Continuing Education Activity

Alogliptin was first approved by the FDA in January 2013 as a therapy to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). It is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to improve glycemic control in conjunction with diet and exercise. This activity outlines the indications, mechanism, pharmacology, contraindications, and adverse events associated with alogliptin drug therapy.

Objectives:

• Identify the mechanism of action of alogliptin.
• Describe the possible adverse effects of alogliptin, including necessary dose adjustments to address them where indicated.
• Summarize the pharmacology of alogliptin.
• Outline the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care when dosing alogliptin to improve patient outcomes for patients requiring glycemic control.

Indications

The FDA first approved alogliptin in January 2013 to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). It is a dipeptidyl peptidase-4 (DPP-4) inhibitor ("gliptin" class) used to improve glycemic control in conjunction with diet and exercise.[1][2][3] The approval in 2013 included three formulations; one as a standalone agent, one combined with metformin, and another combined with pioglitazone.

T2DM is a chronic illness that is becoming a common diagnosis among American children and adults. According to the CDC, in 2015, approximately 100 million US adults had either diabetes or prediabetes. It is the seventh leading cause of death and has a 2- to 4-fold increase in cardiovascular disease. The need for intensive glucose control is great. The American Diabetes Association (ADA) currently recommends a hemoglobin A1C target of less than 7% in most nonpregnant patients. However, some subsets of patients may have a more strict goal of less than 6.5%, while other subsets of patients may have a less stringent goal of less than 8%. 

The ADAs Standards of Care currently consider DPP-4 inhibitors as add-on therapy if patients do not meet their A1C goal after three months of lifestyle modifications and metformin. DPP-4 inhibitors are a useful component of both dual and triple therapy. It is worth noting that current recommendations suggest selecting a second agent (after metformin) based on the patient’s atherosclerotic cardiovascular disease (ASCVD) risk status. If they have ASCVD, the clinician should choose an agent proven to reduce cardiovascular (CV) risks and mortality. Alogliptin has not been shown to reduce CV risks or CV mortality; in fact, there are concerns about a potential risk of heart failure associated with DPP-4 inhibitors. Approximately half of all patients with T2DM will develop heart failure during their life, so this is a significant concern. 

The EXAMINE trial was a multicenter, randomized, double-blind study that assessed alogliptin versus placebo (in addition to standard of care) in 5380 patients with a recent acute coronary syndrome event. This trial showed that alogliptin improved glycemic control and did not increase the risk of hypoglycemia, which was associated with a risk of major adverse cardiovascular outcomes. A study of the same patients in the EXAMINE trial found that alogliptin did not increase the risk of heart failure in patients with T2DM and recent acute coronary syndromes. However, the SAVOR-TIMI 53 study showed that patients treated with saxagliptin (also a DPP-4 inhibitor) were more likely to be hospitalized for heart failure than those given a placebo. DPP-4 use and heart failure is an ongoing area of research due to mixed results from current trials.

Incretin therapies (including DPP-4 inhibitors) are research targets in type 1 diabetes mellitus (T1DM) due to their preserving effects on beta-cell mass. They currently do not have an approved indication for the treatment of T1DM.[4][5]

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]