Empagliflozin and Linagliptin
Medically reviewed on September 10, 2018
(em pa gli FLOE zin & lin a GLIP tin)
- Linagliptin and Empagliflozin
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Glyxambi: Empagliflozin 10 mg and linagliptin 5 mg, Empagliflozin 25 mg and linagliptin 5 mg [contains corn starch]
Brand Names: U.S.
- Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor
- Antidiabetic Agent, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
- Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
Empagliflozin: By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, empagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.
Linagliptin: Inhibits dipeptidyl peptidase 4 (DPP-4) enzyme resulting in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. Decreased glucagon secretion results in decreased hepatic glucose production. Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal; incretin hormones are rapidly inactivated by the DPP-4 enzyme.
Use: Labeled Indications
Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate. Note: Empagliflozin is indicated for risk reduction of cardiovascular mortality in adults with type 2 diabetes mellitus and established cardiovascular disease.
History of serious hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions, urticaria, bronchial hyperreactivity) to empagliflozin, linagliptin, or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m2), ESRD, or dialysis
Canadian labeling: Additional contraindications (not in the US labeling): Diabetic ketoacidosis; type 1 diabetes mellitus; eGFR <45 mL/minute/1.73 m2
Note: If present, correct volume depletion prior to initiation.
Diabetes mellitus, type 2: Oral: Initial: Empagliflozin 10 mg/linagliptin 5 mg once daily; may increase to empagliflozin 25 mg/linagliptin 5 mg once daily
Refer to adult dosing.
Dosing: Renal Impairment
eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 30 to <45 mL/minute/1.73 m2: The manufacturer recommends to not initiate therapy, or in patients already taking empagliflozin, to discontinue therapy when eGFR is persistently <45 mL/minute/1.73 m2. Refer also to individual agents.
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
End-stage renal disease (ESRD) or dialysis: Use is contraindicated.
Dosing: Hepatic Impairment
No dosage adjustment necessary.
Oral: Administer once daily in the morning, with or without food.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Dipeptidyl Peptidase-IV Inhibitors may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy
Antihepaciviral Combination Products: May increase the serum concentration of Linagliptin. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
Insulins: Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Insulins: Dipeptidyl Peptidase-IV Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Loop Diuretics: Empagliflozin may enhance the hypotensive effect of Loop Diuretics. Monitor therapy
Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy
Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification
Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy
Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Ritonavir: May increase the serum concentration of Linagliptin. Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Sulfonylureas: Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Sulfonylureas: Dipeptidyl Peptidase-IV Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Teriflunomide: May increase the serum concentration of OAT3 Substrates. Monitor therapy
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Tolvaptan: May increase the serum concentration of OAT3 Substrates. Consider therapy modification
See individual monographs for additional adverse effects reported with each agent.
>10%: Genitourinary: Urinary tract infection (11% to 13%)
1% to 10%:
Endocrine & metabolic: Hypoglycemia (2% to 4%)
Respiratory: Upper respiratory tract infection (7%), nasopharyngitis (6% to 7%)
Frequency not defined:
Endocrine & metabolic: Increased serum cholesterol
Hematologic & oncologic: Increased hematocrit
<1%, postmarketing, and/or case reports: Ketoacidosis, oral mucosa ulcer, pyelonephritis, stomatitis, urosepsis
Concerns related to adverse effects:
• Arthralgia: Severe and disabling arthralgia has been reported with DPP-4 inhibitor use; onset may occur within 1 day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy resumed.
• Bone fractures: An increased incidence of bone fractures has been observed with other SGLT2 inhibitors in some clinical trials. However, meta-analyses of trial data for canagliflozin, dapagliflozin, and empagliflozin have not demonstrated increased risk of fracture overall (Ruanpeng 2017; Tang 2016).
• Bullous pemphigoid: DPP-4 inhibitor use has been associated with development of bullous pemphigoid; cases have typically resolved with topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor therapy. Advise patients to report development of blisters or erosions. Discontinue therapy if bullous pemphigoid is suspected and consider referral to a dermatologist.
• Genital mycotic infections: Empagliflozin may increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.
• Hypersensitivity reactions: Rare hypersensitivity reactions (including anaphylaxis, angioedema, exfoliative skin conditions, urticaria) have been reported in patients treated with linagliptin or empagliflozin; events have generally been noted within the first 3 months of linagliptin therapy, and may occur with the initial dose. Discontinue if signs/symptoms of hypersensitivity reactions occur. Use is contraindicated in patients with a previous serious hypersensitivity reaction to linagliptin or empagliflozin. Use with caution if patient has experienced angioedema with other DPP-4 inhibitor use.
• Hypotension: Empagliflozin may cause cause symptomatic hypotension due to intravascular volume depletion especially in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m2), elderly, patients on other antihypertensives (eg, diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]), or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose cotransporter 2 (SGLT2) inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL) (Bobart 2016; FDA 2015; Handelsman 2016). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases or discontinuation of insulin, caloric restriction, alcohol abuse, extensive exercise, MI, stroke, severe infection, surgery, any other extreme stress event) (Handelsman 2016). The American Association of Clinical Endocrinologists and American College of Endocrinology recommend considering withholding of SGLT2 inhibitors for at least 24 hours prior to events that may precipitate diabetic ketoacidosis (Handelsman 2016), while others have suggested withholding for 3 to 5 days (Bobart 2016). Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
• Lipid abnormality: Empagliflozin may cause low-density lipoprotein cholesterol (LDL-C) elevation; monitor LDL-C and treat as needed.
• Pancreatitis: Cases of acute pancreatitis, including fatalities, have been reported with linagliptin. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis because it is not known if this population is at greater risk. Empagliflozin/linagliptin has not been studied in patients with a history of pancreatitis.
• Renal effects: Acute kidney injury has been reported with empagliflozin. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, HF, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, or NSAIDs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the EMPA-REG OUTCOMES study, administration of empagliflozin caused early decline in eGFR which tended to stabilize after ~4 weeks (Wanner 2016). Assess renal function prior to initiation and periodically during treatment.
• UTI: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported with empagliflozin; treatment with SGLT2 inhibitors increases the risk for UTIs; monitor for signs and symptoms of UTI and treat as needed.
• Heart failure: In cardiovascular outcome trials of patients with type 2 diabetes and atherosclerotic cardiovascular disease, treatment with other DPP-4 inhibitors has been associated with heart failure. Use linagliptin with caution in patients at risk for heart failure (eg, history of heart failure or renal impairment) and monitor for signs and symptoms of heart failure during therapy; consider discontinuation if heart failure develops.
• Renal impairment: Glycemic efficacy of empagliflozin may be decreased in renal impairment. Assess renal function prior to initiation and periodically during treatment. Use is contraindicated in severe renal impairment (eGFR <30 mL/minute/1.73 m2), ESRD, and in dialysis patients. According to the manufacturer, empagliflozin/linagliptin should not be initiated in patients with eGFR <45 mL/minute/1.73 m2 and should be discontinued when eGFR is persistently <45 mL/minute/1.73 m2. In the EMPA-REG OUTCOME trial, empagliflozin reduced the occurrence of incident or worsening nephropathy (a secondary end-point) in diabetic patients with an eGFR ≥30 mL/minute/1.73 m2 and high cardiovascular risk receiving standard care. Post-hoc analysis suggested that the renal benefits may persist in the subset of patients with baseline renal impairment (eGFR 30 to <60 mL/minute/1.73 m2) (Wanner 2016). An additional post-hoc analysis showed consistent cardiovascular mortality benefits across subgroups with eGFR 30 to <45, 45 to <60, and ≥60 mL/minute/1.73 m2 (Wanner 2018). However, additional trials may be necessary to definitively establish whether empagliflozin improves these outcomes in patients with renal impairment.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Elderly: Use with caution; risk of intravascular volume depletion, renal impairment, and UTI may be increased in elderly patients.
• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.
Blood glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change (ADA 2018a); renal function (baseline and periodically during treatment); volume status (eg, blood pressure, hematocrit, electrolytes); LDL-C; genital mycotic infections and UTI; blood pressure; signs and symptoms of pancreatitis; signs and symptoms of metabolic acidosis; signs and symptoms of heart failure
According to the manufacturer, use is not recommended during the second and third trimesters. Refer to individual monographs.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience pharyngitis, rhinitis, or rhinorrhea. Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), vaginal yeast infection, penile yeast infection, difficulty swallowing, severe headache, severe joint pain, persistent joint pain, skin blisters, skin breakdown, skin edema, or flaking or peeling skin (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
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- Drug class: antidiabetic combinations
Other brands: Glyxambi