NDC Issues Warning Against the Use of Higher Sulfonylurea Doses - Particularly When Used in Combination with Metformin

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Olney, MD (03 May 2000)

c.f. meta-analysis

The National Diabetes Center - a not-for-profit patient advocacy group for physicians located north of DC - announced today that a meta-analysis of diabetes studies suggested that higher doses of a class of drugs known as sulfonylureas are associated with increased mortality. This mortality appears to correlate with risk of hypoglycemia and with metformin combination.

Sulfonylureas represent a class of drugs which bind to receptors controlling the ATP-sensitive "potassium channel" - the major regulator of voltage differences across the cellular membrane. Identified previously as "SUR-1" [for "SulfonylUrea Receptor-1" found initially in the insulin-producing cells of the pancreas and also in the hypothalamus] this receptor is the physiological leptin response element. Leptin is a hormone released by fat cells in direct proportion to cell size (or degree of adiposity) and when leptin binds to this receptor in the pancreas, it opens the potassium channel thereby inhibiting insulin release. This is likely the major mechanism whereby obesity causes type 2 diabetes.

The major pharmacologic response to this abnormality has been the use of sulfonylureas, which close these same potassium channels thereby offsetting the leptin inhibition and increasing insulin release.

Unfortunately other sulfonylurea receptors ["SUR-2a", "SUR-2b", and "mito -kATP") also exists in the myocardial sarcolemma, vascular smooth muscle cells, and myocardial mitochondrial membranes, respectively. SUR-2b potassium channels control blood flow to the heart and other muscles based on metabolic demand. The effect of closing these channels is to diminish blood flow to the heart. Although sulfonylurea agents differ in their affinity to bind to these SUR-2b receptors, the binding of all agents is increased at higher concentrations. The question set out to answer by epidemiologists at the National Diabetes Center was therefore, "Are higher doses of sulfonylureas associated with increased cardiovascular mortality?"

The NDC has reviewed data now from 11 major studies - (1) the UGDP study in the United States (2) the UKPDS study in Great Britain (3) the metformin pivotal trials for registration with the FDA (4) the Digami study of patients with myocardial infarction in Sweden (5) the Bezafibrate Infarction Prevention study in Israel [6] the Swedish [metformin+sulfonylurea] Surveillance Study in Uppsala, Sweden (7) the Garratt study of angioplasties at the Mayo Clinic (8) the Campbell studies of sulfonylurea-induced hypoglycemic mortality{(9) the Serafimerlassarettet Study (10) the Bedford [Intervention ] Study and (11) the Malmohus County [Intervention] Study.
The result of this meta-analysis is that mortality was seen to associate most strongly with sulfonylurea dosage. The further enhancement of mortality seen in combination of sulfonylureas with metformin - another class of potent oral hypoglycemic agents - was seen to correlate not only with sulfonylurea dosage, but also with degree of control and other likely-surrogates for hypoglycemia.

The National Diabetes Center has therefore issued a warning this day not to utilize any of the agents which close ATP-sensitive potassium channels in doses higher than 2.5 mg/day equivalent glipizide activity [or daily doses of 2.5 mg glyburide, 100 mg chlorpropamide, 1 mg glimepiride, 1.5 mg repaglinide.]

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