Glucagon-like peptide-1 (GLP-1) is the peptide hormone of greatest clinical value in the management of overweight and obesity, while GLP-1/GIP dual receptor agonists-exemplified by tirzepatide-represent the current ceiling for weight-loss efficacy.
This assessment is not based merely on a one-dimensional comparison of "magnitude of weight loss," but rather on evidence across three levels: GLP-1 possesses the most robust clinical validation and data regarding cardiovascular benefits; multi-target agonists build upon this foundation to further push the limits of weight-loss efficacy; and the overarching advantage of peptide hormones lies in their mechanism of action, which precisely targets the central regulators of energy metabolism rather than broadly suppressing appetite.
Why GLP-1? Synergistic central and peripheral regulation
GLP-1 is not simply an "appetite suppressant." Secreted by intestinal L-cells, it directly regulates the centers controlling food intake by activating GLP-1 receptors distributed across the hypothalamus, the area postrema, and the nucleus of the solitary tract. Research by the NIH has further elucidated the molecular mechanisms involved: the weight-loss effect of semaglutide relies on sustained elevations of cyclic adenosine monophosphate (cAMP) signaling within neurons of the area postrema. Conversely, some neurons exhibit only transient responses due to receptor internalization or degradation; this explains the inter-patient variability in response to the same drug and identifies potential targets for overcoming therapeutic plateaus.
Peripherally, GLP-1 receptor agonists delay gastric emptying and enhance satiety while simultaneously improving insulin sensitivity. This tripartite mechanism-combining central appetite suppression, delayed peripheral gastric emptying, and metabolic improvement-ensures that weight loss does not rely solely on the willpower required for caloric restriction, but rather recalibrates the physiological set point for energy balance.
Clinical evidence: From magnitude of weight loss to hard clinical endpoints
Regarding efficacy, the weight-loss magnitude achieved by single-target GLP-1 agonists demonstrates clear dose-dependency. When administered according to protocol, semaglutide (2.4 mg once weekly) results in a weight reduction of 5% to 10% of baseline body weight (based on 3-month data). However, this figure must be interpreted within a more comprehensive framework of clinical endpoints. In its 2026 guidelines on pharmacological treatment for obesity, the American College of Physicians (ACP) lists both semaglutide and tirzepatide as first-line options, yet offers a compelling rationale for the distinction: while tirzepatide yields superior weight loss and greater improvements in health-related quality of life, semaglutide is supported by *probable* evidence of reduced all-cause mortality and major adverse cardiovascular events (MACE)-benefits not yet demonstrated for tirzepatide. In other words, the choice of medication is not merely a matter of "who causes more weight loss," but rather a trade-off between weight-loss efficacy and proven survival benefits.
Multi-target agonists: Setting the "ceiling" for weight-loss efficacy through synergy rather than simple addition
As a GLP-1/GIP dual receptor agonist, tirzepatide has pushed weight-loss efficacy to the 15%–22% range. The action of the GIP pathway is not simply additive to that of GLP-1; GIP enhances central satiety signals and acts synergistically with GLP-1 regarding cAMP-biased signaling. Biased GLP-1R/GIPR dual agonism has demonstrated "substantially higher" efficacy in animal models compared to single-target agonism. In the SURMOUNT-1 trial, 91% of participants in the 15 mg tirzepatide group achieved weight loss of ≥5%, compared to only 35% in the placebo group.
More targeted options are emerging. Three-month data for mazdutide (a GLP-1/GCGR dual agonist) in the Chinese obese population showed a 14.7% reduction in body weight; the increased energy expenditure and improved hepatic fat metabolism driven by the GCGR target offer distinct advantages for patients with abdominal obesity and non-alcoholic fatty liver disease (NAFLD). The significance of this class of drugs lies in the fact that obesity is a heterogeneous disease with varying pathological drivers across patients; multi-target agents make it possible to select medications based on specific underlying mechanisms.
Fundamental advantages and limitations of peptide hormones
The reason peptide hormones hold a central position in weight management lies fundamentally in the biological rationale of their sites of action. GLP-1, GIP, glucagon, and amylin are naturally occurring energy-regulating signals in the human body; the drugs in question essentially amplify or prolong these signals. Compared to traditional weight-loss medications acting on monoamine systems (such as phentermine/topiramate), peptide-based drugs offer a more predictable side-effect profile-primarily gastrointestinal reactions-without causing widespread central nervous system agitation.
The limitations are equally clear. Weight regain upon discontinuation is a common pattern; ACP guidelines explicitly advise clinicians to discuss the reality of potential lifelong treatment with patients, rather than framing it as a time-limited intervention. Furthermore, gastrointestinal intolerance is a primary reason for dose reduction or treatment cessation, although most reactions resolve spontaneously within one to two weeks. The preservation of muscle mass is another key area of focus-as the loss of lean body mass during weight loss may impact long-term metabolic health-leading to the exploration of next-generation therapies that combine these agents with myostatin-targeting drugs.
Conclusion
When evaluated by the criteria of "clinical evidence maturity" and "benefits regarding hard cardiovascular endpoints," semaglutide (a single-target GLP-1 agonist) stands out as the most established choice. In terms of "maximum weight-loss efficacy," tirzepatide (a dual GLP-1/GIP agonist) represents the pinnacle among currently approved medications. Meanwhile, next-generation biased GLP-1 agonists and multi-target combinations are shifting the focus of weight-loss therapy from merely "how much weight is lost" to "what is lost" and "whether metabolic health improves post-weight loss." The core advantage of peptide-based therapies lies not in a specific numerical outcome, but in the fact that they mark the first time pharmacological treatment for obesity has moved beyond simple appetite suppression into the realm of precision regulation of energy homeostasis.