EMPAGLIFLOZIN 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.
Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that reduces renal glucose reabsorption, increasing urinary glucose excretion. Metformin is a biguanide that decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
| Metabolism | Empagliflozin: Primarily glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9; minor CYP450 involvement. Metformin: Not metabolized by the liver; excreted unchanged in urine. |
| Excretion | Empagliflozin: ~54% excreted unchanged in urine (renal), ~41% in feces (biliary/fecal). Metformin: ~90% excreted unchanged in urine (renal), <5% in feces. |
| Half-life | Empagliflozin: terminal half-life ~12-14 hours, supports once-daily dosing. Metformin: terminal half-life ~6-8 hours (plasma), prolonged to ~17-18 hours in renal impairment. |
| Protein binding | Empagliflozin: ~86% bound (primarily to albumin). Metformin: negligible (<1% bound). |
| Volume of Distribution | Empagliflozin: Vd ~10.7 L (0.15 L/kg); distribution into tissues. Metformin: Vd 654 ± 358 L (9.3 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Empagliflozin: absolute bioavailability ~78% (oral). Metformin: absolute bioavailability ~50-60% (oral); decreases with food. |
| Onset of Action | Empagliflozin: onset of urinary glucose excretion within 1-2 hours; clinical effect on glycemic control within 1 week. Metformin: onset of glucose-lowering effect within 2-3 days; maximal effect in 1-2 weeks. |
| Duration of Action | Empagliflozin: duration ~24 hours due to half-life; once-daily dosing. Metformin: duration ~24 hours with extended-release; immediate-release requires twice-daily dosing. |
Initial: empagliflozin 5 mg/metformin 500 mg orally twice daily; titrate to maintenance: empagliflozin 10-25 mg/metformin 1000-2000 mg per day in two divided doses.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR ≥60 mL/min/1.73m2: no adjustment; eGFR 45-59: reduce metformin to max 1000 mg/day, empagliflozin max 10 mg/day; eGFR <45: contraindicated. |
| Liver impairment | Avoid metformin in Child-Pugh class B or C; empagliflozin not studied in severe impairment. |
| Pediatric use | Not approved for patients <18 years; no established dosing. |
| Geriatric use | Start at low dose, up-titrate gradually; monitor renal function and volume status; avoid in patients ≥85 years due to limited data. |
| 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 | Metformin: Excreted into human milk; M/P ratio approximately 0.35. Breastfeeding is generally considered acceptable with monitoring for hypoglycemia and gastrointestinal effects in infant. Empagliflozin: No human data; excreted in animal milk. Due to potential for adverse effects on infant kidney development, breastfeeding not recommended while taking empagliflozin. |
| Teratogenic Risk |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis is rare but can occur due to metformin accumulation; risk factors include renal impairment, concomitant use of certain drugs, age >65 years, radiological studies with contrast, surgery, and hypoxic states.
| Common Effects | Diarrhea |
| Serious Effects |
["Severe renal impairment (eGFR < 30 mL/min/1.73 m²)","Acute or chronic metabolic acidosis, including diabetic ketoacidosis","History of hypersensitivity to empagliflozin or metformin","Intravascular iodinated contrast agents (temporary discontinuation recommended)"]
| Precautions | ["Lactic acidosis","Hypoglycemia when used with insulin or sulfonylureas","Volume depletion and hypotension due to empagliflozin","Ketoacidosis in diabetes mellitus","Acute kidney injury or worsening renal function","Urosepsis or pyelonephritis (empagliflozin)","Genital mycotic infections (empagliflozin)","Vitamin B12 deficiency with long-term metformin use","Increased risk of acute pancreatitis (postmarketing)"] |
Loading safety data…
| Metformin: Limited human data suggest no increased risk of major birth defects in first trimester; embryofetal toxicity not evident in animal studies. Empagliflozin: Not recommended in second and third trimesters due to risk of oligohydramnios and potential fetal renal impairment based on animal studies. First trimester risk unknown due to lack of human data. |
| Fetal Monitoring | Monitor renal function (serum creatinine, eGFR), blood glucose, and HbA1c. Assess for hypoglycemia, especially with metformin. Fetal monitoring includes ultrasound for fetal growth and amniotic fluid volume (due to risk of oligohydramnios with empagliflozin). |
| Fertility Effects | Empagliflozin: Animal studies show no significant effects on fertility. Metformin: May restore fertility in women with polycystic ovary syndrome (PCOS) by improving ovulation. No adverse effects on fertility in men or women reported in human studies. |