Reflections on the sulphonylurea story: A drug class at risk of extinction or a drug class worth reviving?

The role of sulphonylureas (SUs) in modern clinical practice poses ongoing clinical debate. With the advent of newer agents in diabetes management, there is an increasing shift away from the prescribing of SUs, but not necessarily to more effective agents. This review provides a different perspective on the debate, reflecting in depth upon the physiology of SUs, drawing on insights gained from monogenic diabetes to highlight the potential benefit of lower doses of SUs, and the probable benefit of gliclazide over most other, if not all SUs, in terms of sulphonylurea failure and cardiovascular outcomes.

Sulfonylureas and meglitinides: historical and contemporary issues.

Insulin secretagogue therapy is commonly used in clinical practice. These agents may be utilized as first, second-line or adjunct therapy behind metformin for treatment of type 2 diabetes mellitus. Sulfonylureas and meglitinides are effective treatments, but cumulative data over decades of research raise concerns regarding universal prescribing. The role of insulin secretagogue therapy in ß-cell failure, blunting of ischemic pre-conditioning, the incidence of hypoglycemia - specifically in at-risk populations, modest weight gain and the unproven link to cancer are discussed. Ultimately, many of the concerns appear to be agent and not class-specific with glibenclamide fairing the worst amongst all of the agents discussed.

The UGDP controversy: thirty-four years of contentious ambiguity laid to rest.

The University Group Diabetes Program (UGDP), launched in 1960, was an early placebo-controlled, multi-center clinical trial devised to determine which, if any, of the treatments for type 2 diabetes was efficacious. Because of an excess of cardiac deaths in patients treated with tolbutamide, a sulfonylurea drug, investigators terminated this limb of the study. This decision was met with strong resistance from the parent drug company and many in the medical community. Subsequent clinical studies both supported and conflicted with the UDGP findings, so that the controversy has persisted. A rationale for sulfonylurea-induced cardiotoxicity emerged with the observation that these drugs block ischemic preconditioning, a protective maneuver that reduces myocardial damage after temporary blockage of coronary blood flow; this action of sulfonylureas provided laboratory support for the UGDP findings. The development of newer sulfonylurea drugs that do not block ischemic preconditioning has rendered the UGDP controversy moot and has preserved a place for sulfonylureas in the treatment of type 2 diabetes.

[Mechanisms of action of peroral antidiabetics. Sulfonylurea preparations block the ATP-dependent potassium channels]. / Perorala antidiabetikas verkningsmekanism. Sulfonylureapreparat stänger ATP-reglerad kaliumkanal.

Although hypoglycaemic sulphonylureas have been used to treat non-insulin-dependent diabetes mellitus (NIDDM) for the past forty years, their mechanisms of action at the molecular level have only recently been elucidated. A combination of electrophysiological and molecular biological techniques showed the target of sulphonylureas to be a sulphonylurea receptor (SUR1) and potassium channel (Kir6.2) complex. Together, these two proteins form the ATP-dependent potassium (KATP) channel occurring in insulin-secreting cells. An increase in the blood glucose level triggers a chain of events in insulin-secreting cells and K(ATP) channel closure which is a prerequisite for insulin secretion. In NIDDM, however, an increase in blood glucose fails to close the K(ATP) channel satisfactorily, but this can be remedied by the administration of sulphonylureas.

Sulfonylureas: background and development of the field.

This paper traces the growth of the field from the incidental finding of the hypoglycemic "side effect" of certain antibacterial sulfonamides and sulfonylureas (1942), to the establishment of islet beta cell stimulation and insulin release as a major mechanism of action of these drugs (1946), to the more recent findings that additional effects exist on the level of cell metabolism and its regulation by hormones. These changing concepts of mechanism have influenced the clinical uses of these drugs.