Redefining treatment success in type 2 diabetes mellitus: Comprehensive targeting of core defects

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The American Heart Association and the ADA initiated a call to action for global risk assessment for CVD and diabetes. 32 According to their joint scientific statement, lifestyle intervention should be reinforced at every physician visit, and HbA1c should be monitored every 3 months until it is less than 7.0% and then rechecked every 6 months. Adjustments in intervention should be made if the HbA1c level is 7.0% or higher. 3 A recent joint statement from the ADA and the EASD revised an earlier treatment algorithm for the initiation of therapy in patients with T2DM; the revision includes incretin therapies (ie, GLP-1 receptor agonists) as a tier 2 option, especially in patients in whom hypoglycemia and weight gain are concerns ( Figure 1 ).3


Traditional antidiabetes agents used in the treatment of patients with T2DM have focused mainly on insulin secretion and insulin resistance, with treatment success defined as achieving HbA1c goals with a reduced incidence of hypoglycemia. 23 Secretagogues, such as sulfonylureas and glinides, stimulate the pancreas to release insulin. Insulin sensitizers, such as TZDs and metformin, enhance the action of insulin in muscle and fat 1,3,23 and lower hepatic glucose production. The alpha-glucosidase inhibitors alter carbohydrate absorption from the gastrointestinal tract. 1 The extent to which each agent achieves treatment success in terms of glucose lowering depends on several factors, including intrinsic attributes, duration of disease, and baseline glycemic control. 3

Newer agents for the treatment of T2DM include the incretin-based therapies—GLP-1 receptor agonists and DPP-4 inhibitors—which influence mechanisms beyond increasing pancreatic insulin secretion and decreasing peripheral insulin resistance ( Table 2 ).22 The GLP-1 signaling pathway has been leveraged by two distinct pharmacologic approaches. The first involves the use of synthetic peptides with glucoregulatory effects similar to those of endogenous GLP-1 (GLP-1 receptor agonists). The second involves the use of DPP-4 inhibitors, small molecules that inhibit the proteolytic activity of DPP-4, leading to enhanced endogenous GLP-1 concentrations. 22

GLP-1 receptor agonists

Exenatide effects. Although many agents are in development, to date exenatide is the only GLP-1 receptor agonist approved by the US Food and Drug Administration (FDA). 8,33 Exenatide is an exendin-4 GLP-1 receptor agonist with multiple glucoregulatory effects, including enhanced glucose-dependent insulin secretion, reduced glucagon secretion and food intake, and slowed gastric emptying. 22,34 Exenatide is detectable in the circulation for up to 10 hours following subcutaneous (SC) administration 22 and has a greater potency in reducing plasma glucose than GLP-1 in preclinical studies. 35,36

By virtue of its beneficial effects on glycemic control, weight, BP, and lipids, exenatide addresses some of the components of the metabolic syndrome. 37–41 In pivotal 30-week studies, exenatide was associated with HbA1c reductions that ranged from –0.40% to –0.86% from baseline and decreases in body weight of approximately –1 kg to –3 kg from baseline, without severe hypoglycemia. 37–39 The percentage of patients who reached the ADA goal of HbA1c less than 7.0% at 30 weeks ranged from 24% to 34%. The addition of exenatide to TZD therapy in a 16-week study was associated with mean reductions in HbA1c of –0.98%, fasting plasma glucose (FPG) concentration of –1.69 mmol/L (–30.42 mg/dL), and body weight of –1.51 kg. 40

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