SULFONYLUREAS















Blood sugar effects
Overview
  • 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 that looked at 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 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]
STUDY
Estimating the Effect of Sulfonylurea on HbA1c in Diabetes, Diabetologia (2013) [PubMed abstract]
  • A meta-analysis in Diabetologia evaluated studies that compared a sulfonylurea to placebo
  • The study included trials that were randomized, double-blinded, and at least 12 weeks in duration
  • Twelve trials that encompassed 1151 patients were included
    The meta-analysis found the following effect:
    • 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%. This effect is at the higher end of the range that is seen with other oral diabetes medications.

Body weight effects

Cholesterol effects

Clinical outcomes

ADA recommendations



Low blood sugar (hypoglycemia)
Overview
  • Because sulfonylureas stimulate insulin secretion, they can cause low blood sugar (hypoglycemia)
  • The risk is higher when sulfonylureas are combined with other diabetes medications
Glyburide
  • Glyburide appears to be associated with more low blood sugar events than other sulfonylureas
  • A review in Diabetes Care found that glyburide was associated with an 83% greater risk of experiencing at least one episode of low blood sugar when compared to other sulfonylureas
  • Because of this, the ADA recommends that glipizide be used instead of glyburide [13,14]
  • See hypoglycemia for a full review of low blood sugar

Weight gain

Disulfiram-reaction (chlorpropamide)

Low sodium (chlorpropamide)

Photosensitivity

Skin reactions






Kidney disease
Glimepiride (Amaryl®)
  • Clearance is decreased in kidney disease
  • Patients with kidney disease (CrCl ≤ 90ml/min) should be started at 1 mg once daily and titrated slowly to decrease the risk of hypoglycemia
Glipizide (Glucotrol®)
  • Clearance may be decreased in kidney disease
  • Manufacturer makes no specific dosage recommendation
Glyburide (DiaBeta®)
  • Clearance may be decreased in kidney disease
  • Manufacturer makes no specific dosage recommendation

Liver disease
Glimepiride (Amaryl®)
  • Has not been studied in patients with significant liver disease
  • Manufacturer makes no specific dosage recommendation
Glipizide (Glucotrol®)
  • Clearance may be decreased in liver disease
  • Manufacturer states that patients with liver disease may be started on 2.5 mg a day
Glyburide (DiaBeta®)
  • Clearance may be decreased in liver disease
  • Manufacturer makes no specific dosage recommendation

Sulfa allergy
Overview
  • Sulfonylureas contain a sulfonamide group in their structure
  • The sulfonamide group is different from the one that is found in sulfa-based antibiotics
  • Patients with a history of allergy to sulfa-based antibiotics may have a slight increase in risk of an allergic reaction to sulfonylureas
STUDY
Cross-reactivity between sulfa-based antibiotics and sulfonamide nonantibiotics, NEJM (2003) [PubMed abstract]
  • 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
    • In addition, 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
  • Sulfonylureas may be prescribed to patients with a history of sulfa-based antibiotic allergy
  • Patients should be aware that a cross-sensitivity reaction may occur with a risk of around 10%
  • Patients with a history of severe reactions to sulfa-based antibiotics should avoid nonantibiotic sulfonamides if they can. If not, then the initial dosing should be done under medical supervision.

G6PD deficiency



Sulfonylurea drug interactions

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.