GLP-1 Therapies and Beyond: A 2026 Clinical Update

Glucagon-like peptide-1 (GLP-1) receptor agonists have quickly expanded beyond their original use in diabetes care and now play a major role in the treatment of obesity and cardiometabolic disease. In recent years, the field has evolved rapidly, with new medications and expanded clinical applications transforming how these conditions are managed.  

As research advances, treatment options are expanding beyond first-generation GLP-1 therapies to include dual- and triple-agonist medications and oral therapies. These newer agents are demonstrating levels of effectiveness that, in some cases, approach the outcomes seen with bariatric surgery. 

Here’s what you need to know about GLP-1 therapies in 2026. 

What is GLP-1?  

GLP-1 (glucagon-like-peptide-1) is a hormone naturally produced in the intestine after meals. It helps regulate blood sugar, slows stomach emptying, and sends signals to the brain that promote satiety (fullness). GLP-1 receptor agonists mimic these effects, thereby reducing hunger while improving glucose metabolism and insulin sensitivity. Although diabetes and weight loss have driven initial public interest, the real significance of these medications extends far beyond the scale. 

The modern GLP-1 era began with liraglutide and dramatically accelerated with semaglutide and tirzepatide. Semaglutide (Ozempic for diabetes, Wegovy for weight loss, and other indications) remains the benchmark, with average weight loss approaching 15% in obesity trials. Tirzepatide (a dual GLP-1/ GIP receptor agonist, known as Mounjaro for diabetes and Zepbound for obesity and other indications) has shown weight loss exceeding 20% in clinical trials. 

Recent FDA Approvals 

Oral semaglutide 25 mg (Wegovy): Approved December 2025 for chronic weight management in adults with obesity or overweight with comorbid conditions; this is the first oral formulation of semaglutide approved for obesity. This is a great option for those who cannot tolerate injections. 

Orforgliron (Foundayo): This was approved in April 2026 as the first oral nonpeptide small molecule GLP-1 receptor agonist for obesity. Dosing starts at 0.8 mg daily with titration up to 17.2 mg. In phase 3 trials, patients achieved up to 11.2% weight reduction at 72 weeks. This medication does not require fasting, can be taken regardless of meal timing, and does not require cold storage, making it far more convenient for many. Notably, the ATTAIN-1 and ATTAIN-2 trials showed that women taking Foundayo lost significant weight across all stages of menopause, including those living with type 2 diabetes. 

Recent Therapeutic Indications 

Semaglutide for Cardiovascular Risk Reduction: Major cardiovascular event (MACE) reduction was shown in the landmark SELECT Trial of over 17,000 patients with obesity or overweight and established cardiovascular disease, without diabetes, who received semaglutide 2.4 mg weekly. This marked a pivotal moment in preventive cardiology, with the trial results showing the composite of CV death, nonfatal MI, or nonfatal stroke was reduced by 20% in patients with BMI greater than or equal to 27 and preexisting CVD but without diabetes. 

Wegovy gained accelerated approval for non-cirrhotic MASH (fatty liver disease) with moderate-to-advanced fibrosis (F2-F3) after the ESSENCE trial showed MASH resolution without fibrosis in 62.9% vs. 34.3% in placebo, and fibrosis improvement in 36.8% vs. 22.4%. 

Ozempic was approved for reducing the risk of sustained kidney decline and cardiovascular death in adults with type 2 diabetes and chronic kidney disease, based on the FLOW Trial. This trial showed that semaglutide 1.0 mg weekly reduced the relative risk of the composite of kidney failure, CV death, and renal events by 24% in this population, leading to early trial termination for efficacy. 

Zepbound was approved for moderate-to-severe obstructive sleep apnea in adults with obesity. In the SURMOUNT-OSA trials, 42–50% of patients achieved apnea-hypopnea indices (AHIs) at which PAP therapy may no longer be needed. 

Therapeutics Ahead 

Perhaps the most exciting drug in development is retatrutide. It’s a combined GLP-1, GIP, and glucagon receptor agonist.  

More specifically, the addition of the glucagon receptor pathway increases energy expenditure (calorie burning) and enhances visceral fat reduction. This “triple threat” approach demonstrated unprecedented weight loss in stage 3 clinical trials, which were just presented at the recent American Diabetes Association (ADA) scientific meeting. FDA approval is expected in 2027.  

In TRIUMPH-1, participants on retatrutide 12 mg lost an average of 28.3% (70.3 pounds) over 80 weeks. In addition to weight loss, retatrutide reduced knee osteoarthritis pain by up to 73% and moderate-to-severe obstructive sleep apnea severity by up to 60.6%.  

In TRANSCEND T2D-1, participants on retatrutide had A1C reductions of up to 2% and weight loss of up to 16.8% at 40 weeks. Both trials also showed significant cardiovascular benefits, with reductions of up to 41% in triglycerides, 24.2% in non-HDL cholesterol, and 12.3 mmHg in systolic blood pressure. 

Numerous other drugs are currently in clinical trials. These include various combinations of receptor agonists mentioned above. Additionally, amylin is a naturally occurring hormone released alongside insulin that regulates satiety and gastric emptying. Amylin receptor agonists and dual amylin-GLP-1 combination therapies are encouraging in early phase studies. These therapies may promote weight loss while preserving lean muscle mass, a particular concern with currently available GLP-1 therapies. 

Emerging Areas of Clinical Interest 

• Cancer: One of the most intriguing areas of therapeutic application is cancer risk reduction. Several recent studies have demonstrated lower rates of obesity-related cancers, including reductions in colorectal, breast, liver, and kidney cancers. At the 2026 ASCO (American Society of Clinical Oncology) annual meeting, one of the largest studies presented evaluated over 100,000 overweight or obese women and found that GLP-1 therapy was associated with 30–35% lower odds of developing breast cancer compared to women not receiving these therapies. These findings remain observational and do not prove causation, but they support the premise that reducing obesity, insulin resistance, and chronic inflammation may notably reduce future cancer risk. 

• Substance Use Disorders: A large VA cohort study found that GLP-1 RA use was associated with a reduced risk of alcohol, opioid, nicotine, and cocaine use compared with SGLT2 inhibitors, and reduced substance use disorder-related mortality. RCT data remain limited. 

• Neurodegenerative Disorders: Alzheimer’s Disease researchers are investigating whether reduced neuroinflammation and improved insulin signaling in the brain via GLP-1 RAs could result in potential slowing of cognitive decline. 

• Inflammatory and Autoimmune Diseases: Researchers are investigating the roles of these conditions in rheumatoid arthritis, psoriasis, osteoarthritis, and inflammatory bowel disease. By lowering systemic inflammation and reducing proinflammatory visceral fat, GLP-1 RAs may play a therapeutic role. 

What’s ‘Microdosing?’ 

Microdosing means taking smaller amounts of a medication than the FDA-approved regimen, often to reduce side effects or save money. While it is appealing to some, it’s not FDA-approved and lacks strong evidence to support it at this time. 

Future Considerations 

This is an exciting time in the world of GLP-1 and related therapies. Although BMI (body mass index) remains the gold-standard criterion for determining overweight and obesity, its limitations are increasingly recognized. It is a measure of weight relative to height and does not distinguish excess weight from body fat, muscle, or bone. There’s interest in redefining obesity using measures such as the waist-to-hip ratio and other body size metrics, in addition to BMI. BMI also misses obesity in certain populations such as South Asians who may have normal BMI but excess body fat and low muscle mass, also known as normal weight obesity. 

The most accurate way to assess overweight or obesity is through DEXA body composition analysis. This test analyzes body fat percentage, muscle mass, and visceral fat (the deep abdominal fat that is proinflammatory and most associated with chronic disease risk). At Canyon Ranch, we provide this useful test and recommend interval follow-up testing to track progress. One notable concern is that muscle loss may account for 25–40% of total weight loss in the absence of concurrent healthy nutrition and resistance training. Body composition analysis is the best way to identify and treat sarcopenic obesity, or overweight with low muscle mass. This is important for tracking and preventing frailty. 

Another exciting future trend is the combined use of GLP-1 RA and disease-specific care. Preservation of lean mass is especially important during GLP-1 therapy, and this is particularly relevant after menopause because estrogen deficiency already contributes to sarcopenia (muscle loss), reduced muscle strength, and osteoporosis (bone loss). The combined use of menopause hormone therapy and GLP-1 RA may be an effective way to approach care in this population. Other examples include GLP-1 RA and statin or PCSK9 inhibitors in established cardiovascular disease, GLP-1 RA and CPAP in obstructive sleep apnea, GLP-1 RA and biologic immunotherapies in psoriatic arthritis, among others.

Safety and Final Thoughts 

While transformative in weight management and cardiometabolic diseases, these medications are not without risk. As always, please note that this is not medical advice; consult your doctor regarding your clinical care needs.  

Common side effects include nausea, vomiting, diarrhea, and constipation. These remain the main reasons for treatment discontinuation. In addition, GLP-1 RAs often suppress appetite and thirst, increasing the risk of dehydration. In my practice, I often encourage patients to intentionally stay hydrated and carry a large water bottle throughout the day. This helps reduce dizziness and the risk of falls associated with dehydration.  

Serial blood pressure monitoring is an important part of care as well, as weight loss often leads to decreased blood pressure, and in turn, patients may need a lower dose or discontinuation of blood pressure medications. Fatigue, often due to undernutrition, dehydration, or both, is another common symptom that needs clinical monitoring. 

At Canyon Ranch, we provide up-to-date comprehensive clinical care in the area of GLP-1 therapies and beyond. We have a team of experts to perform DEXA assessments, personalized nutrition counseling, mental health counseling, and sports and performance training programs specifically tailored to your individual needs.   

Explore our services in Tucson and Lenox to learn how we can support your health journey while taking GLP-1 medications.