What’s in the pipeline for new type 2 diabetes drugs?

Issue: December 2008

ByJune Felice Johnson, BS, PharmD, FASHP, CDM-diabetes

A number of investigational medications for the treatment of type 2 diabetes are being studied in clinical trials.

This column will briefly review the agents in phase-3 clinical trials. The details of these products are limited at this time since they are highly protected due to intellectual property regulations.

DPP-IV inhibitors

This class of oral medications acts by inhibiting the rapid degradation of glucagon-like peptide 1 and gastric inhibitory polypeptide incretin hormones, thus enhancing levels, prolonging half-life, and restoring insulinotropic and other actions of these hormones. Currently, sitagliptin (Januvia, Merck) is the only DPP-IV inhibitor approved by the FDA for marketing in the United States.

June Felice Johnson

Sitagliptin has the advantages of not causing hypoglycemia when used as monotherapy, weight neutrality, oral administration, and approval for combination use with sulfonylureas, metformin, and the thiazolidinediones. The mean reduction in HbA1c is ~0.6%. Clinical trials indicated that it was tolerated well, but postmarketing reports have indicated concerns regarding potentially severe allergic reactions that require vigilant patient monitoring.

Consensus algorithms developed by the American Diabetes Association and the European Association for the Study of Diabetes do not yet include the DPP-IV inhibitors due to the need for more clinical experience and relative expense.

Vildagliptin (Galvus, Novartis) has been shown to have a prolonged half-life and can be administered once daily. It was approved in Europe in early 2008, and as a combination product with metformin (Eucreas, Novartis) last February. A recent trial (GALIANT) was presented at the EASD meeting this fall, and results indicated that it was as effective as TZDs when added to metformin but better tolerated. It also appeared to have a lower overall incidence of negative cardiovascular events compared to placebo.

Saxagliptin (Onglyza, Bristol-Myers Squibb; AstraZeneca) has been studied as monotherapy or in combination with metformin. Although skin toxicity has been observed in primates, it has not yet been demonstrated in humans. A study presented at the ADA 2008 Annual Scientific Meeting showed that it had a safety profile similar to placebo.

The FDA was not able to complete its review of alogliptin (Takeda) by October resulting in a delay in the sponsor’s New Drug Application. Current studies are being conducted in patients naive to medications or failing monotherapy.

GLP-1 mimetics

These medications are functional analogs of human GLP-1 and act by binding to the GLP-1 receptor. Their ability to resist degradation by DPP-IV enhances their potency and duration of action compared with endogenous GLP-1. Exenatide (Byetta, Lilly & Amylin) is currently the only GLP-1 mimetic approved for marketing by the FDA and is used in combination with metformin, sulfonylureas or the TZDs. The newest consensus algorithm does include the GLP-1 mimetic exenatide at tier 2 instead of a sulfonylurea or insulin for certain patients.

Exenatide has the advantages of assisting with weight loss and improving glycemic control, but the disadvantages of needing twice daily injectable administration and having the frequent side effect of nausea. A tantalizing benefit of this class is suggested by in vitro and animal studies that demonstrate a reduction in B-cell apoptosis. A once-weekly formulation is currently in clinical trials and an NDA has been submitted to the FDA for review.

Liraglutide (Novo Nordisk) has a longer half-life than exenatide after subcutaneous administration and can be administered once daily. This is due to fatty acid acylation that slows its absorption and causes binding to albumin. Researchers are conducting trials to explore its safety and efficacy in many different regimens, including comparing it with sitagliptin in patients on metformin, comparison with glimepiride, and comparison with exenatide in patients on either metformin or a sulfonylurea or both. Since its effects on insulin and glucagon are glucose dependent, the risk of hypoglycemia is reduced. It also appears to have a beneficial effect on blood pressure. The company filed its NDA in both the United States and Europe in May.

SGLT-inhibitors: new class

A new class, inhibitors of sodium-glucose cotransporters (SGLT-1 and SGLT-2) in the gut and kidney, is being explored in earlier stages of drug development. The SGLT-2 inhibitors act by inhibiting glucose reabsorption in the renal proximal tubule.

Dapagliflozin is an inhibitor of SGLT-2 in the kidney and is being investigated by Bristol-Myers Squibb.

In conclusion, we will have to stay informed as these agents complete phase-3 clinical trials and are released into the marketplace. Providers will then be able to apply their use in clinical patient care to determine their ultimate utility and position in therapy.

June Felice Johnson, BS, PharmD, FASHP, CDM-Diabetes, is the Director of Faculty & Site Development and an Associate Professor of Pharmacy Practice at Drake University College of Pharmacy & Health Sciences, in Des Moines, Iowa.

For more information:

American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care. 2007;30:S4-S41.

Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT-2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57:1723-1729.

Horton E, Cefalu WT, Haines ST, Siminerio LM. Multidisciplinary interventions. Diabetes Educator. 2008;34:78S-89S.

Madsbad S, Schmitz O, Ranstam J, et al. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211). Diabetes Care. 2004;27:1335-1342.

Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. Published online Oct. 22, 2008. doi:10.2337/dc08-9025.

Vilsboll T. Liraglutide: A once-daily GLP-1 analogue for the treatment of Type 2 diabetes mellitus. Expert Opin Investig Drugs. 2007;16:231-237.