GLP-1 Therapies in Transition: Analytical and Clinical Insights for Experts

In today’s rapidly evolving therapeutic landscape, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a transformative class of drugs, reshaping the management of metabolic diseases and expanding into new clinical applications. In a recent LCGC InternationalPeer Exchange™, we spoke with two experts at the forefront of GLP-1 research and clinical practice: Judith Hey-Hadavi, vice president of Medical Affairs at Worldwide Clinical Trials, and Nicole Snow, clinical pharmacist at Olympia Pharmaceuticals, to explore forward-looking insights and emerging trends in this field.

The conversation examined both the scientific and practical aspects of GLP-1 therapy—from molecular design and clinical trial strategy to patient care and regulatory considerations. For analytical chemists, it provided a comprehensive perspective on how their work supports the development, validation, and safe use of these increasingly complex therapies.

The Shift from Proteins to Small Molecules: What’s Driving the Transition?

Hey-Hadavi opened the conversation by addressing one of the most significant shifts in GLP-1 therapy: the move from injectable protein-based drugs to orally available small molecules. While all currently approved GLP-1 RAs are proteins—requiring daily, weekly, or monthly injections—there is growing interest in small molecule alternatives that could offer oral delivery and improved patient convenience.

This transition is largely patient-driven, she explained. Oral medications are preferred by most patients, especially those managing chronic conditions. However, the shift introduces substantial analytical and formulation challenges. Small molecules must be designed to:

• Bind effectively to GLP-1 receptors.
• Survive the harsh environment of the gastrointestinal (GI) tract.
• Achieve sufficient bioavailability without toxic side effects.

Analytical chemists play a critical role in this transition, particularly in characterizing molecular interactions, optimizing absorption, and ensuring stability. The oral semaglutide formulation, for example, requires an absorption enhancer and strict administration protocols, yet still achieves less than 1% bioavailability.

Each candidate must undergo full clinical development, with rigorous analytical validation, Hey-Hadavi emphasized. Setbacks such as Pfizer’s danuglipron, which was discontinued due to liver toxicity, underscore the importance of early safety profiling, metabolic analysis, and targeted pharmacokinetic studies.

Clinical Trial Design: Analytical Considerations from Phase 1 to Phase 3

When a small molecule GLP-1 RA moves into clinical trials, analytical rigor becomes paramount. Hey-Hadavi walked through the development pipeline, starting with Phase 1 studies that explore single and multiple ascending doses. These early trials rely heavily on pharmacokinetic (PK) and pharmacodynamic (PD) data, which analytical chemists help generate and interpret.

As trials progress into Phase 2 and Phase 3, the focus shifts to:

1. Dose optimization based on PK/PD modeling.
2. Biomarker development to predict therapeutic response.
3. Patient-reported outcomes to assess tolerability and efficacy.

She noted that obesity has become the leading indication for GLP-1 development, surpassing type 2 diabetes due to its broader market and higher unmet need. However, new indications—such as Alzheimer’s disease, addiction, and cardiovascular health—are being explored through life cycle management strategies. Although early-phase data can help guide future research, U.S. Food and Drug Administration (FDA) approval generally requires two rigorously controlled clinical trials for each indication.

Patient-Centered Dosing: Supporting Safe and Effective Use

Snow brought a clinical pharmacist’s perspective to the conversation, emphasizing the importance of individualized dosing strategies. She described how factors like lifestyle, diet, and patient preferences influence therapeutic success. GLP-1s are not magic bullets, she stressed—they are tools that must be integrated into a holistic care plan.

From a clinical standpoint, Snow highlighted several key considerations:

1. Titration is essential to minimize side effects like nausea and diarrhea.
2. Monitoring for GI symptoms, appetite changes, and weight loss is critical.
3. Patient education helps set realistic expectations and improve adherence.

Hey-Hadavi added that patients often start on sub-therapeutic doses and must gradually increase to achieve efficacy. This titration process requires careful monitoring and education, especially as patients may become discouraged if they don’t see immediate results. Analytical chemists support GLP-1 therapy development by advancing formulation science, analyzing real-world outcomes, and conducting stability and degradation studies to ensure safe and consistent dosing.

Managing Side Effects and Interactions

Both panelists addressed the challenge of managing side effects and potential drug interactions. Snow emphasized the importance of starting patients on low doses and adjusting slowly. She shared strategies such as:

1. Timing injections at night to reduce nausea.
2. Using over-the-counter remedies for GI symptoms.
3. Adjusting diets to minimize triggers.

Hey-Hadavi noted that muscle wasting is an emerging concern, particularly in elderly patients. Unlike traditional weight loss, which primarily reduces fat mass, GLP-1s appear to disproportionately affect muscle. This has implications for body composition analysis, metabolic profiling, and formulation strategies to preserve lean mass.

Drug Shortages and Compounding: Ensuring Safety and Reliability

One of the most pressing issues discussed was the rise of compounded GLP-1s amid commercial shortages. Both panelists expressed concern about the lack of oversight and the potential for dosing errors, contamination, and counterfeit products.

Hey-Hadavi explained that compounded versions often lack auto-injectors, requiring patients to manually draw doses from vials—raising the risk of incorrect administration. She also highlighted the proliferation of online pharmacies selling unverified products, some of which may not contain the correct active pharmaceutical ingredient (API).

Snow, speaking from the compounding perspective, noted the challenges in the market when GLP-1s first appeared on the FDA’s drug shortage list. She highlighted the importance of sourcing high-quality APIs and informing patients about the differences between compounded and commercially available medications. For analytical chemists, this underscores the need to ensure API purity and identity, validate the sterility and stability of compounded formulations, and support regulatory compliance through thorough documentation and testing.

Looking Ahead: Trends in GLP-1 Analysis and Therapy

Closing the session, the panelists highlighted key emerging trends in GLP-1 therapy. Snow noted that patients are increasingly experimenting with cycling and microdosing, often adjusting therapies without clinical guidance, and that long-term use may reduce efficacy, prompting new dosing strategies such as reverse titration. She emphasized that ongoing education and counseling remain critical to ensure safe and effective use.

Hey-Hadavi discussed the global expansion of GLP-1 research and development, with countries like China emerging as innovation leaders. She also highlighted efforts to design therapies that maintain weight loss after discontinuation, the potential for personalized medicine through biomarkers predicting responsiveness, and the exploration of novel targets and mechanisms beyond GLP-1 to improve metabolic health. Collectively, these insights point to a future of GLP-1 therapy that balances patient-driven strategies, global innovation, personalized approaches, and sustainable outcomes.

As GLP-1s expand into new indications and patient populations, the demand for analytical rigor will only grow. Whether working in a lab, a regulatory agency, or a clinical trial setting, analytical chemists are essential to shaping the future of metabolic medicine. Their expertise ensures that these therapies are not only effective but also safe, accessible, and aligned with the needs of patients and providers alike.