Most people have heard that a class of gut-hormone-based drugs has changed how researchers and clinicians think about obesity. What gets less attention is the underlying biology, specifically why some newer compounds appear to work better than earlier ones, even when they seem to operate through overlapping pathways.
A 2026 review published in Annual Review of Nutrition, authored by Davies Iona and colleagues, sets out to answer exactly that question. The paper traces the discovery of glucagon-like peptide-1, evaluates the performance of drugs that activate its receptor, and then digs into the puzzle of a second hormone called glucose-dependent insulinotropic polypeptide, or GIP, whose involvement in appetite and body weight turns out to be far more complicated than expected.
The result is a detailed, sometimes counterintuitive picture of how the gut and the brain communicate around food intake, and why the field is moving toward compounds that engage multiple receptor targets at once.
GLP-1 and its receptor
GLP-1 is a short protein fragment, a peptide, released from the gut after a meal. Its primary job involves stimulating insulin secretion in a glucose-dependent manner, meaning it nudges the pancreas to release insulin only when blood sugar is actually elevated. That feature made it medically interesting from the start.
Beyond the pancreas, GLP-1 receptors are found in the brain, particularly in regions associated with hunger signals and reward processing. The review notes that researchers believe a significant portion of the appetite-reducing effects of GLP-1 receptor agonists, the compounds that mimic or amplify this hormone's activity, comes from central nervous system action rather than from the gut alone.
Early GLP-1 receptor agonists demonstrated meaningful reductions in body weight in clinical settings. The review points to semaglutide as the most studied example in this class, describing it as a benchmark against which newer approaches are compared. Semaglutide is a peptide that binds and activates the GLP-1 receptor with high potency and a long half-life, allowing once-weekly dosing in some formulations.
The GIP puzzle
GIP is also released from the gut after eating, and like GLP-1, it stimulates insulin secretion. For years, researchers assumed the two hormones were more or less interchangeable from a metabolic standpoint. The puzzle emerged when studies tried to use GIP receptor agonists alone in humans to reduce appetite or body weight. The literature suggests these efforts largely failed to show meaningful anorectic, meaning appetite-suppressing, effects on their own.
That finding raised an obvious question. If GIP agonism alone does not appear to reduce appetite in humans, why do compounds that combine GLP-1 receptor activation with GIP receptor activation consistently outperform semaglutide in head-to-head research settings?
The review highlights this as the central paradox. The authors note the lack of evidence for appetite reduction through GIP receptor agonism acting independently, yet the data from dual-targeting compounds are hard to dismiss. Something about the combination produces effects that neither pathway seems to generate alone.
Dual agonism and the tirzepatide data
The review examines tirzepatide as the leading example of a GLP-1 receptor and GIP receptor dual agonist. Tirzepatide is a synthetic peptide engineered to activate both receptors, with a structural bias toward GIP receptor engagement while still acting on GLP-1 receptors.
Phase-3 trial data described in the review show that tirzepatide produced greater reductions in body weight and improvements in blood glucose regulation compared with semaglutide across multiple studies. The differences were not marginal. In some comparisons, participants receiving the highest dose of tirzepatide lost roughly twice the percentage of body weight as those on semaglutide.
The review explores several candidate mechanisms for this enhanced effect. One hypothesis centers on the possibility that GIP receptor activation in the brain modulates GLP-1 receptor signaling in a synergistic way. Another focuses on peripheral tissues, including fat cells, where GIP receptors are abundantly expressed and may influence how the body handles stored energy. A third possibility involves the gut itself, where GIP may alter nutrient absorption dynamics that then feed back into appetite-regulating circuits.
Antagonism as an alternative route
The paradox deepens further when the review introduces maridebart cafraglutide, an investigational compound that combines GLP-1 receptor agonism with GIP receptor antagonism. Rather than activating the GIP receptor as tirzepatide does, this compound blocks it.
Early data from clinical investigation suggest maridebart cafraglutide also produces meaningful weight loss, apparently comparable in some measures to results seen with dual agonism approaches. In other words, both activating the GIP receptor and blocking it appear to enhance the effects of GLP-1 receptor agonism.
The review treats this as genuinely paradoxical from a conventional pharmacology standpoint. Two drugs doing opposite things to the same receptor both seem to improve on the single-receptor approach. The authors suggest this may point to context-dependent GIP receptor signaling, where the receptor's effect on metabolism depends heavily on what tissue it is expressed in and what other signals are present simultaneously.
Central nervous system involvement
A recurring theme in the review is the brain's role in mediating these effects. The authors note that both GLP-1 and GIP receptors are expressed in hypothalamic and brainstem regions that regulate food intake and energy balance. Neuroimaging and preclinical studies cited in the review suggest that GLP-1 receptor agonists reduce responses to food cues in reward-related brain areas, consistent with reports from patients of reduced cravings and altered food-seeking behavior.
The extent to which GIP receptor signaling in the brain contributes to the superior performance of dual-targeting compounds remains an active area of investigation. The review acknowledges that the mechanistic picture is incomplete. Animal model findings do not always translate cleanly to humans, and the blood-brain barrier complicates interpretations of how much circulating peptide reaches central receptor populations.
Despite these uncertainties, the authors argue that central mechanisms are likely a meaningful part of the story, particularly for appetite suppression, and that future research will need to separate peripheral from central contributions more cleanly.
Where the research is heading
The review closes by evaluating why researchers and pharmaceutical developers are now exploring compounds that engage three or more hormonal pathways simultaneously. Beyond GLP-1 and GIP, glucagon receptor agonism is one target receiving serious attention. Glucagon raises blood sugar and increases energy expenditure, and the idea of pairing its activation with GLP-1 receptor agonism, in a carefully balanced ratio, has generated both enthusiasm and caution.
The authors also discuss the clinical relevance of understanding these mechanisms more precisely. If researchers can identify which tissues or circuits are responsible for the enhanced effects of dual targeting, it may become possible to design compounds that retain the benefits while reducing side effects, which for current GLP-1 based therapies include nausea, vomiting, and gastrointestinal discomfort.
The broader takeaway from this review is that the gut hormone system is far more redundant and context-dependent than early models suggested. Single-receptor strategies opened an important door, but the literature increasingly suggests that the body's weight-regulation systems are distributed across multiple overlapping signals, and effective research-grade tools will likely need to engage more than one at a time to achieve the most robust results.
