Empagliflozin and Linagliptin
Medically reviewed by Drugs.com. Last updated on Jul 23, 2020.
(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, treatment: 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. Due to lack of additive glycemic benefit, use of linagliptin in combination with a glucagon-like peptide-1 (GLP-1) receptor agonist should be avoided (ADA/EASD [Davies 2018]). May require a gradual dose reduction of insulin and/or insulin secretagogues to avoid hypoglycemia.
Diabetes mellitus, type 2, treatment:
Note: Additional therapeutic considerations may apply; refer to individual agents for information.
Oral: Initial: Empagliflozin 10 mg/linagliptin 5 mg once daily; may increase to empagliflozin 25 mg/linagliptin 5 mg once daily
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Refer to adult dosing.
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 20°C to 25°C (68°F to 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 Agents with Blood Glucose Lowering Effects. 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
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 concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. 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
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
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 (SGLT2) 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
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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 Agents with Blood Glucose Lowering Effects. Monitor therapy
Nitisinone: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any 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
Pretomanid: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. 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 Agents with Blood Glucose Lowering Effects. 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 Agents with Blood Glucose Lowering Effects. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) 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 OAT1/3 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
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
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 dipeptidyl peptidase 4 (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 sodium glucose cotransporter 2 (SGLT2) inhibitors in some clinical trials. However, meta-analyses of trial data for empagliflozin have not demonstrated increased risk of fracture (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 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, angiotensin-converting-enzyme [ACE] inhibitors, or angiotensin receptor blockers [ARBs]), or those with low systolic BP. 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 SGLT2 inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy at least 3 days prior to surgery or any event that may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. 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.
• Lower limb amputation: There is conflicting data involving the risk of lower limb amputations with SGLT2 inhibitor therapy. Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Neal 2017). Trials involving empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Inzucchi 2018; Khouri 2018). The following FDA guidance (developed specifically for canagliflozin) may reasonably apply to use of other SGLT2 inhibitors: Prior to initiation consider risk factors for amputation including prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of preventative foot care. Discontinue therapy if any of the following occur: signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs (FDA Drug Safety Communication 2017).
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving empagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.
• 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, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, ARBs, or nonsteroidal anti-inflammatory drugs]). 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.
• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported with empagliflozin; treatment with SGLT2 inhibitors increases the risk for urinary tract infections (UTIs); monitor for signs and symptoms of UTI and treat as needed.
• Bariatric surgery:
– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2013; Melissas 2013).
– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2013).
– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.
– Glucagon-like peptide-1 exposure and therapeutic efficacy: Closely monitor for signs and symptoms of pancreatitis; gastric bypass and sleeve gastrectomy may increase endogenous secretion of glucagon-like peptide-1 (Korner 2009; Peterli 2012). A single-dose, placebo-controlled study evaluated short-term therapy (4 weeks) with sitagliptin in gastric bypass patients having persistent or recurrent type 2 diabetes and found it to be well tolerated and provided a small but significant reduction in postprandial blood glucose (Shah 2018).
• Cardiovascular disease: 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 (HF). However, in a randomized, double-blind, placebo-controlled trial of patients with type 2 diabetes mellitus and high cardiovascular and renal risks, the occurrence of the primary composite cardiovascular outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) with linagliptin was found to be noninferior to placebo. In addition, the rate of hospitalization for HF did not differ from placebo, including in patients with preexisting HF. Median follow-up was 2.2 years (McGuire 2018; Rosenstock 2018). The American Diabetes Association suggests DPP-4 inhibitors (except saxagliptin) may be considered in patients with HF (ADA 2020).
• 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), end-stage renal disease, 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).
• 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 or patients with type 1 diabetes mellitus.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for hospitalized patients (ADA 2020).
• Patient education: Diabetes self-management education is essential to maximize the effectiveness of therapy.
• Surgical procedures: Consider temporary discontinuation of empagliflozin-containing products at least 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating 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 2020); renal function (baseline and periodically during treatment); volume status (eg, BP, hematocrit, electrolytes); genital mycotic infections and urinary tract infection; BP; signs and symptoms of pancreatitis; signs and symptoms of heart failure; if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).
According to the manufacturer, use is not recommended during the second and third trimesters. Refer to individual monographs.
What is this drug used for?
• It is used to lower blood sugar in patients with high blood sugar (diabetes).
• It is used to lower the chance of death from heart disease in certain people.
All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
• Sore throat
• Stuffy nose
• Common cold symptoms
WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
• Heart problems like 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
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Pain, swelling, or infection in the genitals or rectum
• Vaginal yeast infection
• Penile yeast infection
• Severe headache
• Severe joint pain
• Persistent joint pain
• Skin blisters
• Skin breakdown
• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.
More about empagliflozin / linagliptin
- Side Effects
- During Pregnancy
- Dosage Information
- Drug Interactions
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- Drug class: antidiabetic combinations
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