The Incretin System & Incretin-Targeting Agents

Supported by an
educational grant from
Novo Nordisk A/S

Properties of Incretin-Based Therapies CV benefits for

Incretin mode of action1
DPP-4is GLP-1 RAs GLP-1 RAs: What
• After meal ingestion, the intestine signals to the pancreas via GLP-1
and GIP hormones Administration route do the data tell us?
• These incretin hormones have two major effects: Pooled data set from 8 CV
- Increase glucose secretion in beta cells GLP-1 levels outcome trials with GLP-1 RAs
(meal-related) suggest significant reductions in CV
- Supress glucagon secretion from alpha cells
- In T2DM, incretins are reduced or absent events compared with placebo3
GIP levels
(meal-related)
Three-point
14% RR
Effect on HbA1c 0.6 to 0.8% 1 to 2% MACE
Glucagon
(GLP-1) Effect on BW
CV
mortality
13% RR
α cells
Nutrient Signals Hypoglycemia risk Fatal or
non-fatal MI
10% RR

Side effects
Fatal or
non-fatal stroke
17% RR
uticaria vomiting nausea diarrhea
Neural Signals
PANCREAS CV protection 0.5 1 1.5
Favours GLP-1 RAs Favours placebo

GUT
Hormonal Signals
Main available GLP-1 RA formulations4
• GLP-1 • GIP β cells
Insulin GLP-1RAs are:
GLP-1RAs
Active Inactive (GLP-1, GIP) • Available in different formulations
incretins DPP-4 incretins
- Weekly: Dulaglutide and injectable
semaglutide, and Exenatide ER
GLP-1RAs DPP-4is
Human GLP-1-based therapies Exendin based therapies
- Daily: liraglutide, oral semaglutide
Active incretins Inactive incretins
Active incretins
• Semaglutide and liraglutide
are also available at higher
Dulaglutide Liraglutide Exenatide ER Exenatide BID
doses as anti-obesity
medications in those
The incretin signal can be prolonged therapeutically:2 with(out) diabetes Semaglutide
• GLP-1 RAs: Mimic the action of endogenous GLP-1 - Twice daily: Exenatide BID
• DPP-4i:Prevent the DPP-4 enzyme from degrading endogenous GLP-1 and GIP Approved anti-obesity medications
• Indicated for patients with T2DM in those with(out) diabetes
who have prevalent CVD Oral semaglutide
Adopted with permission from Creutzfeldt W. Diabetologia. 1979;16:75-85. Copyright © 1979 Springer-Verlag.

Abbreviations: BID, twice daily; BW, body weight; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcome trial; DM, diabetes mellitus; DPP-4i, dipeptidyl peptidase-4 inhibitor; ER, extended release; GIP, gastric
inhibitory polypeptide ; GLP-1, glucagon-like peptide-1; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; HbA1c, Hemoglobin A1c; RR, relative reduction; SGLT2i, sodium-glucose co-transporter-2 inhibitors; T2DM, type 2 diabetes
mellitus;
References: 1. Creutzfeldt W. Diabetologia. 1979;16:75-85. 2. Gilbert MP et al. Front Endocrinol (Lausanne). 2020;11:178. 3. Sattar N et al. Lancet Diabetes Endocrinol. 2021;9:653-662. 4. Sharma D et al. Biomed
Pharmacother. 2018;108:952-962.