the increase in insulin and its antilipolytic and trophic action on fat cells, and is probably enhanced by the addition of further agents inhibiting lipolysis, such as beta-blockers or the thiazolidinediones, which promote fat cell differentiation and proliferation.

Glimepiride was shown to translocate glucose transporters to the cell membrane by a direct action in several experimental systems. In human, a modest effect on insulin sensitivity was shown in euglycemic clamps and insulin levels were slightly lower in glimepiride compared with glibenclamide-treated patients (21). A recent report compared glimepiride, glibenclamide, and gliclazide in hyperinsulinemic euglycemic clamps and described an enhanced insulin action for glimepiride and somewhat less for glibenclamide compared with gliclazide (22).

Chlorpropamide has two unique effects: it can cause a flushing reaction after ingestion of alcohol, by inhibiting the metabolism of acetaldehyde, and it sometimes causes a syndrome of inappropriate antidiuretic hormone (ADH) action (SI ADH), by enhancing its effects. Chlorpropamide is not now used in Europe and the United States.

Gliclazide was shown to have potent antioxidative actions in vitro and in vivo. Theoretically, this might be advantageous in patients with type 2 diabetes, but there are no studies with hard endpoints that demonstrate this.

Some studies, such as the University Group Diabetes Program (UGDP) (23) in 1976, suggested that sulfonylureas are associated with a poor outcome after a myocardial infarction, but these studies have been heavily criticized (24), and do not correspond with current standards. Theoretically, sulfonylureas might close ATP-dependent potassium channels possessing a SUR2a/b subunit, which are present on cardiomyocytes and coronary and arterial vessel smooth muscle cells, thereby preventing adaptive changes and relaxation of cardiomyocytes and vascular smooth muscle cells in response to hypoxia. This would occur by preventing smooth muscle cell hyperpolarization caused by potassium efflux, due to the closure of KATP-channels by the sulfonylurea, which might enlarge the infarct area. Although sulfonylureas bind the SURl on beta cells with much higher affinity than SUR2a/b, some activation appears possible. Glimepiride and nateglinide show much lower affinity for the cardiac SUR2b sulfonylurea receptor than for beta cell SURl and are a safer choice in this respect. Most of the increased deaths after myocardial infarction in diabetes appear to be due to poor left ventricular function. There is no convincing evidence for negative effects of sulfonylureas from clinical trials. Moreover, the UKPDS has not provided evidence for an increased mortality of patients treated with glibenclamide or chlorpropamide, which would be expected to become apparent in such a large study. However, in conditions of hypoxia, such as after a myocardial infarction or during coronary interventions, negative effects have not been sufficiently studied. It therefore appears prudent to withdraw high-affinity ligands of SUR2a/b in this condition (25).

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