DAPAGLIFLOZIN AND METFORMIN
Clinical safety rating: safe
Alcohol and contrast dye can increase risk of lactic acidosis Can cause lactic acidosis a rare but serious metabolic complication.
Dapagliflozin 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 glucose absorption, and improves insulin sensitivity.
| Metabolism | Dapagliflozin: primarily metabolized by uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) to an inactive metabolite. Metformin: not metabolized; excreted unchanged in urine. |
| Excretion | Metformin: 90% renal unchanged; ~10% fecal. Dapagliflozin: 75% renal (mostly unchanged glucuronide), 21% fecal. |
| Half-life | Metformin: ~6.2 h (plasma), prolonged in renal impairment. Dapagliflozin: ~12.9 h (terminal), supports once-daily dosing. |
| Protein binding | Metformin: <5% bound to plasma proteins. Dapagliflozin: ~91% bound primarily to albumin. |
| Volume of Distribution | Metformin: 3.1 L/kg (extensive tissue distribution). Dapagliflozin: 1.3 L/kg (moderate distribution). |
| Bioavailability | Metformin: 40-60% (oral). Dapagliflozin: ~78% (oral). |
| Onset of Action | Metformin: 1-2 h (serum glucose reduction), peak effect 4-8 h. Dapagliflozin: Onset of urinary glucose excretion within 1 h post-dose. |
| Duration of Action | Metformin: 8-12 h (glucose lowering). Dapagliflozin: 24 h (sustained UGE), once-daily dosing. |
| Molecular Weight | Metformin: 129.16 Da; Dapagliflozin: 408.87 Da |
Initial: dapagliflozin 5 mg/metformin 500 mg orally twice daily, or dapagliflozin 5 mg/metformin 1000 mg orally twice daily. Titrate based on efficacy and tolerability. Maximum: dapagliflozin 10 mg/metformin 2000 mg per day.
| Dosage form | TABLET |
| Renal impairment | eGFR ≥60 mL/min/1.73m2: no adjustment. eGFR 45-59: maximum dapagliflozin 10 mg/metformin 1000 mg per day; limit metformin dose. eGFR 30-44: initiate dapagliflozin 5 mg once daily; maximum dapagliflozin 10 mg once daily; metformin contraindicated. eGFR <30: contraindicated. |
| Liver impairment | Child-Pugh Class A: no adjustment. Class B: not recommended due to lack of data. Class C: contraindicated (metformin associated with lactic acidosis risk). |
| Pediatric use | Not approved for pediatric patients; safety and efficacy not established in patients <18 years. |
| Geriatric use | Age ≥65 years: initiate dapagliflozin 5 mg once daily; monitor renal function and volume status. Age ≥85 years: not recommended due to reduced renal reserve. |
| 1st trimester | Avoid due to risks of hypoglycemia, teratogenicity, and potential for fetal harm. Metformin is associated with increased risk of congenital malformations, and dapagliflozin has unknown effects in early pregnancy. |
| 2nd trimester | Contraindicated in the second and third trimesters due to dapagliflozin-associated risk of neonatal hypoglycemia, metabolic acidosis, and potential for renal injury in the fetus. Metformin may cause fetal hypoglycemia and long-term metabolic programming effects. |
| 3rd trimester | Contraindicated. Dapagliflozin may cause fetal hypoglycemia, volume depletion, and renal impairment. Metformin increases risk of neonatal hypoglycemia and may affect fetal growth. Both drugs should be discontinued prior to pregnancy or upon detection. |
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 |
■ FDA Black Box Warning
Lactic acidosis associated with metformin accumulation; risk factors include renal impairment, concomitant use of certain drugs, age >65 years, radiologic studies with contrast, surgery, alcohol intake, hepatic impairment, and hypoxic states.
| Common Effects | Diarrhea |
| Serious Effects |
Severe renal impairment (eGFR <30 mL/min/1.73 m²)Metabolic acidosis, including diabetic ketoacidosisHistory of diabetic ketoacidosis or lactic acidosisHypersensitivity to dapagliflozin or metforminType 1 diabetes mellitus
| Precautions | Lactic acidosis risk, acute kidney injury, hypotension, ketoacidosis in type 2 diabetes, lower limb amputation, genital mycotic infections, urinary tract infections, increased LDL-C, pancreatitis, vitamin B12 deficiency (metformin), and hypersensitivity reactions. |
| Food/Dietary |
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| Both drugs cross the placenta. Metformin is actively transported, reaching fetal concentrations similar to maternal. Dapagliflozin crosses placenta in animal studies; human data limited but likely significant. |
| Breastfeeding | Metformin is excreted into breast milk in low amounts, but dapagliflozin is not recommended during breastfeeding due to potential adverse effects on neonatal renal function and hypoglycemia. Limited data on dapagliflozin; avoid use in breastfeeding women unless no alternative. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | First trimester: Limited human data; animal studies show renal toxicity. Second and third trimesters: Dapagliflozin may cause fetal renal dysfunction and oligohydramnios; metformin is associated with reduced risk of congenital anomalies vs insulin but may increase risk of preeclampsia. Overall, dapagliflozin is contraindicated in pregnancy due to SGLT2 inhibitor class effects. |
| Fetal Monitoring | Monitor maternal blood glucose, HbA1c, renal function (serum creatinine, eGFR), and hydration status. Fetal monitoring includes ultrasound for amniotic fluid volume and fetal growth in third trimester; assess for signs of oligohydramnios or fetal renal abnormalities. |
| Fertility Effects | Metformin may improve ovulation in women with polycystic ovary syndrome. Dapagliflozin: No significant effects on fertility in animal studies; human data limited. Combination: Possible favorable effect on metabolic parameters that may improve fertility in insulin-resistant states. |
| Take with food to reduce GI side effects. Avoid alcohol due to increased risk of lactic acidosis and hypoglycemia. No specific food restrictions, but maintain consistent carbohydrate intake. Grapefruit may interact via CYP3A4 (minor, not typically restricted). |
| Clinical Pearls | Monitor renal function before initiation and periodically; contraindicated if eGFR <30 mL/min/1.73 m². Assess volume status due to diuretic effect of dapagliflozin. Risk of lactic acidosis with metformin if renal impairment or acute illness. May increase LDL-C; check lipid panel. Caution in elderly due to hypotension risk. Avoid in type 1 diabetes. |
| Patient Advice | Take with meals to reduce stomach upset. · Drink plenty of water to prevent dehydration and urinary tract infections. · Monitor for signs of genital mycotic infections (itching, discharge). · Check blood sugar regularly; report persistent high or low readings. · Seek immediate medical attention if symptoms of lactic acidosis (unusual tiredness, muscle pain, stomach pain, difficulty breathing). · Do not stop taking without consulting doctor. · Report any swelling of legs or sudden weight gain. · Avoid alcohol while taking metformin. |