ABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Sulfonylurea Compounds/therapeutic use , Diabetes Mellitus/drug therapy , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dose-Response Relationship, Drug , Gliclazide/therapeutic use , Glipizide/therapeutic use , Glucagon-Like Peptide-1 Receptor/agonists , Glyburide/therapeutic use , History, 20th Century , History, 21st Century , Humans , Insulin Secretion , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Metformin/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sulfonylurea Compounds/history , Sulfonylurea Compounds/pharmacology , Treatment FailureABSTRACT
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.
Subject(s)
Benzamides/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Sulfonylurea Compounds/therapeutic use , Animals , Benzamides/adverse effects , Benzamides/history , Biomarkers/blood , Blood Glucose/drug effects , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/history , Glyburide/therapeutic use , History, 20th Century , History, 21st Century , Humans , Hypoglycemia/blood , Hypoglycemia/chemically induced , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/history , Insulin/blood , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Ischemic Preconditioning/adverse effects , Neoplasms/chemically induced , Risk Assessment , Risk Factors , Sulfonylurea Compounds/adverse effects , Sulfonylurea Compounds/history , Treatment Outcome , Weight Gain/drug effectsABSTRACT
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.
Subject(s)
Cardiomyopathies/chemically induced , Clinical Trials as Topic/history , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/adverse effects , Sulfonylurea Compounds/therapeutic use , Tolbutamide/adverse effects , Diabetes Mellitus, Type 2/history , History, 20th Century , Humans , Hypoglycemic Agents/history , Sulfonylurea Compounds/adverse effects , Sulfonylurea Compounds/history , Tolbutamide/history , United StatesABSTRACT
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.
Subject(s)
Adenosine Triphosphate/physiology , Hypoglycemic Agents/pharmacology , Potassium Channels/drug effects , Sulfonylurea Compounds/pharmacology , Administration, Oral , History, 20th Century , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/history , Models, Molecular , Molecular Structure , Sulfonylurea Compounds/administration & dosage , Sulfonylurea Compounds/chemistry , Sulfonylurea Compounds/historyABSTRACT
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.