Anti-Obesity Drugs Show Whole Body Promise and More to Come

The potential for glucagon-like peptide 1 (GLP-1) receptor agonists continues to grow in promise as new studies point to benefits beyond glucose control and weight loss.

With hundreds of studies underway or recently completed on ClinicalTrials.gov, the signs are becoming clearer: GLP-1 drugs appear to improve patient outcomes throughout the body, leading to in the development of cardiovascular (CV), gastric, hepatic and renal. GLP-1 drugs also seem to be linked to cognitive and cognitive changes, and researchers are finding positive changes in addictive and compulsive behaviors.

Apart from the current common options – semaglutide (Ozempic / Wegovy) and tirzepatide (Mounjaro / Zepbound) – new options may be even better for weight loss and improvement system. While semaglutide mimics the GLP-1 hormone to regulate blood sugar, appetite and digestion, tirzepatide acts as both GLP-1 and glucose-based insulinotropic polypeptide (GIP) agonists, usually leading to significant weight loss.

Next-generation drugs (such as Eli Lilly’s retatrutide) will act as triple agonists, targeting GLP-1, GIP, and glucagon receptors and may provide even better results. . Today’s phase 3 trials could pave the way for new options to become available in 2025 and 2026.

“Other pharmaceutical companies are jumping into the research pipeline, and the era of GLP-1 will be like the era of statins,” said Andres Acosta, MD, assistant professor of medicine at the Mayo Clinic and principal investigator of Mayo’s Precision Medicine for Obesity. Laboratory in Rochester, Minnesota. Acosta discussed the potential use of GLP-1 in clinical gastroenterology practice at Digestive Disease Week in May.

“In the next 3 years, we will learn more about how the gut travels to the brain through gut hormones, and we will see other molecular targets such as GLP-1, GIP, glucagon, insulin, amylin , leptin, etc. – we will have peptides that target each receptor,” he said. “Who will win? Retatrutide appears to be leading so far, but we are waiting to see the data on what provides better weight loss and improvement for comorbidities. “

Here is an overview of recent research and promising results:

Heart Health

After trying to treat diabetes and obesity, studies of GLP-1 have focused on risk and CV events. The SELECT trial found that semaglutide consistently reduced major adverse CV events by approximately 20% among patients with prior CV disease and overweight or obesity. A decrease was observed for CV-related death, nonfatal myocardial infarction, and nonfatal stroke. The STEP-Heart Failure With Preserved Ejection Fraction (HFpEF) trial also found significant improvements among patients with obesity-related HFpEF.

In addition, GLP-1 systems seem to have direct effects on blood vessels, blood pressure and lipids, which can influence risks and CV-related events, according to the 2024 analyzes of the SELECT trial data.

“We continue to find new results in the extended population for these drugs, in addition to good results not only in CV risk, weight, and glycemic control, but also in lipid profiles and blood pressure ,” said Darren McGuire, MD, professor in the Department of Internal Medicine. Physician and chair of Cardiovascular Science at the University of Texas Southwestern Medical Center in Dallas. McGuire and colleagues wrote about the SELECT trial and subsequent data analyzes in July Natural Medicine and what the results may mean for nurses.

“The biggest unknown is how we can use it in the community, especially for weight loss,” he said. Medscape Medical News. “And how early can we start them for such – like youth. It would also be good to test the first use in patients known to be the main prevention population to see if we can put CV risk in the long term. ”

Renal Health

After the heart-related results, researchers looked at GLP-1 use and kidney function. The FLOW trial found that semaglutide prevented major kidney disease, CV events, and death in patients with chronic kidney disease (CKD) and type 2 diabetes.

Specifically, patients who took semaglutide had a 24% lower risk for a major kidney event, such as kidney failure, dialysis, or transplantation, as well as kidney-related death. or CV. The risk of death from any cause was also 20% lower.

“GLP-1/GIP can be considered as a tool to completely reduce the risks of heart and kidney disease,” said Katherine Tuttle, MD, executive director of research at Providence Inland Northwest Health and clinical professor of nephrology and kidney. research at the University of Washington, Seattle. Tuttle is a co-investigator of FLOW.

“Semaglutide is a foundational treatment proven to save kidneys, hearts and lives in people with type 2 diabetes and CKD,” he said. “Continued studies of semaglutide – and other GLP-1/GIP agents – will clarify the safety and efficacy of this class of drugs for CKD in non-diabetic and diabetic individuals. type 1 sugar.”

Hepatic Health

Scientists are beginning to recognize the emerging role of anti-obesity drugs in liver function as well. In the September review published on JAMA Internal MedicineGLP-1 use was associated with a statistically significant reduction in the risk of progression to cirrhosis among patients with metabolic dysfunction-related steatotic liver disease, or cirrhosis. fatty liver.

Other studies have shown reduced risks of hepatocellular carcinoma, liver transplant, and liver-related disease as well.

“Pick any organ you like, and obesity is a big part of its most important disease,” Acosta said. “The GLP-1 era is exciting, and we don’t need to hide it. This medicine changes the conversation about obesity. ”

Bone Health

In addition to organ benefits, GLP-1 supplements can also help with musculoskeletal conditions. The STEP 9 trial found semaglutide improved knee pain and physical function in people with knee osteoarthritis (OA). Although weight loss can reduce knee pain, researchers are investigating whether GLP-1 drugs work specifically on joints through metabolic changes.

“These drugs may provide a game-changing effect in the field of osteoarthritis where there are currently no disease-modifying treatments and conventional analgesia is contraindicated or inadequate,” said Co-author Tonia Vincent, MBBS , professor of muscle biology and emeritus. in Rheumatology at the Kennedy Institute of Rheumatology at the University of Oxford, Oxford, England.

“However, there are still many things we do not understand about these drugs and the effects they have on normal muscle function,” he said. “We know that weight loss is one of the few things that really works for OA symptoms and disease progression, but we also need to make sure that this is balanced with supportive care.” nutritional supplement.”

Mental Health

Studies around the world have looked closely at the behavioral and cognitive outcomes associated with GLP-1 use. So far, researchers have found a reduction in unhealthy behaviors, such as heavy drinking, smoking, opioid use, gambling and shopping, as well as lower risks of suicidal thoughts or attempts. kill yourself.

Based on functional MRI studies, GLP-1 drugs appear to reduce the activity of the brain’s reward centers, which can reduce addictive behavior. In addition, psychological benefits can be caused by losing weight or other reasons, Israeli scientists wrote in an October article about suicidal thoughts or attempts of young people with obesity. JAMA Pediatrics.

“Although weight loss associated with GLP-1 therapy may improve body image and overall mental health, other mechanisms may exist,” said Co- author Liya Kerem, MD, a pediatrician at Hadassah Medical Center in Jerusalem. , Israel.

“These may include the effects of neuro-inflammation and neural pathways associated with reward and food addiction,” he said. “However, these are still preliminary, and further research is needed to explore these pathways in depth and establish more specific links.”

Physical Health

Some GLP-1 compounds appear every week, apparently with positive results seen for inflammation, sleep health and Alzheimer’s disease (EVOKE trial).

For example, in the SURMOUNT-OSA trial, tirzepatide reduced symptoms of obstructive sleep apnea and improved patient-reported sleep-related outcomes. Based on data from the SELECT trial, semaglutide led to a 38% reduction in C-reactive protein with high sensitivity, even in patients who did not lose weight.

Recent patient trials are looking at the effects of semaglutide or tirzepatide on the risk factors of breast cancer, psoriatic arthritis and polycystic ovary syndrome.

Phase 1 trials have begun to study the safety and tolerability of GLP-1 in young adults, including children between 6 and 11 years of age with obesity and adolescents between 12 and 17 years of age with obesity. weight-related comorbidities, and a phase 4 study will be completed soon. seniors over 65 years of age.

“Although not shown, in observational studies this drug is associated with improvement in cognitive decline, increased effectiveness for reducing tobacco and alcohol or smoking cessation, improving biomarkers of the disease liver-related metabolism, etc.,” McGuire said. “And while next-generation agents continue to hold the promise of increasing the weight loss achieved, it appears that there is more work to be done.”

McGuire has reported research support for clinical trial leadership from Boehringer Ingelheim, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, and CSL Behring, as well as consulting honoraria from Lilly USA, Pfizer, Boehringer Ingelheim, Lexicon, Novo Nordisk, Applied Therapeutics. , Altimmune, CSL Behring, Bayer, Intercept, and NewAmsterdam Pharma.

Kerem reported receiving personal fees from Novo Nordisk for three invited lectures on childhood obesity given in Israel.