Empagliflozin (Jardiance)
empagliflozin
Indications for Empagliflozin
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Heart failure — reduce risk of CV death and HF hospitalization | Adults (HFrEF and HFpEF) | Add-on to standard HF therapy | FDA Approved |
| Chronic kidney disease — reduce risk of sustained eGFR decline, ESKD, CV death, and hospitalization | Adults with CKD at risk of progression | Add-on to standard of care | FDA Approved |
| CV death reduction in T2DM with established CVD | 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 |
Empagliflozin is the first glucose-lowering agent to demonstrate a significant reduction in cardiovascular death in the landmark EMPA-REG OUTCOME trial (2015). The ADA 2024 Standards of Care recommend SGLT2 inhibitors with proven benefit (including empagliflozin) as preferred agents for patients with T2DM who have established ASCVD, heart failure, or CKD, irrespective of baseline HbA1c or metformin use. Empagliflozin's HF and CKD indications extend beyond diabetes, covering patients with and without T2DM.
Not recommended for glycaemic control in T1DM (increased DKA risk) or in T2DM with eGFR <30 mL/min/1.73 m² (likely ineffective for glucose lowering). Not recommended for CKD in polycystic kidney disease or patients on high-dose immunosuppression for kidney disease.
Dosing of Empagliflozin
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Heart failure (HFrEF or HFpEF) — regardless of diabetes status | 10 mg once daily | 10 mg once daily | 10 mg/day | EMPEROR-Reduced + EMPEROR-Preserved basis No up-titration to 25 mg for HF indication |
| Chronic kidney disease at risk of progression | 10 mg once daily | 10 mg once daily | 10 mg/day | EMPA-KIDNEY basis; effective even at low eGFR No up-titration to 25 mg for CKD indication |
| T2DM with established ASCVD — CV death reduction | 10 mg once daily | 10 mg once daily | 25 mg/day | EMPA-REG OUTCOME basis; may increase to 25 mg for additional glycaemic benefit CV death reduction: HR 0.62 (38% RRR) |
| T2DM — glycaemic control (monotherapy or combination) | 10 mg once daily | 10–25 mg once daily | 25 mg/day | May increase to 25 mg in patients tolerating 10 mg Take in the morning with or without food |
| Paediatric patients ≥10 years — T2DM glycaemic control | 10 mg once daily | 10–25 mg once daily | 25 mg/day | Same PK as adults; higher hypo risk than adults Hypo (<54 mg/dL): 19.2% vs 7.5% placebo in DINAMO |
| Peri-surgical management | Withhold ≥3 days before surgery | Resume when clinically stable and oral intake restored Urinary glucose excretion persists ~3 days after last dose; DKA risk | ||
Empagliflozin 10 mg is the universal starting (and maintenance) dose across all four indications. The 25 mg dose is reserved only for additional glycaemic control in T2DM patients who tolerate 10 mg. For HF, CKD, and CV death reduction, the dose remains fixed at 10 mg. No dose adjustment is needed for renal or hepatic impairment at any severity level. Assess volume status and renal function before initiation. Correct volume depletion before starting, particularly in elderly patients and those on loop diuretics.
Pharmacology of Empagliflozin
Mechanism of Action
Empagliflozin selectively and reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the proximal renal tubule, blocking reabsorption of approximately 30–50% of filtered glucose and causing its excretion in the urine (glycosuria of ~60–90 g/day in hyperglycaemic patients). This insulin-independent mechanism lowers blood glucose while producing caloric loss (weight reduction ~2–3 kg) and mild osmotic diuresis (BP reduction ~3–5/1–2 mmHg). Beyond glycaemic effects, empagliflozin exerts cardiorenal protection through interconnected haemodynamic (reduced preload and afterload, improved ventricular loading conditions), metabolic (ketone body utilisation as myocardial fuel, reduced uric acid), and renal mechanisms (restoration of tubuloglomerular feedback, reduced intraglomerular pressure, attenuation of albuminuria). These pleiotropic effects underpin the benefits observed in HF and CKD patients regardless of diabetes status.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~1.5 h; dose-proportional in 10–25 mg range; food decreases Cmax ~37% and AUC ~16% (not clinically relevant) | Rapid onset; can be given with or without food; take in the morning to align diuresis with waking hours |
| Distribution | Vd 73.8 L (population PK); protein binding 86.2%; RBC partitioning 36.8% | Moderate tissue distribution; protein binding is higher than DPP-4 inhibitors but changes in disease states do not require dose adjustment |
| Metabolism | Glucuronidation by UGT2B7, UGT1A3, UGT1A8, UGT1A9; no active metabolites; glucuronide conjugates each <10% of total; no CYP inhibition/induction | No CYP-mediated drug interactions; UGT induction (e.g., rifampicin) effect not evaluated; very low drug interaction potential overall |
| Elimination | t½ 12.4 h; oral clearance 10.6 L/h; urine 54.4% (~half unchanged), faeces 41.2% (mostly unchanged); 95.6% total recovery | Dual elimination (renal + faecal); no dose adjustment for renal or hepatic impairment; steady-state reached within ~5 days with up to 22% accumulation |
Side Effects of Empagliflozin
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypoglycaemia (with basal insulin ± metformin) | 28.4% (25 mg; vs 20.6% placebo) | Driven by insulin co-therapy; proactively reduce insulin/SU dose when adding empagliflozin |
| Hypoglycaemia (with MDI insulin ± metformin) | 41.3% (25 mg; vs 37.2% placebo) | Modest excess; lower insulin dose at initiation |
| Hypoglycaemia (with metformin + SU) | 16.1% (10 mg; vs 8.4% placebo) | Consider reducing SU dose; 25 mg arm was 11.5% |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Urinary tract infection | 9.3% (10 mg) / 7.6% (25 mg) vs 7.6% placebo | More frequent in females (16.6–18.4%); higher in patients ≥75 years (15.1–15.7% vs 10.5%) |
| Female genital mycotic infections | 5.4% (10 mg) / 6.4% (25 mg) vs 1.5% placebo | Vulvovaginal candidiasis most common; treat with topical antifungals; rarely requires discontinuation |
| Upper respiratory tract infection | 4.0% (25 mg) vs 3.8% placebo | Marginal excess; not clearly drug-related |
| Increased urination (polyuria, pollakiuria, nocturia) | 3.4% (10 mg) / 3.2% (25 mg) vs 1.0% placebo | Mechanism-related osmotic diuresis; usually mild; advise morning dosing |
| Male genital mycotic infections | 3.1% (10 mg) / 1.6% (25 mg) vs 0.4% placebo | Balanitis, balanoposthitis; phimosis reported rarely (<0.1%) |
| Dyslipidaemia | 3.9% (10 mg) / 2.9% (25 mg) vs 3.4% placebo | LDL-C increases: +4.6% (10 mg), +6.5% (25 mg) vs +2.3% placebo |
| Thirst / polydipsia | 1.7% (10 mg) / 1.5% (25 mg) vs 0% placebo | Related to osmotic diuresis; ensure adequate hydration |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Diabetic ketoacidosis (T1DM or T2DM) | Rare in T2DM; markedly increased in T1DM (not indicated) | Any time; risk highest with insulin reduction, illness, fasting, surgery | Assess for DKA regardless of glucose level; discontinue immediately; glucosuria may persist ≥3 days after stopping |
| Volume depletion / hypotension / AKI | 0.3–0.5% (volume depletion events in T2DM trials) | 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 appropriate antibiotics; consider discontinuation |
| Lower limb amputation | 5.0 events/1000 patient-years (JARDIANCE) vs 4.3 (placebo) across 4 outcome trials; HR 1.05 (0.81–1.36) | Variable; highest risk with diabetic foot, PAD, or prior amputation | Routine foot care; monitor for infections, ulcers, new pain; prompt treatment of diabetic foot |
| Hypersensitivity / angioedema | Rare (postmarketing) | Variable | Discontinue; treat per standard of care; contraindicated if prior reaction |
DKA with SGLT2 inhibitors may present with atypically low blood glucose levels (<250 mg/dL), making recognition challenging. Risk factors include insulin dose reduction, acute illness, surgery, reduced caloric intake, ketogenic diet, and alcohol abuse. Withhold empagliflozin at least 3 days before elective surgery. Educate patients to recognise symptoms (nausea, vomiting, abdominal pain, malaise, shortness of breath) and seek immediate medical attention. Note that glucosuria may persist for 3 or more days after the last dose.
Drug Interactions with Empagliflozin
Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms and has negligible CYP-mediated metabolism. It is metabolised by glucuronidation (UGTs) and is a substrate of P-gp, BCRP, OAT3, OATP1B1, and OATP1B3, but does not inhibit these transporters at therapeutic doses. No clinically relevant PK interactions have been identified with any tested co-medication.
Empagliflozin 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 also unreliable during SGLT2 inhibitor therapy. Use HbA1c or capillary/venous blood glucose instead.
Monitoring for Empagliflozin
- Renal Function (eGFR)Before initiation; periodically thereafter
RoutineInitial eGFR dip (up to −9 mL/min at week 4) is expected and reflects haemodynamic changes, not structural damage. Reverses on discontinuation. More frequent monitoring if eGFR <60. - Volume Status / BPBefore initiation; at each visit
RoutineCorrect volume depletion before starting. Risk of hypotension increases in patients ≥75 years (4.4% at 25 mg vs 2.1% placebo), those on loop diuretics, or with eGFR <60. - HbA1c (T2DM patients)Every 3–6 months
RoutineGlycaemic efficacy is eGFR-dependent; not recommended for glycaemic control if eGFR <30. Do not use urine glucose or 1,5-AG for monitoring. - DKA Signs & SymptomsEach visit; patient education
RoutineConsider ketone monitoring in at-risk patients (T1DM, low carb diet, insulin dose reduction, illness, surgery). Assess for DKA regardless of blood glucose level. - Genital / Urinary InfectionsEach visit; patient self-monitoring
Trigger-basedHigher risk in females (genital mycotic infections 5.4–6.4% vs 1.5% placebo). Immediately assess for Fournier’s gangrene if genital/perineal pain with fever or malaise develops. - Foot ExaminationEach visit in patients with diabetes
RoutineMonitor for infections, ulcers, new pain or tenderness of lower limbs. Highest amputation risk in patients with diabetic foot, PAD, or prior amputation. - LDL CholesterolPeriodically
Trigger-basedDose-related LDL-C increase: +4.6% (10 mg), +6.5% (25 mg) vs +2.3% placebo. Reassess statin therapy if needed.
Contraindications & Cautions for Empagliflozin
Absolute Contraindications
- Hypersensitivity to empagliflozin or any excipient (angioedema reported) (FDA PI).
Relative Contraindications (Specialist Input Recommended)
- Type 1 diabetes mellitus — significantly increased DKA risk; not indicated for glycaemic control in T1DM; fatal DKA has occurred.
- Active or recurrent genital mycotic infections or UTIs — empagliflozin increases risk; weigh benefit vs infection burden.
- Volume depletion or severe dehydration — correct before initiation; risk of symptomatic hypotension and AKI.
- Planned surgery or prolonged fasting — withhold empagliflozin for at least 3 days before; resume when stable.
Use with Caution
- Elderly patients (≥75 years) — higher volume depletion risk (4.4% at 25 mg vs 2.1% placebo); higher UTI rates (15.7% vs 10.5%).
- Concomitant loop diuretics — additive diuretic effect; assess volume status before and after initiation.
- eGFR <30 mL/min/1.73 m² for glycaemic control — empagliflozin is unlikely to be effective for glucose lowering at this eGFR level, but HF and CKD indications remain valid at lower eGFR values.
- Pregnancy (2nd/3rd trimester) — animal data show renal pelvic and tubular dilatation during late renal development; not recommended.
- Peripheral artery disease or diabetic foot — monitor for amputation risk; highest concern with prior amputation or active foot ulcer.
The FDA has issued class-wide warnings for SGLT2 inhibitors regarding: (1) diabetic ketoacidosis, which may present with atypically normal glucose levels; (2) necrotising fasciitis of the perineum (Fournier’s gangrene), a rare but life-threatening infection requiring urgent surgical intervention; and (3) an imbalance in lower limb amputations observed in some SGLT2 inhibitor trials. For empagliflozin specifically, the lower limb amputation signal across four outcome trials showed HR 1.05 (95% CI 0.81–1.36), which was not statistically significant but warrants vigilance in high-risk patients.
Patient Counselling for Empagliflozin
Purpose of Therapy
Empagliflozin 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 heart failure hospitalisations, kidney disease progression, and cardiovascular death. It is used in diabetes, heart failure, and chronic kidney disease.
How to Take
Take one tablet once daily in the morning, with or without food. If a dose is missed, take it as soon as remembered. Do not double up on the next dose. Stay well hydrated. Before any planned surgery, stop empagliflozin at least 3 days beforehand as advised by your healthcare provider.
Sources
- Boehringer Ingelheim Pharmaceuticals, Inc. JARDIANCE (empagliflozin) tablets, for oral use. Full Prescribing Information. Revised 10/2025. FDA LabelPrimary regulatory source for all dosing, adverse reaction incidences, PK parameters, and safety warnings in this monograph.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128. doi:10.1056/NEJMoa1504720EMPA-REG OUTCOME: landmark trial demonstrating 38% CV death reduction, 35% HF hospitalization reduction, and 32% all-cause mortality reduction with empagliflozin in T2DM + ASCVD.
- Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413–1424. doi:10.1056/NEJMoa2022190EMPEROR-Reduced: empagliflozin reduced CV death/HF hospitalization by 25% (HR 0.75) in HFrEF patients regardless of diabetes status.
- Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451–1461. doi:10.1056/NEJMoa2107038EMPEROR-Preserved: empagliflozin reduced CV death/HF hospitalization by 21% (HR 0.79) in HFpEF, making it the first SGLT2 inhibitor with proven benefit across the full HF spectrum.
- The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117–127. doi:10.1056/NEJMoa2204233EMPA-KIDNEY: empagliflozin reduced kidney disease progression or CV death by 28% (HR 0.72) in CKD patients with or without diabetes.
- Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk. Eur Heart J. 2016;37(19):1526–1534. doi:10.1093/eurheartj/ehv728Heart failure sub-analysis from EMPA-REG OUTCOME showing consistent HF benefits with and without baseline heart failure.
- 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 ASCVD, HF, or CKD.
- 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 a foundational therapy for HFrEF and a Class 2a recommendation for HFpEF.
- Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14(1):83–90. doi:10.1111/j.1463-1326.2011.01517.xPreclinical characterisation of empagliflozin demonstrating high SGLT2 selectivity (>2500-fold vs SGLT1) and potent glucose-lowering in animal models.
- Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108–2117. doi:10.1007/s00125-018-4670-7Comprehensive review of proposed cardioprotective mechanisms including haemodynamic, metabolic, and renal pathways.
- Scheen AJ. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin Pharmacokinet. 2014;53(3):213–225. doi:10.1007/s40262-013-0126-xComprehensive PK/PD review covering absorption, metabolism, drug interactions, and special populations for empagliflozin.
- Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther. 2013;4(2):331–345. doi:10.1007/s13300-013-0030-2Multiple-dose PK study demonstrating dose-proportional exposure, 10–19 h terminal half-life, and robust urinary glucose excretion at clinical doses.
- Macha S, Rose P, Mattheus M, et al. Pharmacokinetics, pharmacodynamics and safety of empagliflozin in patients with renal impairment. Diabetes Obes Metab. 2014;16(3):215–222. doi:10.1111/dom.12182Renal impairment PK study showing no dose adjustment required despite moderate AUC increases, as UGE decreases with declining GFR.