Sulfonylureas

Definition and Clinical Role
Sulfonylureas are a class of oral hypoglycemic agents used in the management of type 2 diabetes mellitus (T2DM). They are among the earliest non-insulin medications introduced for diabetes treatment and function by stimulating insulin secretion from pancreatic β-cells. Their use has declined with the advent of newer antidiabetic agents; however, they remain a cost-effective and widely used treatment option, especially in low-resource settings or patients not suitable for newer therapies.

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Mechanism of Action

Sulfonylureas function primarily by:

• Binding to the sulfonylurea receptor 1 (SUR1) component of the ATP-sensitive potassium (KATP) channels on pancreatic β-cells.

• This causes closure of KATP channels, leading to cell depolarization.

• Voltage-gated calcium channels open, increasing intracellular calcium.

• This triggers exocytosis of insulin granules, thereby increasing circulating endogenous insulin levels.

They require functional β-cells, thus they are ineffective in type 1 diabetes and less effective in long-standing T2DM with pancreatic β-cell exhaustion.

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Generations and Drug List

First-Generation Sulfonylureas

• Less potent, more drug interactions, longer half-lives

• Rarely used in modern practice

Generic Name	Brand Name(s)
Chlorpropamide	Diabinese
Tolbutamide	Orinase
Tolazamide	Tolinase
Acetohexamide	Dymelor

Second-Generation Sulfonylureas

• More potent, shorter half-life, fewer side effects

Generic Name	Brand Name(s)
Glipizide	Glucotrol
Glyburide (Glibenclamide)	Diabeta, Micronase
Gliclazide	Diamicron
Glimepiride	Amaryl

Indications

• Type 2 Diabetes Mellitus

  • As monotherapy in early disease stages

  • In combination with other antidiabetics (e.g., metformin, DPP-4 inhibitors)

• Patients not obese or unable to afford newer therapies

• Initial therapy in patients contraindicated for metformin

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Pharmacokinetics

Drug	Onset	Duration	Half-life	Excretion
Glipizide	Rapid	12–24 h	~2–4 h	Renal
Glyburide	Intermediate	12–24 h	~10 h	Renal & biliary
Gliclazide	Moderate	~24 h	~10–12 h	Hepatic
Glimepiride	Rapid	~24 h	~5–9 h	Hepatic & renal

Dosing Overview

• Glipizide: 5–40 mg/day (divided doses or extended-release)

• Glyburide: 1.25–20 mg/day

• Glimepiride: 1–8 mg once daily

• Gliclazide: 30–120 mg/day (standard), 30–60 mg/day (MR)

Dose should be individualized and titrated based on fasting plasma glucose and HbA1c levels.

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Adverse Effects

Adverse Effect	Description
Hypoglycemia	Most serious and common risk
Weight gain	Due to increased insulin levels
Nausea, GI upset	Mild, transient
Allergic skin reactions	Rash, photosensitivity (rare)
Hematologic effects	Agranulocytosis, thrombocytopenia (rare)
SIADH (Chlorpropamide)	Causes inappropriate ADH secretion
Liver enzyme elevation	Rare but possible
Cardiovascular risks	Conflicting evidence; older sulfonylureas linked to higher CV risk

Contraindications

• Type 1 diabetes mellitus

• Diabetic ketoacidosis

• Severe hepatic or renal impairment (especially glyburide)

• Pregnancy and lactation (insulin preferred)

• Hypersensitivity to sulfa drugs (though cross-reactivity is rare)

• G6PD deficiency (risk of hemolysis)

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Precautions

• Monitor blood glucose regularly to avoid hypoglycemia

• Use with caution in elderly or those with renal insufficiency

• Educate patients on recognizing and managing hypoglycemia

• Avoid alcohol (especially with chlorpropamide due to disulfiram-like reactions)

• Not effective if pancreatic β-cell function is significantly impaired

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Drug Interactions

Interacting Agent	Interaction
Beta-blockers	Mask hypoglycemia symptoms
Warfarin	Potentiation of hypoglycemia
Salicylates (aspirin)	Increased effect of sulfonylureas
Alcohol	Risk of hypoglycemia, disulfiram-like effects
Thiazides	Hyperglycemic effect
CYP2C9 inhibitors (e.g., fluconazole)	Increased sulfonylurea levels
Rifampin	Reduces sulfonylurea effect

Comparison with Other Antidiabetic Classes

Feature	Sulfonylureas	Metformin	DPP-4 Inhibitors	SGLT2 Inhibitors
Mechanism	Insulin secretagogue	Reduces hepatic glucose	Incretin effect	Blocks glucose reabsorption
Hypoglycemia	Yes	Rare	Rare	Rare
Weight	Gain	Neutral/loss	Neutral	Loss
CV Benefits	Neutral/questionable	Yes	Neutral	Yes (empagliflozin etc.)
Renal Adjust?	Yes	Yes	Yes	Yes

Clinical Guidelines and Positioning

• American Diabetes Association (ADA):

  • Sulfonylureas are not first-line unless cost is a major barrier

  • Considered after metformin in patients requiring greater glucose-lowering

• NICE (UK):

  • Can be used as an add-on or alternative to metformin

• International Diabetes Federation (IDF):

  • Useful in resource-limited countries

• Endocrine Society:

  • Recommends glimepiride or gliclazide due to lower hypoglycemia risk compared to glyburide

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Advantages

• Rapid reduction of blood glucose levels

• Effective in early T2DM with preserved β-cell function

• Inexpensive and widely available

• Oral administration improves adherence

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Limitations

• High risk of hypoglycemia, especially in elderly

• Weight gain counteracts benefits in metabolic syndrome

• Loss of efficacy over time ("secondary failure" due to β-cell burnout)

• Less cardiovascular benefit compared to GLP-1 or SGLT2 agents

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Use in Special Populations

• Elderly:

  • Use shorter-acting agents like glipizide to reduce hypoglycemia

• Pregnancy:

  • Generally not recommended; insulin is preferred

• Renal impairment:

  • Avoid glyburide; glipizide and glimepiride preferred in mild to moderate cases

• Hepatic impairment:

  • Use with caution; increased hypoglycemia risk

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Summary of Second-Generation Sulfonylureas

Drug	Potency	Hypoglycemia Risk	Preferred Use Case
Glipizide	Moderate	Lower	Elderly, renal impairment
Glyburide	High	High	Avoid in renal disease
Gliclazide	High	Low–moderate	Widely used outside the US
Glimepiride	High	Moderate	General use, once-daily dosing