empagliflozin/linagliptin

General

Pronunciation:
em-pag-gli-floe-zin/lin-a-glip-tin


Trade Name(s)

  • Glyxambi

Ther. Class.
antidiabetics

Pharm. Class.
sodium-glucose co-transporter 2 (SGLT2) inhibitors
dipeptidyl peptidase-4 (DDP-4) inhibitors

Indications

  • Adjunct to diet and exercise in the management of type 2 diabetes mellitus.
  • To reduce risk of cardiovascular death in patients with type 2 diabetes and established cardiovascular disease

Action

  • Empagliflozin–Inhibits proximal renal tubular sodium-glucose co-transporter 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 Effect(s):

  • 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 and 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 and Excretion: Approximately 90% excreted unchanged in urine; minimally metabolized.

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

TIME/ACTION PROFILE (decrease in HbA1c)

ROUTEONSETPEAKDURATION
empagliflozin POwithin 6 wk12 wkunknown
linagliptin POunknown1.5 hr†24 hr
†Blood level.

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity
  • Severe renal impairment (eGFR <30 mL/min/1.73 m2/end-stage renal disease/dialysis)
  • Type 1 diabetes;
  • Diabetic ketoacidosis;
  • Lactation: Avoid use, discontinue breastfeeding or discontinue empagliflozin;

Use Cautiously in:

  • Moderate renal impairment (eGFR 30–<45 mL/min/1.73 m2); use not recommended;
  • Hypotension (correct prior to treatment, especially in renal impairment, age >65 yr, or concurrent use of loop diuretics, ACE inhibitors, or ARBs
  • History of bladder cancer;
  • History of pancreatitis, pancreatic surgery, reduced caloric intake due to illness or surgery, or alcohol abuse (↑ risk of ketoacidosis);
  • Hypovolemia, chronic kidney disease, HF (↑ risk of acute kidney injury);
  • History of HF or renal impairment (↑ risk of HF)
  • Geri: ↑ risk of adverse reactions related to ↓ intravascular volume;
  • OB: Use during pregnancy only if clearly needed;
  • Pedi: Safe and effective use in children <18 yr has not been established.

Adverse Reactions/Side Effects

Empagliflozin

CV: hypotension, volume depletion

GU: UROSEPSIS, acute kidney injury, genital mycotic infections, ↑ urination, urinary tract infections (including pyelonephritis), renal impairment

Endo: hypoglycemia (↑with other medications)

F and E: KETOACIDOSIS, hyperphosphatemia

Metabolic: hyperlipidemia

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANGIOEDEMA)

Linagliptin

CV: HF

Resp: bronchial hyperreactivity

GI: PANCREATITIS

Derm: bullous pemphigoid, localized exfoliation, urticaria

Metabolic: hypoglycemia, hypertriglyceridemia

Misc: hypersensitivity reactions including angioedema

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Empagliflozin

Drug-Drug

  • ↑ risk of hypotension with antihypertensives or diuretics.
  • ↑ risk of hypoglycemia with other antidiabetics (dose adjustments maybe required).
  • ↑ risk of acute kidney injury with diuretics, ACE inhibitors, angiotensin receptor blockers, or NSAIDs.

Interactions

Linagliptin

Drug-Drug

  • ↑ risk of hypoglycemia with sulfonylureas or insulin; dose ↓ of sulfonylurea or insulin may be necessary.
  • Concurrent use of P-glycoprotein or CYP3A4 inducers, including rifampin may ↓ blood levels and effectiveness and should be avoided.

Route/Dosage

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

Availability

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 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 hemoglobin 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 <45 mL/min/1.73 m2. Discontinue therapy if eGFR is persistently <45 mL/min/1.73 m2.
  • May cause ↑ serum phosphate levels. Monitor electrolytes periodically during therapy.
  • May cause ↑ LDL-C. Monitor serum lipid levels periodically during therapy.
  • May cause ↑ hematocrit.
  • May cause ↑ uric acid levels.

Potential Diagnoses

Implementation

  • Patients stabilized on a diabetic regimen who are exposed to stress, fever, trauma, infection, or surgery may require administration of insulin.
  • 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 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 tsp 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 notify health care professional promptly if signs and symptoms of pancreatitis, 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.
  • Advise patient 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.

Evaluation/Desired Outcomes

Improved hemoglobin A1C and glycemic control in adults with Type 2 diabetes.

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