empagliflozin/linagliptin

Empagliflozin: Inhibits proximal renal tubular sodium-glucose cotransporter 2 (SGLT2), which determines reabsorption of glucose from the tubular lumen. Inhibits reabsorption of glucose, lowers renal threshold for glucose, and increases excretion of glucose in urine.
Linagliptin: Inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), which slows the inactivation of incretin hormones, resulting in increased levels of active incretin hormones. These hormones are released by the intestine throughout the day and are involved in regulation of glucose. Increased/prolonged incretin levels increase insulin release and decrease glucagon levels.

Therapeutic effects:

Improved glycemic control.
Reduced death due to cardiovascular causes.

Pharmacokinetics ⬆ ⬇

Empagliflozin

Absorption: Well absorbed following oral administration.

Distribution: Enters red blood cells; remainder of distribution unknown.

Metabolism/Excretion: Minimally metabolized; excreted in feces (41.2% mostly as unchanged drug) and urine (54.4% half as unchanged drug, half as metabolites).

Half-Life: 12.4 hr.

Linagliptin

Absorption: 30% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Metabolism/Excretion: Approximately 90% excreted unchanged in urine; minimally metabolized.

Half-Life: >100 hr (due to saturable binding to DPP-4).

Time/Action Profile ⬆ ⬇

(↓ in A1c)

ROUTE	ONSET	PEAK	DURATION
empagliflozin (PO)	within 6 wk	12 wk	unknown
linagliptin (PO)	unknown	1.5 hr‡	24 hr

‡Plasma concentrations.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Severe renal impairment (eGFR <30 mL/min/1.73 m²/end-stage renal disease/dialysis);
Type 1 diabetes;
Diabetic ketoacidosis;
OB: Avoid use during 2nd and 3rd trimesters (may lead to renal impairment in fetus);
Lactation: Lactation.

Use Cautiously in:

eGFR <60 mL/min/1.73 m² or concurrent use of loop diuretics (↑ risk of volume depletion or hypotension);
History of pancreatitis, pancreatic surgery, reduced caloric intake due to illness or surgery, or alcohol abuse (↑ risk of ketoacidosis);
History of HF or renal impairment (↑ risk of HF);
Previous amputation, peripheral vascular disease, neuropathy, or diabetic foot infection (↑ risk of lower limb amputation);
Pedi: Safety and effectiveness not established in children;
Geri: Empagliflozin appears on Beers list. Older adults may have risk of urogenital infections (especially women in the 1st mo of treatment) and euglycemic diabetic ketoacidosis. Use with caution in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

Empagliflozin

CV: hypotension, volume depletion

Endo: hypoglycemia (↑with other medications)

F and E: hyperphosphatemia, KETOACIDOSIS

GU: ↑urination, acute kidney injury, genital mycotic infections, NECROTIZING FASCIITIS OF PERINEUM (FOURNIER'S GANGRENE), renal impairment, urinary tract infections (including pyelonephritis), UROSEPSIS

Metab: hyperlipidemia

MS: lower limb amputation

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANGIOEDEMA)

Linagliptin

CV: HF

Derm: bullous pemphigoid, localized exfoliation, urticaria

GI: PANCREATITIS

Metab: hypoglycemia, hypertriglyceridemia

MS: RHABDOMYOLYSIS

Resp: bronchial hyperreactivity

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANGIOEDEMA)

Interactions ⬆ ⬇

Drug-drug:

↑risk of hypotension when empagliflozin is used with antihypertensives or diuretics.
↑risk of hypoglycemia with sulfonylureas or insulin; dose ↓ of sulfonylurea or insulin may be necessary.
↑risk of acute kidney injury when empagliflozin is used with diuretics, ACE inhibitors, angiotensin receptor blockers, or NSAIDs.
Concurrent use of P-glycoprotein inducers or CYP3A4 inducers, including rifampin, may ↓ linagliptin levels and effectiveness; avoid concurrent use.
Empagliflozin may ↓ lithium levels and effectiveness.

Route/Dosage ⬆ ⬇

PO (Adults ): Empagliflozin 10 mg/linagliptin 5 mg once daily; may ↑ to empagliflozin 25 mg/linagliptin 5 mg once daily.

Availability ⬆ ⬇

(Generic available)

Tablets: empagliflozin 10 mg/linagliptin 5 mg; empagliflozin 25 mg/linagliptin 5 mg

Assessment ⬆ ⬇

Observe patient for signs and symptoms of hypoglycemic reactions (sweating, hunger, weakness, dizziness, confusion, headache, tremor, tachycardia, irritability, drowsiness).
Monitor for signs and symptoms of volume depletion (dizziness, feeling faint, weakness, orthostatic hypotension) after initiating therapy, especially in elderly patients and patients with renal impairment, low systolic BP, or on diuretics.
Monitor for infection, new pain, tenderness, erythema, swelling, sores, or ulcers involving lower limbs, with fever or malaise; discontinue Glyxambi if these occur.
Monitor for signs of pancreatitis (nausea, vomiting, anorexia, persistent severe abdominal pain, sometimes radiating to the back) during therapy. If pancreatitis occurs, discontinue linagliptin and monitor serum and urine amylase, amylase/CCr ratio, electrolytes, serum calcium, glucose, and lipase.
Assess for ketoacidosis in patients presenting with signs and symptoms of dehydration and metabolic acidosis (nausea, vomiting, abdominal pain, malaise, shortness of breath), regardless of blood glucose level. Discontinue Glyxambi and treat promptly (insulin, fluid and caloric replacement) if suspected. Consider risk factors for ketoacidosis (pancreatic insulin deficiency, caloric restriction, alcohol abuse) before starting Glyxambi.
Monitor for signs and symptoms of urinary tract infection (burning during urination, frequent urination, urgency, pain in pelvis, blood in urine, fever, back pain, nausea, vomiting) during therapy. Treat promptly.

Lab Test Considerations:

Monitor A1c prior to and periodically during therapy.
- May ↑ serum creatinine and ↓eGFR. Monitor renal function prior to starting and periodically during therapy. Do not begin therapy if eGFR <30 mL/min/1.73 m². Discontinue therapy if eGFR is persistently <30 mL/min/1.73 m².
- May cause ↑ serum phosphate levels. Monitor electrolytes periodically during therapy.
- May cause ↑ LDL-cholesterol. Monitor serum lipid levels periodically during therapy.
- May cause ↑ hematocrit.
- May cause ↑ uric acid levels.
- Monitor for ketoacidosis, especially during prolonged fasting for illness or surgery. Consider temporarily discontinuing therapy for at least 3 days prior to surgery.

Implementation ⬆ ⬇

Patients stabilized on a diabetic regimen who are exposed to stress, fever, trauma, infection, or surgery may require administration of insulin. Discontinue therapy for at least 3 days before surgery and then resume once patient is clinically stable following surgery and has resumed oral intake.
Correct volume depletion prior to beginning therapy.
PO: Administer once daily in the morning with or without food.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take empagliflozin/linagliptin as directed. Take missed doses as soon as remembered, unless it is almost time for next dose; do not double doses. Advise patient to read the Medication Guide before starting and with each Rx refill; in case of changes.
Explain to patient that empagliflozin/linagliptin helps control hyperglycemia but does not cure diabetes. Therapy is usually long term.
Instruct patient not to share this medication with others, even if they have the same symptoms; it may harm them.
Encourage patient to follow prescribed diet, medication, and exercise regimen to prevent hyperglycemic or hypoglycemic episodes.
Review signs of hypoglycemia and hyperglycemia with patient. If hypoglycemia occurs, advise patient to take a glass of orange juice or 2–3 teaspoons of sugar, honey, or corn syrup dissolved in water, and notify health care professional.
Instruct patient in proper testing of blood glucose and urine ketones. Inform patient that empagliflozin/linagliptin will cause a positive test result when testing for urine glucose. These tests should be monitored closely during periods of stress or illness and health care professional notified if significant changes occur.
Advise patient to inform health care professional of therapy before surgery. Glyxambi should be discontinued for at least 3 days before surgery. Monitor for ketoacidosis during and after surgery. Advise patient to discontinue Glyxambi and to notify health care professional immediately if signs and symptoms of ketoacidosis occur.
Advise patient to notify health care professional if new pain or tenderness, sores or ulcers, or infections involving the leg or foot occur and to immediately seek care if pain or tenderness, redness, or swelling of the genitals or area from the genitals back to the rectum, along with a fever above 100.4°F or malaise, occur.
Advise patient to notify health care professional promptly if signs and symptoms of pancreatitis or HF (shortness of breath, rapid increase in weight, swelling of feet) or if rash; hives; or swelling of face, lips, or throat occur.
Advise patient to notify health care professional if signs and symptoms of hypotension occur and to maintain adequate hydration, as dehydration may increase risk of hypotension.
Inform patient that empagliflozin/linagliptin may cause mycotic (yeast) infections. Women may have signs and symptoms of a vaginal yeast infection (vaginal odor, white or yellow vaginal discharge [may be lumpy or look like cottage cheese], vaginal itching). Men may have signs and symptoms of a yeast infection of the penis (redness, itching, or swelling of penis; rash on penis; foul smelling discharge from penis; pain in skin around penis). Advise patient to notify health care professional if yeast infection occurs.
Advise patient to notify health care professional if signs and symptoms of urinary tract infection (burning feeling when passing urine, cloudy urine, pain in pelvis or back) occur.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially other oral hypoglycemic medications.
Rep: Insulin is the recommended method of controlling blood sugar during pregnancy. Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy.
Encourage patient to follow up with routine lab tests for blood glucose and renal function.

section name header

Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇