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Sunday, July 27, 2025

Empagliflozin


Empagliflozin is an oral antidiabetic medication that belongs to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors. It is indicated primarily for the treatment of type 2 diabetes mellitus (T2DM) but is also approved for reducing the risk of cardiovascular death in adults with T2DM and established cardiovascular disease, and for managing heart failure (both with reduced and preserved ejection fraction). By inhibiting SGLT2 in the proximal renal tubules, empagliflozin reduces glucose reabsorption in the kidney, thereby promoting glycosuria and lowering blood glucose levels independently of insulin.

Pharmacological Classification

  • Therapeutic class: Antidiabetic, Antihyperglycemic

  • Pharmacologic class: SGLT2 Inhibitor

  • ATC Code: A10BK03

  • Available forms: Oral tablets – 10 mg and 25 mg

  • Brand names: Jardiance (Boehringer Ingelheim), Glyxambi (empagliflozin + linagliptin), Synjardy (empagliflozin + metformin), Trijardy XR (triple combo)

  • Legal classification: Prescription only (Rx)

Mechanism of Action

Empagliflozin selectively inhibits sodium-glucose co-transporter 2 (SGLT2), a protein located in the proximal renal tubules responsible for the reabsorption of about 90% of filtered glucose from the glomerular filtrate back into the bloodstream.

By inhibiting SGLT2:

  • Glucose reabsorption is blocked

  • Urinary glucose excretion is increased

  • Blood glucose concentrations are reduced

  • Caloric loss via urine occurs (~200–300 kcal/day)

  • Osmotic diuresis and natriuresis are induced, leading to modest blood pressure reduction

  • No direct stimulation of insulin secretion, thus lower risk of hypoglycemia

Empagliflozin’s cardiovascular and renal benefits are considered independent of glycemic control, involving mechanisms such as hemodynamic changes, reduced intraglomerular pressure, and improved myocardial energetics.

Therapeutic Indications

Approved Uses

  1. Type 2 Diabetes Mellitus (T2DM)

    • As monotherapy (if metformin is inappropriate)

    • In combination with other antidiabetics (e.g., metformin, insulin)

    • Improves glycemic control and promotes weight loss

  2. Heart Failure (HFrEF and HFpEF)

    • Reduces risk of cardiovascular death and hospitalization in adults with:

      • Heart Failure with Reduced Ejection Fraction (HFrEF)

      • Heart Failure with Preserved Ejection Fraction (HFpEF)

  3. Cardiovascular Risk Reduction in T2DM

    • Reduces risk of CV death in adults with T2DM and established atherosclerotic cardiovascular disease

  4. Chronic Kidney Disease (emerging indication)

    • Not yet globally approved, but trials (EMPA-KIDNEY) support renal protective effects

Dosage and Administration

  • Initial dose: 10 mg orally once daily in the morning, with or without food

  • Max dose: 25 mg once daily (if tolerated and more glycemic control is needed)

  • Renal dose adjustments:

    • eGFR ≥60 mL/min/1.73m²: No adjustment needed

    • eGFR 30–59: 10 mg may be used for heart failure or CV protection

    • eGFR <30: Not recommended for glycemic control, but may be continued for heart failure indications

  • Hepatic impairment: No dose adjustment required

Pharmacokinetics

  • Absorption: Peak plasma concentration in 1.5 hours (Tmax)

  • Bioavailability: ~78%

  • Protein binding: ~86%

  • Half-life: 10–13 hours (once-daily dosing)

  • Metabolism: Mainly glucuronidation (UGT enzymes)

  • Excretion: 54% feces, 41% urine (mostly unchanged)

Contraindications

  • Hypersensitivity to empagliflozin or any excipient

  • Severe renal impairment (eGFR <30 mL/min/1.73m²) for glycemic control

  • End-stage renal disease or dialysis

  • Diabetic ketoacidosis (DKA)

  • Type 1 diabetes mellitus (off-label use is discouraged)

  • Volume depletion or hypotension

  • Pregnancy (risk of fetal renal damage)

  • Lactation (unknown if excreted in breast milk)

Warnings and Precautions

Genital Mycotic Infections

  • Due to glycosuria, increased risk of fungal infections (especially in females and uncircumcised males)

Urinary Tract Infections

  • Possible increased risk, although not consistently observed in all studies

Volume Depletion

  • Causes osmotic diuresis; monitor in elderly, diuretic users, or hypotensive patients

Ketoacidosis

  • Risk of euglycemic diabetic ketoacidosis (blood glucose may be normal)

  • Risk increased with insulin reduction, alcohol abuse, or surgery

Fournier's Gangrene

  • Rare but serious necrotizing fasciitis of the perineum

Renal Function

  • Modest initial eGFR drop expected due to hemodynamic changes

  • Long-term renal protective effects

Fractures and Amputations

  • Risk unclear; more data on canagliflozin than empagliflozin

  • Monitor patients with peripheral vascular disease or neuropathy

Adverse Effects

Common (≥1%)

  • Genital fungal infections (especially Candida)

  • Urinary tract infections

  • Increased urination (polyuria)

  • Thirst

  • Hypoglycemia (when used with insulin or sulfonylureas)

  • Mild hypotension

  • Nausea

  • Dyslipidemia (mild LDL increase)

Less Common

  • Ketoacidosis (euglycemic DKA)

  • Volume depletion symptoms (dizziness, dehydration)

  • Pruritus

  • Back pain

  • Increased hematocrit

Rare/Serious

  • Fournier’s gangrene

  • Anaphylaxis or angioedema

  • Acute kidney injury (transient)

  • Hypersensitivity reactions

Drug Interactions

Additive Hypoglycemia Risk

  • Insulin or sulfonylureas increase risk of hypoglycemia

  • Dose adjustment may be needed

Diuretics

  • Additive risk of volume depletion and hypotension

RAAS inhibitors (ACEi/ARBs)

  • Used together safely, but monitor blood pressure and renal function

Lithium

  • Empagliflozin may reduce lithium levels; monitor serum lithium

Other Antidiabetics

  • Safe in combination with metformin, DPP-4 inhibitors, GLP-1 agonists, and thiazolidinediones

Vaccines or surgery

  • Discontinue temporarily in cases of surgery or acute illness to avoid ketoacidosis

Use in Special Populations

Pregnancy

  • Avoid use; may impair fetal renal development (especially in second/third trimesters)

Breastfeeding

  • Excretion unknown; use alternative therapy

Elderly

  • Higher risk of dehydration and renal effects; monitor volume status

Pediatrics

  • Not approved for use in children

Renal Impairment

  • May continue for heart failure and CV protection down to eGFR 20–25

  • Avoid for glucose lowering if eGFR <30

Monitoring Parameters

  • Renal function (eGFR): Baseline, periodically

  • Serum glucose and HbA1c

  • Ketones in patients at risk for DKA

  • Volume status: Especially in elderly or diuretic use

  • Signs of genital infections or UTI

  • Blood pressure

Clinical Trial Evidence

EMPA-REG OUTCOME (2015)

  • Landmark cardiovascular outcomes trial

  • In T2DM patients with ASCVD, empagliflozin:

    • Reduced CV death by 38%

    • Reduced hospitalization for heart failure by 35%

    • Reduced all-cause mortality by 32%

EMPEROR-Reduced (2020)

  • In HFrEF patients, regardless of diabetes:

    • Reduced combined endpoint of CV death or HF hospitalization

    • Slowed renal function decline

EMPEROR-Preserved (2021)

  • In HFpEF patients:

    • Reduced risk of CV death or hospitalization

    • First agent to show benefit in preserved EF heart failure

EMPA-KIDNEY (2022)

  • Showed renal protective effect in patients with CKD (diabetic and non-diabetic)

  • Reduced risk of progression to kidney failure or CV death

Comparison with Other SGLT2 Inhibitors

  • Canagliflozin: Higher fracture and amputation risks; renal protective

  • Dapagliflozin: Similar CV and renal effects; more data in HFpEF early on

  • Ertugliflozin: Less CV outcomes data

  • Empagliflozin: Strongest evidence for CV mortality reduction

Patient Counseling Points

  • Take once daily, preferably in the morning

  • May be taken with or without food

  • Stay hydrated to avoid dehydration

  • Monitor for genital symptoms (itching, discharge)

  • Report symptoms of ketoacidosis: nausea, vomiting, abdominal pain, confusion, fatigue

  • Avoid alcohol excess and low-carb diets, which increase DKA risk

  • Inform your doctor before surgery or fasting

  • Do not use in type 1 diabetes




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