Intelligence

Designing a GLP-1 Clinical Trial in 2026: What the Pipeline Data Tells Us About Protocol Strategy

April 3, 20267 min read

GLP-1 receptor agonists have moved beyond diabetes and obesity. With 34 active pipeline candidates spanning 14 therapeutic indications — from Alzheimer's to addiction to autoimmune disease — protocol designers are facing a set of challenges that didn't exist 18 months ago.

We analyzed the full GLP-1 trial landscape using data from ClinicalTrials.gov, openFDA, and PubMed to identify the protocol design patterns that distinguish successful trials from those heading for amendments. This article breaks down what the data tells us and how to apply it to your next GLP-1 protocol.

For the full pipeline data, see our GLP-1 Trial Landscape Intelligence dashboard.

The GLP-1 Protocol Design Problem Has Changed

Two years ago, designing a GLP-1 trial meant working within well-established parameters: Type 2 diabetes or obesity indication, HbA1c or body weight primary endpoint, 24–68 week duration, standard GI tolerability monitoring. The protocol design playbook was mature.

That playbook no longer covers the landscape.

Novo Nordisk is running a Phase 3 semaglutide trial for Alzheimer's disease. Harvard's Brigham and Women's Hospital has active trials for opioid and alcohol use disorder. Eli Lilly is testing tirzepatide in combination with ixekizumab for psoriasis and psoriatic arthritis, and with mirikizumab for ulcerative colitis and Crohn's disease. Pfizer is advancing a monthly injectable with 20+ planned studies across its obesity pipeline.

Each of these indications requires fundamentally different endpoint strategies, patient populations, safety monitoring protocols, and study durations. A protocol designer working on a GLP-1 MASH trial has more in common with a hepatology trialist than with the team running the next obesity study.

This is the new challenge: GLP-1s are becoming a multi-system therapeutic platform, and protocol design must adapt accordingly.

What the Pipeline Data Reveals About Endpoint Strategy

Looking at the current distribution of GLP-1 trials across indications, three endpoint patterns emerge that protocol designers should be building around.

Metabolic Indications: The Established Framework

For obesity and Type 2 diabetes — which still represent the majority of GLP-1 trial volume — the endpoint framework is well validated. Primary endpoints cluster around percent change in body weight from baseline, HbA1c reduction, and achievement of clinically meaningful weight loss thresholds (typically ≥5%, ≥10%, ≥15%, and increasingly ≥20% as newer agents show greater efficacy).

CagriSema (cagrilintide + semaglutide) demonstrated approximately 20% mean body weight loss at 68 weeks in clinical trials, and retatrutide (Eli Lilly's triple agonist) is pushing these thresholds even higher. Protocol designers working on next-generation metabolic GLP-1 trials should calibrate their power calculations against these benchmarks — a new entrant showing 10% weight loss at 52 weeks will struggle to differentiate in a market where 20%+ is becoming the bar.

The tools covered in our Protocol Design AI Stack are well suited for this category. TriNetX can pressure-test eligibility criteria against real-world patient populations, and Medidata's protocol optimization suite is trained on thousands of comparable metabolic trials.

Cardiovascular and Cardiometabolic: Imaging Endpoints Enter the Picture

GLP-1 trials in cardiovascular indications — heart failure with preserved ejection fraction (HFpEF), peripheral artery disease (PAD), and MACE risk reduction — introduce imaging-based and functional endpoints that add protocol complexity.

For HFpEF trials, primary endpoints typically involve the Kansas City Cardiomyopathy Questionnaire (KCCQ) combined with hierarchical composite endpoints including cardiovascular death, heart failure hospitalization, and urgent heart failure visits. Echocardiography-based secondary endpoints require standardized imaging protocols and core lab adjudication.

Protocol designers in this space should be planning for centralized imaging review from the outset. Our Medical Imaging AI Stack covers the AI tools available for imaging endpoint standardization and quality control.

Non-Metabolic Indications: Uncharted Protocol Territory

This is where the most significant protocol design challenges lie. GLP-1 trials in Alzheimer's, addiction, autoimmune conditions, and PCOS are operating without established endpoint precedents for this drug class.

Alzheimer's trials are using cognitive scales (Montreal Cognitive Assessment), tau-PET imaging, TSPO-PET for neuroinflammation, GFAP protein levels, and neurofilament light chain as biomarkers. The semaglutide Alzheimer's program includes MRI-based hippocampal volume measurement as a secondary endpoint.

Addiction trials present unique endpoint challenges around substance use biomarkers, self-reported use diaries, and relapse rates. There are currently more than 15 GLP-1 trials globally for substance use disorders, but the measurement frameworks are still being established.

Autoimmune indications (psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease) use dermatology-specific endpoints like PASI-90, EASI-90, and IGA 0/1, or gastroenterology endpoints like clinical remission and endoscopic response.

The protocol design implication is clear: teams designing GLP-1 trials in non-metabolic indications need to bring in therapeutic area expertise for endpoint selection and measurement strategy, rather than relying on the metabolic trial playbook.

Safety Monitoring: What openFDA Data Tells Protocol Designers

The FDA safety signal landscape for GLP-1s should directly inform your safety monitoring plan. Our GLP-1 Intelligence dashboard tracks nine active safety signals; here's how they translate to protocol design decisions.

Standard GI Monitoring Is Table Stakes

Gastrointestinal adverse events (nausea, vomiting, diarrhea) remain the most common class effect across all GLP-1 receptor agonists. Every GLP-1 protocol needs a structured dose-titration scheme to manage GI tolerability, with pre-specified criteria for dose modification and discontinuation.

Signals That Should Change Your Protocol Design

Pancreatitis monitoring. Acute and necrotizing pancreatitis are listed as post-market adverse reactions for semaglutide and tirzepatide. Protocols should include baseline and periodic amylase/lipase monitoring, with clear stopping rules for suspected pancreatitis.

Diabetic retinopathy. Semaglutide trials have shown higher rates of diabetic retinopathy complications compared to placebo. For T2D trials, protocols should include baseline retinal examination and periodic monitoring, with stratification or exclusion criteria for patients with unstable retinopathy.

Pulmonary aspiration risk. GLP-1 receptor agonists delay gastric emptying, and pulmonary aspiration has been reported in patients undergoing procedures requiring general anesthesia. Any GLP-1 trial protocol that includes procedures under sedation should address pre-procedural fasting requirements.

Suicidal ideation. In March 2026, the FDA issued a warning letter to Novo Nordisk for failing to adequately report serious adverse events related to semaglutide, including unreported cases of suicidal ideation. Protocols should incorporate validated mental health screening instruments (PHQ-9 or C-SSRS) at baseline and periodically throughout the study.

Eligibility Criteria: What the Competitive Landscape Tells You

With 34 active GLP-1 candidates recruiting simultaneously, many targeting the same patient populations, site-level competition for eligible patients is real. In obesity, where trial volume is highest, overly restrictive eligibility criteria don't just reduce your theoretical pool — they put you in direct competition with less restrictive trials recruiting at the same sites.

Using the GLP-1 Intelligence dashboard, you can identify exactly which companies are recruiting for which indications and at which phases. If you're designing a Phase 3 obesity trial, knowing that Novo Nordisk, Eli Lilly, Pfizer, Amgen, Viking, and Roche all have active or upcoming Phase 2/3 obesity programs tells you that your criteria need to be competitive.

Protocol Duration and Retention

GLP-1 trials face a specific retention challenge: the drugs work, patients feel better, and the temptation to discontinue study participation (especially in placebo-controlled trials) is high.

CagriSema's pivotal trials run 68+ weeks. Retatrutide's Phase 3 program is designed for extended follow-up. Cardiovascular outcome trials require years of follow-up for MACE endpoints. The days of 24-week GLP-1 efficacy trials are largely over for pivotal programs.

The approval of oral Wegovy 25mg in December 2025 and oral Ozempic tablets in February 2026, plus Eli Lilly's pending oral orforglipron, means protocol designers now have oral comparator options for the first time. Oral GLP-1 trials have different adherence profiles, different PK considerations, and potentially different patient populations willing to participate.

Designing a GLP-1 trial? Our analysis of 22,704 Phase 2 oncology trials found that 36.1% of terminations were due to slow accrual — a risk that applies across therapeutic areas. Protocol Risk Scan helps teams validate enrollment assumptions before protocol lock.