Glucagon-like peptide-1 (GLP-1) agonists are medications that mimic a natural gut hormone to regulate appetite, slow stomach emptying, and help the pancreas release insulin. Initially developed for type 2 diabetes, their effectiveness in promoting weight loss has expanded their use. The safety and efficacy of all new treatments are established through clinical trials, which are research studies involving human volunteers to answer specific health questions. Before a treatment can be widely used, it must undergo this structured testing to evaluate its effects and identify potential side effects.
Landmark Trials for Weight Loss and Diabetes
The approval of GLP-1 agonists for chronic weight management and type 2 diabetes rests on the outcomes of clinical trial programs. These studies are designed as randomized, double-blind, placebo-controlled trials, meaning participants are randomly assigned to receive either the active medication or a placebo. Neither the participants nor the researchers know who is receiving which treatment until the study concludes, ensuring unbiased results.
The Semaglutide Treatment Effect in People with Obesity (STEP) program provided the foundation for the approval of Wegovy. In the STEP 1 trial, individuals with obesity but not diabetes lost an average of 14.9% of their body weight over 68 weeks, compared to a 2.4% loss in the placebo group. For participants with type 2 diabetes in the STEP 2 trial, semaglutide led to a 9.6% average weight loss, versus 3.4% for placebo.
Tirzepatide was studied in the SURMOUNT trial program, leading to the approval of Zepbound. The SURMOUNT-1 trial, involving participants with obesity but without diabetes, showed an average weight loss of 20.9% at the highest dose. In the SURMOUNT-2 trial, which focused on individuals with both obesity and type 2 diabetes, participants achieved an average weight reduction of 15.7%.
Across these trial programs, the most common side effects were gastrointestinal. Participants frequently reported nausea, diarrhea, vomiting, and constipation, particularly as the dose increased. These effects were mild to moderate, though they led a small percentage of participants to discontinue treatment.
Investigating Cardiovascular and Kidney Protection
Beyond weight and blood sugar, large-scale trials have been designed to determine if GLP-1 agonists can protect major organ systems. These studies focus on cardiovascular and kidney outcomes to see if the drugs can reduce major health events in high-risk populations.
The SELECT trial evaluated semaglutide in patients with preexisting cardiovascular disease and overweight or obesity, but without diabetes. The findings showed that semaglutide reduced the risk of major adverse cardiovascular events (heart attack, stroke, or cardiovascular death) by 20% compared to placebo. Further analysis confirmed a sustained protective effect, lowering the total number of subsequent events for those who continued the therapy and also contributing to a modest reduction in systolic blood pressure.
The protective effects of GLP-1 agonists also extend to the kidneys. A meta-analysis of over 85,000 patients found this drug class reduces the risk of kidney failure and slows the progression of chronic kidney disease. In the FLOW trial, semaglutide lowered the risk of major kidney disease events by 24% in people with type 2 diabetes and chronic kidney disease.
Emerging Research in New Medical Fields
The scientific community is exploring the potential of GLP-1 agonists in other medical fields beyond their established uses. Research is focused on conditions where the mechanisms of these drugs, such as their influence on brain reward pathways, might offer therapeutic benefits.
Addiction is an active area of new research. Anecdotal reports of reduced cravings for alcohol and nicotine have prompted formal investigations. Clinical trials are now assessing if these drugs can treat substance use disorders by dampening the brain’s reward circuits associated with these behaviors.
Another frontier is liver disease, specifically metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease. A phase 3 trial found that semaglutide resolved liver inflammation in nearly 63% of participants and improved liver scarring in 37%. These findings suggest GLP-1 agonists could become a treatment for this progressive condition.
There is also interest in the neuroprotective effects of GLP-1 agonists for diseases like Parkinson’s and Alzheimer’s. Researchers theorize the drugs’ anti-inflammatory properties and ability to improve insulin sensitivity in the brain could slow disease progression. After encouraging signals from phase 2 trials, larger phase 3 studies are underway to provide more definitive answers.
Finding and Joining a GLP-1 Trial
For individuals interested in contributing to medical science and potentially accessing new treatments, participating in a clinical trial is an option. The process is structured into distinct phases to ensure volunteer safety and gather reliable data.
Clinical trials are conducted in a sequence of phases. Phase 1 involves a small number of volunteers to assess safety and dosage. Phase 2 expands to a larger group to evaluate effectiveness and further study safety. Phase 3 trials are much larger, involving thousands of participants to confirm effectiveness, monitor side effects, and compare the new treatment to standard options. A treatment must pass through these phases before being considered for approval.
The most comprehensive resource for finding clinical trials is ClinicalTrials.gov, a searchable database of studies conducted worldwide. Users can search by condition, drug name, or location to find studies that are actively recruiting. The site provides details on a trial’s purpose, eligibility criteria, and contact information for study sites.
Before joining a trial, volunteers go through an informed consent process where researchers provide details about the study, including its purpose, procedures, risks, and benefits. Participants must meet specific eligibility criteria, such as age and medical history. Volunteers should also understand that they may be randomly assigned to receive a placebo instead of the active drug.