GLIPIZIDE AND METFORMIN HYDROCHLORIDE
Clinical safety rating: safe
Alcohol and contrast dye can increase risk of lactic acidosis Can cause lactic acidosis a rare but serious metabolic complication.
Glipizide stimulates insulin secretion from pancreatic beta cells by binding to sulfonylurea receptors and closing ATP-sensitive potassium channels, leading to depolarization and calcium influx. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
| Metabolism | Glipizide is extensively metabolized in the liver via CYP2C9 to inactive metabolites. Metformin is not metabolized and is excreted unchanged in urine. |
| Excretion | Glipizide: primarily hepatic metabolism (inactive metabolites) with ~97% excreted in urine (mainly metabolites) and ~3% in feces. Metformin: ~90% excreted unchanged in urine via tubular secretion and glomerular filtration (renal). |
| Half-life | Glipizide: terminal t1/2 2–5 hours (prolonged in hepatic impairment). Metformin: plasma t1/2 ~6.2 hours, terminal t1/2 ~17.6 hours (prolonged in renal impairment; clinical accumulation risk). |
| Protein binding | Glipizide: 98–99% bound to albumin. Metformin: negligible (<5%) bound to plasma proteins. |
| Volume of Distribution | Glipizide: Vd ~0.1 L/kg (low, consistent with high protein binding). Metformin: Vd ~1.5 L/kg (large, indicating extensive tissue distribution including hepatic and renal). |
| Bioavailability | Glipizide: ~100% orally (immediate-release); slightly reduced with food. Metformin: ~50–60% orally (immediate-release); reduced to ~30% with extended-release formulations. |
| Onset of Action | Glipizide: peak plasma glucose-lowering effect at 1–3 hours post oral dose. Metformin: onset of glucose lowering within 2 hours, maximal effect within 1–2 weeks. |
| Duration of Action | Glipizide: duration ~12–24 hours (single dose); up to 24 hours with extended-release. Metformin: duration ~12–24 hours (immediate-release requires multiple daily dosing; extended-release once daily). |
Initial: 2.5 mg glipizide / 250 mg metformin orally twice daily. Titrate gradually based on glycemic control. Maximum: 20 mg glipizide / 2000 mg metformin per day in divided doses.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if eGFR <30 mL/min/1.73 m². If eGFR 30–45 mL/min/1.73 m², do not initiate; discontinue if eGFR falls below 45 mL/min/1.73 m². No dose adjustment needed for eGFR ≥45 mL/min/1.73 m². |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). Avoid use in Child-Pugh class B due to risk of lactic acidosis. No specific adjustment for mild impairment (Child-Pugh A), but use with caution. |
| Pediatric use | Not approved in pediatric patients. Safety and efficacy not established. |
| Geriatric use | Start at the low end of dosing range (2.5 mg/250 mg once or twice daily) due to increased risk of hypoglycemia and renal impairment. Titrate slowly. Monitor renal function frequently. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Alcohol and contrast dye can increase risk of lactic acidosis Can cause lactic acidosis a rare but serious metabolic complication.
| FDA category | Human |
| Breastfeeding | Glipizide: Excreted in small amounts; M/P ratio unknown; risk of neonatal hypoglycemia. Metformin: Low excretion with M/P ratio ~0.35; considered compatible. Generally avoided due to lack of safety data. |
| Teratogenic Risk | First trimester: Glipizide crosses placenta, but studies show low malformation risk. Metformin is considered low risk. Second/third trimester: Glipizide may cause neonatal hypoglycemia; metformin is associated with lower risk of macrosomia and preeclampsia. Overall, limited data for glipizide; metformin preferred. |
■ FDA Black Box Warning
Lactic acidosis associated with metformin. Risk factors include renal impairment, concomitant use of certain drugs (e.g., topiramate), age ≥65 years, radiological studies with contrast, surgery or other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Symptoms include malaise, myalgia, respiratory distress, increasing somnolence, and non-specific abdominal distress.
| Common Effects | Diarrhea |
| Serious Effects |
Renal disease or renal dysfunction (e.g., serum creatinine ≥1.5 mg/dL in males, ≥1.4 mg/dL in females, or abnormal creatinine clearance); acute or chronic metabolic acidosis including diabetic ketoacidosis; known hypersensitivity to glipizide, metformin, or any components; type 1 diabetes mellitus; severe hepatic impairment; concomitant use of bosentan or certain drugs that increase metformin levels (e.g., cimetidine); acute or chronic alcohol use; unstable or severe cardiac or respiratory disease; pregnancy and lactation (relative).
| Precautions | Lactic acidosis risk (see black box warning); hypoglycemia (especially in elderly, debilitated, or malnourished patients, and those with renal or hepatic impairment); cardiovascular considerations (sulfonylureas may increase cardiovascular mortality); hematologic effects (metformin may decrease vitamin B12 levels); acute alcohol consumption; concurrent medications that affect blood glucose; renal function monitoring; surgical procedures; radiologic studies with iodinated contrast. |
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| Fetal Monitoring | Maternal: Blood glucose monitoring, HbA1c, renal function, liver enzymes, signs of hypoglycemia/hyperglycemia. Fetal: Ultrasound for growth, anatomy; neonatal monitoring for hypoglycemia, especially with glipizide near term. |
| Fertility Effects | Glipizide: No known adverse effects on fertility. Metformin: May improve ovulation in PCOS; no detrimental impact on fertility. Combination not studied. |