Alogliptin

Mechanism of Action

DPP-4 is an abundant enzyme present on the surface of most cells. It rapidly deactivates some incretin hormones, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). These hormones are both released by intestinal cells in response to a meal. Antagonizing DPP-4 slows incretin metabolism, prolonging active postprandial incretin levels, resulting in increased insulin synthesis and release and decreased glucagon secretion, all of which can help regulate glucose homeostasis.[6][7][8]

The drug has a half-life of approximately 21 hours and is excreted in the urine (76%) and feces (13%).[9]

Administration

Alogliptin is available as a 6.25 mg, 12.5 mg, and 25 mg oral tablet taken once daily without regard to food.

The standard dosing for patients with type 2 diabetes mellitus is 25 mg by mouth daily. A reduced dose of insulin or the secretagogue may be necessary for patients who are also taking insulin and/or secretagogues (i.e., sulfonylureas, meglitinides).

No dosage adjustment is necessary for patients with mild renal impairment (creatinine clearance [CrCl] greater than 60 mL/min); however, the total daily dose should be reduced to 12.5 mg once daily if CrCl is between 30 to 60 mL/min, and further reduced to 6.25 mg once daily if CrCl is between 15 to 30 mL/min. For patients with CrCl less than 15 mL/min or patients requiring hemodialysis, the dose should be reduced to 6.25 mg daily, and administration can be without regard to the timing of hemodialysis. There are no recommendations for adjusting the dose in patients with hepatic impairment. 

In patients with hepatic impairment, dosing for Child-Pugh Class A or B requires no dose adjustment; dosing for Child-Pugh Class C is undefined.

As mentioned above, there are also formulations of alogliptin in combination with metformin and pioglitazone. Alogliptin-metformin is available in strengths of 12.5-500 mg and 12.5-1000 mg, and dosing is twice daily. Alogliptin-pioglitazone is available in strengths of 12.5-15 mg, 12.5-30 mg, 12.5-45 mg, 25-15 mg, 25-30 mg, and 25-45 mg and is taken once daily.

Alogliptin is not currently approved for use in pediatric patients.[10]

Adverse Effects

According to the drug manufacturer's package insert, there are reports of serious hypersensitivity reactions with alogliptin, including anaphylaxis.[9] Other serious adverse reactions include the following:

• Stevens-Johnson syndrome
• Hepatic failure
• Heart failure (alogliptin and saxagliptin; FDA drug safety communication bulletin)
  • Alogliptin is not associated with an increase in cardiovascular event risk[11][12]
• Tubulointerstitial nephritis
• Pancreatitis
• Severe or even disabling arthralgia (DPP-4 inhibitor class effect; FDA drug safety communication bulletin - see below for additional details)
• Hypoglycemia; typically mild[13][14]
• Bullous pemphigoid - see below for additional details
• Rhabdomyolysis

More common reactions include nasopharyngitis, which occurred in 4.4% of patients, while a headache and upper respiratory tract infection both occurred in 4.2% of patients. Renal function abnormalities appeared to occur more often in patients with high CV risk (3% without CV risk versus 23% with CV risk).

One concern related to adverse events includes arthralgias. The FDA cautioned in 2015 that treatment with DPP-4 inhibitors might cause serious arthralgias. In a meta-analysis published in 2017 evaluating 67 randomized controlled trials, there was a suggestion of a significantly increased risk of overall arthralgia (p = 0.003) but a non-significant increase in serious arthralgias (p = 0.20). The benefits of glycemic control versus the risk of arthralgia should be a factor when prescribing DPP-4 inhibitors, including alogliptin.

Bullous pemphigoid (a cutaneous autoimmune blistering disorder) is also a reported side effect of DPP-4 inhibitor use. Cases have typically resolved following discontinuation of the offending drug and topical or immunosuppressive therapy. If patients develop blisters, they should be advised to stop the DPP-4 inhibitor and seek care from a dermatologist.

Baseline liver function tests are a recommendation because reports exist of fatal and nonfatal hepatic failure in postmarketing surveillance. Ruling out underlying liver disease may be warranted.

There are case reports of pancreatitis, and alogliptin should be discontinued immediately if pancreatitis is suspected.

Alogliptin is not associated with weight gain like some other oral glycemic control medications.[15]

Contraindications

Alogliptin is contraindicated in patients with a history of hypersensitivity to the drug or any component of the formulation. ALogliptin is not indicated for use in treating type 1 diabetes mellitus.

Caution is advised in patients with increased LFTs, those who have a risk of heart failure, or with renal impairment (see Administration section for details.)

There is no human data regarding alogliptin use and pregnancy. Clinicians are advised to weigh the risk vs. benefit of alogliptin use during pregnancy. Animal data shows no risk of fetal harm at doses significantly higher than the recommended human dose. There is also no human data regarding milk production or potential infant harm regarding alogliptin use in breastfeeding.[16]

Alogliptin is contraindicated for use concomitantly with other DPP-4 inhibitors (e.g., linagliptin, saxagliptin, sitagliptin).

Monitoring

Patients taking alogliptin should have their A1C monitored every three months if their A1c is not at goal and every six months if they meet their goal. Serum glucose, renal function, and baseline liver function tests (as indicated) also should be monitored. Patients also should be monitored for signs and symptoms of heart failure, pancreatitis, and dermatologic or allergic reactions.

Toxicity

In clinical trials, doses of 800 mg were given to healthy participants, and participants with T2DM received doses of 400 mg. No serious adverse effects occurred with these high doses.[17]

Enhancing Healthcare Team Outcomes

Members of the interprofessional healthcare team, including physicians (MDs or DOs), endocrinology specialists, and mid-level practitioners (NPs or PAs) who prescribe alogliptin for type 2 diabetes, should also educate the patient on the importance of changes in lifestyle, diet, and exercise. Nursing can play a crucial role in this aspect of care, particularly a nurse who is certified as a diabetes educator. The pharmacist should also have input into the regimen, check for interactions, note the appropriateness and synergy of the chosen agents, and offer counsel to the patient on dosing and administration. Both nurses and pharmacists need to be able to reach out to the prescribing clinician regarding any concerns or adverse events they may encounter.

At the same time, serum glucose, renal function, and baseline liver function tests (as indicated) also should be monitored. Patients should also be monitored for signs and symptoms of heart failure, pancreatitis, and dermatologic or allergic reactions, which is another area where nursing will make a significant contribution. All providers, including clinicians, pharmacists, and nursing staff, need to exercise open collaboration and communication and function as an interprofessional team when a patient receives therapy with alogliptin to direct the case towards optimal outcomes while simultaneously reducing potential adverse events. Research demonstrates the interprofessional team approach to healthcare is the most effective paradigm. [Level 5]