Alogliptin

Article Author:
Jamie Terrell
Article Editor:
Tibb Jacobs
Updated:
6/11/2018 1:36:01 PM
PubMed Link:
Alogliptin

Indications

Alogliptin was first approved by the FDA in January 2013 and is indicated to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). It is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is used to improve glycemic control in conjunction with diet and exercise.

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 also has a 2- to 4-fold increase in cardiovascular disease. The need for intensive glucose control is great, and the American Diabetes Association (ADA) currently recommends a hemoglobin A1C target of less than 7% in most nonpregnant patients, though some subsets of patients may have a more strict goal of less than 6.5%, while other subsets of patients may have a less strict goal of less than 8%. 

The ADAs Standards of Care currently considers 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 should be noted 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, an agent proven to reduce cardiovascular (CV) risks, and mortality is chosen. 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 major 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 in patients with T2DM and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure. 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 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 being studied in Type 1 diabetes mellitus (T1DM) due to their preserving effects on beta cell mass. They are not currently indicated for the treatment of T1DM.

Mechanism of Action

DPP-4 is an abundant enzyme that is found on the surface of most cells. It rapidly deactivates some incretin hormones, such as a 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. By antagonizing DPP-4, active postprandial incretin levels can be prolonged, which can result in increased insulin synthesis and release and decreased glucagon secretion, all of which can help regulate glucose homeostasis.

Administration

Alogliptin is available as a 6.25 mg, 12.5 mg, and 25 mg oral tablet that is taken once daily without regard to food. In patients that are also taking insulin and/or secretagogues (i.e., sulfonylureas, meglitinides) a reduced dose of insulin or the secretagogue may be warranted. No dosage adjustment is needed for patients with mild renal impairment 9creatinine 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 in patients requiring hemodialysis, the dose should be reduced to 6.25 mg daily and can be given without regard to timing of hemodialysis. There are no recommendations for adjusting the dose in patients with hepatic impairment. 

Alogliptin can also be found in combination with metformin and pioglitazone. Alogliptin-metformin is available in strengths of 12.5-500 mg and 12.5-1000 mg and is dosed 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.

Adverse Effects

According to the package insert, serious hypersensitivity reactions have been reported with alogliptin. These reactions include anaphylaxis, angioedema, and cutaneous reactions and are rare. 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, it was suggested that there was a significantly increased risk of overall arthralgia (p = 0.003), but a non-significant increase in serious arthralgias (p = 0.20). Benefits of glycemic control versus the risk of arthralgia should be conducted when prescribing DPP-4 inhibitors, including alogliptin.

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

Baseline liver function tests are recommended because cases of fatal and nonfatal hepatic failure have been reported in postmarketing surveillance. Ruling out underlying liver disease may be warranted.

Case reports of pancreatitis have been reported, and alogliptin should be discontinued immediately if pancreatitis is suspected.

Contraindications

Alogliptin is contraindicated in patients with a history of hypersensitivity to the drug or any component of the formulation.

Monitoring

Patients taking alogliptin should have their A1C monitored every 3 months if their A1c is not at goal and every 6 months if they are meeting 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 800mg were given to healthy participants and doses of 400mg were given to participants with T2DM. No serious adverse effects were seen with these high doses.