Incretin-Based Therapies: Viewpoints on the way to consensus

Diabetes Progression, Prevention, and Treatment

Incretin-Based Therapies

¹Diabetes Center Bad Lauterberg, Bad Lauterberg im Harz, Germany;
²Department of Internal Medicine, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark;
³Department of Medicine IV, Eberhard-Karls University Tübingen, Tübingen, Germany;
⁴Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, Houston, Texas;
⁵Department of Endocrinology, Hvidovre University Hospital, University of Copenhagen, Copenhagen, Denmark.

Diabetes Care 2009 Nov; 32(suppl 2): S223-S231. https://doi.org/10.2337/dc09-S315

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Figure 1
Schematic diagram explaining the physiological (postprandial) secretion of GLP-1 from the gut, its binding to GLP-1 receptors (e.g., on pancreatic endocrine β-cells), and its degradation by the ubiquitous protease DPP-4 as well as its rapid renal elimination (A). Incretin mimetics are peptide GLP-1 receptor agonists more or less structurally similar to GLP-1, which bind and activate the GLP-1 receptor, but are not degraded by DPP-4 and have much slower elimination pharmacokinetics (B). DPP-4 inhibitors prevent the degradation/inactivation of the biologically active form of GLP-1 and, thereby, augment the biological activity of GLP-1 released from endogenous sources (C).

Table 1

Similarities of incretin-based therapies

Properties/action	Incretin mimetics	DPP-4 inhibitors
Glucose-dependent insulin secretion	Yes	Yes
Glucose-dependent glucagonostatic effect	Yes	Yes
Effect on fasting plasma glucose (reduction)	By 1.4–3.4 mmol/l	By 1.0–1.4 mmol/l
Effect on postprandial glucose	Yes	Yes (but weaker)
Effect on A1C (reduction)	By 0.8–1.8%	By 0.5–1.1%
Effect on (pro)insulin biosynthesis	Yes	Yes (weaker?)
Improved in vivo β-cell function (in humans)	Yes^*	Yes^*
Beneficial cardiovascular effects	Probable	Not proven

↵*As determined while patients received treatment (lasting effects need to be proven after washing out treatment).

Table 2

Differences of incretin-based therapies

Properties/action	Incretin mimetics	DPP-4 inhibitors
Administration	Subcutaneous	Oral
GLP-1 levels (or equivalent)	Pharmacological (six- to tenfold)	Physiological (two- to threefold)
Main mechanism of GLP-1 receptor stimulation	Interaction with receptors on target organs/cells	Interaction with receptors on afferent nerves (autonomous nervous system)
Other mediators	No	GIP, PACAP, others (questionable)
Effects on gastric emptying	Yes	No (hardly)
Effects on appetite	Reduced	Hardly influenced
Effects on body weight	Weight loss	Weight neutrality
Adverse events	Nausea, vomiting, antibodies (exenatide, relevance?), pancreatitis (causal relation?)	Upper respiratory tract infections, elevations in liver enzymes (vildagliptin), skin reactions (sitagliptin)