AHFS Class:

• Dipeptidyl Peptidase-4 (DPP-4) Inhibitors 68:20.05

Generic Name(s):

• Linagliptin

• Linagliptin and Empagliflozin

• Linagliptin and Metformin Hydrochloride

Chemical Name:

• 8-[(3R)-3-Aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione

Molecular Formula:

• C₂₅H₂₈N₈O₂

Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an antidiabetic agent.1

Type 2 Diabetes Mellitus

Linagliptin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,2,7,8 Linagliptin also is used as initial therapy in combination with metformin hydrochloride as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 Linagliptin also is used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [ thiazolidinedione]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with oral antidiabetic agent monotherapy.1,3,4,5,6 Linagliptin is commercially available in fixed combination with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (Glyxambi^®) or immediate- or extended-release metformin hydrochloride (Jentadueto^®, Jentadueto^® XR, respectively); these fixed-combination preparations are used as adjuncts to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both drugs in the fixed combination is appropriate.70,72,74

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action. 698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,704,705,706 Some experts recommend DPP-4 inhibitors as one of several classes of drugs for use in combination therapy, particularly in patients with both postprandial and fasting plasma glucose elevations.22,698,704 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

The manufacturer states that linagliptin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.1

Linagliptin Monotherapy

Efficacy of linagliptin as monotherapy for the management of type 2 diabetes mellitus has been established in 2 double-blind, placebo-controlled studies of 18 or 24 weeks' duration.1,2,8 Linagliptin (5 mg once daily) improved glycemic control as evidenced by reductions in glycosylated hemoglobin (HbA_1c) as well as in fasting and 2-hour postprandial plasma glucose concentrations.1,2,8 HbA_1c was reduced by a mean of 0.4% (from a mean baseline concentration of about 8%) in patients receiving linagliptin 5 mg daily, compared with an increase in HbA_1c of 0.1-0.3% in those receiving placebo.1,2

Combination Therapy

Efficacy of linagliptin in combination with metformin, an SGLT2 inhibitor, a sulfonylurea, or a thiazolidinedione in the management of type 2 diabetes mellitus has been established in several randomized, placebo- or active-controlled, double-blind studies.1,3,4,5,6,70 In these studies, the addition of linagliptin (5 mg once daily) to current therapy (metformin and/or a sulfonylurea; pioglitazone; metformin and empagliflozin) improved glycemic control as evidenced by reductions in HbA_1c as well as in fasting and/or 2-hour postprandial plasma glucose concentrations.1,3,4,6,70,72,74

Efficacy of the combination of linagliptin and metformin as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise is supported by results of a 24-week, randomized, double-blind trial.1 In this trial, concurrent therapy with linagliptin and metformin hydrochloride improved glycemic control (as evidenced by reductions in HbA_1c and fasting plasma glucose) compared with linagliptin or metformin hydrochloride monotherapy or placebo.1 Reductions in HbA_1c were 1.2 or 1.6% with linagliptin 2.5 mg plus metformin hydrochloride 0.5 or 1 g twice daily, respectively; 0.5% with linagliptin 5 mg once daily; 0.6 or 1.1% with metformin hydrochloride 0.5 or 1 g twice daily, respectively; and 0.1% with placebo.1

In a 24-week study in patients receiving metformin hydrochloride monotherapy (at least 1.5 g daily), add-on therapy with linagliptin resulted in a reduction of 0.5% in HbA_1c compared with an increase of 0.15% in patients receiving metformin hydrochloride and add-on placebo.1,3 In a 104-week, active-controlled, noninferiority study in patients receiving metformin hydrochloride monotherapy (at least 1.5 g daily), add-on therapy with linagliptin was noninferior at 52 weeks and resulted in a reduction of 0.4% in HbA_1c from baseline, compared with a reduction of 0.6% from baseline in patients receiving add-on therapy with glimepiride (initiated at 1 mg daily and titrated over 12 weeks to a maximum dosage of 4 mg daily [mean dosage: 3 mg daily]).1,26 At 104 weeks, add-on therapy with linagliptin resulted in a reduction of 0.2% in HbA_1c from baseline, compared with a reduction of 0.4% from baseline in those receiving add-on glimepiride therapy.1 Patients receiving add-on linagliptin therapy had a mean decrease in body weight (loss of 1.1 kg), while those receiving add-on glimepiride had a mean increase in body weight (gain of 1.4 kg).1 In a 24-week study in treatment-naive patients with type 2 diabetes mellitus, initial therapy with linagliptin and metformin hydrochloride produced substantially greater reductions in HbA_1c compared with linagliptin therapy alone (reduction of 2.9 versus 2%, respectively).72

In a 24-week study in patients receiving pioglitazone monotherapy (30 mg daily), add-on linagliptin or placebo resulted in a reduction of 1.1 or 0.6%, respectively, in HbA_1c.1,4

In an 18-week study in patients receiving a sulfonylurea antidiabetic agent (sulfonylurea not specified), add-on therapy with linagliptin resulted in a reduction of 0.5% in HbA_1c compared with a reduction of 0.1% in patients receiving add-on placebo.1,5

In a 24-week study in patients receiving metformin and a sulfonylurea (generally glimepiride, glyburide [glibenclamide], or gliclazide [not commercially available in the US]), add-on therapy with linagliptin or placebo resulted in a reduction of 0.7 or 0.1%, respectively, in HbA_1c.1,6

In an international, phase 3, randomized, double-blind trial, add-on therapy with linagliptin and empagliflozin in fixed combination was more effective in reducing HbA_1c and fasting plasma glucose concentrations than add-on linagliptin or empagliflozin monotherapy in 686 adults with type 2 diabetes mellitus inadequately controlled with metformin hydrochloride (dosage of at least 1.5 g daily, or maximum tolerated dosage, or maximum labeled dosage).45,70 At 24 weeks, reduction in mean HbA_1c from baseline was 1.19% with linagliptin 5 mg/empagliflozin 25 mg, 1.08% with linagliptin 5 mg/empagliflozin 10 mg, 0.62% with empagliflozin 25 mg, 0.66% with empagliflozin 10 mg, and 0.7% with linagliptin 5 mg.45 Glycemic efficacy (HbA_1c reductions) with the fixed combinations of linagliptin and empagliflozin was maintained at week 52.45,70 The fixed combinations of linagliptin and empagliflozin also were associated with reductions from baseline in systolic blood pressure compared with linagliptin monotherapy.45 Body weight was reduced in patients receiving the fixed combinations of empagliflozin/linagliptin compared with linagliptin but not empagliflozin monotherapy.45,70

Efficacy of linagliptin in combination with insulin in patients with type 2 diabetes mellitus inadequately controlled with insulin (with or without oral antidiabetic agents) is supported by the results of a 24-week randomized, placebo-controlled trial.1 In this trial, addition of linagliptin (5 mg once daily) to existing stable therapy with insulin resulted in improvements in HbA_1c and fasting plasma glucose concentrations at week 24 compared with addition of placebo.1 Mean reductions in HbA_1c were 0.6% in patients receiving linagliptin and 0.1% in those receiving placebo.1

Administration

When administered as monotherapy, linagliptin is administered orally once daily without regard to meals.1

The fixed combination of linagliptin and empagliflozin is administered orally once daily in the morning with or without food.70

The fixed combination of linagliptin and immediate-release metformin hydrochloride is administered orally twice daily with meals.72

The fixed combination of linagliptin and extended-release metformin hydrochloride is administered orally once daily with a meal.74

If a dose of linagliptin alone or in fixed combination with empagliflozin or immediate- or extended-release metformin hydrochloride is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.1,70,72,74 If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed.1,70,72,74 The dose should not be doubled to replace a missed dose.1,70,72,74

Dosage

Type 2 Diabetes Mellitus

Linagliptin Monotherapy

When used as monotherapy for the management of type 2 diabetes mellitus, the recommended dosage of linagliptin is 5 mg once daily.1

Combination Therapy with a Sulfonylurea

When used concomitantly with a sulfonylurea for the management of type 2 diabetes mellitus, the recommended dosage of linagliptin is 5 mg once daily; dosage of the sulfonylurea may need to be reduced to decrease risk of hypoglycemia.1

Linagliptin/Empagliflozin Fixed-combination Therapy

The recommended initial dosage of the fixed combination of linagliptin and empagliflozin is 5 mg of linagliptin and 10 mg of empagliflozin once daily in the morning.70 If this dosage is well tolerated, the dosage may be increased to 5 mg of linagliptin and 25 mg of empagliflozin once daily.70

Linagliptin/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Dosage of the fixed combinations of linagliptin and immediate- or extended-release metformin hydrochloride should be individualized based on effectiveness and patient tolerability.72,74 Dosage of these fixed combinations may be increased up to a daily maximum of 5 mg of linagliptin and 2 g of metformin hydrochloride.72,74

In patients not currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is 5 mg of linagliptin and 1 g of metformin hydrochloride administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).72,74

In patients currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is 5 mg of linagliptin and a total daily metformin hydrochloride dosage similar to the patient's existing dosage, administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).72,74

In patients currently receiving linagliptin and metformin hydrochloride as individual components, the recommended initial dosage of the fixed combination of linagliptin and immediate-release metformin hydrochloride is the same total daily dosage of each component administered in 2 divided doses daily.72

In patients currently receiving linagliptin and metformin hydrochloride as individual components or the fixed combination of linagliptin and immediate-release metformin, the recommended initial dosage of the fixed combination of linagliptin and extended-release metformin is 5 mg of linagliptin and a total daily dosage of metformin hydrochloride similar to the patient's existing dosage, administered once daily.74

Special Populations

Hepatic Impairment

Linagliptin Monotherapy

Dosage adjustment is not routinely required based on hepatic impairment.1

Linagliptin/Empagliflozin Fixed-combination Therapy

The fixed combination of linagliptin and empagliflozin may be used in patients with hepatic impairment.70

Linagliptin/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

The fixed combinations of linagliptin and immediate- or extended-release metformin hydrochloride are not recommended in patients with hepatic impairment.72,74

Renal Impairment

Linagliptin Monotherapy

Dosage adjustment is not routinely required based on renal impairment.1,16

Linagliptin/Empagliflozin Fixed-combination Therapy

Dosage adjustment of the fixed combination of linagliptin and empagliflozin is not necessary in patients with an estimated glomerular filtration rate (eGFR) of at least 45 mL/minute per 1.73 m².70

The fixed combination of linagliptin and empagliflozin should not be initiated in patients with an eGFR less than 45 mL/minute per 1.73 m².70 The fixed combination should be discontinued if the eGFR is persistently less than 45 mL/minute per 1.73 m².70

Linagliptin/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Initiation of the fixed combinations of linagliptin and immediate- or extended-release metformin hydrochloride is not recommended in patients with an eGFR of 30-45 mL/minute per 1.73 m².72,74

If the eGFR decreases to 30-45 mL/minute per 1.73 m² during therapy with a fixed combination of linagliptin and metformin hydrochloride, the risks and benefits of continuing therapy with the fixed combination should be assessed.72,74

The fixed combinations of linagliptin and immediate- or extended-release metformin hydrochloride are contraindicated in patients with an eGFR less than 30 mL/minute per 1.73 m².72,74

If a fixed combination of linagliptin and metformin is discontinued due to evidence of renal impairment, linagliptin may be continued as a single-entity tablet at the same total daily dosage of 5 mg.72,74

Geriatric Patients

Linagliptin Monotherapy

Dosage adjustment of linagliptin is not recommended in geriatric patients based solely on age.1

Contraindications

Linagliptin is contraindicated in patients with a history of hypersensitivity reaction (e.g., anaphylaxis, urticaria, angioedema, bronchial hyperreactivity) to linagliptin.1

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal pancreatitis, has been reported in patients receiving linagliptin therapy.1,72,74 In a multicenter, randomized, placebo-controlled trial evaluating linagliptin, acute pancreatitis was reported in 9 patients receiving linagliptin (0.3%) versus 5 patients receiving placebo (0.1%); 2 patients who developed acute pancreatitis while receiving linagliptin died.72,74

FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cell changes (pancreatic duct metaplasia) in patients with type 2 diabetes mellitus receiving incretin mimetics (alogliptin, exenatide, linagliptin, liraglutide, saxagliptin, and sitagliptin).36,37 These findings are based on examination of a small number of pancreatic tissue specimens taken from patients who died from unspecified causes while receiving an incretin mimetic.36 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when the agency has additional information to report.36

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.36 The manufacturer states that patients receiving linagliptin therapy should be monitored for signs and symptoms of pancreatitis.1,27 (See Advice to Patients.) If pancreatitis is suspected, linagliptin should be promptly discontinued and appropriate management instituted.1,27 Safety and efficacy of linagliptin have not been established in patients with a history of pancreatitis and it is not known whether such patients are at increased risk for pancreatitis with linagliptin therapy.1

Severe Arthralgia

Severe, disabling joint pain has been reported during postmarketing experience in patients receiving dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).1,41 Onset of such symptoms has ranged from 1 day to years following initiation of therapy.1,41 Fever, chills, rash, and swelling accompanied joint pain in some patients, suggesting an immunologic reaction; some patients required hospitalization.41 Symptoms resolved upon discontinuance of the DPP-4 inhibitor, usually in less than a month.1,41 In some patients, symptoms recurred when the same or another DPP-4 inhibitor was restarted.1,41 DPP-4 inhibitors should be considered as a possible cause of severe joint pain and should be discontinued if appropriate.1,41 (See Advice to Patients.)

Heart Failure Risk

In cardiovascular outcomes studies conducted with 2 other DPP-4 inhibitors (alogliptin, saxagliptin) in patients with type 2 diabetes mellitus and ASCVD, an association between DPP-4 inhibitor treatment and heart failure was observed.1,42,43,44 The potential risks and benefits of linagliptin therapy should be considered prior to use in patients at risk for heart failure (e.g., history of heart failure or renal impairment).1 Patients receiving linagliptin-containing therapy should be monitored for manifestations of heart failure.1 (See Advice to Patients.) If heart failure develops, appropriate evaluation and management according to current standards of care should be instituted and consideration given to discontinuing linagliptin.1

Concomitant Therapy with Hypoglycemic Agents

Use of linagliptin in combination with an insulin secretagogue (e.g., a sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial.1 Use of linagliptin in combination with insulin in patients with severe renal impairment also was associated with a higher rate of hypoglycemia compared with placebo in another clinical trial.1 A reduced dosage of an insulin secretagogue or insulin may be required to decrease the risk of hypoglycemia when used in combination with linagliptin.1,27

Dermatologic and Sensitivity Reactions

There have been postmarketing reports of serious allergic and hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative skin conditions) with linagliptin; rash also has been reported.1 The onset of such reactions usually was within the first 3 months following treatment initiation, but such reactions may occur after the first dose.1 (See Cautions: Contraindications.)

If a serious hypersensitivity reaction is suspected, promptly discontinue linagliptin, assess for other potential causes of the event, and initiate alternative antidiabetic therapy.1 (See Advice to Patients.) Linagliptin should be used with caution in patients with a history of angioedema with other DPP-4 inhibitors because it is unknown whether such patients will be predisposed to angioedema with linagliptin.1

Cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use during postmarketing experience.1 These cases usually resolved after discontinuance of the DPP-4 inhibitor and treatment with topical or systemic immunosuppressive therapy.1 In a multicenter, randomized, placebo-controlled trial, bullous pemphigoid was reported in 7 patients (0.2%) receiving linagliptin versus none of the patients receiving placebo.72,74 Patients should be advised to report the development of blisters or erosions while receiving linagliptin.1 If bullous pemphigoid is suspected, the drug should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.1

Macrovascular Outcomes

The manufacturer states that evidence of macrovascular risk reduction with linagliptin has not been conclusively demonstrated in clinical trials.1

Use of Fixed Combinations

When linagliptin is used in fixed combination with empagliflozin, metformin hydrochloride, or other drugs, the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with linagliptin.1,70,72,74

Specific Populations

Pregnancy

Data on use of linagliptin in pregnant women are insufficient to inform a drug-associated risk for major birth defects or miscarriage.1

In animal reproduction studies, no adverse developmental effects were observed when linagliptin was administered to pregnant rats during the period of organogenesis.1

Lactation

Linagliptin is distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 The developmental and health benefits of breast-feeding and the importance of linagliptin to the woman should be considered along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of linagliptin alone or in fixed combination with empagliflozin or fixed combination with immediate- or extended-release metformin hydrochloride have not been established in patients younger than 18 years of age.1,70,72,74

Geriatric Use

Of 4040 patients in clinical studies of linagliptin, 27% were 65 years of age and older and 3% were 75 years of age and older.1 No substantial differences in safety and efficacy relative to younger adults were observed, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh class A), linagliptin area under the concentration-time curve (AUC) and peak plasma concentration were reduced by 25 and 36%, respectively, compared with values in healthy individuals.1 In patients with moderate hepatic impairment (Child-Pugh class B), linagliptin AUC and peak plasma concentration were reduced by 14 and 8%, respectively, compared with values in healthy individuals.1 In patients with severe hepatic impairment (Child-Pugh class C), linagliptin AUC was comparable to that in healthy individuals, and peak plasma concentration was reduced by 23% relative to that in healthy individuals.1

The fixed combination of linagliptin and empagliflozin may be used in patients with hepatic impairment.70

Use of the fixed combinations of linagliptin and immediate- or extended-release metformin hydrochloride is not recommended in patients with hepatic impairment.72,74

Renal Impairment

In patients with mild renal impairment (creatinine clearance 50 to less than 80 mL/minute), linagliptin exposure was comparable to that in healthy individuals.1,16 In patients with moderate renal impairment (creatinine clearance 30 to less than 50 mL/minute), linagliptin AUC and peak plasma concentration were increased by 71 and 46%, respectively, compared with values in healthy individuals.1,16 In patients with severe renal impairment (creatinine clearance less than 30 mL/minute) and type 2 diabetes mellitus, linagliptin AUC and peak plasma concentration were increased by 42 and 35%, respectively, compared with those values in patients with type 2 diabetes mellitus and normal renal function.1

The fixed combination of linagliptin and empagliflozin should not be initiated in patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/minute per 1.73 m².70 (See Renal Impairment under Dosage and Administration: Special Populations.)

Initiation of the fixed combinations of linagliptin and immediate- or extended-release metformin hydrochloride is not recommended in patients with an eGFR between 30-45 mL/minute per 1.73 m² and is contraindicated in patients with an eGFR less than 30 mL/minute per 1.73 m².72,74 (See Renal Impairment under Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in at least 5% of patients receiving linagliptin monotherapy include nasopharyngitis.1

Adverse effects reported in at least 2% of patients receiving linagliptin concomitantly with pioglitazone, a sulfonylurea, metformin, or basal insulin include nasopharyngitis, hyperlipidemia, cough, hypertriglyceridemia, weight gain, urinary tract infection, constipation, back pain, arthralgia, upper respiratory tract infection, headache, and pain in extremity.1

Adverse effects reported in at least 5% of patients receiving linagliptin and empagliflozin in clinical trials include urinary tract infection,70 nasopharyngitis,70 and upper respiratory tract infection.70

Adverse effects reported in at least 5% of patients receiving linagliptin and metformin hydrochloride in clinical trials include nasopharyngitis72,74 and diarrhea.72,74

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Linagliptin is a weak to moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4; however, it does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 4A11 in vitro.1

In vivo studies indicate that drug interactions are unlikely with substrates of CYP isoenzymes 3A4, 2C9, or 2C8.1 No adjustment of linagliptin dosage is recommended based on results of pharmacokinetic studies.1

Inducers of CYP3A4 (e.g., rifampin) decrease exposure to linagliptin, resulting in subtherapeutic and likely ineffective concentrations.1,23 The manufacturer states that alternatives to linagliptin are strongly recommended in patients who require therapy with potent CYP3A4 inducers.1

Drugs Affecting or Affected by P-glycoprotein Transport

Linagliptin is a P-glycoprotein substrate and inhibits P-glycoprotein-mediated transport of digoxin at high concentrations.1 At therapeutic concentrations, linagliptin is considered unlikely to cause interactions with other P-glycoprotein substrates; no adjustment of linagliptin dosage is recommended based on results of pharmacokinetic studies.1

Inducers of P-glycoprotein (e.g., rifampin) decrease exposure to linagliptin, resulting in subtherapeutic and likely ineffective concentrations.1,23 The manufacturer states that alternatives to linagliptin are strongly recommended in patients who require therapy with potent P-glycoprotein inducers.1

Drugs Affected by Organic Cation Transporter

In vivo studies indicate that drug interactions are unlikely with substrates of organic cation transporter (OCT).1 No adjustment of linagliptin dosage is recommended based on results of pharmacokinetic studies.1

Digoxin

Concomitant use of linagliptin (5 mg once daily) and digoxin (0.25 mg once daily) in healthy individuals did not appreciably alter the pharmacokinetics of digoxin (e.g., a 2% increase in area under the concentration-time curve [AUC] and a 6% decrease in peak plasma concentration with concomitant use);1,15 no digoxin dosage adjustment is necessary.15

Estrogens or Progestins

Concomitant use of linagliptin (5 mg once daily) and an estrogen-progestin contraceptive (ethinyl estradiol 30 mcg with levonorgestrel 0.15 mg once daily) increased AUC and peak plasma concentration by 1 and 8%, respectively, for ethinyl estradiol and by 9 and 13%, respectively, for levonorgestrel.1 No dosage adjustments are necessary for ethinyl estradiol or levonorgestrel when given concomitantly with linagliptin.1

Metformin

Concomitant use of linagliptin (10 mg once daily) and metformin hydrochloride (850 mg 3 times daily) in healthy individuals increased linagliptin AUC and peak plasma concentration by 20 and 3%, respectively.1,10 Such concomitant use did not affect metformin AUC but reduced metformin peak plasma concentration by 11%.1,10 These alterations in pharmacokinetic parameters were not associated with clinically relevant effects (e.g., hypoglycemia), and no dosage adjustments are necessary for either drug.10

Pioglitazone

Concomitant use of linagliptin (10 mg once daily) and pioglitazone (45 mg once daily) in healthy individuals increased linagliptin AUC and peak plasma concentration by 13 and 7%, respectively.1,11 Pioglitazone AUC and peak plasma concentration were reduced by 6 and 14%, respectively, during concomitant linagliptin therapy; small changes (5% or less) in AUC and peak plasma concentrations of 2 pioglitazone active metabolites also occurred with such concomitant therapy.1,11 No dosage adjustments are necessary for either drug when given concomitantly.11

Rifampin

Concomitant use of linagliptin (5 mg once daily) and rifampin (600 mg once daily) reduced linagliptin AUC and peak plasma concentration by 40 and 44%, respectively; such concomitant therapy is not recommended.1 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes and see Drugs Affecting or Affected by P-glycoprotein Transport under Drug Interactions.)

Ritonavir

Administration of a single dose of linagliptin (5 mg) to patients receiving ritonavir (200 mg twice daily) resulted in approximately a twofold increase in linagliptin AUC and approximately a threefold increase in linagliptin peak plasma concentration.1 The increase in exposure was not associated with an increase in linagliptin accumulation.26 No adjustment of linagliptin dosage is necessary when linagliptin is administered concurrently with ritonavir.1

Simvastatin

Concomitant use of linagliptin (10 mg once daily) and simvastatin (40 mg once daily) in healthy individuals increased simvastatin AUC and peak plasma concentration by 34 and 10%, respectively; these changes were not considered clinically important.1,12 No simvastatin dosage adjustment is necessary when given concomitantly with linagliptin.1,12

Sulfonylureas

When a sulfonylurea is administered concomitantly with linagliptin, reduction in the dosage of the sulfonylurea may be required to reduce the risk of hypoglycemia.1

A single dose of glyburide (1.75 mg) given on day 6 to healthy individuals receiving linagliptin therapy (5 mg once daily for 6 days) decreased glyburide exposure (AUC and peak plasma concentration) by about 14%; these changes were not considered clinically important.1,13 No dosage adjustments are necessary for either drug when given concomitantly.1

Warfarin

Administration of a single dose of warfarin sodium (10 mg) to healthy individuals receiving linagliptin (5 mg once daily) had no apparent effect (i.e., change of 3% or less) on R - or S -warfarin AUC and peak plasma concentration1 and no clinically relevant effect on international normalized ratio (INR) or prothrombin time (PT); no warfarin dosage adjustment is necessary.14

Description

Linagliptin is a xanthine-derived inhibitor of dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1,2,3,21 The drug selectively inhibits DPP-4 with no effect on DPP-8 or DDP-9 in vitro at concentrations approximating those achieved with therapeutic dosages.1,19 Linagliptin increases the concentrations of active incretin hormones (e.g., GLP-1, GIP), stimulating the release of insulin in a glucose-dependent manner and decreasing circulating levels of glucagon.1,3 GLP-1 and GIP are secreted at low basal levels throughout the day, and levels increase immediately after a meal.1,21 Both incretin hormones increase insulin biosynthesis and secretion from pancreatic β-cells in the presence of normal and elevated blood glucose concentrations.1,21 GLP-1 also reduces glucagon secretion from pancreatic α-cells, resulting in a reduction in hepatic glucose output.1,21

Linagliptin monotherapy usually is not associated with hypoglycemia or substantial changes in body weight.2,7,8

Peak plasma linagliptin concentrations usually are attained within 1.5 hours after a 5-mg oral dose, and the drug has an absolute oral bioavailability of approximately 30%.1,17,18,20 Administration of linagliptin with a high-fat meal reduced peak plasma concentration by 15% and increased area under the concentration-time curve (AUC) by 4%; these changes are not considered clinically important.1 Metabolism represents a minor elimination pathway for linagliptin; approximately 90% of a dose is excreted unchanged.1,20 Following administration of a radiolabeled dose of linagliptin, approximately 85% of administered radioactivity was eliminated via the enterohepatic system (80%) or in urine (5%).1 Terminal half-life of linagliptin exceeds 100 hours; plasma concentrations decline in at least a biphasic manner.1,17,18,20 The effective half-life for accumulation of linagliptin based on 5-mg multiple oral dosing is approximately 12 hours.1

Results of bioequivalence studies indicate that the fixed-combination tablets containing linagliptin and empagliflozin or linagliptin and immediate-release metformin hydrochloride are bioequivalent to single-entity tablets of linagliptin given concomitantly with single-entity tablets of empagliflozin or single-entity tablets of immediate-release metformin hydrochloride, respectively, in corresponding doses.70,72

Advice to Patients

When linagliptin is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).1,70,72,74

Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1,27,70,71,72,73,74,75

Importance of informing patients of the potential risks and benefits of linagliptin and of alternative therapies.1,27 Importance of not using linagliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1,27

Importance of informing patient about possibility of acute pancreatitis, which may be severe or fatal, with linagliptin therapy.1,27 Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or high triglyceride levels.1,27 Importance of informing patients about signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting; importance of patient discontinuing linagliptin and promptly notifying clinician if such signs or symptoms are present.1,27

Importance of informing patients about possibility of heart failure with linagliptin therapy.1 Importance of clinicians asking patients about a history of heart failure or renal impairment prior to initiating linagliptin therapy.1 Importance of informing patients about signs and symptoms of heart failure (e.g., shortness of breath, weight gain, edema); importance of patients immediately contacting a clinician if manifestations of heart failure occur.1

Importance of informing patients of the possibility of severe and disabling joint pain with dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).1,27,41 Advise patients to contact a clinician promptly if severe and persistent joint pain occurs; patients should not discontinue the DPP-4 inhibitor without consulting their clinician.1,27,41

Importance of informing patients that bullous pemphigoid may occur with the use of a DPP-4 inhibitor.1 Advise patients to contact a clinician if blisters or erosions occur.1

Increased risk of hypoglycemia when linagliptin is used in combination with a sulfonylurea or insulin.1,27 Importance of informing patients that a lower dosage of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia if used concomitantly with linagliptin.1,27

Risk of serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions.1 If signs or symptoms of such reactions occur (e.g., rash, blisters, skin flaking or peeling/erosion, hives, swelling of the skin, swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing), importance of discontinuing linagliptin-containing therapy and informing clinician promptly.1

Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA_1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of complications of diabetes mellitus.1,27

Importance of seeking medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as medication requirements may change.1,27

Importance of informing patients that response to all antidiabetic therapies should be monitored by periodic measurements of blood glucose and HbA_1C, with a goal of decreasing these levels toward the normal range.1,27

Importance of informing clinicians if any unusual symptom develops or if any existing symptom persists or worsens.1,27

Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1,27

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,27

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Boehringer Ingelheim. Tradjenta^® (linagliptin) tablets prescribing information. Ridgefield, CT; 2017 Aug.

2. Del Prato S, Barnett AH, Huisman H et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab . 2011; 13:258-67. [PubMed 21205122]

3. Taskinen MR, Rosenstock J, Tamminen I et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab . 2011; 13:65-74. [PubMed 21114605]

4. Gomis R, Espadero RM, Jones R et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab . 2011; 13:653-61. [PubMed 21410628]

5. Lewin AJ, Arvay L, Liu D et al. Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes. Poster presented at the European Association for the Study of Diabetes 46th Annual Meeting. Stockholm, Sweden: 2010 Sept 20-24. Poster 821.

6. Owens DR, Swallow R, Jones P et al. Linagliptin improves glycemic control in type 2 diabetes patients inadequately controlled by metformin and sulfonylurea without weight gain or hypoglycemia. Poster presented at the 70th American Diabetes Association Scientific Sessions. Orlando, Florida: 2010 June 25-29. Poster 548.

7. Forst T, Uhlig-Laske B, Ring A et al. The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus. Diabetes Obes Metab . 2011; 13:542-50. [PubMed 21352464]

8. Barnett AH, Harper R, Toorawa R et al. Linagliptin monotherapy improves glycaemic control in type 2 diabetes patients for whom metformin therapy is inappropriate. Poster presented at the European Association for the Study of Diabetes 46th Annual Meeting. Stockholm, Sweden: 2010 Sept 20-24. Poster 823.

9. Forst T, Uhlig-Laske B, Ring A et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet Med . 2010; 27:1409-19. [PubMed 21059094]

10. Graefe-Mody EU, Padula S, Ring A et al. Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects. Curr Med Res Opin . 2009; 25:1963-72. [PubMed 19552619]

11. Graefe-Mody EU, Jungnik A, Ring A et al. Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers. Int J Clin Pharmacol Ther . 2010; 48:652-61. [PubMed 20875371]

12. Graefe-Mody U, Huettner S, Stähle H et al. Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin. Int J Clin Pharmacol Ther . 2010; 48:367-74. [PubMed 20497745]

13. Graefe-Mody U, Rose P, Ring A et al. Assessment of the pharmacokinetic interaction between the novel DPP-4 inhibitor linagliptin and a sulfonylurea, glyburide, in healthy subjects. Drug Metab Pharmacokinet . 2011; 26:123-9. [PubMed 21084763]

14. Graefe-Mody EU, Brand T, Ring A et al. Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. Int J Clin Pharmacol Ther . 2011; 49:300-10. [PubMed 21543033]

15. Friedrich C, Ring A, Brand T et al. Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers. Eur J Drug Metab Pharmacokinet . 2011; 36:17-24. [PubMed 21340661]

16. Graefe-Mody U, Friedrich C, Port A et al. Linagliptin, a novel DPP-4 inhibitor: no need for dose adjustment in patients with renal impairment. Poster presented at the European Association for the Study of Diabetes 46th Annual Meeting. Stockholm, Sweden: 2010 Sept 20-24. Poster 822.

17. Retlich S, Duval V, Ring A et al. Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg-10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects. Clin Pharmacokinet . 2010; 49:829-40. [PubMed 21053992]

18. Heise T, Graefe-Mody EU, Hüttner S et al. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab . 2009; 11:786-94. [PubMed 19476474]

19. Thomas L, Eckhardt M, Langkopf E et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther . 2008; 325:175-82. [PubMed 18223196]

20. Blech S, Ludwig-Schwellinger E, Gräfe-Mody EU et al. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos . 2010; 38:667-78. [PubMed 20086031]

21. Drucker DJ. The biology of incretin hormones. Cell Metab . 2006; 3:153-65. [PubMed 16517403]

22. Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract . 2009 Sep-Oct; 15:540-59.

23. Niemi M, Backman JT, Fromm MF et al. Pharmacokinetic interactions with rifampicin : clinical relevance. Clin Pharmacokinet . 2003; 42:819-50. [PubMed 12882588]

24. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care . 2009; 32:193-203. [PubMedCentral][PubMed 18945920]

25. Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med . 2007; 147:386-99. [PubMed 17638715]

26. Boehringer Ingelheim, Ridgefield, CT: Personal communication.

27. Boehringer Ingelheim. Tradjenta^® (linagliptin) tablets medication guide. Ridgefield, CT; 2017 Aug.

36. Food and Drug Administration. Early communication: reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas. Silver Spring, MD; 2013 Mar 14. From FDA website.[Web]

37. Singh S, Chang HY, Richards TM et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med . 2013; 173:534-9. [PubMed 23440284]

41. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Rockville, MD; 2015 Aug 28. From FDA website. [Web]

42. Food and Drug Administration. FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. Silver Spring, MD; 2016 April 5. From FDA website. [Web]

43. Scirica BM, Braunwald E, Raz I et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation . 2014; 130:1579-88. [PubMed 25189213]

44. Zannad F, Cannon CP, Cushman WC et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet . 2015; 385:2067-76. [PubMed 25765696]

45. DeFronzo RA, Lewin A, Patel S et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diab Care . 2015 Mar; 38:384-93.

50. Boehringer Ingelheim. Tradjenta^® (linagliptin) tablets prescribing information. Ridgefield, CT; 2017 Aug.

51. Boehringer Ingelheim. Tradjenta^® (linagliptin) tablets medication guide. Ridgefield, CT; 2017 Aug.

70. Boehringer Ingelheim. Glyxambi^® (empagliflozin and linagliptin) tablets prescribing information. Ridgefield, CT; 2018 Oct.

71. Boehringer Ingelheim. Glyxambi^® (empagliflozin and linagliptin) tablets medication guide. Ridgefield, CT; 2019 Jul.

72. Boehringer Ingelheim. Jentadueto^® (linagliptin and immediate-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2019 Jul.

73. Boehringer Ingelheim. Jentadueto^® (linagliptin and immediate-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2017 Aug.

74. Boehringer Ingelheim. Jentadueto^® XR (linagliptin and extended-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2019 Jul.

75. Boehringer Ingelheim. Jentadueto^® XR (linagliptin and extended-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2019 Jul.

698. Garber AJ, Handelsman Y, Grunberger G et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2020 executive summary. Endocr Pract . 2020; 26:107-139. [PubMed 32022600]

704. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S98-S110. [PubMed 31862752]

705. American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S111-S134. [PubMed 31862753]

706. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S135-S151. [PubMed 31862754]