DAPAGLIFLOZIN 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.
Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor, which reduces renal glucose reabsorption, increasing urinary glucose excretion. Metformin is a biguanide that primarily decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity.
| Metabolism | Dapagliflozin is primarily metabolized via UGT1A9 (glucuronidation). Metformin is not metabolized and is excreted unchanged in urine. |
| Excretion | Metformin is excreted unchanged in urine (90%) via tubular secretion and glomerular filtration; dapagliflozin is eliminated primarily via renal excretion (75% as parent and glucuronide metabolites) and fecal excretion (21% as parent and metabolites). Renal clearance accounts for ~70% of total clearance for dapagliflozin. |
| Half-life | Metformin: terminal elimination half-life ~6.2 hours (range 4–9 hours) in patients with normal renal function; accumulates in renal impairment. Dapagliflozin: terminal elimination half-life ~12.9 hours after single dose, ~10.3 hours at steady state; supports once-daily dosing. |
| Protein binding | Metformin: negligible plasma protein binding (<5%). Dapagliflozin: ~91% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Metformin: apparent volume of distribution 654 ± 358 L (single dose) indicating extensive tissue distribution; Vd/F ~6.5 L/kg (calculated from mean Vd and weight). Dapagliflozin: steady-state volume of distribution ~118 L (1.5 L/kg for 70 kg), suggesting distribution into tissues. |
| Bioavailability | Metformin: absolute bioavailability ~50–60% for immediate-release; high-fat meal decreases Cmax by ~30% and delays absorption; extended-release has ~70% relative to immediate-release. Dapagliflozin: absolute bioavailability ~78% after oral administration; food does not significantly affect AUC or Cmax. |
| Onset of Action | Metformin: onset of antihyperglycemic effect occurs within 2–3 days after oral administration; maximal effect may take 1–2 weeks. Dapagliflozin: onset of urinary glucose excretion occurs within 1 hour; maximal SGLT2 inhibition and glycemic effect observed within 1–2 weeks. |
| Duration of Action | Metformin: duration of action ~8–12 hours; immediate-release formulation requires twice-daily dosing; extended-release provides up to 24-hour glucose lowering. Dapagliflozin: duration of action supports once-daily dosing due to half-life; SGLT2 inhibition persists for at least 24 hours. |
Oral: 5 mg dapagliflozin / 500 mg metformin hydrochloride twice daily; maximum daily dose: 10 mg dapagliflozin / 2000 mg metformin.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR 30-59 mL/min/1.73m²: Maximum dapagliflozin dose 10 mg daily; metformin dose maximum 1000 mg daily. eGFR <30 mL/min/1.73m²: Contraindicated. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Not recommended (dapagliflozin exposure increased). Child-Pugh Class C: Contraindicated. |
| Pediatric use | Not approved for use in pediatric patients. |
| Geriatric use | Initiate at 5 mg dapagliflozin / 500 mg metformin twice daily; titrate gradually; monitor renal function (eGFR) frequently; avoid if eGFR <45 mL/min/1.73m² due to increased risk of metformin accumulation. |
| 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 | Dapagliflozin: Unknown if excreted in human milk; animal data show excretion in milk with potential for renal effects in nursing infants. Metformin: Excreted in human milk in low amounts (M/P ratio ~0.35). Peak milk concentration ~0.13 μg/mL. Use only if benefit outweighs risk; monitor infant for hypoglycemia and gastrointestinal effects. |
| Teratogenic Risk |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis (MALA) is a rare but serious adverse effect. Risk factors include renal impairment, hepatic disease, acute heart failure, excessive alcohol intake, and use of contrast agents.
| Common Effects | Diarrhea |
| Serious Effects |
["Severe renal impairment (eGFR <30 mL/min/1.73 m²) for metformin","Acute or chronic metabolic acidosis (including diabetic ketoacidosis)","Hypersensitivity to dapagliflozin, metformin, or any component of the formulation","History of severe allergic reactions to dapagliflozin or metformin"]
| Precautions | ["Lactic acidosis (metformin)","Ketoacidosis (dapagliflozin, including euglycemic ketoacidosis)","Acute kidney injury and impairment in renal function","Hypotension and volume depletion","Urosepsis and pyelonephritis","Necrotizing fasciitis of the perineum (Fournier's gangrene)","Hypoglycemia when used with insulin or sulfonylureas","Vitamin B12 deficiency (metformin)","Increased risk of lower limb amputation (dapagliflozin)"] |
Loading safety data…
| First trimester: Limited human data; animal studies with dapagliflozin show renal pelvic dilation at exposures ≥15 times human dose. Metformin is associated with reduced risk of miscarriage and gestational diabetes but no major malformations. Second and third trimesters: Dapagliflozin is not recommended due to risk of fetal renal tubular maturation impairment; metformin crosses placenta but no consistent association with adverse outcomes. SGLT2 inhibitors are generally avoided in second and third trimesters due to potential neonatal hypoglycemia and renal effects. |
| Fetal Monitoring | Monitor renal function (serum creatinine, eGFR) and electrolytes in mother. Monitor blood glucose and HbA1c. Fetal assessment includes ultrasound for growth and anatomy, as well as monitoring for polyhydramnios or oligohydramnios. Neonatal monitoring for hypoglycemia, renal function, and volume status. |
| Fertility Effects | Dapagliflozin: No significant effects on fertility in animal studies; human data insufficient. Metformin: May restore ovulatory function in women with polycystic ovary syndrome (PCOS) by improving insulin sensitivity. No direct adverse effects on male fertility; may improve sperm quality in metabolic syndrome. |
| Food/Dietary | Metformin absorption can be reduced by high-fat meals; take with food to minimize GI upset. Alcohol consumption increases risk of metformin-associated lactic acidosis; avoid or limit alcohol intake. Dapagliflozin may cause volume depletion; avoid excessive salt intake that worsens fluid retention. No specific food interactions with dapagliflozin. |
| Clinical Pearls | Combine dapagliflozin and metformin for additive glycemic control in type 2 diabetes. Monitor renal function before initiation and periodically; contraindicated if eGFR <45 mL/min/1.73m². Dapagliflozin increases risk of euglycemic diabetic ketoacidosis; educate patients on symptoms. Metformin may cause lactic acidosis; hold for acute illness or IV contrast. Avoid use with loop diuretics due to volume depletion risk. Monitor for genital mycotic infections and necrotizing fasciitis of perineum. |
| Patient Advice | Take with meals to reduce gastrointestinal side effects from metformin. · Drink plenty of fluids to prevent dehydration and maintain kidney function. · Report symptoms of nausea, vomiting, abdominal pain, or fatigue (signs of lactic acidosis) immediately. · Seek emergency care for rapid weight loss, abdominal pain, nausea/vomiting, or difficulty breathing (possible diabetic ketoacidosis). · Monitor for genital itching, redness, or discharge; inform healthcare provider if occurs. · Avoid alcohol while taking metformin due to increased risk of lactic acidosis. · Do not skip meals or fast for prolonged periods while on this combination. |