Evolving Therapeutic Options for Type 2 Diabetes Mellitus: An Overview

Abstract

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.

Hepatitis C virus infection and insulin resistance

“…Early sulfonylureas although useful in lowering blood glucose level, were associated with significant off-target effects, and the biguanide phenformin was discontinued due to adverse events [60] . Although metformin is in the same drug class, it has a better safety profile and is now recommended as first-line treatment of diabetes during HCV infection.…”

“…Agents used in diabetic therapy include the following: sulfonylureas, biguanides, alphaglucosidase inhibitors, thiazolidinediones, Meglitinide derivatives etc [60] . 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 [60] . Although metformin is in the same drug class, it has a better safety profile and is now recommended as first-line treatment.…”

Kidney Disease End Points in a Pooled Analysis of Individual Patient–Level Data From a Large Clinical Trials Program of the Dipeptidyl Peptidase 4 Inhibitor Linagliptin in Type 2 Diabetes

“…1 The primary goal of these agents is to effectively lower elevated blood glucose concentrations in order to reduce the risk of long-term complications that result from chronic hyperglycemia. 2,3 However, it is equally critical for any new agent to also be proved to be safe.…”

Periprocedural Glycemic Control in Patients With Diabetes Mellitus Undergoing Coronary Angiography With Possible Percutaneous Coronary Intervention

“…Both of these patients were on both full dose insulin and a sulfonylurea agent. Since hypoglycemia is more common with sulfonylureas than with other oral glucose-lowering agents, caution should be taken in continuing the combination of sulfonylureas and full dose insulin prior to procedure (21). Clinicians should note that biguanides, which are not associated with hypoglycemia, are now recommended as first-line medications, and sulfonylurea use is declining (22).…”