Empagliflozin


Article Author:
Omeed Sizar


Article Editor:
Raja Talati


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Evelyn Metz
Julie Sewell
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Tehmina Warsi


Updated:
5/16/2019 1:53:02 PM

Indications

Empagliflozin is an antidiabetic agent used in adult patients with type 2 diabetes mellitus. It was FDA-approved in 2014. Empagliflozin can be used as a single agent or as a combination agent with other antidiabetic products. Combination products include empagliflozin and linagliptin, and empagliflozin in combination with metformin. These newer agents can be more expensive for patients thus impeding the physician's ability to prescribe them based on patient financial considerations. However, the American Diabetes Association (ADA) is calling for agents with proven mortality reduction to be used as second-line therapy after metformin. Such agents include empagliflozin and liraglutide. The primary treatment for diabetes is lifestyle management and exercise, followed by metformin use. Per Standards of Medical Care in Diabetes, if the A1c is greater than 9%, then combination therapy with metformin is recommended. In 2016, the FDA (United States Food and Drug Administration) approved a new indication for empagliflozin, which was to reduce the risk of cardiovascular death in adult patients with type 2 diabetes and cardiovascular disease. Empagliflozin has been shown to reduce hospitalizations for heart failure and death from cardiovascular causes. Patients are at an increased risk of cardiovascular mortality with type 2 diabetes, so prescribers should be made aware of the benefits of empagliflozin.[1][2][3]

Mechanism of Action

Empagliflozin works by inhibiting the sodium glucose co-transporter-2 (SGLT-2) found in the proximal tubules in the kidneys. Through SGLT2 inhibition, empagliflozin reduces renal reabsorption of glucose and increases urinary excretion of glucose. In type 2 diabetes patients, urinary glucose excretion increased by approximately 64 grams per day with 10mg of empagliflozin and 78 grams per day with 25mg. Empagliflozin reduces sodium and volume load causing intravascular contraction through its diuretic and natriuretic properties[4]. Moreover, empagliflozin is associated with weight loss, with reductions in blood pressure without an increase in heart rate.

Administration

Empagliflozin is an oral medication dosed at either 10mg daily or 25mg daily. The recommended dose is 10mg once daily in the morning taken with or without food. If tolerated at the initial, dosing may be increased to 25mg.

Adverse Effects

Empagliflozin has several adverse effects to be of note including hypotension, ketoacidosis, acute kidney injury, genital mycotic infections, hypoglycemia when used with insulin, dyslipidemia, Fournier gangrene, and pyelonephritis.

Empagliflozin causes intravascular volume contraction and thus can cause symptomatic hypotension particularly in patients on diuretics, the elderly, patients with renal impairment, and patients with low systolic blood pressure. Empagliflozin increases serum creatinine and decreases eGFR. Renal function should thus be initially evaluated and further monitored periodically. Use of Empagliflozin is not recommended if GFR is less than 45mL/min and when GFR is less than 30 mL/min/1.73m2 it is contraindicated.

Empagliflozin is associated with ketoacidosis, particularly in patients with type 1 diabetes which is why it is not used in that patient population. Factors predisposing to ketoacidosis are pancreatic disorders, history of pancreatitis, pancreatic surgery, alcohol abuse.

Hypoglycemia risk increases when Empagliflozin is used in combination with a sulfonylurea or insulin. Use caution if co-prescribing and consider lowering the sulfonylurea dose.

Empagliflozin increases the risk for genital mycotic infections and urinary tract infections. Evaluate for signs and symptoms and treat appropriately. Male genital mycotic infections include balanitis, balanoposthitis, scrotal abscess, and penile infection. Female mycotic infections include vulvitis and vulvovaginal candidiasis. In women, urinary tract infections and genital mycotic infections were more common than in males.

A rare but serious bacterial infection is necrotizing fasciitis of the perineum; Fournier gangrene. Symptoms begin as early as week one of treatment and as late as two years after starting the medication. Patients taking SGLT2 inhibitors should be counseled about the risk for necrotizing fasciitis of the perineum. Confirmed infections should be reported to the FDA.

Contraindications

In instances of severe renal impairment, defined as GFR less than 30/mL/min/1.73m2, empagliflozin is contraindicated. Use of Empagliflozin is not recommended if GFR is less than 45mL/min. Other contraindications include those with end-stage renal disease, those on dialysis, and those with a severe hypersensitivity reaction to empagliflozin. Empagliflozin may be used in cases of hepatic impairment. Empagliflozin is not to be used for patients with Type 1 diabetes or those with diabetic ketoacidosis.

Monitoring

Monitoring for empagliflozin includes a hemoglobin A1c (HbA1c) reading every 3 to 6 months. Renal function, blood pressure, lipid profile, and pregnancy test need to be checked before initiation. Empagliflozin should not be given during the second and third trimester of pregnancy due to a potential fetal risk. Renal function and blood pressure are routinely monitored during treatment course due to effects on intravascular contraction. Moreover, patient’s should be asked whether they experience any urinary symptoms or issues to rule out mycotic and urinary tract infections. Geriatric patients are more prone to suffering adverse effects related to reduced renal function and volume depletion. Patients should be carefully monitored for hypoglycemia and hypotension if they are co-prescribed insulin, sulfonylureas, or diuretics.

Toxicity

The most commonly reported side effects were urinary tract infections, genital mycotic infections, and dyslipidemia. Due to its diuretic properties related to volume depletion, dehydration, hypotension, hypovolemia, and syncope were also reported. The FDA issued a warning for Fournier gangrene, a type of necrotizing fasciitis of the perineum. There were twelve reported cases, and all twelve were hospitalized requiring surgical debridement. If suspected, stop the drug and have the patient report to the ED promptly for a surgical evaluation. [5][6]

Enhancing Healthcare Team Outcomes

The landmark trial for Empagliflozin is called the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes mellitus patients (EMPA REG OUTCOME) which pooled a total of 7020 patients and found significantly lower rates of death from cardiovascular causes, hospitalizations for heart failure, and death from any co-transporter in the empagliflozin group[7]. This trial was the first of its kind to show a reduction in cardiovascular death in patients with type 2 diabetes and cardiovascular risk.  Due to findings in the EMPA REG and LEADER trial, societies are now favoring SGLT2 inhibitors and GLP 1 agonists as second-line therapy over insulin depending on patient characteristics. According to the Efficacy and Durability of Initial Combination (EDICT) for Type 2 diabetes trial, triple dose combination therapy of metformin, SGLT 2 inhibitor, and pioglitazone in patients with newly diagnosed type 2 diabetes had a greater reduction in HbA1c levels than patients who sequentially added on therapy with medications[8].


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Empagliflozin - Questions

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A 76-year-old male with a history of congestive heart failure, coronary heart disease, and type 2 diabetes mellitus is prescribed empagliflozin. The patient's current medications include metformin, furosemide, aspirin, atorvastatin, carvedilol, and losartan. What should the prescriber be aware of when adding empagliflozin to his current medications?



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What is the mechanism of action of empagliflozin?



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A 74-year-old male with a PMH of coronary heart disease, congestive heart failure, and type 2 diabetes was just started on empagliflozin 2 weeks ago. The patient's last A1c was 8.5% 2 weeks ago. The patient is now complaining of dysuria and itching around the genitals. What should be considered?



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Empagliflozin - References

References

Heise T,Jordan J,Wanner C,Heer M,Macha S,Mattheus M,Lund SS,Woerle HJ,Broedl UC, Acute Pharmacodynamic Effects of Empagliflozin With and Without Diuretic Agents in Patients With Type 2 Diabetes Mellitus. Clinical therapeutics. 2016 Oct     [PubMed]
Zinman B,Wanner C,Lachin JM,Fitchett D,Bluhmki E,Hantel S,Mattheus M,Devins T,Johansen OE,Woerle HJ,Broedl UC,Inzucchi SE, Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine. 2015 Nov 26     [PubMed]
Abdul-Ghani MA,Puckett C,Triplitt C,Maggs D,Adams J,Cersosimo E,DeFronzo RA, Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes, obesity     [PubMed]
Home P, Cardiovascular outcome trials of glucose-lowering medications: an update. Diabetologia. 2019 Jan 3;     [PubMed]
Fitchett D,Inzucchi SE,Cannon CP,McGuire DK,Scirica BM,Johansen OE,Sambevski S,Kaspers S,Pfarr E,George JT,Zinman B, Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial. Circulation. 2018 Dec 6;     [PubMed]
Schwaiger E,Burghart L,Signorini L,Ristl R,Kopecky C,Tura A,Pacini G,Wrba T,Antlanger M,Schmaldienst S,Werzowa J,Säemann MD,Hecking M, Empagliflozin in posttransplantation diabetes mellitus: A prospective, interventional pilot study on glucose metabolism, fluid volume and patient safety. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018 Dec 26;     [PubMed]
Smyth B,Perkovic V, New hypoglycemic agents and the kidney: what do the major trials tell us? F1000Research. 2018;     [PubMed]
Cheng JWM,Colucci VJ,Kalus JS,Spinler SA, Managing Diabetes and Preventing Heart Disease: Have We Found a Safe and Effective Agent? The Annals of pharmacotherapy. 2018 Dec 5;     [PubMed]

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