Clinical Overview: Empagliflozin for Type 2 Diabetes Patients With Cardiovascular Disease or Heart Failure, Reduced Ejection Fraction

Introduction

Insulin resistance due to genetic factors, inactive lifestyle, or being overweight causes type 2 diabetes (T2D). The resultant hyperglycemia can lead to heart disease, kidney failure, amputations, and blindness.¹ Patients with diabetes should control hyperglycemia to prevent these complications by eating a healthy diet and exercising, but drug therapy may be necessary.¹

Empagliflozin (Jardiance) is a sodium-glucose transporter 2 (SGLT2) inhibitor approved by the FDA in August 2014 for treating T2D in combination with diet modifications and exercise.² Empagliflozin monotherapy reduced HbA1c, fasting plasma glucose, and body weight in a double-blind, placebo-controlled study using 986 treatment-naïve patients with T2D.²

Empagliflozin also reduced these parameters in clinical trials conducted in patients inadequately treated with insulin and insulin secretagogues, alone or in combination.²

In December 2016, the FDA expanded empagliflozin’s use for reducing death due to cardiovascular events in patients with T2D and cardiovascular disease.³ Empagliflozin lowered the risk of first occurrence of a major adverse cardiac event in a multicenter, multinational, randomized, double blind, parallel group trial using 7020 patients with T2D and atherosclerotic cardiovascular disease.³

In August 2021, the FDA further approved empagliflozin’s indications to include reducing death due to cardiovascular events and hospitalization due to heart failure (HF) in patients with HF and reduced ejection fraction.⁴ In a double-blind, placebo-controlled study (N = 3730 patients with chronic HF with 40% or less left ventricular ejection fraction), researchers demonstrated that empagliflozin reduced the risk of death due to cardiovascular events and the number of first and recurrent HF hospitalizations.⁴

Mechanism of action

SGLT2 located in the proximal tubule reabsorbs glucose from the glomerular filtrate.⁵ Empagliflozin inhibits SGLT2, thereby lowering glucose reabsorption back into the circulation to reduce blood glucose levels.^4,6

Dosage and administration⁴

The manufacturer supplies empagliflozin as pale yellow, film-coated tablets in 10 mg and 25 mg strengths. Health care professionals should prescribe empagliflozin 10 mg once daily to patients with T2D.

They may increase it to 25 mg once daily in patients who do not achieve adequate control of hyperglycemia. Pharmacists should advise patients to store empagliflozin between 20°-25°C (68°-77°F) and swallow 1 tablet in the morning, with or without food.

Adverse events⁴

During clinical trials, patients on empagliflozin experienced polydipsia, polyuria, urinary tract infections, genital mycotic infections, and hypoglycemia more frequently than those on placebo. Researchers also observed greater increase in low-density lipoprotein cholesterol (LDL-C) and hematocrit values in patients treated with empagliflozin than those on placebo. Patients and health care professionals have reported occurrence of rash, urticaria, acute kidney injury, and angioedema during post marketing surveillance.

Warnings/precautions⁴

Health care professionals should not prescribe empagliflozin to treat type 1 diabetes due to increased risk of ketoacidosis in these patients. Patients with T2D on empagliflozin can also develop ketoacidosis, particularly those who have pancreatic insulin deficiency, reduced caloric intake, and those who abuse alcohol.

Health care professionals should counsel patients that euglycemic ketoacidosis (metabolic acidosis with blood glucose < 250 mg/dL) can occur and patients should seek medical care if they observe any signs and symptoms of metabolic acidosis. If ketoacidosis is present, health care professionals should discontinue empagliflozin and administer fluids, carbohydrates, and insulin, as needed. If empagliflozin is used with insulin or an insulin secretagogue, health care professionals should lower the dose of these agents to minimize the risk of hypoglycemia.

If eGFR is < 30 mL/min/1.73 m² in patients with T2D and cardiovascular disease or if eGFR is < 20 mL/min/1.73 m² in patients who have HF with reduced ejection fraction, health care professionals should not use empagliflozin. Before prescribing empagliflozin to elderly patients, those on loop diuretics, or those with eGFR < 60 mL/min/1.73 m², health care professionals should assess and correct their volume status, and monitor them.

They should also educate patients to maintain adequate fluid intake, be vigilant about signs and symptoms of hypotension, and contact them if those occur. If eGFR falls below 30 mL/min/1.73 m², health care professionals should discontinue empagliflozin.

Health care professionals should educate patients about the signs and symptoms of urinary tract infections, genital mycotic infections, and Fournier’s gangrene, which is a life-threatening necrotic infection in the perineal, genital, or perianal region. They should monitor, evaluate, and treat patients if genital mycotic infections or urosepsis, pyelonephritis, or other urinary tract infections develop.

They should discontinue empagliflozin if Fournier’s gangrene occurs and treat patients with broad-spectrum antibiotics and surgical debridement, if needed. Health care professionals should monitor blood glucose levels and prescribe alternative therapy for hyperglycemia in these patients.

If patients miss a dose, they should take it as soon as they remember it but should not double their next dose.

Contraindications⁴

Health care professionals should not prescribe empagliflozin if patients are hypersensitive to empagliflozin or any component used in the tablets. If hypersensitivity develops, health care professionals should treat and monitor these patients until their symptoms subside.

Empagliflozin is contraindicated in patients undergoing dialysis.

Pregnancy and lactation⁴

Hyperglycemia during pregnancy can cause several issues for the mother and fetus necessitating tight control of blood sugar in pregnant women. Empagliflozin crosses the blood-placental barrier and has caused kidney damage in rat fetuses if used during a period corresponding to the second and third trimesters of humans.

Empagliflozin also crosses into the milk in lactating rats and therefore has the potential to cause kidney and other developmental issues in the newborn. Patients should notify their prescribers if they plan to or become pregnant and health care professionals should not use empagliflozin during pregnancy and lactation.

Other populations⁴

Health care professionals should not use empagliflozin in pediatric patients and should be aware of empagliflozin’s capacity to cause higher incidence of adverse effects in elderly patients or those with renal dysfunction.

About the Author

Alok Sharma is a professor of Pharmaceutical Sciences at Massachusetts College of Pharmacy and Health Sciences in Manchester, NH.

References

1. Type 2 Diabetes: Gateway to Health Communication (CDC). Accessed May 12, 2022. https://www.cdc.gov/diabetes/basics/type2.html

2. Jardiance full prescribing information. August 2014. Accessed May 17, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf

3. Jardiance full prescribing information. December 2016. Accessed May 17, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204629s008lbl.pdf

4. Jardiance full prescribing information. August 2021. Accessed May 18, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/204629s026lbl.pdf

5. Ghezzi C, Loo DDF, Wright EM. Physiology of Renal Glucose Handling via SGLT1, SGLT2 and GLUT2. Diabetologia. 2018;61(10): 2087-2097. doi: 10.1007/s00125-018-4656-5

6. Ndefo UA, Anidiobi NO, Basheer E, Eaton AE. Empagliflozin (Jardiance): A Novel SGLT2 Inhibitor for the Treatment of Type-2 Diabetes. Pharmacy & Therapeutics. 2015;40(6): 364-368.