SGLT2i and GLP-1 Mechanisms of Action, Uses in Type II DM, Obesity, and the General Population, and Benefits vs. Risks and Side Effects That We May Anticipate in Patients with Rheumatic Diseases

Speaker: Dr. Louis Aronne, MD – Weill Cornell Medicine

Key Highlights

Understanding Obesity as a Multisystem Disease: 

Obesity is a complex condition driven by hormonal dysregulation and inflammation. Excess adipose tissue disrupts metabolic and inflammatory pathways, exacerbating conditions such as type II diabetes, cardiovascular disease, and even breast cancer. Treating obesity not only addresses weight loss, but also improves related comorbidities, reducing the need for additional medications.

Advances in Obesity Pharmacotherapy:

New drugs like GLP-1 receptor agonists (e.g., semaglutide, tirzepatide) and dual GLP-1/GIP agonists mimic nutrient-stimulated hormones. These agents act on brain regions (e.g., arcuate nucleus), to enhance satiety, improve metabolism, and support sustainable weight loss. Tirzepatide has shown exceptional efficacy, achieving up to 21% weight loss and rivalling bariatric surgery outcomes.

Anti-Inflammatory and Rheumatic Benefits:

Beyond weight loss, GLP-1 agonists exhibit anti-inflammatory properties, potentially benefiting conditions like osteoarthritis and reducing cardiovascular risks. Anecdotal evidence from clinics suggests improved symptoms in patients with inflammatory arthritis using GLP-1 agonists; however, robust clinical trials are needed to confirm these findings.

Challenges in Obesity Management:

Obesity is challenging to treat due to hormonal resistance and the brain’s maladaptive response to weight loss. Long-term pharmacotherapy is often required to maintain weight reduction and prevent rebound. Access and affordability are significant hurdles, as many insurance plans exclude obesity treatments despite their lower costs compared to biologics.

Side Effects and Tolerability:

GLP-1 receptor agonists are generally well-tolerated but can cause nausea, vomiting, diarrhea, and constipation, especially during dose initiation. Mitigation strategies include slow dose escalation and the use of anti-nausea medications like ondansetron. Persistent side effects, such as constipation, are manageable with conventional therapies.

Comparing Efficacy with Bariatric Surgery: 

Medications like semaglutide and tirzepatide offer weight loss outcomes that are comparable to invasive procedures like gastric bypass. These therapies provide an effective non-surgical alternative, especially for patients who are unwilling or unable to undergo surgery.

Future Directions in Obesity Treatments:

The development pipeline for obesity drugs is robust, with dual and tri-agonists like retatrutide and cagrilintide showing promise. By 2031, new options are expected to achieve weight loss exceeding 25%, further expanding treatment opportunities.

Dr. Louis Aronne concluded by emphasizing the transformative potential of GLP-1 and related therapies in managing obesity, its comorbidities, and inflammatory conditions. These advancements highlight the need for greater integration into clinical practice, while addressing access and affordability challenges. 

American College of Rheumatology Convergence 2024, November 14–19, Washington, D.C