The Pharmacologic Basis for Clinical Differences among GLP-1 Receptor Agonists and DPP-4 Inhibitors

Nov 23, 2011Postgraduate medicine

How differences in drug actions explain varying effects of GLP-1 receptor activators and DPP-4 blockers

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Abstract

GLP-1 receptor agonists may reduce glycated hemoglobin levels by 0.4%-1.7%, compared to a 0.4%-1.0% reduction with DPP-4 inhibitors.

GLP-1 receptor agonists act directly on the GLP-1 receptor, while DPP-4 inhibitors increase levels of native GLP-1 indirectly.
GLP-1 receptor agonists generally lead to greater reductions in fasting and postprandial glucose levels than DPP-4 inhibitors.
Most patients using GLP-1 receptor agonists experience a mean weight loss of 1 to 4 kg over several months, whereas DPP-4 inhibitors are weight-neutral.
Both GLP-1 receptor agonists and DPP-4 inhibitors have a low incidence of hypoglycemia due to their glucose-dependent mechanisms.
Transient nausea occurs in 26% to 28% of patients treated with GLP-1 receptor agonists, but this can be mitigated with a dose-escalation strategy.

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The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists-which can be dosed to pharmacologic levels-act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%-1.7%) compared with DPP-4 inhibitors (0.4%-1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

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The Pharmacologic Basis for Clinical Differences among GLP-1 Receptor Agonists and DPP-4 Inhibitors

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