Sulfonylureas are oral medications that lower blood glucose by stimulating insulin release from the pancreas. They lower A1C by about 1 to 1.5 percent, cost a few dollars a month as generics, and carry two consistent downsides: hypoglycemia and weight gain. This guide is a comprehensive sulfonylureas list with first-generation, second-generation, and third-generation agents, plus the related meglitinide class. Use it to compare doses, half-lives, and where each drug fits in current care.
How the Class Works
All sulfonylureas bind the SUR1 (sulfonylurea receptor 1) subunit on the surface of pancreatic beta cells. This binding closes ATP-sensitive potassium channels, depolarizes the cell membrane, opens voltage-gated calcium channels, and triggers the release of stored insulin granules. The stimulation is largely glucose-independent — the pancreas releases insulin whether or not blood glucose is elevated — which is why hypoglycemia is the dominant class side effect.
First-Generation Sulfonylureas
| Drug | Brand | Dose Range | Half-Life | Notes |
|---|---|---|---|---|
| Chlorpropamide | Diabinese | 100 to 500 mg/day | ~35 hours | Severe hyponatremia, disulfiram-like alcohol reaction; obsolete |
| Tolbutamide | Orinase | 500 to 3,000 mg/day | ~5 to 7 hours | Shortest acting first-gen; rarely used |
| Tolazamide | Tolinase | 100 to 1,000 mg/day | ~7 hours | Rarely used |
| Acetohexamide | Dymelor | 250 to 1,500 mg/day | ~5 hours (active metabolite ~5 hours) | Discontinued in many markets |
First-generation drugs were the original oral diabetes medications, introduced in the 1950s. They are now rarely prescribed because their high doses, long half-lives, drug interactions, and side-effect profiles compare unfavorably with later generations.
Second-Generation Sulfonylureas
| Drug | Brand | Dose Range | Frequency | Half-Life | Renal Use |
|---|---|---|---|---|---|
| Glipizide IR | Glucotrol | 5 to 40 mg/day | Once or twice daily; before meals | ~2 to 4 hours | Preferred SU in mild to moderate CKD |
| Glipizide XL | Glucotrol XL | 5 to 20 mg/day | Once daily with breakfast | Extended via osmotic delivery | Preferred SU in mild to moderate CKD |
| Glyburide | DiaBeta, Micronase | 1.25 to 20 mg/day | Once or twice daily with meals | ~4 hours, but active metabolites longer | Avoid in older adults; Beers criteria |
| Glyburide micronized | Glynase | 0.75 to 12 mg/day | Once or twice daily | Similar to non-micronized | Avoid in older adults |
Third-Generation Sulfonylureas
| Drug | Brand | Dose Range | Frequency | Notes |
|---|---|---|---|---|
| Glimepiride | Amaryl | 1 to 8 mg/day | Once daily with breakfast | Different SUR1 binding kinetics; lower hypoglycemia than glyburide |
| Gliclazide (non-US) | Diamicron, Diamicron MR | 40 to 320 mg/day | Once or twice daily | Lowest hypoglycemia rates in class; used in ADVANCE trial |
Glimepiride is once-daily and well tolerated; gliclazide is widely used outside the US, including in the UK, Europe, Australia, and most of Asia, but is not FDA-approved in the United States.
Meglitinides — Related Secretagogues
| Drug | Brand | Dose Range | Frequency | Notes |
|---|---|---|---|---|
| Repaglinide | Prandin | 0.5 to 4 mg before each meal | Up to 4 times daily, before meals | Fast on, fast off; can skip dose if meal skipped |
| Nateglinide | Starlix | 60 to 120 mg before each meal | Up to 3 times daily, before meals | Lower potency than repaglinide; modest A1C drop |
Meglitinides act on the same SUR1 receptor as sulfonylureas but with much faster onset and offset. They are taken before each meal and cause less between-meal hypoglycemia. Pill burden and cost (especially for repaglinide) are higher than for generic sulfonylureas.
Hypoglycemia Profiles Compared
| Drug | Relative Hypoglycemia Risk | Severity When It Occurs | Comments |
|---|---|---|---|
| Chlorpropamide | Highest among historic options | Very prolonged | Largely obsolete |
| Glyburide | High | Prolonged because of active metabolites | Avoid in older adults |
| Glipizide | Moderate | Less prolonged than glyburide | Preferred SU in older or CKD patients |
| Glimepiride | Moderate | Less prolonged than glyburide | Once-daily convenience |
| Gliclazide MR | Lowest in class | Generally manageable | Not US-available |
| Repaglinide | Lower than sulfonylureas | Short-lived | Meal-tied dosing |
| Nateglinide | Lowest of secretagogues | Short-lived | Smaller A1C drop |
Side Effects Common to the Class
- Hypoglycemia — class-defining; varies by specific drug
- Weight gain — 2 to 5 kg typical first year
- Photosensitivity (rare)
- Allergic skin reactions (sulfa-class; true cross-reactivity with sulfa antibiotics overstated)
- Hyponatremia (especially chlorpropamide)
- Hemolytic anemia in G6PD deficiency
- Rare hepatic enzyme elevations
- Disulfiram-like alcohol reaction (especially chlorpropamide)
Cost — All Generic, All Cheap
- Glipizide, glyburide, glimepiride: $4 to $15 per month
- Repaglinide: $30 to $80 per month
- Nateglinide: $30 to $80 per month
- Gliclazide: similar to other SUs where available
For context, GLP-1 agonists and SGLT2 inhibitors typically cost $500 to $1,300 per month without insurance.
What the Trials Showed
- UKPDS 33 (Lancet 1998) showed that intensive glucose control with sulfonylureas or insulin reduced microvascular complications in newly diagnosed type 2 diabetes. The trial established sulfonylureas as a foundational therapy and contributed to the case for tight glucose control.
- ADVANCE (NEJM 2008) used gliclazide MR as the backbone of intensive control in 11,140 patients with type 2 diabetes; A1C fell from a median of 7.5 to 6.5 percent and major macrovascular plus microvascular events were reduced by 10 percent.
- ADOPT (NEJM 2006) compared glyburide, metformin, and rosiglitazone as monotherapy in newly diagnosed type 2 diabetes; sulfonylureas had the highest rate of secondary failure at 5 years.
Where Sulfonylureas Fit in 2024 Care
The ADA Standards of Care 2024 favor metformin as first-line, with GLP-1 agonists or SGLT2 inhibitors as preferred second-line options when there is cardiovascular disease, heart failure, or kidney disease. Sulfonylureas are used:
- As cost-conscious add-on to metformin
- In patients without indications that favor newer classes
- In global settings where access to newer drugs is limited
Within the class, glipizide and glimepiride are preferred over glyburide because of lower severe hypoglycemia rates.
Choosing Among Sulfonylureas
- Older adult: glipizide preferred; glimepiride acceptable with caution; avoid glyburide
- Mild to moderate CKD: glipizide is the typical first choice
- Once-daily preference: glimepiride or glipizide XL
- Variable meals: meglitinide (repaglinide) may be more flexible
- Cost-sensitive: any second-generation SU at $4 a month
Related Reading
See our drug-specific guides on glipizide, glyburide, and glimepiride, plus the class-level sulfonylureas side effects and the head-to-head glipizide vs metformin. For broader context see the treatment overview.
The Bottom Line
Sulfonylureas remain a clinically useful, inexpensive class of oral diabetes drugs. The list above covers first-generation drugs (largely obsolete), second-generation glipizide and glyburide, third-generation glimepiride, and the related meglitinides. All lower A1C by about 1 to 1.5 percent, all stimulate insulin release through the SUR1 receptor, and all carry hypoglycemia and weight gain as their main downsides. Within the class, glipizide and glimepiride are usually preferred over glyburide; gliclazide is preferred where available outside the US. Modern guidelines place sulfonylureas behind metformin, GLP-1 agonists, and SGLT2 inhibitors as first or second-line therapy, but their cost keeps them in wide global use. Discuss with your clinician which specific agent suits your kidney function, age, daily routine, and budget.
