After several years of reviews and rejections, the dipeptidyl peptidase IV inhibitor alogliptin has finally been approved by the Food and Drug Administration.

The FDA approved three versions of the product: as a single agent (Nesina); in combination with metformin (Kazano); and, in combination with pioglitazone (Oseni). All are indicated for treatment of type 2 diabetes in combination with diet and exercise.

Alogliptin is designed to slow the inactivation of incretin hormones GLP-1 (glucagonlike peptide–1) and GIP (glucose-dependent insulinotropic peptide), according to the drug’s maker, Takeda Pharmaceutical Company Ltd. Oseni is the first product approved in the United States that includes a DPP-4 inhibitor and a thiazolidinedione in a single tablet, the company said.

That unique combination may be of interest to clinicians, said Dr. Paul Jellinger, professor of clinical medicine at the University of Miami, Division of Endocrinology. First, a one-pill combination offers convenience for patients. And, the combination of a DPP-4 inhibitor and a TZD robustly drops hemoglobin A_1C and also makes physiologic sense since they work by two different mechanisms, added Dr. Jellinger.

He notes that in carefully selected patients, pioglitazone is useful to reverse or diminish insulin resistance and also to treat and minimize the appearance of fatty liver. “The same patient that you would think of using pioglitazone for is probably an ideal candidate for a combination of pioglitazone and a DPP-4 inhibitor like alogliptin,” said Dr. Jellinger, who practices at The Center for Diabetes & Endocrine Care in Hollywood, Florida.

Patients should be monitored for pioglitazone side effects such as heart failure, weight gain, edema, and more rarely, small bone fractures, he said. They should also be screened for bladder cancer several times yearly.Alogliptin is the fourth DPP-4 inhibitor to win FDA approval. Merck’s sitagliptin (Januvia) is the market leader; the others in the class are saxagliptin (Onglyza, marketed by AstraZeneca and Bristol-Myers Squibb) and linagliptin (Tradjenta, marketed by Boehringer Ingelheim and Lilly).

These approvals are 5 years in the making. Takeda submitted an application for the drug in 2008, but was tripped up by several developments. First, shortly after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction, the FDA in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety. Takeda had to restart its clinical development to incorporate trials with cardiovascular endpoints. The company subsequently received two requests – one for alogliptin as a single agent and another for the combination with pioglitazone – for more information, because of safety concerns.

As a result, the agency’s approval for each product is a mixed bag, with each carrying different warnings and requirements.

The single agent, Nesina, showed in more than 14 trials that it reduced hemoglobin A_1c by 0.4-0.6 percentage points compared with placebo over 26 weeks. It will be available in 6.25-mg, 12.5-mg, and 25-mg tablets. But the agency is requiring five postmarketing studies for alogliptin as a single agent: an enhanced pharmacovigilance program to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions; and three pediatric studies under the Pediatric Research Equity Act (PREA), including a dose-finding study and two safety and efficacy studies, one with Nesina as a monotherapy and one with Nesina and metformin.

The metformin combination, Kazano, reduced HbA_1c by 1.1 percentage points more than Nesina, and 0.5 percentage points more than metformin alone in four clinical trials. The two dosages are 12.5 mg alogliptin/500 mg metformin and 12.5 mg/1,000 mg. The FDA is requiring two postmarketing studies for Kazano: a program to monitor for liver abnormalities, serious pancreatitis, and severe hypersensitivity reactions; and a pediatric safety and efficacy study. Kazano will carry a boxed warning for lactic acidosis.

Oseni, the alogliptin/pioglitazone combination, in six fixed-dose formulations (5 mg/15 mg, 25 mg/30 mg, 25 mg/45 mg, 12.5 mg/15 mg, 12.5 mg/30 mg, and 12.5 mg/45 mg), reduced HbA_1c by 0.4-0.9 percentage points more than alogliptin alone, and 0.4-0.6 percentage points better than pioglitazone alone in studies. Takeda will have to conduct a postmarketing study on liver abnormalities, pancreatitis, and hypersensitivity reactions for Oseni, as well. The drug will have a boxed warning for heart failure.

Both Oseni and Nesina are approved in Japan, but those are the only other global approvals for the products.

Although there has been some concern with all diabetes therapeutics and cardiovascular safety, a recent meta-analysis showed that DPP-4 inhibitors may substantially reduce the risk of major cardiovascular events. The study, funded by Bristol-Myers Squibb and AstraZeneca, was reported at the annual scientific sessions of the American Heart Association in late November.

a.ault@elsevier.com

Twitter @aliciaault

FDA approves alogliptin, alone and in combinations