Sulfonylureas were the first oral antihyperglycemic agents and remain widely used because of their low cost and reliable glucose-lowering efficacy. They act by closing adenosine triphosphate-sensitive potassium channels in pancreatic beta cells, stimulating insulin secretion independent of blood glucose — which is both their mechanism of action and the explanation for their most important adverse effect.

Sulfonylureas bind to the sulfonylurea receptor 1 subunit of the adenosine triphosphate-sensitive potassium channel complex in beta cells, closing the channel and triggering the same downstream cascade as glucose — membrane depolarization, calcium influx, and insulin granule exocytosis. Because this occurs regardless of the prevailing blood glucose level, insulin is secreted even when glucose is already normal or low, making hypoglycemia an intrinsic pharmacological risk rather than a dose error.

First-generation sulfonylureas (tolbutamide, chlorpropamide) have largely been replaced by second-generation agents. Second-generation sulfonylureas in clinical use include glipizide, glyburide (glibenclamide), and glimepiride. Glimepiride and glipizide are generally preferred over glyburide in older adults because glyburide has active metabolites that accumulate in renal impairment, substantially increasing hypoglycemia risk. Glimepiride has the lowest hypoglycemia incidence among the class and some evidence of insulin-sensitizing effects at peripheral tissues.

The primary adverse effect is hypoglycemia, which can be severe and prolonged, particularly with glyburide in elderly patients or those with chronic kidney disease. Weight gain of 2 to 5 kg is common due to the anabolic effects of the additional insulin secreted. Secondary failure — diminishing efficacy over time as beta cell reserve further declines — occurs in a substantial proportion of patients over 5 to 10 years.

Metformin is the first-line oral agent for type 2 diabetes mellitus in all major guidelines. It lowers blood glucose primarily by reducing hepatic glucose output, does not stimulate insulin secretion, and carries no intrinsic hypoglycemia risk when used as monotherapy. Its weight-neutral to weight-reducing profile and decades of safety data make it the backbone of most type 2 diabetes mellitus regimens.

Metformin's primary action is suppression of hepatic gluconeogenesis. The molecular mechanism involves inhibition of mitochondrial complex I of the respiratory chain, reducing hepatic energy state and activating adenosine monophosphate-activated protein kinase. Activated adenosine monophosphate-activated protein kinase phosphorylates and inactivates key gluconeogenic enzymes and transcription factors, reducing glucose output from the liver. Metformin also improves peripheral insulin sensitivity in muscle, though the hepatic effect is dominant.

Metformin is not metabolized and is excreted unchanged by the kidneys. It is not protein bound and does not interact with cytochrome P450 enzymes, giving it a clean drug interaction profile. It is taken with meals to reduce gastrointestinal adverse effects. The extended-release formulation improves gastrointestinal tolerability for patients who experience nausea or diarrhea with immediate-release tablets.

Current guidelines from the American Diabetes Association position metformin as the preferred initial pharmacological agent for type 2 diabetes mellitus in patients without cardiovascular disease, chronic kidney disease, or heart failure (for whom glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors may be preferred first-line regardless of glycated hemoglobin). Sulfonylureas remain a common second agent when cost is a concern.

When metformin alone is insufficient, the choice of add-on agent is driven by patient-specific factors: presence of atherosclerotic cardiovascular disease or chronic kidney disease (favoring glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors with outcome trial data), hypoglycemia risk (favoring agents that do not stimulate insulin secretion), weight considerations (favoring glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter-2 inhibitors over sulfonylureas), and cost (favoring sulfonylureas or neutral protamine Hagedorn insulin). Sulfonylureas are effective add-on agents when glycated hemoglobin reduction is the primary goal and hypoglycemia risk is acceptable.