EMPAGLIFLOZIN;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 co-transporter 2 (SGLT2) inhibitor that reduces renal glucose reabsorption, increasing urinary glucose excretion. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
| Metabolism | Empagliflozin: Primarily metabolized via glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9, with minor CYP metabolism (CYP3A4). Metformin: Not metabolized; excreted unchanged in urine (90% via renal tubular secretion). |
| Excretion | Empagliflozin: ~54% renal (unchanged), ~41% fecal (unchanged and metabolites). Metformin: ~90% renal (unchanged); fecal elimination negligible. |
| Half-life | Empagliflozin: terminal t1/2 ~12.4 h, supports once-daily dosing. Metformin: terminal t1/2 ~6.2 h (plasma), prolonged to ~17.6 h in blood (accumulation in RBCs); requires dose adjustment in renal impairment. |
| Protein binding | Empagliflozin: ~86% bound (primarily to albumin). Metformin: negligible (<5% bound to plasma proteins). |
| Volume of Distribution | Empagliflozin: Vd ~0.5 L/kg (moderate tissue distribution). Metformin: Vd 1-5 L/kg (large distribution, with accumulation in GI tract, liver, and renal tissue; clinical significance: dose loading not required). |
| Bioavailability | Empagliflozin: absolute oral bioavailability ~78% (fasted); high-fat meal slightly reduces peak concentration but not AUC. Metformin: immediate-release oral bioavailability ~50-60% (fasted), decreased by food; extended-release bioavailability ~50%. |
| Onset of Action | Empagliflozin: glycemic effect onset 24 h (steady state); SGLT2 inhibition maximal by 2 h post-dose. Metformin: immediate-release, onset 2-3 h; extended-release, onset ~7 h. |
| Duration of Action | Empagliflozin: duration ~24 h (once-daily dosing). Metformin: immediate-release, duration 8-12 h; extended-release, duration ~24 h. |
| Molecular Weight | Empagliflozin: 450.91 Da; Metformin hydrochloride: 165.62 Da |
Oral: one tablet twice daily. Starting dose: empagliflozin 5 mg/metformin hydrochloride 500 mg or empagliflozin 5 mg/metformin hydrochloride 1000 mg. Titrate based on glycemic response; maximum dose: empagliflozin 25 mg/metformin hydrochloride 2000 mg per day.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR ≥60 mL/min/1.73 m²: no adjustment. eGFR 45-59 mL/min/1.73 m²: limit to empagliflozin 5 mg/metformin hydrochloride 1000 mg twice daily. eGFR 30-44 mL/min/1.73 m²: do not initiate; if already on, reduce to empagliflozin 5 mg/metformin hydrochloride 500 mg twice daily. eGFR <30 mL/min/1.73 m²: contraindicated. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: avoid metformin due to increased risk of lactic acidosis. Child-Pugh Class C: contraindicated. |
| Pediatric use | Not approved for pediatric patients under 18 years of age. |
| Geriatric use | No specific dose adjustment recommended based on age alone. Assess renal function before initiation and periodically; eGFR should be ≥45 mL/min/1.73 m². Use cautiously due to potential for volume depletion and renal impairment. |
| 1st trimester | Avoid use due to potential risk of metformin-associated fetal malformations and empagliflozin's unknown effects; alternative therapies preferred. |
| 2nd trimester | Avoid; empagliflozin lacks safety data and may affect fetal renal development; metformin associated with fetal growth restriction. |
| 3rd trimester | Avoid; empagliflozin can cause neonatal hypoglycemia and renal impairment; metformin increases risk of neonatal hypoglycemia and may cause lactic acidosis. |
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 |
| Placental transfer | Metformin crosses the placenta readily (F/M ratio ~0.5-1.0); empagliflozin is likely transferred based on animal studies, but human data are lacking. |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis is a rare but serious complication. Risk factors include renal impairment, use of iodinated contrast media, surgery, hypoxic states, excessive alcohol intake, and hepatic impairment. Discontinue metformin if lactic acidosis is suspected.
| Common Effects | Diarrhea |
| Serious Effects |
Severe renal impairment (eGFR <45 mL/min/1.73 m²)Acute or chronic metabolic acidosis, including diabetic ketoacidosisHypersensitivity to empagliflozin or metforminAcute kidney injury or severe infection (empagliflozin-related)Intravascular volume depletion (empagliflozin)History of lactic acidosis (metformin)
| Precautions | Lactic acidosis (metformin-associated), Pancreatitis (empagliflozin), Ketoacidosis (empagliflozin, including euglycemic DKA), Acute kidney injury (empagliflozin), Hypoglycemia when used with insulin or sulfonylureas, Urinary tract infections and urosepsis (empagliflozin), Necrotizing fasciitis of the perineum (Fournier gangrene, empagliflozin), Vitamin B12 deficiency (metformin, long-term use), Hypersensitivity reactions |
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| Breastfeeding |
| Metformin is excreted in breast milk in low amounts; empagliflozin is excreted in animal milk, human data absent. Use during breastfeeding only if clearly needed, monitor infant for hypoglycemia and diarrhea. |
| Lactation Rating | L3 - Limited Data / Probably Compatible (metformin); No data for empagliflozin, rating N/A |
| Teratogenic Risk | First trimester: Metformin is not associated with major malformations; empagliflozin has limited human data, but animal studies show renal toxicity at high doses. Second and third trimesters: Metformin may increase risk of preterm birth and neonatal hypoglycemia; empagliflozin may cause fetal renal impairment and oligohydramnios. Avoid in second and third trimesters. |
| Fetal Monitoring | Monitor maternal renal function, blood glucose, HbA1c, and fetal growth via ultrasound. Assess for oligohydramnios if empagliflozin used. |
| Fertility Effects | Metformin may improve ovulation in women with PCOS; empagliflozin effects unknown. No adverse effect on male fertility reported. |
| Food/Dietary | Alcohol consumption increases risk of lactic acidosis; avoid or limit intake. No specific food restrictions, but consistent carbohydrate intake is advised to maintain glycemic control. |
| Clinical Pearls | Monitor renal function before initiating and periodically; contraindicated if eGFR <30 mL/min/1.73 m² (empagliflozin) or <30 mL/min (metformin). Hold metformin for 48 hours after iodinated contrast; assess risk of lactic acidosis. Empagliflozin may cause euglycemic DKA; check ketones even if glucose normal. Avoid in severe hepatic impairment. Titrate metformin gradually to minimize GI side effects. |
| Patient Advice | Take with meals to reduce stomach upset. · Drink plenty of water to prevent dehydration and urinary tract infections. · Monitor blood sugar regularly. · Report symptoms of lactic acidosis (unusual fatigue, muscle pain, trouble breathing, stomach discomfort with nausea or vomiting) or diabetic ketoacidosis (nausea, vomiting, abdominal pain, fatigue, shortness of breath) even if blood sugar is normal. · Avoid alcohol while taking metformin to reduce risk of lactic acidosis. · Inform healthcare provider before any surgery or imaging procedures requiring contrast dye (may need to temporarily stop metformin). · Do not break, crush, or chew extended-release tablets. |