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. |
| Molecular Weight | Empagliflozin: 450.91 Da; Metformin hydrochloride: 165.62 Da; (Tablet combination: reported as 450.9 + 165.6) |
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 | Both empagliflozin and metformin cross the placenta. Metformin is commonly used in gestational diabetes; empagliflozin is contraindicated due to potential renal toxicity in the developing fetus. Use only if benefit outweighs risk. |
| 2nd trimester | Metformin use may be considered for diabetes; empagliflozin is not recommended due to lack of safety data and risk of acute kidney injury in neonates. |
| 3rd trimester | Empagliflozin should be avoided, especially in the third trimester, due to risk of neonatal hypoglycemia and renal impairment. Metformin use may be continued if clinically indicated. |
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 | Both drugs cross the placenta. Metformin shows substantial transfer; empagliflozin transfer is documented in animals and likely in humans. |
■ 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) due to metformin accumulation riskAcute metabolic acidosis (including diabetic ketoacidosis)Hypersensitivity to empagliflozin, metformin, or any componentSevere hepatic impairmentBreastfeeding (relative, see notes)
| 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) |
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| Breastfeeding | Metformin is excreted into breast milk in low amounts; it is generally considered compatible with breastfeeding. Empagliflozin is excreted in animal milk; human data are lacking. Caution is advised, especially when breastfeeding a neonate or preterm infant. |
| Lactation Rating | L3 (Limited Data) - Metformin is L2 (Safer), but combination with empagliflozin increases uncertainty. |
| Teratogenic Risk | 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. |
| Food/Dietary | Avoid excessive alcohol consumption (increases risk of lactic acidosis and hypoglycemia). Limit high-fat meals (may slow metformin absorption). No other specific food restrictions, but consistent carbohydrate intake recommended. |
| Clinical Pearls | Monitor renal function before initiation and periodically; eGFR <45 mL/min/1.73 m² contraindicated. Discontinue at time of or before iodinated contrast procedures if eGFR <60. Assess for lactic acidosis (rare but serious) and pancreatectomy/pancreatitis history. Avoid in type 1 diabetes. Risk of ketoacidosis, even with normal glucose. Consider dose adjustment of metformin when co-administered with drugs that reduce renal excretion (e.g., cimetidine). |
| Patient Advice | Take with meals to reduce gastrointestinal side effects. · Monitor blood glucose regularly; never stop without consulting doctor. · Report symptoms of lactic acidosis (unexplained muscle pain, dyspnea, somnolence, severe abdominal pain) or pancreatitis (persistent vomiting, abdominal pain). · Drink plenty of water to prevent dehydration, especially during hot weather or illness. · Stop medication and seek immediate medical attention if you become severely dehydrated or have a serious infection. · Tell all healthcare providers you are taking this combination, especially before surgery or contrast studies. |