National PBM Drug Monograph s1

Alogliptin Monograph

National PBM Drug Monograph

Alogliptin (Nesina)

VHA Pharmacy Benefits Management Strategic Healthcare Group

Medical Advisory Panel and VISN Pharmacist Executives

The purpose of VACO PBM-SHG drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

EXECUTIVE SUMMARY

§  Alogliptin is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), which metabolizes the naturally occurring incretins glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) resulting in enhanced glucose-dependent insulin secretion from the pancreas and decreased hepatic glucose production.

§  Alogliptin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. It has been studied as monotherapy and in combination with metformin, sulfonylureas (SU), pioglitazone, and insulin.

§  Alogliptin is administered as 25mg orally once daily without regard to meals. Dosage adjustment is required for patients with renal insufficiency. When used with insulin or an insulin secretagogue such as SUs, the dose of the insulin or insulin secretagogue may need to be reduced in order to decrease the risk of hypoglycemia.

§  Duration of the published phase III trials ranged from 26-52 weeks. Monotherapy with alogliptin decreased mean hemoglobin A1c (A1C) by 0.6%. When used as add-on therapy to metformin, SU or pioglitazone, the mean reduction in A1C ranged from 0.5-0.9%. Add-on to insulin therapy resulted in a mean A1C decrease of 0.7%.

§  In general, the rate of hypoglycemia was low with alogliptin monotherapy or in combination with metformin or pioglitazone. When combined with glyburide, the rate was 9.6% versus 11.6% with glyburide alone. When combined with insulin ± metformin, the rate was 27.1% versus 24% with insulin ± metformin alone.

§  Alogliptin is considered to be weight neutral.

§  Hypersensitivity reactions have been reported with the DPP-4 inhibitor class. Based on the pooled analysis, the incidence of hypersensitivity reactions was 0.6% with alogliptin 25mg compared to 0.8% with all comparators.

§  The FDA-required major cardiovascular adverse events (MACE) meta-analysis and results from the EXAMINE trial do not show a cardiovascular safety risk with alogliptin.

§  Concerns have been raised that the DPP-4 inhibitors may be associated with an increased risk of infection. The rate of infection with alogliptin appears to be similar to that of the active-comparators.

§  There have been post-marketing reports of acute pancreatitis, including hemorrhagic or necrotizing pancreatitis with incretin class (i.e., DPP-4 inhibitors and GLP-1 agonists). In the clinical trial program, pancreatitis was reported in 11/5902 (0.2%) patients receiving alogliptin 25mg compared to < 0.1% of all comparators.

§  There have been post-marketing reports of fatal and non-fatal hepatic failure in patients taking alogliptin. In a pooled analysis of randomized controlled trials, ALT elevation > than 3 times the upper limit of normal was observed in 1.3% and 1.5% of patients in the alogliptin and comparator/placebo groups respectively.

§  There are no significant drug-interactions with CYP-substrates or inhibitors that were tested or with other renally excreted drugs.

Introduction

Alogliptin was approved in January 2013 and is the fourth dipeptidyl peptidase-4 (DPP-4) inhibitor on the market to join sitagliptin, saxagliptin, and linagliptin.

Pharmacology

Incretins such as glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are naturally occurring hormones released from the gastrointestinal tract in response to the ingestion of food. Meal-stimulated circulating levels of GLP-1 are reduced in type 2 diabetes whereas the insulinotropic effect of GIP is impaired. GLP-1 and GIP enhance glucose-dependent insulin secretion from the pancreas. Also, GLP-1 suppresses inappropriately elevated glucagon secretion from pancreatic α-cells ultimately leading to decreased hepatic glucose production. Incretins do not suppress normal counter-regulatory increase in glucagon secretion during hypoglycemia.

GLP-1 has a short plasma half-life; therefore, its utility as a pharmacologic agent is limited. Dipeptidyl peptidase-4 is the enzyme responsible for metabolizing GLP-1 and GIP. Inhibition of DPP-4 activity results in meal-based enhancement of GLP-1 and GIP. Alogliptin selectively inhibits the inactivation of the DPP-4 enzyme.

Pharmacokinetics

Table 1: Pharmacokinetics of Alogliptin

Information obtained from product package insert

FDA approved indications

Alogliptin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes.

Alogliptin has been studied as monotherapy or in combination with metformin, sulfonylureas, thiazolidinediones (TZDs), and insulin.

Current VA alternatives

Metformin, glipizide, glyburide, acarbose, regular insulin, insulin aspart, NPH insulin, long-acting insulin analogs (glargine, detemir)

Dosing

The recommended dose is 25mg once daily and may be taken with or without food. Dosage adjustment is needed for patients with renal impairment (Table 2). Assessment of renal function is recommended prior to initiation of alogliptin and periodically thereafter.

No dosing adjustments are needed in patients with mild to moderate hepatic impairment (Childs-Pugh Grade A and B). Persons with severe hepatic impairment (Childs-Pugh Grade C) have not been evaluated. Use caution when administering alogliptin to patients with hepatic impairment.

Table 2: Dosing of Alogliptin in Renal Impairment

*patients undergoing peritoneal dialysis have not been evaluated

Dosage form/strengths

Alogliptin is available as 25mg, 12.5mg, and 6.25mg film-coated tablets.

Efficacy

The clinical trial program for alogliptin is comprised of 14 randomized, double-blind, controlled trials. The number of patients randomized to alogliptin 25mg, active comparator, or placebo was 5902, 2257, and 2926 respectively. At the time of this writing, 9 out of the 14 trials have been published in peer-reviewed journals. Among the 9 published trials, 7 were 26 weeks and 2 were 52 weeks. Depending on the trial, patients were either treatment naïve or on one or more anti-glycemic agents prior to the study. Patients failing to meet specific glycemic goals during the study received rescue treatment with another oral agent.

Glycemic Efficacy

Average baseline A1C was approximately 8.0% for the majority of studies (3 studies had higher baseline values). Rescue therapy with another anti-glycemic agent was allowed as defined by protocol.

Alogliptin significantly reduced A1C compared to placebo. Results were variable and depended on factors such as baseline A1C (higher baseline had greater absolute reduction) and with which agent alogliptin was combined (Table 3).

Table 3: Glycemic Efficacy and Change in Weight

ALO=alogliptin; FPG=fasting plasma glucose; GLY=glyburide; GPZ=glipizide; INS=insulin; MET=metformin; OHA=oral hypoglycemic agent; PBO=placebo; PIO=pioglitazone; TZD=thiazolidinedione

§ Value shown is difference versus placebo

^ The results for the 3 PIO groups (15, 30, 45mg) have been combined

Weight

The DPP-4 inhibitors including alogliptin are considered to be weight neutral. Table 3

Renal safety studies

Renal safety was demonstrated in 1-year renal safety studies with the other 3 DPP-4 inhibitors. A long-term renal safety study has not been conducted with alogliptin.

In the EXAMINE trial change in estimated glomerular filtration rate (eGFR) and incidence of renal dialysis was assessed as part of the safety evaluation. Change in eGFR from baseline and initiation of dialysis were similar in the alogliptin and placebo groups.

Long-term Data or Extension Trials

There is an ongoing 2-year study (NCT#00856284) comparing the addition of alogliptin or glipizide to metformin and several extension trials. Results are not available at this time.

Adverse Events

The frequency of reported adverse events using a pooled analysis of 11 clinical trials, including the 9 discussed in this review, is shown in Table 4. The exposure rate was 2022.7 patient-years in the alogliptin groups and 966.2 patient-years in the comparator groups. Mean duration of treatment was 177.5 days and 190.2 days for alogliptin and comparators respectively. Severe adverse events were more common in the alogliptin group. The most common AE leading to discontinuation was headache (alogliptin) and hypoglycemia (comparators). For information broken down by study (where available) refer to

Appendix 2.

Table 4: Frequency of Adverse Events

Pancreatitis

In the clinical trial program, pancreatitis was reported in 11/5902 (0.2%) patients receiving alogliptin 25mg compared to 5/5183 (<0.1%) of all comparators. All individuals had risk factors for pancreatitis.

There have been post-marketing reports of acute pancreatitis in patients taking alogliptin.

In the EXAMINE trial, incidence of pancreatitis was included as an additional safety endpoint. Acute pancreatitis was reported in 0.4% and 0.3% in the alogliptin and placebo groups respectively. Chronic pancreatitis was reported in 0.2% and 0.1% respectively. The values versus placebo were not statistically significant.

Hypoglycemia

Mild to moderate hypoglycemia was defined as blood glucose <60mg/dL with symptoms or blood glucose <50mg/dL without symptoms. Severe hypoglycemia was defined as an episode requiring the assistance of another person to actively administer carbohydrate or glucagon associated with a blood glucose < 60mg/dL unless the clinical situation is such that obtaining blood glucose is difficult. In general, the rate of hypoglycemia was low with alogliptin monotherapy or in combination with metformin or pioglitazone. When combined with other drugs known to cause hypoglycemia such as insulin or SUs the incidence of hypoglycemia is similar to or slightly greater with the addition of alogliptin compared to the addition of placebo. In the comparative trials versus glipizide, the incidence of hypoglycemia was lower with alogliptin.

Table 5: Reported Hypoglycemia

ALO=alogliptin; GLY=glyburide; GPZ=glipizide; INS=insulin; MET=metformin; PBO=placebo; PIO=pioglitazone