Version May 2024
Dosage guidance:
Clinical considerations: Correct hypovolemia, if present, prior to initiation of empagliflozin. May require a gradual dose reduction of insulin and/or insulin secretagogues (eg, sulfonylureas, meglitinides) to avoid hypoglycemia.
Diabetes mellitus, type 2, treatment:
Note: Due to lack of additive glycemic benefit, avoid use of linagliptin in combination with glucagon-like peptide-1 receptor agonist-based therapies (Ref). 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 after 4 to 12 weeks if needed to achieve glycemic goals (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: The glycemic efficacy of empagliflozin decreases as kidney function declines.
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <30 mL/minute/1.73 m2: The US manufacturer does not recommend use. Refer also to individual agents.
Dialysis: Use is contraindicated.
No dosage adjustment necessary.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults. Also see individual agents.
>10%: Genitourinary: Urinary tract infection (11% to 13%)
1% to 10%:
Endocrine & metabolic: Hypoglycemia (2% to 4%)
Respiratory: Nasopharyngitis (6% to 7%), upper respiratory tract infection (7%)
Frequency not defined:
Endocrine & metabolic: Increased serum cholesterol
Hematologic & oncologic: Increased hematocrit
Postmarketing:
Dermatologic: Bullous pemphigoid, exfoliative dermatitis, skin rash, urticaria
Endocrine & metabolic: Ketoacidosis
Gastrointestinal: Acute pancreatitis, constipation, oral mucosa ulcer, stomatitis
Genitourinary: Urinary tract infection with sepsis
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction
Infection: Necrotizing fasciitis (of the perineum [Fournier’s gangrene])
Neuromuscular & skeletal: Rhabdomyolysis, severe arthralgia (including disabling)
Renal: Acute kidney injury, pyelonephritis
History of hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions, urticaria, bronchial hyperreactivity) to empagliflozin, linagliptin, or any component of the formulation; patients on dialysis.
Canadian labeling: Additional contraindications (not in the US labeling): Diabetic ketoacidosis; type 1 diabetes mellitus; eGFR <45 mL/minute/1.73 m2.
Concerns related to adverse effects:
• Arthralgia: Severe and disabling arthralgia has been reported with linagliptin 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 linagliptin or other DPP-4 inhibitor therapy is 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.
• 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. 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; risk may be increased in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m2), who are >75 years of age, who are taking other antihypertensives (eg, diuretics, angiotensin-converting-enzyme [ACE] inhibitors, or angiotensin receptor blockers [ARBs]), or with low systolic BP.
• 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.
• 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). 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.
• 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.
• Pancreatitis: Cases of acute pancreatitis, including fatalities, have been reported with linagliptin. Use with caution in patients with a history of pancreatitis because it is not known if this population is at greater risk; has not been studied. Discontinue use and institute appropriate therapy if pancreatitis is suspected.
• 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]). 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, but also an overall reduction in adverse kidney outcomes (eg, initiation of renal replacement therapy, doubling of serum creatinine with eGFR ≤45 mL/minute/1.73 m2, progression to macroalbuminuria, death from kidney disease) (Wanner 2016).
• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported with empagliflozin; treatment with empagliflozin increases the risk for urinary tract infections (UTIs).
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; 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 2020).
– 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 2023).
Special populations:
• Older adult: Use with caution; risk of intravascular volume depletion, renal impairment, and UTI may be increased in patients >75 years of age.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or for glycemic control in patients with type 1 diabetes mellitus.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for glycemic control in hospitalized patients (ADA 2023).
• 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Glyxambi: Empagliflozin 10 mg and linagliptin 5 mg, Empagliflozin 25 mg and linagliptin 5 mg [contains corn starch]
No
Tablets (Glyxambi Oral)
10-5 mg (per each): $24.44
25-5 mg (per each): $24.44
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Glyxambi: Empagliflozin 10 mg and linagliptin 5 mg [DSC], Empagliflozin 25 mg and linagliptin 5 mg [DSC] [contains corn starch]
Oral: Administer once daily in the morning, with or without food.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Glyxambi: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/206073s036lbl.pdf#page=34
Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Note: Empagliflozin is indicated for risk reduction of cardiovascular mortality in adults with type 2 diabetes mellitus and established cardiovascular disease.
Beers Criteria: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to increased risk of urogenital infections, especially in women during the first month of use. In addition, a higher risk of euglycemic diabetic ketoacidosis has been observed in older adults (Beers Criteria [AGS 2023]).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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. Risk C: Monitor therapy
Antihepaciviral Combination Products: May increase the serum concentration of LinaGLIPtin. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of LinaGLIPtin. Risk C: 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. Risk D: Consider therapy modification
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification
Lithium: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Loop Diuretics: Empagliflozin may enhance the hypotensive effect of Loop Diuretics. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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. Risk D: Consider therapy modification
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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 (SGLT2) inhibitor and monitor patients for hypoglycemia. Risk D: 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. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
According to the manufacturer, use is not recommended during the second and third trimesters.
Refer to individual monographs for information related to the treatment of diabetes mellitus in pregnancy.
It is not known if empagliflozin or linagliptin is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.
Refer to individual monographs for additional information.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Blood glucose; renal function (baseline and periodically during treatment); volume status (eg, BP, signs and symptoms of hypotension, hematocrit, electrolytes); signs and symptoms of genital mycotic infection and urinary tract infection; assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis; signs and symptoms of diabetic foot infection (including osteomyelitis), including new pain or tenderness, sores or ulcers involving the lower limbs; 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]).
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2023; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (AACE [Samson 2023]; ADA 2023):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (SI: <10 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2023): Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (healthy); 90 to 150 mg/dL (SI: 5 to 8.3 mmol/L) (complex/intermediate health); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (SI: 4.4 to 10 mmol/L) (healthy); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (complex/intermediate health); 110 to 200 mg/dL (SI: 6.1 to 11.1 mmol/L) (very complex/poor health).
Classification of hypoglycemia (ADA 2023):
Level 1: 54 to 70 mg/dL (SI: 3 to 3.9 mmol/L); hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL (SI: <3 mmol/L); threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
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.
See individual agents.
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