Symposium Articles
Evolving Treatment Strategies for the Management of Type 2 Diabetes

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Abstract

It is well known that improved metabolic control significantly reduces both micro- and macrovascular complications in diabetes. As it relates to specific treatment of type 2 diabetes mellitus, clinicians have traditionally initiated lifestyle intervention and progressed therapy using various drug treatments first as monotherapy and then as combination therapy throughout the course of the disease. This “stepwise” strategy has not always achieved the desired outcome of normal glycemic control; consequently, several clinical problems, such as hypoglycemia, weight gain and postprandial hyperglycemia, persist. However, new therapies that improve glycemic control and have favorable effects to address the unmet clinical problems have recently been developed or are still in development. These therapies include 2 classes of incretin-directed therapy, the dipeptidyl peptidase-4 inhibitors and the glucagon-like peptide-1 agonists, which help restore physiologic levels and activity of the incretin glucagon-like peptide-1. Also in development are additional therapies that have effects on the kidney to promote glucose excretion. These therapies are proposed to treat the key metabolic abnormalities associated with type 2 diabetes mellitus and minimize the side effects noted with conventional therapies.

Section snippets

TRADITIONAL APPROACH TO TREATMENT

To achieve the suggested glycemic targets for glucose control of T2DM, lifestyle intervention, that is, diet and exercise, has traditionally been the first step. However, diabetes is a progressive disease that is characterized not only by the presence of insulin resistance but also by the abnormalities in hepatic glucose production (HGP) and a progressive decline in β-cell function over time.9 To treat patients with T2DM effectively, the provider must have a good understanding of both the

EVOLVING TREATMENTS

As outlined earlier and recently reviewed in detail, available treatments for patients with T2DM include oral medications—including secretagogues, such as sulfonylureas and “glinides” (repaglinide and nateglinide); metformin; TZDs and dipeptidyl peptidase-4 (DPP-4) inhibitors—and parenterally administered agents, for example, insulin and glucagon-like peptide-1 (GLP-1) receptor agonists.9., 10., 11. Clearly, the traditional agents, such as sulfonylureas, insulin and metformin, have served

PHYSIOLOGIC ROLE OF INCRETINS

Two major incretin hormones in humans are GLP-1, which is secreted mainly by L cells in the distal intestine (ileum and colon), and glucose-dependent insulinotropic polypeptide from K cells of the small intestine (duodenum and proximal jejunum).23 Both peptides are released from the gastrointestinal tract in response to meal ingestion, and both are reported to play a major role in nutrient uptake. One of the key observations for incretins was the demonstration of the “incretin effect,” which

INCRETIN MODALITIES AS THERAPY FOR T2DM

Despite the promise of GLP-1 as a modality in humans, GLP-1 is not considered to be a practical incretin therapy that can be used for the treatment of T2DM based on its secretion and metabolism, which is outlined schematically in Figure 2.24., 25., 26. As aforementioned, GLP-1 is released predominantly by the L cells in the small intestine into the plasma in its active form and becomes rapidly inactivated by an enzyme that has been termed DPP-4 (Figure 2). On the basis of the observation of

DPP-4 Inhibitors

As outlined earlier, one mechanism by which one could increase endogenous GLP-1 activity is to inhibit the activity of DPP-4, the enzyme that rapidly converts GLP-1 to its inactive state, thereby increasing the levels of GLP-1 (Figure 2). Such a strategy provides a rationale for the use of DPP-4 inhibitors, oral agents that are also called “incretin enhancers.” Sitagliptin, linagliptin vildagliptin and saxagliptin are already available in many countries and are representative compounds of the

NOVEL THERAPEUTIC APPROACHES: THE KIDNEY AS A NEW TARGET FOR DIABETIC THERAPIES

It seems that the next class of agents that will be available for the clinical treatment of T2DM may involve those that address abnormalities in the kidney. It is well known that the kidney plays a major role in carbohydrate metabolism based on its role in gluconeogenesis and because of the glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. As recently reported, the kidney filters approximately 180 g of glucose daily for a normal healthy adult, and the

CONCLUSIONS

Over the recent past, considerably new information has been reported in regard to the need and approach to treat individuals with T2DM. New therapies that improve glycemic control and have favorable effects to address the unmet clinical problems are now commercially available, and many are still in development. The current approach to treatment is one that has a goal to meet the recommended glycemic targets by improving the key metabolic abnormalities associated with T2DM. The treatment regimen

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    This paper was presented as part of the Joint Plenary Session Symposium, which was held at the annual Southern Regional Meeting on February 18, 2011, New Orleans, Louisiana.

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