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

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All treatments improved measures of beta-cell function (eg, homeostasis model assessment [HOMA]-beta, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1%–3%) across treatment groups. The incidence of gastrointestinal adverse experiences was evaluated with the coadministration of sitagliptin and metformin and appeared similar to that observed with use of metformin as monotherapy. 56 Thus, this study suggested that an initial combination of a DPP-IV inhibitor with metformin can improve glycemic control and markers of beta-cell function in patients with T2DM.

Incretin-based therapies compared

Studies in both healthy individuals and in patients with T2DM have shown that oral DPP-4 inhibitors such as sitagliptin increase endogenous GLP-1 concentrations by about twofold compared with placebo. 22,50 The pharma­cologic concentration of subcutaneously administered exenatide available for activating the GLP-1 receptor is significantly greater than the increased endogenous GLP-1 concentrations achieved with sitagliptin. In a recent clinical study comparing exenatide and sitagliptin in patients with T2DM, the mean 2-hour plasma concentration for exenatide was 64 pM compared with the mean 2-hour postprandial GLP-1 concentration of 15 pM for sitagliptin (baseline GLP-1 concentration was 7.2 pM). 57 While both agents were shown to be effective, exenatide appeared to have had a greater effect than sitagliptin in increasing insulin secretion and reducing postprandial glucagon secretion, leading to significantly ( P < 0.0001) greater reductions in PPG. 57

Sitagliptin has been minimally associated with nausea, whereas patients who take exenatide need to be informed of the risk of usually mild to moderate, but sometimes severe, nausea and vomiting that tends to decrease over time.

For a detailed comparison of the effects of GLP-1 receptor agonists and DPP-4 inhibitors on HbA1c, weight, and hypoglycemia, see “ Advances in therapy for type 2 diabetes: GLP–1 receptor agonists and DPP–4 inhibitors .”


Despite advances in diagnosis and treatment, T2DM, overweight/obesity, CVD, and their complications remain major public health burdens worldwide. The concepts that explain the pathophysiology of T2DM include the contribution of various factors beyond insulin secretion and insulin resistance, such as the role of incretin hormones in disease progression. A comprehensive approach to managing patients with T2DM requires targeting the fundamental defects of the disease and its comorbidities. Newer agents, including incretin-based therapies such as GLP-1 receptor agonists and DPP-4 inhibitors, address the fundamental defects of T2DM. The definition of treatment success in the management of T2DM will be redefined as more data become available on agents that exert beneficial effects not only on glycemia but on parameters that may influence overall CV health, such as weight, BP, and lipid profiles.

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