What is the recommended dosing regimen for glimepiride in adults with type 2 diabetes, including starting dose, titration intervals, maximum dose, and adjustments for elderly patients or those with mild renal impairment (creatinine clearance 30–50 mL/min)?

Glimepiride Dosing in Type 2 Diabetes

Starting Dose and Initial Titration

Start glimepiride at 1 mg once daily with breakfast or the first main meal, particularly in elderly patients or those with any degree of renal impairment (including mild impairment with creatinine clearance 30–50 mL/min). 1

• The FDA-approved starting dose is either 1 mg or 2 mg once daily, but 1 mg is mandatory for patients at increased risk of hypoglycemia, which includes all elderly patients and anyone with renal impairment. 1
• Always administer glimepiride with breakfast or the first main meal to align insulin secretion with postprandial glucose peaks and reduce hypoglycemia risk. 1

Dose Titration Schedule

Increase the dose by 1–2 mg increments every 1–2 weeks based on glycemic response, but use only 1 mg increments in elderly patients or those with renal impairment. 1

• After reaching 2 mg daily, further increases can be made in 1 mg or 2 mg steps depending on glucose control. 1
• The usual maintenance dose range is 1–4 mg once daily, which provides optimal efficacy for most patients. 2, 3
• Titration intervals should not be shorter than 1–2 weeks to allow full assessment of glycemic response and hypoglycemia risk. 1

Maximum Dose

The maximum recommended dose is 8 mg once daily in the United States (6 mg in some countries), though doses above 4 mg provide minimal additional glycemic benefit. 1, 3

• Clinical trials demonstrate little difference in efficacy between 4 mg and 8 mg daily doses, so escalation beyond 4 mg should prompt consideration of adding a second agent rather than further glimepiride titration. 3, 4

Special Population Adjustments

Elderly Patients

In elderly patients, always start at 1 mg once daily and use conservative 1 mg increments every 2 weeks, as this population has markedly increased hypoglycemia risk. 1, 2

• Glimepiride pharmacokinetics are largely unaltered in elderly patients, but age-related changes in renal function and reduced counterregulatory responses to hypoglycemia necessitate cautious dosing. 3
• The American Diabetes Association guidelines emphasize that sulfonylureas (including glimepiride) should be used with extreme caution in older adults due to two-fold higher all-cause mortality and seven-fold higher risk of major hypoglycemic events compared to metformin. 5

Mild Renal Impairment (CrCl 30–50 mL/min)

Start at 1 mg once daily and titrate conservatively in 1 mg increments every 2 weeks when creatinine clearance is 30–50 mL/min. 1, 2

• Glimepiride has fewer active metabolites than glyburide and can be used more safely in mild-to-moderate renal impairment, though caution is still required. 3, 6
• When eGFR falls below 30 mL/min/1.73 m², switch from glimepiride to glipizide (starting at 2.5 mg once daily) because glipizide lacks active metabolites that accumulate in advanced renal disease. 2

Hepatic Impairment

Use glimepiride with caution in patients with impaired hepatic function, starting at 1 mg daily, as hepatic metabolism is the primary elimination route. 3, 4

Critical Drug Interactions

When prescribing fluoroquinolones or sulfamethoxazole-trimethoprim, reduce glimepiride dose by at least 50% or temporarily discontinue it, as these antimicrobials increase sulfonylurea exposure by approximately 50% and can precipitate severe hypoglycemia. 2

• Colesevelam reduces glimepiride absorption; administer glimepiride at least 4 hours before colesevelam. 1

Monitoring Requirements

• Measure HbA1c every 3 months until glycemic control is stable, then every 6 months. 2
• Check eGFR every 3–6 months in patients with baseline eGFR <60 mL/min/1.73 m² to guide ongoing dose adjustments. 2
• Assess hypoglycemia frequency at every visit, particularly during the first month of therapy when risk is highest. 2, 3

Common Pitfalls and Safety Considerations

Never use glyburide in any patient regardless of renal function, as it is contraindicated by the American Geriatrics Society due to prolonged duration of action and severe hypoglycemia risk. 2

• Glimepiride has a lower incidence of hypoglycemia than glyburide, particularly in the first month of treatment, but hypoglycemia still occurs in 10–20% of patients on monotherapy. 3, 4
• When combining glimepiride with insulin, reduce the glimepiride dose by at least 50% or discontinue it to avoid severe hypoglycemia. 2
• Patients being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effects for 1–2 weeks and require close hypoglycemia monitoring. 1

Position in Treatment Algorithm

Sulfonylureas including glimepiride are not recommended as first-line therapy in 2025; reserve them for second-line use when cost considerations are paramount, as metformin combined with an SGLT2 inhibitor is the preferred initial dual therapy. 2

• In patients with established cardiovascular disease, heart failure, or chronic kidney disease, prioritize SGLT2 inhibitors or GLP-1 receptor agonists over glimepiride due to proven cardiovascular and renal benefits. 2, 7
• When used as second-line therapy, glimepiride lowers HbA1c by approximately 1.5 percentage points. 2