350. GLP-1 Agonists: Mechanisms to Appli...

Calling all those with a passion for cardiovascular prevention! In this episode of the CardioNerds Cardiovascular Prevention Series, we take a deep dive into the world of glucagon-like peptide-1 (GLP-1) receptor agonists. Along the way, you’ll hear about the biology of the GLP-1 molecule and its related peptides, learn more about how GLP-1 agonists promote glycemic control, weight loss, and cardiometabolic health, and explore the current body of literature supporting the individualized application of these medications to patients with diabetes, obesity, and/or ASCVD.

Join Dr. Christian Faaborg-Andersen (CardioNerds Academy Fellow and Internal Medicine Resident at MGH), Dr. Gurleen Kaur (Director of the CardioNerds Internship, Chief of House Einthoven, and Internal Medicine resident at BWH), and Dr. Rick Ferraro (CardioNerds Academy House Faculty and Cardiology Fellow at JHH) for a wide-ranging discussion on GLP-1 and GIP agonists with Dr. Dennis Bruemmer (Cardiologist and Director of the Center for Cardiometabolic Health in the section of Preventive Cardiology at the Cleveland Clinic).

Show notes were drafted by Dr. Christian Faaborg-Andersen. Audio editing was performed by CardioNerds Academy Intern, student Dr. Tina Reddy.

This episode was produced in collaboration with the American Society of Preventive Cardiology (ASPC) with independent medical education grant support from Novo Nordisk. See below for continuing medical education credit.

Claim CME for this episode HERE.

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Pearls and Quotes – GLP-1 Agonists: Mechanisms to Applications

1. The selection and dosing of GLP-1 and GIP agonists (GLP-1s and GIPs) depends on their intended use as an anti-glycemic or anti-obesity agent.
2. The cardiovascular benefits of GLP-1s and GIPs may be independent of improvements in glycemic control, and in part be driven by reduction in inflammation, a key driver of arterial plaque formation.
3. In patients with comorbid coronary artery disease, obesity, and diabetes, GLP-1 agonists and SGLT-2 inhibitors should be used as first-line agents, over metformin.
4. Tirzepatide is a dual agonist that activates GIP and GLP-1 receptors. GIP is highly expressed in the brain, which may mediate satiety, promote energy expenditure, and enhance peripheral glucose metabolism.
5. Caution should be used with GLP-1 agonists in patients with long-standing diabetes complicated by gastroparesis, as well as incompletely treated diabetic retinopathy.
6. GI upset is not uncommon with GLP-1/GIP agonists, and switching to a different agonist is unlikely to help. 

Show notes – GLP-1 Agonists: Mechanisms to Applications

What are the mechanisms of action by which GLP-1 and GIP controls blood sugar and body weight?

• Glucagon-like peptide-1 (GLP-1) is an endogenous hormone that is secreted in response to an oral glucose load. It promotes insulin release, inhibits glucagon secretion, and slows gastric emptying via the brain-intestine axis, leading to satiety. GLP-1 agonists are medications that mimic the effect of this hormone and, on average, lower hemoglobin A1C by 0.8% to 1.5%. These medications include semaglutide, liraglutide, and dulaglutide.
• Glucose-dependent insulinotropic polypeptide (GIP) is also an endogenous hormone, similarly secreted by the body in response to an oral glucose load such as a meal. GIP is highly expressed in the arcuate nucleus and hypothalamus, which may mediate satiety, promote energy expenditure, and enhance peripheral glucose metabolism. Tirzepatide is a dual GLP-1/GIP agonist.

What is the role of GLP-1/GIP agonists in patients with overweight/obesity and/or type 2 diabetes? How does the dosing of GLP-1/GIP medications change with their intended disease target?

• The STEP-1 trial showed that once-weekly semaglutide led to a net 15% weight loss in non-diabetic, obese/overweight patients. The SELECT trial builds on these results, showing that once-weekly semaglutide resulted in a 20% reduction in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with pre-existing cardiovascular disease and BMI ≥ 27kg/m². Other notable trials in this space include the LEADER trial (liraglutide), the SUSTAIN-6 trial (semaglutide), and the REWIND trial (dulaglutide). 
• The dosing of GLP-1 agonists depends on their intended use as either an anti-glycemic or anti-obesity agent. For weight management, the current FDA-approved therapies are semaglutide 2.4mg weekly and liraglutide 3mg daily. For diabetes, the approved medications are semaglutide 2mg weekly, dulaglutide 4.5mg weekly, and tirzepadite 15mg weekly.

What are the cardiometabolic benefits of GLP-1/GIP agonist therapy, beyond glycemic control and/or weight loss? When are GLP-1/GIP agonists considered first-line therapy?

• The cardiovascular benefits of GLP-1s may be independent of improvements in glycemic control, and in part be driven by reductions in inflammation and cytokine response driving plaque formation in the arterial wall. In the SELECT trial, once weekly 2.4mg semaglutide led to a 20% reduction in MACE in non-diabetic, obese/overweight patients with established ASCVD.
• In patients with comorbid coronary artery disease, obesity, and diabetes, national guidelines recommend GLP-1 agonists and SGLT-2 inhibitors as first-line agents, over metformin. 

How does tirzepatide differ from GLP-1 agonists?

• Tirzepetide is a dual GLP-1/GIP agonist. GIP is highly expressed in the arcuate nucleus and hypothalamus, which may mediate satiety, promote energy expenditure, and enhance peripheral glucose metabolism.
• The SURMOUNT trial showed 20% net weight loss with tirzepatide in patients with overweight/obesity, nearly as effective as metabolic surgery. 

What are the absolute and relative contraindications to GLP-1/GIP agonist therapy?

• GLP-1/GIP agonists are contraindicated in patients with a personal or family history of medullary thyroid cancer.
• Caution should be used in patients with long-standing diabetes with neuropathy and gastroparesis, as well as incompletely treated diabetic retinopathy.
• Gallstone pancreatitis should not be considered a contraindication to GLP-1/GIP therapy after cholecystectomy, though a history of recent pancreatitis should give one pause in prescribing a GLP-1/GIP agonist.
• GLP-1 agonists should not be prescribed for type 1 diabetes, during pregnancy, or with breastfeeding. 

What are the most common side effects of GLP-1 agonists?

• GI upset is the most common side effect with GLP-1/GIP agonist therapy, and the incidence of these side effects is similar between tirzepadite and semaglutide in randomized control trials.

References – GLP-1 Agonists: Mechanisms to Applications

• Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183 https://pubmed.ncbi.nlm.nih.gov/33567185/
• Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827 https://pubmed.ncbi.nlm.nih.gov/27295427/
• Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141 https://pubmed.ncbi.nlm.nih.gov/27633186/
• Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. doi:10.1016/S0140-6736(19)31149-3 https://pubmed.ncbi.nlm.nih.gov/31189511/