Demand for GLP-1s has led to unprecedented market dynamics. The obesity drug sector, once stagnant, has exploded, with combined Novo Nordisk and Eli Lilly valuations exceeding $1 trillion. A two-day workshop from AAPS, Beyond GLP-1s: Where the Science Will Take Business Next, included presentations from leading scientists and industry experts about the sector. Although GLP-1s have seen incredible successes, there are still issues with tolerability issues and access – not to mention opportunities for more convenient formulations. As one of the presenters, Richard DiMarchi, put it: “Innovation never stands still. As impressive as today’s GLP-1 therapies are, I can assure you that what lies in the foreground – whether you think of it as the Learjet or Gulfstream equivalent – will likely deliver superior performance to what we’ve been applauding up to this point.”
In a previous article, I shared insights from the workshop on the pressures created by soaring demand and where the market might go next. Below, you’ll find summaries from three further presentations. Zach Zalewski examined the legal and regulatory position of compounders during shortages, and raised difficult questions about how to distinguish between compounding as a safeguard for patients and compounding as a commercial enterprise. Richard DiMarchi shifted the conversation away from obstacles and toward future opportunities. He argued that the most transformative advances will come not from GLP-1 monotherapy, but from combinations that integrate multiple gut hormones and perhaps even extend beyond metabolism to address obesity’s comorbidities. Caroline Geisler presented preclinical data highlighting the role of glial cells in mediating GLP-1 action in the brain. Her work suggests that differences in brain access and signaling may help explain why patients with type 2 diabetes often experience less weight loss than non-diabetic patients on the same drugs.
The compounding issue and preventing poor practices
The presentation from Zach Zalewski, Strategic Director at the United States Pharmacopeia, focused on compounding – primarily regulatory policies, litigation and drug quality issues.
Under US law, pharmacies are not supposed to compound copies of FDA-approved medicines that are commercially available. However, this changes when a drug is listed on the FDA shortage list. The aim is that compounding pharmacies can provide an important stop gap to prevent patient care from being interrupted.
With huge demand for GLP-1s, however, some compounders implemented large-scale production and online sales, without offering the same brand control as the main manufacturers. FDA has documented over 400 adverse‑event reports with compounded semaglutide and 300 with compounded tirzepatide, though the Alliance for Pharmacy Compounding disputes the reliability of those data. Zalewski’s presentation raised the question of how do we ensure that good compounders can do their work whilst weeding out the bad actors?
“The problem is that patients don't know the difference, and they'll often be looking for the most accessible route to get to the medication that they want. In this case, it was for a rather enticing condition, which is weight loss. This created something of a perfect storm of incentives for folks to not only fill that gap, but perhaps also for bad actors to make a quick buck,” said Zalewski.
The problem was compounded (no pun intended) by the lack of CMS coverage for GLP-1s for weight loss – as well as patchy private insurance. This meant that many patients were desperately looking for cheaper, compounded versions.
Shortages are now winding down, but the regulatory and legal battles continue. FDA guidance gives compounders 60 days to cease once a shortage is resolved, and both Novo Nordisk and Eli Lilly have moved aggressively in the courts to enforce this, as well as suing compounding pharmacies, telehealth platforms, and weight-loss clinics – alleging unsafe practices, false advertising, and misuse of trademarks.
At the same time, policymakers are grappling with broader structural issues. Without consistent insurance coverage for obesity treatment, patients remain vulnerable to turning toward unregulated sources. And with public enthusiasm for GLP-1s showing no signs of slowing, the tension between access, affordability, and safety will persist.
Zalewski stressed that compounding was never intended to be a large-scale substitute for mass-market drugs. It was designed as a safety valve for exceptional circumstances. The challenge now is to balance that principle. He says, “When market forces create, or the nature of a drug product, creates demand that is far surpassing perhaps what was initially envisioned, or that branded manufacturers have capacity to meet, we have to think very carefully how we're allowing compounders to backstop; making sure that the bad actors get weeded out, and that the good actors can continue to do the good work that they're doing.”
The opportunities ahead: combination therapies
“In my 50 years in life sciences research, I’ve often observed that for every ten people focused on what stands in the way, there is usually only one who can identify the opportunities and inspiration for moving ahead.”
Richard DiMarchi – Distinguished Professor and Gill Chair in Biomolecular Sciences at Indiana University – was invited to the workshop to discuss challenges, but he thought it more prudent to focus on opportunities. He described data on the first generation GLP-1 liraglutide (Saxenda) as “breaking the sound barrier of obesity pharmacology.” He explained: “The results went far beyond anything previously seen, and they captured the industry’s attention – not only to obesity as a disease but also to its many comorbidities as areas worthy of investment. Much of the field is now being built on multi-mechanism approaches: tirzepatide combining GLP-1 and GIP, retatrutide adding glucagon to that mix, and cagrilintide plus semaglutide taking yet another route to polyagonism.
“But the important questions remain,” said DiMarchi. “What is the precise mechanism by which we achieve body weight reduction? What limits the truly transformative advances from the perspective of both patient and provider? Which mechanisms of action have demonstrated efficacy in obesity’s common comorbidities? And what lessons from other therapeutic areas can be integrated here to go further than we might if we remained narrowly focused on metabolism alone?”
Much of today’s innovation pipeline builds on combining GLP-1 with other gut hormones. DiMarchi described his and Matthias Tschöp’s early work using glucagon not as an antagonist but as a catabolic partner to GLP-1. The work broadened the therapeutic index beyond glucose control and opened the door to co-agonists. Adding GIP – long considered inactive – showed powerful results. GLP-1 appeared to resensitize metabolism so GIP could again deliver glycemic and weight-loss benefits.
“Now, if you look at the industry pipeline, two-thirds of development efforts involve some form of incretin combination. GLP-1/GIP, GLP-1/glucagon, and even triple agonists are the dominant focus, though the spectrum extends to other mechanisms as well—amylin, GIP antagonism, NK2 receptor agonism, and more,” said DiMarchi
Looking further ahead, DiMarchi sees potential for oral therapies, including oral peptides. As an example, he points to Novo Nordisk’s Rybelsus (oral semaglutide), which uses an absorption enhancer to temporarily permeabilize the stomach lining. The science is intriguing but low bioavailability has led the company to pursue very high doses.
Some companies, including Lilly, are also exploring oral GLP-1 receptor agonists, which DIMarchi refers to as “small molecule mimetrics.” These molecules, however, are far more complex than traditional oral small molecules. Lilly’s candidate has shown good efficacy at 24–45 mg/day oral dosing. However, long-term safety remains unproven. Peptides, by design, degrade naturally and are cleared predictably, but newer mimetics lack that built-in safeguard.
DiMarchi also suggested that the industry could revisit leptin. Leptins have previously failed in obesity studies, but there could be potential in exploring combination therapies.
“Finally, it is important to remember that obesity rarely exists in isolation. Most patients present with multiple comorbidities – hypertension, type 2 diabetes, joint pain, osteoporosis, and more – often requiring half a dozen or more medications. The heavier the patient, the more likely they are to accumulate such conditions. While we currently treat these patients as a single group defined simply as ‘obese,’ the future will likely demand more personalized approaches,” said DiMarchi. “Looking ahead, I think we’ll see the obesity market segmented more precisely. A patient who is obese and diabetic may ultimately receive a different therapy than someone who is obese and hypertensive, or obese with rheumatoid arthritis, or obese with cognitive decline – if we can design drugs that are turbo-charged to address these additional pharmacologies.”
Rounding up his presentation, DiMarchi encouraged the industry to also embrace observation. “Some of the most remarkable findings with GLP-1 therapies were unexpected: reductions in addictive behaviors, potential cognitive improvements, and striking benefits in chronic kidney disease. These are effects that preclinical models could not have predicted. They underscore the need for careful clinical observation to reveal opportunities we might otherwise miss.”
Weight loss differences in diabetics and non-diabetics
Data show that GLP-1 receptor agonists are less effective for weight loss in people with type 2 diabetes compared to those without diabetes.
In her presentation, Caroline Geisler, Assistant Professor at the University of Kentucky College of Pharmacy, explained: “For example, one study of about 9,000 matched individuals on tirzepatide or semaglutide found that after six months, non-diabetic patients had, on average, a 2% greater weight loss than those with type 2 diabetes. Extending treatment to one year, the gap widens: about 4% greater weight loss in non-diabetics on semaglutide, and about 5.5% greater on tirzepatide.”
Some researchers suggest that behavioral differences such as motivation, adherence and engagement in lifestyle changes might help explain this gap. As a metabolic neuroscientist specializing in the neuroendocrine control of energy balance and the metabolic dysregulation that accompanies obesity, Geisler was interested in the role of glial cells – specifically tanycytes and astrocytes. She highlighted studies showing how GLP-1 drugs get into the brain to exert their effects.
Tanycytes appear to actively transport GLP-1 ligands from circulation into hypothalamic tissue. When tanycytic transcytosis was blocked – either by preventing vesicle release or by eliminating GLP-1 receptors from tanycytes – the ability of liraglutide to suppress appetite was abolished.
Because many patients are prescribed both insulin and GLP-1 agonists, Geisler also examined how the two might interact. Research found that insulin treatment enhanced the brain signal of fluorescent exendin-4. Some of this was expected, since insulin is a vasodilator, but the ligand also spread more widely into hypothalamic tissue, suggesting insulin was actively promoting transport into the brain. To test whether this was due to insulin itself or to the drop in blood glucose that insulin causes, animals were clamped with high insulin while their glucose was either kept normal or made low. When glucose was low, more exendin-4 entered the median eminence, showing that glucose levels themselves influence how much of the drug reaches the brain.
“After 10 weeks on a high fat, high sugar diet, there's an uncoupling between low blood glucose being able to facilitate brain entry of exendin-4,” said Geisler. “This points to the hypothesis that chronic hyperglycemia in diabetes, along with dysregulated central sensing of glucose concentrations in diabetics, may impair central transport of GLP-1 receptor agonist and explain the reduced efficacy for weight loss in type two diabetic patients.”
Geisler also discussed astrocytes. Literature has shown that GLP-1 receptor signaling in astrocytes, particularly in the hindbrain, can partly mediate GLP-1-induced suppression of food intake. It also alters astrocyte metabolism in ways that enhance their cooperation with neurons. Beyond energy balance, astrocytes have become a major focus in studies of the neuroprotective and anti-inflammatory effects of GLP-1s, especially in the context of obesity-related neurodegeneration. Essentially, astrocytes are not just “support cells” but active regulators of energy balance.
“My group became interested in studying a protein called diazepam-binding inhibitor (DBI). It is a glial-produced hormonal peptide that suppresses appetite. Because of its known role in feeding behavior, and high expression in the postrema area, we wanted to understand how it might be regulated by nutritional state and if GLP-1 ligands, by chance, regulated DBI expression,” said Geisler.
Data show that fasting reduces DBI expression in the subpostrema border and fourth ventricle region, but treatment with exendin-4 restored expression to fed-state levels. By contrast, DBI expression in the area postrema itself was not strongly influenced by nutritional state. This suggested that regulation is concentrated in glial-rich border zones that control access to the brain.
Geisler’s team also examined whether GLP-1 drugs act directly on DBI-producing cells. In rats, DBI and GLP-1 receptors were not usually co-expressed, but the two cell populations were often found in close proximity, suggesting cross-talk between them. To test whether DBI contributes to GLP-1’s appetite-suppressing effect, the team used an antibody to neutralize DBI. Exendin-4 reduced food intake as expected, but the effect was weakened when DBI was blocked. Importantly, neutralization of DBI did not affect nausea-like behavior (measured by kaolin intake), and only slightly blunted weight loss, indicating that DBI is specifically tied to appetite suppression rather than side effects.
DBI is processed into smaller fragments, and one of these – octadecaneuropeptide (ODN) – is thought to drive its appetite-suppressing effects. Geisler’s team tested a natural fragment they called TDN in obese mice. Daily injections of TDN caused about 5% body weight loss in nine days, and clamp studies showed improved insulin sensitivity, with faster clearance of glucose from the blood. When tested in musk shrews (a species that, unlike rodents, can vomit), TDN reduced weight without triggering emesis, while exendin-4 caused rapid, dose-dependent vomiting.
The work suggests that astrocytes and glial peptides like DBI/ODN are active participants in the GLP-1 pathway, shaping appetite suppression and offering potential as new therapeutic targets. TDN, in particular, may represent a complementary anti-obesity or anti-diabetes agent with the benefits of weight and glucose control, but without the gastrointestinal side effects that often limit GLP-1 therapies.
The AAPS workshop featured more than ten experts, including Tim Opler, Jens Holst, Adam Mendelsohn, Jonathan Duoros, and more. Learn more about the workshop here.
Newsletters
Receive the latest pharmaceutical news, personalities, education, and career development – weekly to your inbox.
