Alogliptin

Mechanism of Action

DPP-4 is an abundant enzyme present on the surface of most cells, where it rapidly deactivates incretin hormones such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). These hormones are released by intestinal cells in response to a meal and play a key role in glucose regulation. Inhibiting DPP-4 slows incretin metabolism, prolonging active postprandial incretin levels, which enhances insulin synthesis and release while reducing glucagon secretion—key mechanisms for maintaining glucose homeostasis.[11][12][13] According to product labeling, alogliptin selectively inhibits DPP-4 without affecting DPP-8 or DPP-9 at therapeutic concentrations. This selective binding minimizes the risk of off-target toxicity compared to other DPP-4 inhibitors, such as vildagliptin and saxagliptin, which exhibit concentration-dependent inhibition of DPP-8 or DPP-9.[14]

Pharmacokinetics

Absorption: After a single oral dose, alogliptin reaches peak plasma concentration (Tmax) within 1 to 2 hours. With an absolute bioavailability of approximately 100%, the drug is nearly completely absorbed. Administering alogliptin with a high-fat meal does not significantly alter total or peak exposure, suggesting that food intake does not affect its absorption or efficacy.

Distribution: The volume of distribution during the terminal phase of alogliptin is 417 liters, indicating extensive distribution into body tissues. Alogliptin is approximately 20% bound to plasma proteins.

Metabolism: Alogliptin undergoes limited metabolism primarily mediated by the enzymes CYP2D6 and CYP3A4. The 2 minor metabolites are formed—M-I, which is an active metabolite that inhibits DPP-4 similarly to the parent compound, and M-II, which does not exhibit DPP-4 inhibitory activity.

Excretion: The mean terminal half-life (t_1/2) of alogliptin is approximately 21 hours, supporting its prolonged duration of action. The majority of the administered dose is excreted unchanged in the urine (76%), with a smaller amount excreted in the feces (13%).[15] Renal clearance is 9.6 L/h, indicating some active renal tubular secretion, while systemic clearance is 14.0 L/h.

Administration

Available Dosage Forms and Strengths 

Alogliptin is available as an oral tablet form in strengths of 6.25 mg, 12.5 mg, and 25 mg, and it can be administered to patients once daily, with or without food.

Adult Dosage

The standard dosing for patients with T2D is 25 mg orally once daily.[6] A reduced insulin dose or adjustment of the secretagogue may be necessary for patients taking insulin and/or secretagogues (such as sulfonylureas and meglitinides). Additionally, alogliptin is available in combination formulations with metformin and pioglitazone.[16][17] The alogliptin-metformin combination is available in strengths of 12.5 to 500 mg and 12.5 to 1000 mg, with twice-daily dosing. The alogliptin-pioglitazone combination is available in various strengths, including 12.5 to 15 mg, 12.5 to 30 mg, 12.5 to 45 mg, 25 to 15 mg, 25 to 30 mg, and 25 to 45 mg, with once-daily dosing.

Specific Patient Populations

Hepatic impairment: Alogliptin can be used without dosage adjustment in patients with mild-to-moderate hepatic impairment (Child-Pugh Grade A and B). However, it should be used with caution in patients with severe hepatic impairment (Child-Pugh Grade C), as it has not been studied in this population.

Renal impairment: No dosage adjustment is necessary for patients with mild renal impairment (creatinine clearance [CrCl] >60 mL/min). However, for patients with CrCl between 30 and 60 mL/min, the total daily dosage should be reduced to 12.5 mg once daily. For those with CrCl between 15 and 30 mL/min, the dosage should be further reduced to 6.25 mg once daily. In patients with CrCl less than 15 mL/min or those requiring hemodialysis, the dosage should be reduced to 6.25 mg daily, and administration can occur regardless of the timing of hemodialysis. No dosage adjustments are recommended for patients with hepatic impairment. 

Pregnancy considerations: Human data regarding alogliptin use are unavailable during pregnancy. Clinicians should carefully weigh the risks and benefits of using alogliptin during pregnancy. Animal studies have shown no evidence of fetal harm at doses significantly higher than the recommended human dose.[18]

Breastfeeding considerations: The use of alogliptin during breastfeeding is not well-documented. An alternative medication should be considered, particularly when breastfeeding a newborn or preterm infant. If alogliptin is used while nursing, monitoring the infant's blood glucose levels is advisable.[13]

Pediatric patients: Alogliptin is not currently approved for use in pediatric patients.[19]

Older patients: No significant differences in the safety or effectiveness of alogliptin have been observed in older patients. However, dosage adjustments may be necessary based on renal function and other comorbidities.

Adverse Effects

According to the drug manufacturer's package insert, severe hypersensitivity reactions, including anaphylaxis, have been reported with alogliptin.[15] Other severe adverse reactions include:

• Stevens-Johnson syndrome
• Hepatic failure
• Heart failure (associated with alogliptin and saxagliptin; per FDA drug safety communication bulletin)
• Tubulointerstitial nephritis [20]
• Pancreatitis
• Severe or disabling arthralgia (a class effect of DPP-4 inhibitor; per FDA drug safety communication bulletin; see below for additional details)
• Hypoglycemia; typically mild [21][22]
• Bullous pemphigoid (see below for additional details)
• Rhabdomyolysis

More common adverse reactions include nasopharyngitis, which occurred in 4.4% of patients, as well as headache and upper respiratory tract infections, which were reported in 4.2% of patients. Renal function abnormalities were more frequently observed in patients with high cardiovascular risk, occurring in 23% of those with cardiovascular risk compared to 3% in those without cardiovascular risk.

A concern related to adverse events is arthralgia. In 2015, the FDA issued a warning that DPP-4 inhibitors, including alogliptin, may be associated with serious arthralgias. A meta-analysis published in 2017, which evaluated 67 randomized controlled trials, suggested a significantly increased risk of overall arthralgia (P=.003), but a nonsignificant increase in serious arthralgias (P=.20). When prescribing DPP-4 inhibitors, including alogliptin, clinicians should weigh the benefits of glycemic control against the potential risk of arthralgia.

Bullous pemphigoid, a cutaneous autoimmune blistering disorder, has been reported as an adverse effect of DPP-4 inhibitors. In most cases, symptoms resolve after discontinuation of the drug and treatment with topical or immunosuppressive therapy. Patients who develop blisters should discontinue the DPP-4 inhibitor and consult a dermatologist for further evaluation and management.[23]

Baseline liver function tests are recommended due to reports of fatal and nonfatal hepatic failure in postmarketing surveillance. Evaluating for underlying liver disease may be warranted.

Cases of pancreatitis have been reported, and alogliptin should be discontinued immediately if pancreatitis is suspected.[24]

Alogliptin is not associated with weight gain, unlike some other oral glycemic control medications.

Drug-Drug Interactions

• Alogliptin is contraindicated for use with other DPP-4 inhibitors (such as linagliptin, saxagliptin, and sitagliptin).
• Insulin and insulin secretagogues, including sulfonylureas, increase the risk of hypoglycemia. Reducing the insulin dosage may be necessary to minimize this risk when used with alogliptin tablets.

Contraindications

Alogliptin is contraindicated in patients with a history of hypersensitivity to the drug or any of its components. Reports include angioedema, anaphylaxis, and severe cutaneous adverse reactions.[25] Alogliptin is not indicated for treating T1D.

Warnings and Precautions

Heart failure: The guidelines from the AHA/ACC recommend that DPP-4 inhibitors, such as alogliptin, be avoided in patients with T2D and a high risk of cardiovascular issues, as their use may increase the risk of hospitalization due to heart failure.[5]

Pancreatitis: Cases of acute pancreatitis have been reported with alogliptin use. If pancreatitis is suspected, the drug should be discontinued, and appropriate management should be initiated.[24] Although a meta-analysis of randomized trials found no significant association between DPP-4 inhibitors and the risk of pancreatitis or pancreatic cancer in patients with T2D,[26] a cautious approach is still recommended. Serum lipase levels and imaging should be obtained if pancreatitis is suspected.

Hypersensitivity reactions: Severe hypersensitivity reactions, including anaphylaxis, angioedema, and severe cutaneous reactions such as Stevens-Johnson syndrome, have been reported with alogliptin. If any of these reactions occur, alogliptin should be discontinued, and an alternative diabetes treatment should be initiated. Caution is advised when prescribing alogliptin to patients with a history of angioedema from other DPP-4 inhibitors, as their susceptibility to alogliptin-induced angioedema is not well established.

Hepatotoxicity: Both fatal and nonfatal hepatic failure have been reported in association with alogliptin use. In patients presenting with symptoms of liver injury, such as fatigue or jaundice, liver function should be closely monitored. If clinically significant elevations in alanine aminotransferase (ALT) persist, alogliptin should be discontinued until the underlying cause is determined.

Disabling arthralgia: Severe and disabling arthralgia has been reported with DPP-4 inhibitors. Symptoms may develop shortly after treatment initiation and often resolve upon discontinuation. If symptoms persist or recur after restarting the medication, consider DPP-4 inhibitors as the cause and discontinue if necessary.[27] Potential mechanisms for DPP-4 inhibitor-induced arthralgia include increased cytokine levels, matrix metalloproteinases, and genetic factors.[28]

Bullous pemphigoid: Bullous pemphigoid requiring hospitalization has been reported in patients using DPP-4 inhibitors. Symptoms generally improve with drug discontinuation and immunosuppressive therapy. Patients should be advised to report the development of blisters or erosions. If bullous pemphigoid is suspected, alogliptin should be discontinued, and a dermatology consult should be sought.

Monitoring

Patients taking alogliptin should have their HbA1c monitored every 3 months if it is not at goal and every 6 months if it is at goal. Serum glucose, renal function, and baseline liver function tests (as indicated) should also be regularly monitored.[29] Additionally, patients should be monitored for signs and symptoms of heart failure, pancreatitis, and dermatologic or allergic reactions.[5] 

In patients with hemoglobinopathies, where HbA1c may be inaccurate, fructosamine and glycated albumin measurements provide valuable alternatives for assessing glycemic control. Expanding the use of continuous glucose monitoring could further enhance diabetes management in these patients.[30][31]

Toxicity

Signs and Symptoms of Overdose

In clinical trials, healthy participants were given doses of up to 800 mg, whereas participants with T2D received doses of 400 mg. No severe adverse effects were observed at these high doses.[32]

Management of Overdose

In the event of an overdose, clinical monitoring and supportive therapy should be provided. Alogliptin is minimally dialyzable, with only 7% removed during a 3-hour hemodialysis session, making hemodialysis unlikely to be effective. A medical toxicologist or the Poison Control Center should be contacted (at 1-800-222-1222) for current recommendations.

Enhancing Healthcare Team Outcomes

The interprofessional healthcare team members, including physicians, endocrinologists, and advanced practice providers who prescribe alogliptin for T2D, should educate patients on the importance of lifestyle changes, including diet and exercise. Nursing staff, particularly those certified as diabetes educators, are crucial in this aspect of care. Pharmacists should review the regimen, check for potential interactions, assess the appropriateness and synergy of the prescribed agents, and counsel patients on dosing and administration. Both nurses and pharmacists should communicate with the prescribing clinician regarding any concerns or adverse events.

A systematic review assessed adherence to newer second-line oral antidiabetic drugs (OADs) marketed between 2012 and 2022, showing better adherence to medications such as alogliptin and SGLT2 inhibitors (61.7%-94.9%) compared to older OADs. However, treatment discontinuation rates were significant (29%-44% within 12 months), emphasizing the need for further studies comparing new and old OADs directly.[33] At the same time, serum glucose, renal function, and baseline liver function tests (as indicated) should also be monitored. Patients should also be monitored for signs and symptoms of heart failure, pancreatitis, and dermatologic or allergic reactions, areas where nursing staff can make a significant contribution.

All healthcare providers, including clinicians, pharmacists, and nursing staff, should collaborate and communicate effectively, as well as function as an interprofessional team when a patient receives alogliptin therapy. This approach helps direct the case toward optimal outcomes while minimizing potential adverse events. A systematic review and meta-analysis indicate that interprofessional care for managing T2D in primary care settings enhances patient satisfaction, promotes collaboration among healthcare professionals, and fosters active patient engagement in care. Such collaboration is crucial for improving outcomes and addressing chronic disease management.[34]