Drug Monograph
Dapagliflozin (Farxiga)
dapagliflozin
Pharmacokinetic Profile
Half-Life
12.9 h
Metabolism
Glucuronidation (UGT1A9, primary); minor CYP contribution
Protein Binding
91%
Bioavailability
78%
Volume of Distribution
118 L (steady-state)
Clinical Information
Drug Class
SGLT2 Inhibitor
Available Doses
5 mg, 10 mg tablets
Route
Oral, once daily
Renal Adjustment
Glycaemic: not recommended if eGFR <45; CKD/HF: do not initiate if eGFR <25
Hepatic Adjustment
Not required (mild/moderate); assess risk-benefit in severe
Pregnancy
Not recommended (2nd/3rd trimester — fetal renal risk)
Lactation
Not recommended (risk to developing kidney)
Schedule / Legal Status
Prescription only (not scheduled)
Generic Available
No (patent-protected)
Landmark CKD Outcome
DAPA-CKD: 39% reduction in kidney progression/CV death (HR 0.61)
Indications for Dapagliflozin
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Chronic kidney disease — reduce risk of sustained eGFR decline, ESKD, CV death, and HF hospitalization | Adults with CKD at risk of progression | Add-on to standard of care | FDA Approved |
| Heart failure — reduce risk of CV death, HF hospitalization, and urgent HF visit | Adults (HFrEF and HFpEF) | Add-on to standard HF therapy | FDA Approved |
| HF hospitalization reduction in T2DM with established CVD or multiple CV risk factors | Adults | Add-on to standard of care | FDA Approved |
| Type 2 diabetes mellitus — glycaemic control (adjunct to diet and exercise) | Adults and paediatric ≥10 years | Monotherapy or combination | FDA Approved |
Dapagliflozin was the first SGLT2 inhibitor to demonstrate significant kidney protection in a dedicated nephrology trial (DAPA-CKD, 2020), reducing kidney disease progression and cardiovascular death by 39% regardless of diabetes status. The ADA 2024 Standards of Care and the 2022 AHA/ACC/HFSA Heart Failure Guideline recommend SGLT2 inhibitors with proven benefit, including dapagliflozin, as foundational therapy for patients with HFrEF and as preferred agents for T2DM with CKD, ASCVD, or heart failure.
Limitations of Use (FDA PI)
Not recommended for glycaemic control in T1DM (increased DKA risk) or in T2DM with eGFR <45 mL/min/1.73 m² (likely ineffective). Not recommended for CKD in polycystic kidney disease or patients on immunosuppressive therapy for kidney disease.
Dosing of Dapagliflozin
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CKD at risk of progression — regardless of diabetes status | 10 mg once daily | 10 mg once daily | 10 mg/day | DAPA-CKD basis; eGFR ≥25 to initiate May continue if eGFR falls below 25 during treatment |
| Heart failure (HFrEF or HFpEF) — regardless of diabetes status | 10 mg once daily | 10 mg once daily | 10 mg/day | DAPA-HF + DELIVER basis; eGFR ≥25 to initiate Fixed dose; no 5 mg option for HF indication |
| T2DM with CVD or multiple CV risk factors — HF hospitalization reduction | 10 mg once daily | 10 mg once daily | 10 mg/day | DECLARE-TIMI 58 basis HF hosp: HR 0.73 (27% RRR) |
| T2DM — glycaemic control (monotherapy or combination) | 5 mg once daily | 5–10 mg once daily | 10 mg/day | May increase to 10 mg for additional glycaemic control eGFR ≥45 required; not effective for glucose lowering if eGFR <45 |
| Paediatric patients ≥10 years — T2DM glycaemic control | 5 mg once daily | 5–10 mg once daily | 10 mg/day | Same dosing as adults; safety profile similar to adults eGFR ≥45 required for glycaemic control |
| Peri-surgical management | Withhold ≥3 days before major surgery | Resume when clinically stable and oral intake restored Urinary glucose excretion persists ~3 days after last dose; DKA risk | ||
Clinical Pearl: Two Dosing Tiers
Unlike empagliflozin (which uses 10 mg universally), dapagliflozin has a two-tier dosing structure. For glycaemic control in T2DM, the starting dose is 5 mg with optional titration to 10 mg. For all cardiorenal indications (CKD, HF, HF hospitalization reduction), the dose is fixed at 10 mg from the start. For non-glycaemic indications, do not initiate if eGFR <25 mL/min/1.73 m², but patients may continue treatment if eGFR falls below 25 while on therapy. Assess volume status and renal function before initiation. Correct volume depletion before starting.
Pharmacology of Dapagliflozin
Mechanism of Action
Dapagliflozin selectively inhibits SGLT2 in the proximal renal tubule, reducing glucose reabsorption and increasing urinary glucose excretion (approximately 60–80 g/day in hyperglycaemic patients). This insulin-independent mechanism lowers plasma glucose while producing caloric loss (weight reduction of approximately 2–3 kg) and mild osmotic diuresis. Dapagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal tubule, restoring tubuloglomerular feedback and reducing intraglomerular pressure. These haemodynamic and metabolic effects — including reduced preload and afterload, enhanced ketone body utilisation by the myocardium, and attenuation of renal hyperfiltration — underpin the cardiorenal protective benefits observed independently of diabetes status.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~2 h (fasted); oral bioavailability 78%; high-fat meal reduces Cmax up to 50% and delays Tmax ~1 h but does not alter AUC | Rapid absorption; can be given with or without food; dose-proportional over 0.1–500 mg |
| Distribution | Vd 118 L (steady-state); protein binding ~91%; extensive extravascular distribution | Wide tissue distribution supports cardiorenal effects beyond the kidney; protein binding not altered by renal or hepatic impairment |
| Metabolism | Primarily UGT1A9 glucuronidation (liver and kidney); major metabolite: dapagliflozin 3-O-glucuronide (inactive, not an SGLT2 inhibitor); minor CYP pathways; no active metabolites | Low drug interaction potential; rifampicin decreases AUC by 22% (not clinically significant); no CYP inhibition or induction |
| Elimination | t½ 12.9 h; urine 75% (<2% unchanged), faeces 21% (~15% unchanged) | Supports once-daily dosing; predominantly eliminated as inactive metabolite via renal excretion; removal by haemodialysis not known |
Side Effects of Dapagliflozin
≥10%
Very Common (with insulin co-therapy)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypoglycaemia (glucose <54 mg/dL, with insulin ± OADs) | 25.9% (5 mg) / 23.0% (10 mg) vs 21.8% placebo | Modest excess driven by insulin co-therapy; proactively reduce insulin dose when adding dapagliflozin |
1–10%
Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Female genital mycotic infections | 8.4% (5 mg) / 6.9% (10 mg) vs 1.5% placebo | Most common: vulvovaginal mycotic infection; patients with prior history at highest risk (23–25% vs 5–6% without history); rarely requires discontinuation (0.2%) |
| Nasopharyngitis | 6.6% (5 mg) / 6.3% (10 mg) vs 6.2% placebo | Marginal excess; not clearly drug-related |
| Urinary tract infections | 5.7% (5 mg) / 4.3% (10 mg) vs 3.7% placebo | Includes UTI, cystitis, pyelonephritis; more frequent in females |
| Back pain | 4.2% (10 mg) / 3.1% (5 mg) vs 3.2% placebo | No consistent dose-response; not clearly drug-related |
| Increased urination (pollakiuria, polyuria) | 3.8% (10 mg) / 2.9% (5 mg) vs 1.7% placebo | Mechanism-related osmotic diuresis; generally mild and transient |
| Male genital mycotic infections | 2.8% (5 mg) / 2.7% (10 mg) vs 0.3% placebo | Balanitis, balanoposthitis; treat with topical antifungals |
| Dyslipidaemia | 2.5% (10 mg) / 2.1% (5 mg) vs 1.5% placebo | LDL-C increase: +2.9% (10 mg) vs −1.0% placebo at week 24 |
| Discomfort with urination | 2.1% (10 mg) / 1.6% (5 mg) vs 0.7% placebo | Related to glycosuria; typically mild |
Serious
Serious (regardless of frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Diabetic ketoacidosis | 0.3% (27/8574) vs 0.1% (12/8569) placebo in DECLARE | Any time; risk highest with insulin reduction, illness, fasting, surgery | Assess for DKA regardless of glucose level; discontinue; glucosuria may persist ≥3 days after stopping |
| Volume depletion / hypotension / AKI | 0.8% (10 mg) vs 0.4% placebo (12-trial pool); higher with loop diuretics (up to 9.7%) | Early after initiation; especially in elderly or on diuretics | Correct volume depletion before starting; monitor renal function; temporarily discontinue during acute illness or fluid loss |
| Fournier’s gangrene (necrotising fasciitis of perineum) | Very rare (SGLT2 class, postmarketing) | Variable | Immediately evaluate genital/perineal pain, erythema, swelling with fever; discontinue; urgent surgical intervention |
| Urosepsis / pyelonephritis | Rare (postmarketing) | Any time during therapy | Evaluate for serious UTI; treat with antibiotics; consider discontinuation |
| Hypersensitivity (anaphylaxis, angioedema) | 0.3% (dapagliflozin) vs 0.2% (comparators) | Variable | Discontinue; treat per standard of care; contraindicated if prior serious reaction |
Discontinuation
Discontinuation Rates
Genital mycotic infection-related discontinuation (glycaemic trials)
0.2% vs 0% placebo
Context: Despite higher infection rates, discontinuation was rare due to the mild and treatable nature of most events
Genital mycotic infection-related discontinuation (DECLARE)
0.9% vs <0.1% placebo
Context: Longer trial duration (median 4.2 years) likely explains higher discontinuation rate than short-term glycaemic trials
Managing Genital Mycotic Infections
Genital mycotic infections are the most clinically relevant adverse effect of dapagliflozin, affecting up to 8.4% of females. Patients with a history of prior infections are at substantially higher risk (23–25% recurrence). Educate patients on genital hygiene, recognise symptoms early, and treat promptly with topical antifungals. The infections are usually mild and rarely require dapagliflozin discontinuation. Counsel patients that this side effect should not deter use of a drug with proven cardiorenal benefits.
Drug Interactions with Dapagliflozin
Dapagliflozin is primarily metabolised by UGT1A9 with minor CYP contributions. It does not inhibit or induce CYP isoenzymes at therapeutic concentrations and has very low drug interaction potential. No clinically meaningful pharmacokinetic interactions have been observed in dedicated interaction studies with commonly co-prescribed medications.
ModerateInsulin / Sulphonylureas
MechanismPharmacodynamic: combined glucose-lowering effects
EffectIncreased hypoglycaemia risk (glucose <54: up to 25.9% with insulin vs 21.8% placebo; 6.4% with met+SU vs 2.8%)
ManagementConsider reducing insulin or SU dose when initiating dapagliflozin
FDA PIModerateDiuretics (loop, thiazide)
MechanismAdditive volume depletion (osmotic diuresis + diuretic effect)
EffectIncreased risk of hypotension, dehydration, and AKI; loop diuretic users: volume depletion up to 9.7% (10 mg) in pooled trials
ManagementAssess and correct volume status before initiation; monitor BP, renal function, and hydration
FDA PIModerateLithium
MechanismSGLT2 inhibitor-induced osmotic diuresis may decrease serum lithium concentrations
EffectPotential loss of lithium efficacy (SGLT2 class effect)
ManagementMonitor serum lithium more frequently during dapagliflozin initiation and dose changes
LexicompMinorRifampicin (UGT1A9 inducer)
MechanismUGT induction increases dapagliflozin metabolism
Effect22% decrease in dapagliflozin AUC; no meaningful change in urinary glucose excretion
ManagementNo dose adjustment recommended; monitor glycaemic control
FDA PIMinorMetformin, Pioglitazone, Sitagliptin, Glimepiride, Voglibose, HCTZ, Bumetanide, Valsartan, Simvastatin
MechanismNo CYP or UGT inhibition/induction at therapeutic doses
EffectNo clinically relevant changes in PK of either drug
ManagementNo dose adjustments needed
FDA PI
Laboratory Interference
Dapagliflozin causes glycosuria and will produce positive urine glucose tests. Do not use urine glucose for glycaemic monitoring. The 1,5-anhydroglucitol (1,5-AG) assay is unreliable during SGLT2 inhibitor therapy. Use HbA1c or blood glucose instead.
Monitoring for Dapagliflozin
- Renal Function (eGFR)Before initiation; periodically thereafter
RoutineInitial eGFR dip is expected and reflects haemodynamic changes. For glycaemic control: eGFR ≥45 required. For CKD/HF: eGFR ≥25 to initiate; may continue if eGFR falls below 25 on therapy. - Volume Status / BPBefore initiation; at each visit
RoutineCorrect volume depletion before starting. Elderly patients, those on loop diuretics, or with eGFR <60 are at increased risk. Volume depletion risk with loop diuretics reached 9.7% (10 mg) in pooled trials. - HbA1c (T2DM patients)Every 3–6 months
RoutineGlycaemic efficacy is eGFR-dependent; not recommended for glycaemic control if eGFR <45. Do not use urine glucose or 1,5-AG for monitoring. - DKA Signs & SymptomsEach visit; patient education
RoutineConsider ketone monitoring in at-risk patients. DKA rate in DECLARE: 0.3% vs 0.1% placebo over median 4.2 years. Assess for DKA regardless of blood glucose level. - Genital / Urinary InfectionsEach visit; patient self-monitoring
Trigger-basedHigher risk in females (up to 8.4%). Patients with prior genital mycotic infections at highest risk (23–25%). Immediately assess for Fournier’s gangrene if genital/perineal pain with fever develops. - HaematocritPeriodically
Trigger-basedMean hematocrit increase +2.30% (10 mg) vs −0.33% placebo at week 24. Values >55% in 1.3% (10 mg) vs 0.4% placebo. Reflects haemoconcentration from volume depletion. - LDL CholesterolPeriodically
Trigger-basedLDL-C increase: +2.9% (10 mg) vs −1.0% placebo at week 24. Reassess statin therapy if needed.
Contraindications & Cautions for Dapagliflozin
Absolute Contraindications
- History of serious hypersensitivity reaction to dapagliflozin or any excipient — anaphylaxis and angioedema have been reported (FDA PI).
Relative Contraindications (Specialist Input Recommended)
- Type 1 diabetes mellitus — significantly increased DKA risk; not indicated for glycaemic control in T1DM.
- Active or recurrent genital mycotic infections — dapagliflozin increases risk; weigh benefit vs infection burden.
- Volume depletion or severe dehydration — correct before initiation; risk of symptomatic hypotension and AKI.
- eGFR <25 mL/min/1.73 m² (for non-glycaemic indications) — initiation not recommended; however, may continue if eGFR drops below 25 while on therapy.
Use with Caution
- Elderly patients — higher incidence of adverse reactions related to hypotension (FDA PI Section 8.5).
- Concomitant loop diuretics — additive diuretic effect; up to 9.7% volume depletion with 10 mg in the pooled trial subgroup.
- eGFR <45 mL/min/1.73 m² for glycaemic control — dapagliflozin is likely ineffective for glucose lowering; CKD and HF indications remain valid at lower eGFR.
- Pregnancy (2nd/3rd trimester) — animal data show renal pelvic and tubular dilatation at ≥15 times clinical dose; not recommended.
- Severe hepatic impairment — safety and efficacy not specifically studied; assess risk-benefit individually.
FDA Safety Communication (SGLT2 Class)
Diabetic Ketoacidosis and Fournier’s Gangrene
The FDA has issued class-wide warnings for SGLT2 inhibitors regarding: (1) diabetic ketoacidosis, which may present with atypically normal glucose levels — DKA rate in DECLARE was 0.3% (dapagliflozin) vs 0.1% (placebo); and (2) necrotising fasciitis of the perineum (Fournier’s gangrene), a rare but life-threatening infection requiring urgent surgical intervention, reported in both females and males.
Patient Counselling for Dapagliflozin
Purpose of Therapy
Dapagliflozin works by helping the kidneys remove excess sugar from the body through the urine. Beyond blood sugar control, it protects the heart and kidneys — reducing the risk of kidney disease progression, heart failure hospitalisations, and cardiovascular death. It is used in diabetes, heart failure, and chronic kidney disease.
How to Take
Take one tablet once daily, with or without food. If a dose is missed, take it as soon as remembered the same day. Do not double up on the next dose. Stay well hydrated. Before any planned surgery, stop dapagliflozin at least 3 days beforehand as instructed by your healthcare provider.
Diabetic Ketoacidosis (DKA)
Tell patientA rare but serious condition called DKA can occur, sometimes even when blood sugar is not very high. Risk increases during illness, fasting, reduced food intake, or if insulin dose is lowered.
Call prescriberStop dapagliflozin and seek emergency care if you develop nausea, vomiting, abdominal pain, excessive tiredness, or difficulty breathing.
Genital Yeast Infections
Tell patientBecause this medicine causes sugar to pass into the urine, yeast infections of the genital area are more common, particularly in women. Good hygiene and keeping the area dry can help prevent them. Most infections are mild and treatable with over-the-counter antifungal creams.
Call prescriberSeek urgent care if you develop pain, redness, or swelling in the genital or groin area accompanied by fever — this could indicate a rare but serious infection requiring emergency treatment.
Dehydration and Low Blood Pressure
Tell patientThis medicine has a mild diuretic effect. Drink adequate fluids, especially in hot weather or during illness. You may notice more frequent urination, which is expected and usually mild.
Call prescriberReport dizziness, lightheadedness, or fainting, especially when standing up. Temporarily stop dapagliflozin during vomiting, diarrhoea, or inability to eat or drink normally.
Hypoglycaemia with Insulin or Sulphonylurea
Tell patientLow blood sugar is more likely if you take insulin or a sulphonylurea alongside dapagliflozin. Know the signs: shaking, sweating, fast heartbeat, dizziness, and confusion.
Call prescriberIf low blood sugar occurs frequently, your insulin or sulphonylurea dose may need to be reduced.
Urinary Tract Infections
Tell patientUTIs may be slightly more common. Drink adequate water, practise good hygiene, and report symptoms such as burning during urination, frequent urge to urinate, or cloudy urine.
Call prescriberSeek prompt care if you develop fever, back or side pain, or blood in the urine, as these may indicate a more serious kidney infection.
Sources
Regulatory (PI / SmPC)
- AstraZeneca Pharmaceuticals. FARXIGA (dapagliflozin) tablets, for oral use. Full Prescribing Information. Revised 06/2024. FDA LabelPrimary regulatory source for all dosing, adverse reaction incidences, PK parameters, and safety warnings in this monograph.
Key Clinical Trials
- Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–1446. doi:10.1056/NEJMoa2024816DAPA-CKD: dapagliflozin reduced sustained eGFR decline ≥50%, ESKD, or renal/CV death by 39% (HR 0.61) in CKD patients with albuminuria, regardless of diabetes status.
- McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. doi:10.1056/NEJMoa1911303DAPA-HF: dapagliflozin reduced CV death/HF hospitalization/urgent HF visit by 26% (HR 0.74) in HFrEF patients regardless of diabetes status (N=4,744; median follow-up 18.2 months).
- Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089–1098. doi:10.1056/NEJMoa2206286DELIVER: dapagliflozin reduced CV death/HF worsening by 22% (HR 0.78) in HFmrEF/HFpEF patients (N=6,263), extending SGLT2 inhibitor HF benefit across the full EF spectrum.
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–357. doi:10.1056/NEJMoa1812389DECLARE-TIMI 58: in T2DM with ASCVD/risk factors (N=17,160; median 4.2 years), dapagliflozin reduced HF hospitalization by 27% (HR 0.73) and met non-inferiority for MACE.
- Jhund PS, Kondo T, Butt JH, et al. Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER. Nat Med. 2022;28(9):1956–1964. doi:10.1038/s41591-022-01971-4Pooled analysis of DAPA-HF and DELIVER demonstrating consistent dapagliflozin benefit across the entire ejection fraction spectrum in heart failure.
Guidelines
- American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1–S321. doi:10.2337/dc24-SINTCurrent ADA guidelines recommending SGLT2 inhibitors with proven benefit as preferred agents for T2DM with CKD, ASCVD, or HF.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure. Circulation. 2022;145(18):e895–e1032. doi:10.1161/CIR.0000000000001063Guideline recommending SGLT2 inhibitors as foundational therapy for HFrEF (Class 1) and for HFpEF (Class 2a).
- KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117–S314. doi:10.1016/j.kint.2023.10.018KDIGO guideline recommending SGLT2 inhibitors for adults with CKD and eGFR ≥20, with or without T2DM, to slow progression.
Mechanistic / Basic Science
- Meng W, Ellsworth BA, Nirschl AA, et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008;51(5):1145–1149. doi:10.1021/jm701272qDiscovery paper describing the structure-activity relationship leading to dapagliflozin and its high SGLT2 selectivity.
Pharmacokinetics / Special Populations
- Kasichayanula S, Liu X, Lacreta F, Griffen SC, Boulton DW. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014;53(1):17–27. doi:10.1007/s40262-013-0104-3Comprehensive PK/PD review covering absorption, UGT1A9 metabolism, drug interactions, and special populations for dapagliflozin.
- Kasichayanula S, Chang M, Hasegawa M, et al. Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus. Diabetes Obes Metab. 2011;13(4):357–365. doi:10.1111/j.1463-1326.2011.01359.xPK study demonstrating no clinically relevant ethnic differences in dapagliflozin exposure or pharmacodynamics.
- Kaku K, Watada H, Iwamoto Y, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients. Diabetes Ther. 2014;5(2):415–433. doi:10.1007/s13300-014-0086-7Phase III monotherapy trial providing additional safety and efficacy data across multiple dapagliflozin doses.