Abstract

With growing awareness that long-term hyperglycemia is directly implicated in the tissue damage characteristic of diabetes, there has been a corresponding increase in clinicians’ willingness to employ intensive treatment to achieve euglycemia, which may require diabetes drugs in combination. The expanding array of drugs with different mechanisms of action calls for a clear method of classification to guide rational combination therapy. Contemporary and historical literature was surveyed to document changes in awareness of toxicity from hyperglycemia and consequent changes in treatment strategy. References were selected for clinical applicability and explanation of drug mechanisms of action, with the goal of proposing a useful schema for classification. Diabetes drugs may be classified in the following categories: insulin providers, which increase the supply of insulin through administration of exogenous human insulin or analogues or drugs that stimulate endogenous insulin secretion (sulfonylureas and meglitinides are direct insulin secretagogues, whereas glucagon- like peptide-1 analogues and dipeptidyl peptidase-4 inhibitors act to increase the supply of insulin); insulin sensitizers (metformin, thiazolidinediones), which offset the effects of insulin resistance; and insulin-independent drugs, which work in the gut to impede intestinal absorption of glucose into the circulation (α-glucosidase inhibitors) or in the kidney to prevent renal reabsorption of glucose back into the circulation (sodium-glucose cotransporter 2 inhibitors, currently investigational). Awareness of these categories facilitates rational combinations of drugs with differing mechanisms of action to address hyperglycemia from separate directions, in accordance with current treatment guidelines.

Keywords: Diabetes drugs, classification, combination therapy, insulin, insulin-independent, type 2 diabetes, hyperglycemia, sulfonylureas, meglitinides, direct insulin secretagogues