- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- CrCl - Creatinine clearance
- DRUGS IN CLASS
- First generation sulfonylureas
- Acetohexamide
- Chlorpropamide (Diabinese®)
- Tolazamide
- Tolbutamide (Orinase®)
- Second generation sulfonylureas
- Glimepiride (Amaryl®)
- Glipizide (Glucotrol® and Glucotrol XL®)
- Glyburide (DiaBeta®)
- also called Glibenclamide
- Micronized Glyburide (Glynase®)
- Combination products with metformin
- Glucovance® (glyburide + metformin)
- Metaglip® (glipizide + metformin)
- Combination products with glitazones
- Duetact® (glimepiride + pioglitazone)
- MECHANISM OF ACTION
- Sulfonylureas inhibit potassium channels in the cell membrane of pancreatic beta cells. This leads to calcium influx, which stimulates insulin exocytosis from secretory granules. Sulfonylurea-induced insulin secretion occurs independent of glucose levels and can lead to hypoglycemia. Other possible glucose-lowering actions of sulfonylureas include inhibiting insulin metabolism, suppressing glucagon secretion, and increasing insulin sensitivity in peripheral tissues. [23]
- TYPE 2 DIABETES
- Blood sugar effects
- Sulfonylureas have been prescribed for many years. Most studies evaluating their effects on blood sugars are older and not readily available. A trial presented in the Amaryl PI is detailed below, along with a meta-analysis examining their effects on A1C values.
- Amaryl PI
- A placebo-controlled, 22-week trial compared glimepiride 1 - 8 mg/day (N=123) to placebo (N=126) in treatment-naïve type 2 diabetics
- Glimepiride was titrated to a fasting blood sugar goal of 90 - 150 mg/dl. Baseline A1C was ∼ 9.2% in both groups.
- Primary outcome was the average change in A1C level at 22 weeks
- Results: Glimepiride -2.2%, Placebo -1.1% [2]
- A meta-analysis in Diabetologia looked at randomized placebo-controlled studies comparing sulfonylureas to placebo. Twelve trials encompassing 1151 patients were included.
- Sulfonylureas lowered Hg A1C values by an average of 1.51% when compared to placebo
- Trial drugs were as follows: glimepiride - 6 trials (827 patients); glyburide - 3 trials (151 patients); glipizide - 2 trials (154 patients); tolbutamide - 1 trial (19 patients) [18]
- Summary
- Sulfonylureas lower A1C values by about 1 - 1.5%, which is on the higher end of effect for oral diabetes medications
STUDY
-
The meta-analysis found the following effect:
- Body weight effects
- Sulfonylurea-induced insulin secretion can promote weight gain through increased cellular glucose uptake
- In a 22-week study that compared glimepiride (1 - 8 mg/day) to placebo, the average weight change at 22 weeks was -2 pounds in the placebo group (N=122) and +4 pounds in the glimepiride group (N=119). The average baseline weight was ∼ 191 pounds in both groups. [2]
- Cholesterol effects
- Sulfonylureas do not appear to have a significant effect on lipid parameters [8]
- Clinical outcomes
- Sulfonylureas improve diabetes outcomes by lowering blood sugars, but beneficial effects beyond their glucose-lowering properties have not been observed, and there is some indication they may worsen cardiac outcomes. Sulfonylurea receptors are found in tissues outside the pancreas, specifically the heart and vasculature. These receptors are thought to be involved in the cardiac response to ischemia, and sulfonylurea binding may exert an adverse effect. First-generation sulfonylureas have a higher affinity for cardiac receptors, and an early study found that tolbutamide increased the risk of cardiac death compared to diet or insulin. Second-generation sulfonlyureas are more specific for pancreatic tissue, and studies examining their effects on cardiovascular risk have been mixed. Of all the sulfonylureas, glimepiride has the lowest affinity for cardiac tissue and does not appear to pose any adverse cardiovascular risk. [23,24]
- ADA recommendations
- SIDE EFFECTS
- Low blood sugar (hypoglycemia)
- Sulfonylureas stimulate insulin secretion independent of glucose levels, increasing the risk of hypoglycemia. Glyburide has a longer half-life than other sulfonylureas, and there is some evidence that it carries a higher risk of hypoglycemia. Because of this, the ADA recommends that it be avoided in high-risk patients and the elderly. [13,14]
- See hypoglycemia for a review of managing low blood sugars
- Weight gain
- Sulfonylureas can cause weight gain in some patients. See body weight effects for more.
- Disulfiram-reaction (chlorpropamide)
- Chlorpropamide has been associated with a disulfiram-like reaction (e.g. facial flushing) in patients who consume alcohol. This effect has not been observed with second-generation sulfonylureas. [17]
- Hyponatremia (chlorpropamide)
- Chlorpropamide has been associated with hyponatremia in some patients. Second-generation sulfonylureas do not appear to have this effect. [17]
- Photosensitivity
- Sulfonylureas may cause photosensitivity. Wearing sunscreen and limiting sun exposure can help to prevent reactions. [21]
- Skin reactions
- Skin reactions, including pruritus, erythema, urticaria, morbilliform (measles-like) eruptions, and maculopapular rashes, have been reported in about 1.5% of patients. These reactions may be transient and disappear with continued use. Other more serious reactions, including bullous formation, erythema multiforme, and exfoliative dermatitis, have also been reported. Sulfonylureas should be discontinued if serious or persistent reactions occur. [3]
- CONTRAINDICATIONS
- All sulfonylureas
- History of hypersensitivity reaction to sulfonamide derivatives (see sulfa allergy below)
- Type 1 diabetes mellitus and/or diabetic ketoacidosis
- Glyburide
- Concomitant administration with bosentan (Tracleer®)
- PRECAUTIONS
- Kidney disease
- Glimepiride (Amaryl)
- CrCl < 90 ml/min: exposure is increased. Use a starting dose of 1 mg once daily and titrate slowly.
- Glipizide (Glucotrol, Glucotrol XL)
- Exposure is increased. Consider a starting dose of 2.5 mg and titrate slowly.
- Glyburide (Micronase, DiaBeta, Glynase)
- Exposure may be increased. Use a lower starting dose and titrate slowly.
- Liver disease
- Glimepiride (Amaryl)
- Has not been studied. Use caution.
- Glipizide (Glucotrol, Glucotrol XL)
- Exposure may be increased. Consider a starting dose of 2.5 mg and titrate slowly.
- Glyburide (Micronase, Diabeta, Glynase)
- Exposure may be increased. Use a lower starting dose and titrate slowly.
- Sulfa allergy
- Sulfonylureas contain a sulfonamide group in their structure, but it is different from the one found in sulfa-based antibiotics. Patients with a history of sulfa-based antibiotic allergy have a small risk of having an allergic reaction to sulfonylureas. A cohort study that examined the issue is detailed below.
- STUDY
- A cohort study in the NEJM looked at the risk of an allergic reaction to nonantibiotic sulfonamides in patients who had a previous reaction to a sulfa-based antibiotic
- The study found the following:
- Patients with a history of sulfa-based antibiotic allergy who subsequently took nonantibiotic sulfonamides (including sulfonylureas) had a 10% risk of having a reaction to the nonantibiotic sulfonamide
- In patients without a history of allergic reaction to a sulfa-based antibiotic, 1.6% had a reaction to a nonantibiotic sulfonamide
- Patients with a history of sulfa-based antibiotic allergy had a 14% chance of having a reaction to a penicillin antibiotic. This finding led researchers to conclude that a history of allergic reactions, in general, may be more predictive of a reaction than reactions to any specific medication [15]
- Summary
- Patients with a history of sulfa-based antibiotic allergy have about a 10% chance of reacting to a sulfonylurea. Patients with a history of severe reaction to sulfa-based antibiotics should avoid nonantibiotic sulfonamides if possible. If not, the initial dosing should be done under medical supervision.
- G6PD deficiency
- There are case reports of sulfonylurea-induced hemolytic anemia occurring in patients with G6PD deficiency. Avoid use in these patients. [1,2,3]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All sulfonylureas
- Aspirin - Aspirin may potentiate the effects of sulfonylureas. The significance of this effect with low-dose aspirin is unclear.
- Beta blockers (ex. propranolol, metoprolol, etc.) - Beta blockers may potentiate the effect of sulfonylureas. The significance of this effect is unclear.
- Clarithromycin (Biaxin®) - Clarithromycin may potentiate the effect of sulfonylureas. The significance of this effect is unclear.
- Colesevelam (Welchol™) - colesevelam decreases the absorption of sulfonylureas. Take sulfonylureas at least 4 hours prior to colesevelam.
- CYP2C9 inhibitors and inducers - may affect blood levels of sulfonylureas
- NSAIDs (ibuprofen, naprosyn, Motrin®, etc.) - NSAIDs may potentiate the effect of sulfonylureas. The significance of this effect is unclear.
- Quinolone antibiotics (Levaquin®, Cipro®, gatifloxacin, etc.) - Quinolone antibiotics may potentiate the effects of glyburide and glipizide. Monitor for hypoglycemia.
- Sulfamethoxazole (Bactrim®) - Sulfamethoxazole may potentiate the effect of sulfonylureas. The significance of this effect is unclear.
- Topiramate (Topamax®) - Topiramate may decrease glyburide levels
- Warfarin (Coumadin®) - In an observational study, the combined use of warfarin with glimepiride or glipizide was associated with a higher risk of hypoglycemia in patients ≥ 65 years old. The mechanism behind this possible interaction is unclear. [22]
- Glyburide (Diabeta®)
- Bosentan (Tracleer®) - glyburide should not be given with bosentan. Liver enzyme elevations have occurred.
- Metabolism and clearance
- LONG-TERM SAFETY
- Second-generation sulfonylureas have been widely prescribed in the U.S. since the early 1980s. When prescribed appropriately, they have proven to be safe and effective.
- DOSING
- BIBLIOGRAPHY
- 1 - Glipizide PI
- 2 - Amaryl PI
- 3 - Glyburide PI
- 4 - PMID 17145742
- 5 - PMID 12401757
- 6 - PMID 11790217
- 7 - PMID 18945920
- 8 - PMID 21403054
- 9 - PMID 9742976
- 10 - PMID 21471135
- 11 - PMID 16186261
- 12 - PMID 18955635
- 13 - PMID 17259518
- 14 - PMID 19407068
- 15 - PMID 14573734
- 16 - PMID 20215447
- 17 - PMID 10789825
- 18 - PMID 23494446
- 19 - PMID 4185978 - SU vs met MA
- 20 - PMID 23633364 - Cochrane MA
- 21 - FDA special feature
- 22 - PMID 26643108 - Warfarin and sulfonylurea
- 23 - PMID 30020597 - Costello RA, Nicolas S, Shivkumar A. Sulfonylureas. [Updated 2022 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
- 24 - PMID 25598727 - Cardiovascular safety profile of currently available diabetic drugs, Ochsner J. (2014)