GLP-1 receptor agonists have garnered widespread attention due to their remarkable weight-loss and diabetes-treatment effects. However, despite the stellar achievements of existing GLP-1 drugs, many pharmaceutical companies-including Novo Nordisk and Eli Lilly, which are already leading the weight-loss drug market-are still striving to break through the market with new drugs, aiming to develop more convenient and effective treatment options.
After the resounding success of Zepbound, which "brings in wealth beyond measure," Eli Lilly has set its sights on the next breakthrough: the small-molecule asset orforglipron, hoping to provide an oral alternative for treating obesity and diabetes.
All Fronts in Crisis
Although orforglipron showed promising results in early clinical trials-particularly achieving a 15% weight loss in the short term-its efficacy significantly declined in later-stage trials, dropping to just 11.2%.
In comparison, existing injectable GLP-1 drugs (such as Wegovy and Zepbound) demonstrate weight losses of 15% to 21%. This stark gap poses a serious challenge for orforglipron in market competition. In fact, orforglipron's clinical results have exposed the limitations of small-molecule drugs in certain specific indications and targets, sparking deeper comparisons and reflections on the therapeutic effects and indications of small-molecule versus peptide drugs.
Before orforglipron, two of Pfizer's glipron small-molecule weight-loss drug pipeline assets had already "died before achieving glory." Lotiglipron and Danuglipron were both oral GLP-1 receptor agonists developed by Pfizer, but neither made it to the market, ultimately being discontinued due to clinical challenges.
Danuglipron showed significant weight-loss and blood-sugar-lowering effects in early clinical trials, but subsequent trials-especially at higher doses-revealed liver toxicity issues. This safety concern forced Pfizer to announce the termination of the drug's development in 2025. Liver toxicity has become a major hurdle for oral small-molecule GLP-1 drugs, affecting their market competitiveness.
Lotiglipron, another of Pfizer's oral GLP-1 drugs, demonstrated effective weight-loss and blood-sugar-lowering effects in early studies but failed to meet expectations in terms of efficacy and side effects (such as gastrointestinal discomfort), hindering its clinical development. While it offered the convenience of oral administration, its weight-loss effects and long-term treatment tolerability still lagged behind existing injectable GLP-1 drugs, leading Pfizer to discontinue further development.
The discontinuation of these two drugs highlights the dual challenges faced by oral GLP-1 receptor agonists: limited efficacy and safety concerns, particularly in managing long-term side effects. These issues make them difficult to compete with existing injectable GLP-1 drugs, especially in the markets for obesity and diabetes treatments.
Clinical data directly impacts orforglipron's market competitiveness, especially against the backdrop of the tremendous success of existing GLP-1 drugs. Orforglipron's performance pales in comparison. This outcome has not only disappointed Eli Lilly but also prompted investors and clinicians to reevaluate the potential of small-molecule drugs in treating complex diseases like obesity and diabetes.
Beyond subpar efficacy, orforglipron's side-effect profile has also affected its clinical performance. According to clinical data, high-dose orforglipron caused significant gastrointestinal discomfort, such as nausea and vomiting, with about 10% of patients discontinuing treatment due to these side effects. Such common adverse reactions pose practical challenges for real-world clinical use, particularly among patients requiring long-term medication, where poor tolerability may impact adherence.
Why the Underperformance?
Limitations in Target Selectivity and Affinity
Small-molecule drugs typically have smaller molecular structures, giving them less targeting ability and affinity compared to larger molecules (such as antibodies or peptide drugs). Small-molecule drugs work by binding to target receptors, but their simple structures result in lower affinity, often failing to form strong and stable bindings with target receptors, thus compromising efficacy. In diseases requiring highly targeted and precise treatment, small-molecule drugs often cannot achieve therapeutic effects comparable to peptide drugs.
In contrast, peptide-based GLP-1 receptor agonists (such as Wegovy and Zepbound) mimic the natural GLP-1 hormone, enabling highly specific binding to GLP-1 receptors and exerting multifaceted mechanisms. These drugs significantly promote insulin secretion, suppress appetite, and delay gastric emptying, achieving superior blood sugar control and weight loss. Compared to orforglipron, which has lower binding affinity to GLP-1 receptors, the weaker biological response limits its efficacy.
Challenges in Bioavailability and Pharmacokinetics
Pharmacokinetics refers to the processes of drug absorption, distribution, metabolism, and excretion in the body. Small-molecule drugs usually require intestinal absorption and entry into the bloodstream to take effect. Due to limitations in molecular structure and hydrophilicity, their oral bioavailability may be low, making it difficult to maintain effective drug concentrations in the body. Although orforglipron can be administered orally, its low bioavailability prevents it from matching the efficacy of existing injectable GLP-1 drugs.
In contrast, injectable GLP-1 drugs like Wegovy and Zepbound enter the bloodstream directly, rapidly reaching their targets and providing potent, long-lasting therapeutic effects. Small-molecule drugs must undergo intestinal absorption, liver metabolism, and other processes, with faster metabolism and shorter half-lives, resulting in inferior efficacy and duration compared to injectable drugs.
Side Effects and Tolerability Issues
While small-molecule drugs generally have lower production costs and more convenient administration, their side effects are often more complex and unpredictable during treatment. Small-molecule drugs may bind to multiple non-target molecules, leading to adverse reactions. For example, orforglipron caused significant gastrointestinal discomfort in high-dose groups, prompting some patients to discontinue treatment.
In contrast, peptide drugs, due to their higher targeting, usually avoid these nonspecific side effects. Even if peptide drugs cause some gastrointestinal side effects, their action on specific receptors results in fewer adverse reactions and better patient tolerability.
Although small-molecule drugs have advantages in cost and production, when therapeutic efficacy is paramount, the high efficiency and targeting of peptide drugs make them more competitive in the market.
Do They Have a Future?
Although small-molecule drugs still hold a place in many therapeutic areas-especially in terms of administration convenience, production costs, and broad applicability-they often underperform in treating specific indications and targets, particularly those requiring highly targeted and precise therapy.
If small-molecule drugs cannot compete with peptide drugs in weight-loss efficacy, their future development must focus on leveraging their unique strengths while seeking innovative paths to bridge existing gaps. Below are several potential development directions that could help small-molecule drugs maintain a foothold in the weight-loss drug market:
Enhancing Efficacy: Precise Target Selection, Differentiation, and Multi-Target Combination Therapy
The weight-loss effects of small-molecule drugs are generally inferior to those of peptide drugs, primarily due to poorer target selectivity and simpler mechanisms of action. Peptide drugs can act through multiple pathways, including promoting insulin secretion, suppressing appetite, and delaying gastric emptying. In contrast, small-molecule drugs often rely on a single mechanism, limiting their effects.
Small-molecule drugs need to improve efficacy through precise target selection. Beyond traditional targets (such as GLP-1 and GIP receptors), future approaches could explore multi-target combination therapies. By simultaneously acting on multiple key biological pathways, small-molecule drugs can more comprehensively regulate weight-control mechanisms. For example, combining appetite suppression, metabolic regulation, and fat breakdown could enhance weight-loss effects. Advances in drug screening and high-throughput platforms will enable more precise target identification, allowing the design of small-molecule drugs that act on multiple targets. For instance, regulating fat metabolism by targeting adipose tissue breakdown pathways could enhance fat burning and conversion, thereby promoting weight loss.
Combination with Other Therapies
Small-molecule drugs lag behind peptide drugs in weight-loss efficacy, and their standalone use may not match the potency of injectable drugs. Combination therapy could be a key direction for small-molecule weight-loss drug development. By pairing small-molecule drugs with other treatments (such as peptide drugs), the limitations of single-drug efficacy can be overcome. Small-molecule drugs could be combined with injectables or other novel weight-loss drugs to form synergistic regimens, improving patient outcomes. For example, small-molecule drugs could serve as adjuncts to GLP-1 receptor agonists or SGLT-2 inhibitors, regulating different biological pathways for synergistic effects.
A notable example is Madrigal's recent acquisition of Stone Pharmaceutical's preclinical oral small-molecule weight-loss drug asset SYH2086 for up to $2 billion. SYH2086, developed by Stone, is an oral small-molecule GLP-1 receptor agonist. Madrigal plans to combine it with its existing MASH (metabolic dysfunction-associated steatohepatitis) drug Rezdiffra to create a new mechanistic combination, enhancing efficacy and long-term management. This approach aims to break away from the homogenized competition of GLP-1 drugs and develop a broader metabolic intervention system. The SYH2086-Rezdiffra combination could achieve bidirectional improvements in efficacy and patient adherence, contrasting sharply with single GLP-1 drug therapies. Madrigal's strategy centers on MASH treatment, driving the joint development of small-molecule oral GLP-1 agonists for multi-mechanism combination regimens.
Better Side-Effect Control and Personalized Treatment
Small-molecule drugs face challenges in side-effect management, particularly gastrointestinal discomfort (nausea, vomiting) and other systemic effects, leading to poor tolerability and low adherence.
Developing small-molecule drugs with fewer side effects-especially in controlling gastrointestinal issues-will be a crucial direction. Optimizing molecular structures and adjusting dose-release mechanisms can reduce adverse effects. Extended-release formulations and targeted delivery systems (such as nanoparticles or liposomes) can minimize systemic side effects. Personalized treatment will also be vital. Using genomic and metabolic response data to tailor therapies can maximize weight-loss efficacy while minimizing side effects. For example, optimizing delivery systems to reduce gastrointestinal burden could improve tolerability. Genomic data could also identify patients who respond better to certain small-molecule drugs, enabling personalized regimens.
Metabolic Regulation and Gut Microbiota Modulation
The gut microbiota plays a key role in metabolism, appetite control, and fat storage, but research on small-molecule drugs' ability to modulate it is still in its infancy. Small-molecule drugs could enhance weight-loss effects by regulating the gut microecology. Studies show that gut microbiota dysbiosis is closely linked to metabolic diseases like obesity and diabetes. Future small-molecule weight-loss drugs could improve metabolic states by balancing gut flora, further boosting efficacy. For instance, microecological modulators could promote beneficial bacteria while suppressing harmful ones, improving metabolic disorders and obesity. Regulating gut inflammation could also reduce fat storage driven by chronic low-grade inflammation, aiding weight loss.
Innovations in Molecular Design and Drug Delivery
The relatively simple structures and mechanisms of small-molecule drugs limit their efficacy in complex diseases, particularly weight loss. Advances in drug delivery and molecular design could enable breakthroughs. For example, targeted delivery systems (like nanoparticle or liposome-based carriers) could precisely deliver drugs to adipose tissue or key metabolic targets, enhancing efficacy while reducing side effects. Long-acting small-molecule drugs with optimized molecular structures could achieve extended half-lives, enabling sustained weight-loss effects.
Better Alignment with Global Market Needs
Although oral small-molecule drugs offer cost and convenience advantages for obesity treatment, their efficacy still lags behind peptide drugs, limiting their share in the high-efficiency weight-loss market. Their global potential lies in accessibility. Compared to peptide drugs, small-molecule drugs are cheaper to produce and more flexible in administration, making them more accessible to low- and middle-income countries, helping address obesity there. Thus, the low-cost production and broad applicability of oral small-molecule drugs will make them a vital supplement to the future weight-loss drug market.
References:
Waldron, J. Madrigal pens $2B pact for CSPC's preclinical GLP-1 with eye on Rezdiffra MASH pairing. Fierce Biotech. 30.07.2025.
Leatherwood, H. M. Top 200 Small Molecule Drugs by Retail Sales in 2024. The University of Arizona.
Liu, A. Madrigal's Rezdiffra, the first-ever MASH drug, beats sales projections for 4 quarters in a row. Fierce Pharma. 02.05.2025.
Chen, E. Eli Lilly's much-anticipated obesity pill yields modest results. STAT. 07.08.2025.
