New molecular entities

New molecular entities

Nesina

Alogliptin

Takeda

Oseni

Alogliptin and pioglitazone

Takeda

Kazano

Alogliptin and metformin HCl

Takeda

Nesina: a new dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes as an adjunct to diet and exercise. Oseni: a fixed-dose combination of alogliptin and pioglitazone. Kazano: a fixed-dose combination of alogliptin and metformin HCl

On January 26, 2013, FDA approved 3 new type 2 diabetes therapies: alogliptin (Nesina, Takeda) and 2 fixed-dose combinations, alogliptin and pioglitazone (Oseni, Takeda) and alogliptin and metformin HCl (Kazano, Takeda).

Alogliptin is a 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. Type 2 diabetes is a chronic disease in which there are high levels of glucose in the blood. Type 2 diabetes is the most common form of diabetes, with more than 23 million people currently diagnosed in the United States alone. In addition to diet and exercise, patients often need combination pharmacotherapy in order to achieve glycemic control.  According to the International Diabetes Federation, global healthcare expenditures for diabetes (both type 1 and type 2) were estimated at $471.6 billion in 2012. This number is projected to exceed $595 billion by 2030.

On March 14, 2013, FDA released a drug safety communication for the incretin mimetic class of drugs. The agency is investigating unpublished new findings from a group of academic researchers that suggest a possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from the use of incretin mimetic drugs for type 2 diabetes. Patients should continue to take their medications as directed until they consult with their healthcare professional. FDA has not reached any conclusions about safety risks with incretin mimetics yet.

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 A_1c 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 A_1c 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 A_1c 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 didn’t respond to current antihyperglycemic therapy. When added to a regimen of insulin with or without metformin, alogliptin significantly reduced A_1c by 0.6% compared to continuation of the insulin regimen. In addition to glyburide, alogliptin significantly reduced A_1c by 0.5% compared to continuing glyburide. Last, when added to a regimen of pioglitazone with or without metformin, alogliptin significantly reduced A_1c 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 analysis 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, although the incidence of hypersensitivity reactions was low in clinical trials; 0.6% with alogliptin compared to 0.8% with all comparators. Acute pancreatitis has also been reported in post-marketing. In all alogliptin trials, 11 of 5,902 (0.2%) patients receiving alogliptin 25 mg daily compared to 5 of 5,183 (<0.1%) patients receiving all comparators developed pancreatitis. Alogliptin does not appear to increase the risk of hypoglycemia when used as monotherapy. In patients treated with alogliptin, 1.5% experienced hypoglycemia compared to 1.6% of patients treated with placebo. However, when alogliptin is used in combination with insulin or sulfonylureas, the manufacturer suggests reducing the dose of insulin or sulfonylurea to reduce the risk of hypoglycemia. In patients taking alogliptin, hepatic failure has been reported. Therefore, if a patient develops hepatic injury while taking alogliptin with no other identifiable cause, 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 6.25 mg daily is recommended in patients with a CrCl <30 mL/min, 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, although 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 prior to 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.