After what likely seemed forever for drug manufacturer Takeda, the US Food and Drug Administration (FDA) recently announced the approval of alogliptin, the company’s dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin was actually the first DPP-4 inhibitor slated for approval, but because of cardiovascular concerns with Avandia® (rosiglitazone), the FDA made a rule change that any new diabetes drug must demonstrate cardiovascular safety prior to approval. Takeda, having put together their submission package prior to this change, was not prepared and had to go back to the drawing board. At about the same time, competing drug manufacturer Merck was able to adjust its submission package for Januvia® (sitagliptin), which became the first DPP-4 inhibitor approved. Now Takeda’s aloglipitin will be the fourth DPP-4 inhibitor to arrive on the US market, behind Januvia, Onglyza®, and Tradjenta®.
However, all may not be lost for Takeda. Alogliptin was approved as a monotherapy (called Nesina®) as well as in fixed-dose combinations: Kazano™ (alogliptin and metformin hydrochloride) and Oseni™ (alogliptin and pioglitazone) tablets, for use with diet and exercise to improve blood glucose control in adults with type 2 diabetes. While all 3 other companies have a DPP-4/metformin combination, Takeda is the first with a DPP-4/thiazolidinedione combination.
Recently, the FDA’s endocrinology advisory committee gave a favorable rating to the SGLT2 inhibitor canagliflozin. This class of drugs works as an inhibitor of sodium glucose cotransporter-2 (SGLT2) and blocks the kidney’s normally tight reabsorption of glucose. Glucose is lost through the kidneys, and therefore lowered in the bloodstream. In addition to facilitating better sugar control by eliminating sugar (and therefore calories) from the body, SGLT2 inhibitors offer the additional benefit of weight loss. It appeared that dapagliflozin was going to be the first in this class to market, but the same FDA advisory committee rejected the approval of dapagliflozin by a 9-6 vote, citing concerns about cancer and the possibility of liver disease.
What’s interesting about these 2 developments is the possibility of a 2-pill, 4-drug combination regimen: Oseni (alogliptin and pioglitazone) and canagliflozin/metformin. There are few studies with a 3-drug combination and none (to my knowledge) of a 4-drug combination that includes an SGLT2 inhibitor. Since all 4 drugs work by different mechanisms, their actions should be complementary.
In studies with add-on therapy to metformin,[1,2] a single agent generally yields about a 0.5% drop in A1c. By itself, this is not a lot, but it might be possible that this 2-by-4 (reference to a piece of lumber intentional) combination could yield well over a 3% reduction in A1c, which would likely get most patients with type 2 diabetes to their blood glucose goals — and without the hypoglycemia associated with the sulfonylureas. Though far from a cure, this regimen has the potential to substantially reduce A1c to under 7% for most patients, decrease complications from diabetes, and reduce the number of patients on subcutaneous insulin.
From www.medscape.com
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