Evolving Therapeutic Options for Type 2 Diabetes Mellitus: An Overview

Abstract

Introduction: Many oral antidiabetic drugs (OADs) are available for patients with type 2 diabetes mellitus (T2DM). However, it is recognized that additional therapies are needed and several new compounds are in advanced stages of development. Purpose: This narrative review considers the essential features of a successful OAD, the main classes of OADs that are currently used, and the therapies that may be available in the upcoming years. Results and Conclusions: The first OADs (sulfonylureas and biguanides) were discovered by chance. Although effective in reducing blood glucose levels, early sulfonylureas were associated with significant off–target effects, and the biguanide phenformin was discontinued due to adverse events. Although metformin is in the same drug class, it has a better safety profile and is now recommended as first–line treatment, except when contraindicated. Nonetheless, many patients require additional glucose control (even on metformin) with an agent that has a complementary mechanism of action. Developments in bench science have facilitated the selection of agents for specific therapeutic targets, with the thiazolidinediones providing an interesting example. This OAD class initially appeared encouraging, yet in clinical practice was associated with safety concerns. As a result, newer agents, such as dipeptidyl peptidase–4 inhibitors, are undergoing more rigorous safety evaluations than OADs of previous generations. Promising compounds with novel mechanisms of action include the sodium–glucose co–transporter 2 inhibitors, the G–protein–coupled receptor agonists, and the balanced dual peroxisome proliferator–activated receptor–α/γ agonists. There is optimism that in the next few years, novel classes of OADs that are currently under development will offer additional blood glucose control options via complementary mechanisms of action. However, history has shown that compounds of the same class can have different safety profiles and treatment effects. Therefore, high–quality clinical trial evidence is needed for every compound.

Keywords:

• dipeptidyl peptidase-4 inhibitor
• sodium-glucose co-transporter 2 inhibitor
• type 2 diabetes mellitus
• G-protein-coupled receptor 40 agonist
• G-protein-coupled receptor 119 agonist
• dual peroxisome proliferator-activated receptor modulator