Dosage guidance:
Clinical considerations: May require a dose reduction of insulin and/or insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia.
Diabetes mellitus, type 2, treatment:
Note: May be used as an adjunctive agent or alternative monotherapy for select patients, including those in whom initial therapy with lifestyle intervention and metformin failed, or who cannot take metformin. May be preferred in patients who are close to glycemic goals when avoidance of hypoglycemia and/or weight gain is desirable; use has not been associated with improved or worsened cardiovascular or renal outcomes (Ref). Due to lack of additive glycemic benefit, avoid use in combination with glucagon-like peptide-1 receptor agonist-based therapies (Ref).
Oral: 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.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: Mild to severe impairment: No dosage adjustment necessary (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed: No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Unlikely to be dialyzed (Ref): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
No dosage adjustment necessary.
Refer to adult dosing.
Arthralgia, including severe and disabling cases, has been reported with dipeptidyl peptidase-4 (DPP-4) inhibitors, including linagliptin (Ref). Specific inflammatory joint complications with DPP-4 inhibitors may include polyarthritis, polyarthropathy, rheumatoid arthritis, and severe synovitis (Ref). Patients may or may not exhibit an increase in rheumatoid factors (Ref).
Mechanism: Not well established; one hypothesis includes cytokine-induced inflammation (Ref).
Onset: Varied; onset may occur within 1 day to years after treatment initiation. Symptoms may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy resumes (Ref).
In one study, most patients who reported arthralgias did so within 3 months of initiation of DPP-4 inhibitors and symptoms resolved within 1 month after discontinuation (Ref).
Risk factors:
• Longer duration of therapy; data are conflicting (Ref)
Dipeptidyl peptidase-4 (DPP-4) inhibitor use, including linagliptin, has been associated with development or exacerbation of bullous pemphigoid (Ref). Although most DPP-4 inhibitors have been associated with the development of bullous pemphigoid, vildagliptin is associated with a higher risk (Ref). In addition, severe cutaneous adverse reactions (SCARs) (eg, exfoliative skin conditions) have been reported with linagliptin (Ref).
Mechanism: Non–dose-related; immunologic
Bullous pemphigoid: Exact mechanism unknown (Ref). Some skin cells (including keratinocytes) express DPP-4, leading to an increase in cytokine production, tissue differentiation, and collagen metabolism; whether this leads to an alteration in the properties of the epidermal basement membrane is unknown.
Delayed hypersensitivity reactions (including SCARs): Mediated by T-cells (Ref)
Onset:
Bullous pemphigoid: Delayed; median onset of ~6 months (range: 6 to 1,751 days) (Ref). Most cases of bullous pemphigoid typically resolve following discontinuation; some require symptomatic treatment (Ref).
Delayed hypersensitivity reactions: Varied; typically occur days to weeks after drug exposure (Ref)
Risk factors:
• Age; although older age may be a risk factor for the development of bullous pemphigoid (Ref), some studies have not shown age to be a factor (Ref)
• Males; some studies have suggested that male patients with diabetes may be at higher risk than female patients (Ref), although a meta-analysis of case-controlled studies did not find sex to be a predisposing risk factor (Ref)
An increased risk of hospitalization due to heart failure (HF) was identified as a potential issue with dipeptidyl peptidase-4 (DPP-4) inhibitors, specifically saxagliptin and alogliptin, following results from the SAVOR TIMI 53 and EXAMINE trials, respectively (Ref). In contrast, the TECOS and CARMELINA trials showed no increased risk of hospitalization due to HF with sitagliptin or linagliptin, respectively, including in patients with preexisting HF (Ref). A meta-analysis of 182 trials found that, overall, use of a DPP-4 inhibitor was not associated with an increased risk of HF (OR: 1.05; 95% CI: 0.96 to 1.15; I2 = 0%); however, a significantly higher risk of HF was seen with saxagliptin (OR: 1.22; 95% CI: 1.03 to 1.45), but not for other DPP-4 inhibitors (Ref). The American Diabetes Association suggests DPP-4 inhibitors (except saxagliptin) may be considered in patients with HF; however, other agents are preferred (Ref).
Mechanism: Unknown (Ref)
Onset: Variable; the American Heart Association suggests the impact of DPP-4 inhibitors on myocardial dysfunction may be seen within weeks to ≥1 year (Ref).
Risk factors:
• Presence of risk factors for HF or preexisting HF (Ref); however, linagliptin has not been associated with an increased risk of hospitalization due to HF, including in patients with preexisting HF (Ref)
Anaphylaxis and angioedema have been reported (Ref). Vildagliptin may be associated with higher risk of angioedema than other DPP-4 inhibitors (Ref).
Mechanism: Non–dose-related; immunologic
Angioedema: Considered a non–mast-cell-mediated process involving impaired catabolism of bradykinin (Ref). Linagliptin and other dipeptidyl peptidase-4 (DPP-4) inhibitors can inactivate substance P and bradykinin (Ref).
Anaphylaxis: Considered to be an IgE-mediated reaction (Ref)
Onset: Varied; events associated with DPP-4 inhibitors have generally been noted within the first 3 months of therapy and may occur with the initial dose.
Risk factors:
• Concomitant use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (Ref)
• Hereditary angioedema (Ref)
• History of angioedema with other DPP-4 inhibitors
Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities), chronic pancreatitis, and pancreatic cancer have been reported with use of incretin-based therapies (eg, dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagon-like peptide 1 [GLP-1] receptor agonists), including linagliptin (Ref).
Mechanism: Causality has not been firmly established (Ref). DPP-4 inhibitors indirectly stimulate GLP-1 receptors in pancreatic islet beta cells and exocrine duct cells which may cause an overgrowth of the cells that cover the smaller ducts, thereby resulting in hyperplasia, increased pancreatic weight, duct occlusion, back pressure, and subsequent acute or chronic pancreatic inflammation (Ref).
Risk factors:
• Patients with a prior history of pancreatitis may be at an increased risk for acute pancreatitis.
• Patients with acute pancreatitis due to any cause are at an increased risk for progression to recurrent acute pancreatitis and then to chronic pancreatitis; patients with chronic pancreatitis are at an increased risk for pancreatic cancer (Ref).
• Risk factors for pancreatitis due to any cause include, but are not limited to, hypertriglyceridemia, cholelithiasis, alcohol use, and obesity.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Incidences may include use in combination therapy regimens.
1% to 10%:
Endocrine & metabolic: Increased uric acid (3%)
Gastrointestinal: Increased serum lipase (>3 × ULN: 8%)
Respiratory: Cough (2%), nasopharyngitis (7%)
Frequency not defined:
Endocrine & metabolic: Hypoglycemia (including severe hypoglycemia)
Neuromuscular & skeletal: Myalgia
Postmarketing:
Cardiovascular: Heart failure (FDA 2016)
Dermatologic: Alopecia (Someili 2019), bullous pemphigoid (Someili 2019), skin rash
Gastrointestinal: Cholecystitis (He 2022), oral mucosa ulcer, pancreatitis (including acute pancreatitis) (Sharko 2021), stomatitis
Hypersensitivity: Anaphylaxis (Huang 2020), angioedema (Huang 2020)
Neuromuscular & skeletal: Arthralgia (including severe arthralgia) (Gomes 2018), rhabdomyolysis
Hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity) to linagliptin or any component of the formulation
Canadian labeling: Additional contraindications: Use in type 1 diabetes mellitus or diabetic ketoacidosis
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).
– 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).
Other warnings/precautions:
• Appropriate use: Not indicated for use in patients with type 1 diabetes mellitus or with diabetic ketoacidosis.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Tradjenta: 5 mg [contains corn starch]
No
Tablets (Tradjenta Oral)
5 mg (per each): $21.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Trajenta: 5 mg
Oral: May be administered with or without food.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/201280s027lbl.pdf#page=16, must be dispensed with this medication.
Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes as monotherapy or in combination with other antidiabetic agents.
LinaGLIPtin may be confused with linaCLOtide
Tradjenta may be confused with Tanzeum [DSC], Toujeo, Tresiba, Trulicity
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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 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: 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
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: 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
Dipeptidyl peptidase 4 (DPP-4) inhibitors are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2021; Blumer 2013).
Agents other than linagliptin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).
It is not known if linagliptin is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Serum glucose; signs/symptoms of pancreatitis; signs/symptoms of heart failure; signs/symptoms of bullous pemphigoid (eg, blisters, erosions).
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 2021; 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.
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.
Distribution: Extensive.
Protein binding: 70% to 80%; concentration dependent.
Metabolism: Not extensively metabolized.
Bioavailability: ~30%.
Half-life elimination: ~11 hours; Terminal (DPP-4 saturable binding): ~200 hours.
Time to peak: 1.5 hours.
Excretion: 80% feces unchanged; 5% urine unchanged.
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