Incretin-based therapies for type 2 diabetes mellitus: New therapeutic mechanisms

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Almost a decade into the 21st century, the global epidemic of diabetes—which accelerated in the 1970s—shows no sign of slowing. At the same time, our insights into both type 1 and type 2 diabetes mellitus (T2DM) have increased at a similarly rapid rate.

At the beginning of the 1970s, it was far from clear whether improved glycemic control made much difference in the long-term well-being of people with diabetes other than to relieve their symptoms of hyperglycemia and decrease the likelihood of diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma. Concerns were expressed about the risk/benefit ratio of antihyperglycemic drugs—so there is nothing new under the sun! The drugs available in the United States were limited to insulin and sulfonylureas. The rest of the world also had access to metformin, but, in truth, its potential was underestimated until much later.


Out of this milieu of scientific uncertainty grew the two clinical trials that effectively ended the debate about the value of glycemic control: the Diabetes Control and Complications Trial (DCCT) 1 for type 1 diabetes, and the United Kingdom Prospective Diabetes Study (UKPDS) 2,3 for T2DM. The conduct of these trials was facilitated by the timely demonstration of the utility of glycosylated hemoglobin (HbA1c) as an objective measure of glycemic control, and of microalbuminuria as a marker of early nephropathy.

Both the DCCT and the UKPDS, in their initial “end of study” analyses in the 1990s, established the role of glycemic control in reducing the risk of retinopathy, neuropathy, and nephropathy—the microvascular complications of diabetes. Additionally, the UKPDS demonstrated that in T2DM, hypertension management was at least as important as glycemic control in reducing the risk of microvascular complications.

Neither the DCCT nor the UKPDS was powered to determine initially whether glycemic control was a risk factor for cardiovascular disease; however, careful longer-term surveillance of the patient cohorts in the studies has recently borne fruit in this regard. Reports from both studies have shown that efforts to control glycemia early in the course of diabetes are rewarded many years later by a decreased risk of cardiovascular events and death. 4,5 This is true even when excellent glycemic control achieved early on is not sustained indefinitely. It has also become widely recognized that the management of diabetes, with prevention of microvascular and cardiovascular disease as major aims, involves much more than a simple preoccupation with glycemic control—important as that is.


Concurrent with the DCCT and the UKPDS being conducted with, in effect, the therapeutic tools of the 1970s, considerable strides were being made in the development of new classes of antihyperglycemic agents for use in T2DM. These include the thiazolidinediones (TZDs), alpha-glucosidase inhibitors, nonsulfonylurea insulin secretagogues (also known as glinides), and, more recently, the incretin-based drugs that are the focus of this supplement to the Cleveland Clinic Journal of Medicine .

Understandable enthusiasm for tapping into the hitherto unexploited pathways and mechanisms targeted by a new drug class is inevitably tempered by known, or sometimes unforeseen, adverse effects. Some of the adverse effects typically associated with antihyperglycemic drugs used before the incretin-based therapies became available include hypoglycemia, weight gain, and fluid retention; all of these are perceived as possibly increasing the risk of the very thing we are striving to avoid in diabetes—cardiovascular morbidity and mortality. Such is the concern about this risk—epitomized, rightly or wrongly, in the controversial meta-analysis of clinical trials involving rosiglitazone 6—that the US Food and Drug Administration now requires new antihyperglycemic drugs not only to meet efficacy standards for improving glycemia but also to show no sign of increased cardiovascular risk. The requirement must be met in preapproval trials, to be followed by postmarketing studies to prove the lack of cardiovascular risk.

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Current antihyperglycemic treatment strategies for patients with type 2 diabetes mellitus

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