Vascular effects of GLP-1 receptor activation
Description: More than a third of Americans are obese. Obesity is associated with inflammation, endothelial dysfunction, fibrinolytic dysfunction and increased risk of cardiovascular disease (CVD). Recently, the long acting glucagon-like peptide (GLP)-1 agonist liraglutide was approved by the FDA for the treatment of obesity. Liraglutide, and the longer acting GLP-1 agonist semaglutide, reduce cardiovascular morbidity and mortality in patients with type 2 diabetes (T2DM). Whether this results directly from GLP-1 receptor (GLP1R) activation or indirectly from weight loss is not known. The dipeptidyl peptidase 4 (DPP4) inhibitors prevent breakdown of endogenous GLP-1, but do not cause weight loss or reduce cardiovascular events. Understanding the mechanism(s) by which GLP-1 analogues reduce cardiovascular risk has major public health implications in obesity. Long-acting GLP-1 analogues have neutral or detrimental effects on diabetic retinopathy and chronic treatment is expensive. In addition, individual factors may modify the effect of GLP-1 analogues, weight loss, or DPP4 inhibition on cardiovascular risk. For example, a common missense variant (Gly168Ser, rs6923761) has been associated with greater weight loss and blood pressure lowering to liraglutide. This goal of this project is to test the overarching hypothesis that stable GLP-1 analogues have specific GLP1R-dependent beneficial effects on endothelial function, fibrinolysis and inflammation in obesity that exceed the benefits of weight loss, and that genetic or other individual factors that modulate GLP1R sensitivity modify the effect of these analogues on cardiovascular risk. To this end, Aim 1 will compare the effect of liraglutide to the effect of comparable weight loss (hypocaloric diet) to the effect of increasing endogenous GLP-1 without causing weight loss (sitagliptin) on endothelial vasodilator and fibrinolytic function, inflammation and other CVD risk factors. In Aim 2, we will assess the contribution of GLP1R activation to the effects of liraglutide and sitagliptin using the GLP1R antagonist Exendin (9-39), complementing studies of GLP1R signaling in Project 1. In Aim 3, we will determine whether rs6923761 and other genotypes or obesity phenotypes (informed by Project 3) predict the effect of liraglutide on metabolism, weight loss, and markers of CVD risk. Understanding the GLP1R-specific mechanisms of these treatments promises to lead to personalized approaches to reducing CVD in obese patients.
Funder: American Heart Association
Amount: $1,774,000
Funding type: research
Funder scheme: Strategically Focused Research Network
Start date: 2017-04-01
End date: 2021-03-31
Investigators: James Luther, James Luther
Institution: Vanderbilt University Medical Center (VUMC)
Funded outputs count: 2
Funder award ID: 17SFRN33520059
OpenAlex ID: G4304741973