FDA approves 3 new therapies for type 2 diabetes

April 15, 2013

Alogliptin approved as monotherapy and in two combinations

New Drug Review

On January 26, 2013, FDA approved three new type 2 diabetes therapies: alogliptin (Nesina, Takeda) and two fixed-dose combinations, alogliptin and pioglitazone (Oseni, Takeda) and alogliptin and metformin HCl (Kazano, Takeda).

Alogliptin is a dipeptidyl peptidase-4 S(DPP-4) inhibitor designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). Alogliptin is approved for use either as monotherapy as an adjunct to diet and exercise or in a combination regimen to improve glycemic control in patients with type 2 diabetes. Alogliptin is not indicated for treatment of type 1 diabetes or diabetic ketoacidosis.

In mid-March, FDA announced that it was evaluating reports of possible increased risk of pancreatitis and precancerous findings of the pancreas associated with incretin mimetics, which includes alogliptin monotherapy and the fixed-dose combinations. FDA has not reached any conclusions about the safety risks linked to incretin mimetics. In June, FDA will participate in the National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute’s Workshop on Pancreatitis-Diabetes-Pancreatic Cancer to obtain and share additional information.

 

Efficacy. Alogliptin has been studied in more than 13,000 patients internationally, as monotherapy in addition to diet and exercise and in combination with metformin, insulin, thiazoladinediones, and sulfonylureas. In a placebo-controlled trial of 329 patients over 26 weeks, alogliptin reduced A1c significantly compared to placebo (-0.6%, 95% CI -0.8 to -0.3), when added to diet and exercise. In another randomized trial, alogliptin monotherapy was compared to 30 mg pioglitazone dosed daily and to alogliptin combined with pioglitazone. In reducing A1c at 26 weeks, the combination was superior to either alogliptin or pioglitazone alone (-0.8%, 95% CI -1.0 to -0.5 and -0.6%, 95% CI -0.8 to -0.3, respectively). Similarly, in a third trial, alogliptin combined with metformin was superior in reducing A1c compared to either drug alone at 26 weeks (difference from metformin monotherapy ranged from -0.4 to -0.6 and from alogliptin monotherapy ranged from -0.7 to -1.0).

Several trials have been conducted in patients who were failing current antihyperglycemic therapy. When added to a regimen of insulin with or without metformin, alogliptin significantly reduced A1c by 0.6% compared to continuation of the insulin regimen. When added to glyburide, alogliptin significantly reduced A1c by 0.5% compared to continued glyburide alone. And when added to a regimen of pioglitazone with or without metformin, alogliptin significantly reduced A1c by 0.4%.

Alogliptin also has a significant impact on fasting blood glucose and appears to be more effective in reducing glucose in patients with higher baseline values.

Safety. Safety data are derived from pooled analyses of 14 trials. Adverse events reported in ≥4% with alogliptin include nasopharyngitis (4.4%), headache (4.2%), and upper respiratory tract infection (4.2%). Post-marketing reports of hypersensitivity have been reported. Acute pancreatitis has also been reported in post-marketing. Alogliptin does not appear to increase the risk of hypoglycemia when used as monotherapy. To reduce the risk of hypoglycemia when alogliptin is combined with insulin or sulfonylureas, the manufacturer suggests that the dose of insulin or sulfonylurea should be reduced. Hepatic failure has been reported in patients taking alogliptin. If a patient develops hepatic injury with no other identifiable cause while taking alogliptin, alogliptin should be discontinued.

Dosing. The recommended dose of alogliptin is 25 mg once daily, taken with or without food. A dose of 12.5 mg is recommended in patients with a creatinine clearance (CrCl) of ≥30 to <60 mL/min and a dose of 6.25mg daily is recommended in patients with a CrCl <30, including those with end-stage renal disease or requiring hemodialysis. Alogliptin may be administered without regard to the timing of dialysis. Pharmacokinetic data indicate that alogliptin can be used in patients with mild-to-moderate liver disease without the need for dose adjustment. It has not been studied in patients with severe liver disease. Because there is a need for dose adjustment based upon renal function, assessment of renal function is recommended before initiation of alogliptin therapy and periodically thereafter. Given the renal elimination of alogliptin and negligible CYP-450 metabolism, no significant drug-drug interactions are known to date.