Empagliflozin

What Is Empagliflozin and What Is It Used For?

Empagliflozin belongs to a class of medications known as sodium-glucose co-transporter 2 (SGLT2) inhibitors. Developed by Boehringer Ingelheim in collaboration with Eli Lilly, empagliflozin has played a pivotal role in transforming the treatment landscape for type 2 diabetes, heart failure, and chronic kidney disease. Its groundbreaking cardiovascular mortality data from the EMPA-REG OUTCOME trial in 2015 ushered in a new era of diabetes treatment where cardiovascular protection became a central therapeutic goal alongside glycemic control.

The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the European Society of Cardiology (ESC) now recommend SGLT2 inhibitors such as empagliflozin as first-line therapy for patients with type 2 diabetes who have established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease — independent of baseline HbA1c levels or the need for additional glucose lowering.

Mechanism of Action

SGLT2 is a sodium-dependent glucose transporter protein located in the proximal convoluted tubule of the kidney. Under normal physiological conditions, SGLT2 is responsible for reabsorbing approximately 90% of the glucose filtered by the glomeruli back into the bloodstream. By selectively and reversibly inhibiting SGLT2, empagliflozin lowers the renal threshold for glucose, causing the kidneys to excrete approximately 64 grams of glucose per day in the urine at the 25 mg dose (glycosuria). This mechanism is entirely independent of insulin secretion and insulin sensitivity, meaning empagliflozin continues to work effectively regardless of beta-cell function or the degree of insulin resistance.

Beyond its glucose-lowering effect, empagliflozin exerts multiple additional physiological actions that are believed to underpin its cardiovascular and renal benefits. It promotes natriuresis and osmotic diuresis, reducing plasma volume by approximately 7% and lowering both cardiac preload and afterload. This haemodynamic offloading occurs without activating the sympathetic nervous system or the renin-angiotensin-aldosterone system, a unique feature compared with conventional diuretics. Empagliflozin activates tubuloglomerular feedback, reducing intraglomerular pressure and hyperfiltration — a key mechanism behind its nephroprotective effects. It also promotes a metabolic shift from glucose to fatty acid and ketone body oxidation, providing a more efficient energy substrate for the failing heart. Additionally, empagliflozin modestly reduces body weight (approximately 2–3 kg) through caloric loss from glycosuria and lowers systolic blood pressure by 3–5 mmHg.

Approved Indications

Regulatory agencies including the FDA (United States) and EMA (European Union) have approved empagliflozin for the following indications:

• Type 2 diabetes mellitus: As an adjunct to diet and exercise to improve glycemic control in adults. In the EU, empagliflozin is approved as monotherapy when metformin is not tolerated, or as add-on combination therapy with other glucose-lowering agents including insulin. The FDA also specifically notes empagliflozin’s indication to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease.
• Heart failure: To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure, regardless of ejection fraction (HFrEF and HFpEF) and regardless of diabetes status. This indication is supported by the EMPEROR-Reduced and EMPEROR-Preserved trials.
• Chronic kidney disease (CKD): To reduce the risk of sustained decline in kidney function, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression. The EMPA-KIDNEY trial established empagliflozin’s renal protective effects across a broad spectrum of kidney disease.

Key Clinical Trials

Empagliflozin’s clinical evidence base is exceptionally strong, supported by four major randomized controlled trials involving over 27,000 patients:

• EMPA-REG OUTCOME (NEJM, 2015): In 7,020 patients with type 2 diabetes and established cardiovascular disease, empagliflozin reduced cardiovascular death by 38% (HR 0.62, 95% CI 0.49–0.77, p < 0.001), all-cause mortality by 32% (HR 0.68), and hospitalization for heart failure by 35% (HR 0.65). This was the first cardiovascular outcome trial to demonstrate a mortality benefit with any glucose-lowering agent since metformin in the UKPDS.
• EMPEROR-Reduced (NEJM, 2020): In 3,730 patients with heart failure and reduced ejection fraction (LVEF ≤40%), empagliflozin reduced the combined endpoint of cardiovascular death or hospitalization for worsening heart failure by 25% (HR 0.75, p < 0.001), with consistent benefits in patients with and without diabetes.
• EMPEROR-Preserved (NEJM, 2021): In 5,988 patients with heart failure and preserved ejection fraction (LVEF >40%), empagliflozin reduced the combined endpoint of cardiovascular death or hospitalization for heart failure by 21% (HR 0.79, p < 0.001), making it one of the first therapies to demonstrate efficacy in this historically treatment-resistant population.
• EMPA-KIDNEY (NEJM, 2023): In 6,609 patients with chronic kidney disease (eGFR 20–45 or eGFR 45–90 with UACR ≥200), empagliflozin reduced the primary composite endpoint (progression of kidney disease or cardiovascular death) by 28% (HR 0.72, p < 0.001). The trial was stopped early for overwhelming efficacy and demonstrated benefits across a broad range of kidney disease aetiologies, including patients without diabetes.

What Should You Know Before Taking Empagliflozin?

Before starting empagliflozin, it is essential that your healthcare provider has a complete picture of your medical history, current medications, and any planned procedures. While empagliflozin is generally well-tolerated with a favourable benefit-risk profile, certain conditions and circumstances require special consideration or may preclude its use entirely. Open communication with your prescriber ensures safe and effective therapy.

Contraindications

Empagliflozin must not be used in the following situations:

• Hypersensitivity: Known allergy to empagliflozin or any excipient in the formulation. Post-marketing reports have included angioedema and anaphylactic reactions, although these are very rare.
• Type 1 diabetes: Empagliflozin is not approved for type 1 diabetes due to a significantly increased risk of diabetic ketoacidosis (DKA) in this population.
• Severe renal impairment (for glycemic control): For the glycemic indication in type 2 diabetes, empagliflozin should not be initiated if eGFR is below 30 mL/min/1.73 m² (FDA) or 20 mL/min/1.73 m² (EMA for heart failure/CKD), as glucose-lowering efficacy is reduced at very low eGFR levels.
• End-stage renal disease: Do not initiate in patients on dialysis, as there is no therapeutic experience in this population.

Warnings and Precautions

Several important warnings and precautions apply to empagliflozin therapy:

• Volume depletion: Empagliflozin causes osmotic diuresis, which can lead to intravascular volume contraction, symptomatic hypotension, and acute kidney injury. Risk is greatest in elderly patients, those on loop diuretics, those with low systolic blood pressure, and patients with impaired renal function. Assess and correct volume status before initiating therapy.
• Genital mycotic infections: The increased urinary glucose concentration provides a substrate for fungal growth. Vulvovaginal candidiasis in women and balanitis or balanoposthitis in men occur more frequently with empagliflozin than placebo. In EMPA-REG OUTCOME, genital infections occurred in 6.4% of empagliflozin-treated women versus 1.8% on placebo. Patients with a history of genital infections are at higher risk.
• Urinary tract infections (UTIs): Glycosuria may increase UTI risk. Complicated UTIs including pyelonephritis and urosepsis have been reported in post-marketing surveillance. If a complicated UTI develops, consider temporarily discontinuing empagliflozin.
• Fournier’s gangrene: Rare but life-threatening necrotizing fasciitis of the perineum has been reported with all SGLT2 inhibitors. The FDA identified 55 cases across the class between March 2013 and January 2019. If suspected (pain, tenderness, erythema, or swelling in the genital or perineal area with fever or malaise), discontinue immediately and initiate broad-spectrum antibiotics and surgical debridement.
• Lower limb amputation: While primarily associated with canagliflozin in the CANVAS program, the EMPA-REG OUTCOME trial did not show a significantly increased risk of lower limb amputation with empagliflozin. Nevertheless, caution is advised in patients with prior amputation, peripheral vascular disease, neuropathy, or diabetic foot ulcers.
• Hypoglycemia: Empagliflozin alone has a very low risk of hypoglycemia. However, when combined with insulin or insulin secretagogues (sulfonylureas, meglitinides), the risk increases substantially. Dose reduction of the concomitant insulin or sulfonylurea may be needed.

Pregnancy and Breastfeeding

Empagliflozin is not recommended during pregnancy, particularly during the second and third trimesters. While no adequate human studies exist, animal studies have shown adverse effects on renal development in juvenile rats. Because SGLT2 is expressed in the developing fetal kidney, inhibition during organogenesis could adversely affect nephrogenesis and renal maturation. In animal reproduction studies, empagliflozin at exposures up to 48 times the maximum human dose caused renal pelvic and tubular dilatations and ossification delays. Women of childbearing potential should use effective contraception during treatment. If pregnancy is detected, empagliflozin should be discontinued.

Empagliflozin is not recommended during breastfeeding. The drug is excreted in the milk of lactating rats at a milk-to-plasma ratio of approximately 0.5, and it is unknown whether empagliflozin passes into human breast milk. Given the potential effects on renal development in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. No effects on fertility have been observed in animal studies at exposures up to 48 times the human dose.

How Does Empagliflozin Interact with Other Drugs?

Drug interactions with empagliflozin are generally manageable but require clinical awareness. Empagliflozin is primarily metabolized by glucuronidation via UGT2B7, UGT1A3, UGT1A8, and UGT1A9. It is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Importantly, empagliflozin does not significantly inhibit or induce cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4), resulting in a relatively limited pharmacokinetic interaction profile. Clinical studies have confirmed no clinically meaningful interactions with metformin, sitagliptin, pioglitazone, ramipril, digoxin, warfarin, or oral contraceptives.

Major Interactions

Minor Interactions

What Is the Correct Dosage of Empagliflozin?

Empagliflozin dosing is straightforward with a once-daily oral administration, usually taken in the morning. The tablet should be swallowed whole with water and can be taken with or without food, as food does not significantly affect its pharmacokinetics. The bioavailability of empagliflozin is not clinically affected by meals.

Adults

Children

Empagliflozin is approved by the FDA for type 2 diabetes in pediatric patients aged 10 years and older, at a dose of 10 mg once daily (which may be increased to 25 mg once daily). This pediatric indication was supported by a Phase 3 study showing efficacy and safety comparable to adults. Empagliflozin is not approved for children under 10 years of age, and the heart failure and CKD indications are limited to adult patients (≥18 years) as safety and efficacy have not been established in paediatric populations for these conditions.

Elderly

No dose adjustment is required based on age alone. However, elderly patients are more likely to have reduced renal function and to be taking concomitant medications that may affect renal function or volume status (diuretics, ACE inhibitors, ARBs). Particular attention should therefore be paid to renal function monitoring, volume status assessment, and signs of hypotension in patients over 65 years of age. Clinical trial data from EMPA-REG OUTCOME, EMPEROR-Reduced, and EMPEROR-Preserved included substantial numbers of elderly patients (approximately 46% were ≥65 years in EMPA-REG OUTCOME), and benefits were consistent across age subgroups.

Renal Impairment

Hepatic Impairment

No dose adjustment is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C). Pharmacokinetic studies have shown that empagliflozin exposure (AUC) increases by approximately 23%, 47%, and 75% in patients with mild, moderate, and severe hepatic impairment, respectively. However, these changes are not considered clinically significant and no dose modification is needed. Experience in patients with severe hepatic impairment is limited, and clinical judgement should guide therapy in this population.

Missed Dose

If you miss a dose, take it as soon as you remember on the same day. If it is already close to your next scheduled dose, skip the missed dose and take your next dose at the regular time. Do not take two doses at the same time or take extra doses to make up for a missed dose. If doses are frequently missed, speak with your healthcare provider about strategies to improve medication adherence, such as using a pill organiser or setting a daily reminder.

Overdose

In clinical pharmacology studies, single doses of up to 800 mg empagliflozin (32 times the maximum recommended daily dose of 25 mg) were well tolerated in healthy volunteers. There is no specific antidote for empagliflozin overdose. In the event of an overdose, treatment should be supportive and symptomatic, with monitoring for dehydration, electrolyte imbalances, hypotension, and hypoglycemia. Empagliflozin is not expected to be significantly removed by haemodialysis due to its high protein binding (approximately 86%).

What Are the Side Effects of Empagliflozin?

Like all medications, empagliflozin can cause side effects, although not everybody experiences them. The safety profile of empagliflozin is well-characterised from extensive clinical trial data involving over 15,000 patients in the empagliflozin treatment arms across multiple Phase 3 trials and cardiovascular outcome studies. Most adverse effects are directly related to its pharmacological mechanism of action — primarily the excretion of glucose and sodium in the urine.

The side effects below are classified according to the MedDRA (Medical Dictionary for Regulatory Activities) frequency convention, based on pooled data from randomised controlled trials and post-marketing surveillance reports:

Post-Marketing Reports

The following adverse reactions have been identified during post-marketing surveillance of empagliflozin and the broader SGLT2 inhibitor class. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

• Acute pancreatitis (very rare, causal relationship not established)
• Severe skin reactions including erythema multiforme
• Phimosis in uncircumcised males with recurrent balanitis
• Hypersensitivity reactions (urticaria, angioedema)

Managing Common Side Effects

Many common side effects of empagliflozin can be effectively prevented or managed with straightforward measures. Drinking adequate water throughout the day (at least 1.5–2 litres) helps counteract the osmotic diuresis and reduces the risk of dehydration and urinary tract infections. Maintaining good genital hygiene — including wearing breathable cotton underwear, keeping the genital area clean and dry, and changing promptly after swimming or exercise — significantly reduces the risk of fungal infections. If genital infections do occur, they typically respond well to standard topical antifungal treatment. Taking empagliflozin in the morning rather than in the evening can help minimise the impact of increased urination on sleep quality.

Patients already on insulin or sulfonylureas should be advised about the potential for increased hypoglycemia and should have clear instructions for self-management, including blood glucose monitoring and appropriate carbohydrate intake. Your healthcare provider may proactively reduce the dose of insulin or sulfonylurea when starting empagliflozin to minimise this risk.

How Should You Store Empagliflozin?

Proper storage of empagliflozin ensures the medication remains effective and safe throughout its shelf life. The following guidelines apply to all formulations of empagliflozin:

• Temperature: Store below 25°C (77°F). In the United States, the labelling recommends storage at 20–25°C (68–77°F), with excursions permitted to 15–30°C (59–86°F).
• Moisture protection: Store tablets in the original blister packaging until the time of use to protect from moisture. Keep the bottle tightly closed if dispensed in a bottle.
• No refrigeration: Do not freeze or refrigerate. No special storage conditions beyond the stated temperature range are required.
• Shelf life: 3 years from the date of manufacture (as stated on the packaging).
• Expiry date: Do not use empagliflozin after the expiry date printed on the blister and carton. The expiry date refers to the last day of that month.
• Children: Keep out of the sight and reach of children.
• Disposal: Do not dispose of medications via wastewater or household waste. Return unused or expired medicine to your pharmacist for proper disposal to help protect the environment.

What Does Empagliflozin Contain?

Understanding the composition of empagliflozin tablets is important for patients with known allergies or intolerances to specific excipients. The tablet formulation is designed to ensure optimal drug delivery, stability, and bioavailability.

Active Substance

The active pharmaceutical ingredient is empagliflozin. Each 10 mg tablet contains 10 mg empagliflozin. Each 25 mg tablet contains 25 mg empagliflozin. Empagliflozin has the molecular formula C₂₃H₂₇ClO₇ and a molecular weight of 450.91 g/mol. It is a white to yellowish crystalline, non-hygroscopic powder. The compound is a competitive, selective, and reversible inhibitor of SGLT2 with approximately 2,500-fold selectivity over SGLT1, the other sodium-glucose transporter involved in intestinal glucose absorption.

Inactive Ingredients (Excipients)

Tablet core (Jardiance):

• Microcrystalline cellulose
• Hydroxypropyl cellulose
• Croscarmellose sodium
• Colloidal silicon dioxide (colloidal anhydrous silica)
• Magnesium stearate

Film coating:

• Hypromellose (hydroxypropyl methylcellulose)
• Titanium dioxide (E171)
• Talc
• Macrogol 400 (polyethylene glycol)
• Yellow iron oxide (E172) — 10 mg tablets

Available Brand Names and Generics

Empagliflozin is available worldwide under the original brand name and as EMA-approved generic formulations:

• Jardiance — Boehringer Ingelheim / Eli Lilly; available worldwide including US, EU, UK, Japan, Australia, and all major international markets. Available in 10 mg and 25 mg strengths.
• Empagliflozin Devatis — Devatis GmbH; EMA-authorized generic formulation available in select European markets.
• Empagliflozin Labiana — Labiana Pharmaceuticals; EMA-authorized generic available in the EU.

Combination products containing empagliflozin include Synjardy and Synjardy XR (empagliflozin + metformin), Glyxambi (empagliflozin + linagliptin), and Jardiance Duo (empagliflozin + metformin, select markets).

Frequently Asked Questions