New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics
Open accessAbstract
Nearly half of Americans are projected to have obesity by 2030, underscoring the pressing need for effective treatments. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) represent the first agents in a rapidly evolving, highly promising landscape of nascent hormone-based obesity therapeutics. With the understanding of the neurobiology of obesity rapidly expanding, these emerging entero-endocrine and endo-pancreatic agents combined or coformulated with GLP-1 RAs herald a new era of targeted, mechanism-based treatment of obesity. This article reviews GLP-1 RAs in the treatment of obesity and previews the imminent future of nutrient-stimulated hormone-based anti-obesity therapeutics.
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Written from the paper’s full text.
TL;DR
This review summarizes GLP-1 receptor agonists and emerging nutrient-stimulated hormone-based therapies for obesity, including approved liraglutide and semaglutide and investigational dual/triple agonists. It reports that semaglutide 2.4 mg and tirzepatide 15 mg produce average placebo-subtracted weight reductions of 12.5% and 17.8%, respectively, while amylin/GLP-1 combinations and other multi-hormone agents show promise.
Key findings
- Liraglutide 3.0 mg and semaglutide 2.4 mg are approved for chronic weight management, with average placebo-subtracted weight reduction of 5.2% and 12.5%, respectively. In STEP 1, semaglutide produced 14.9% weight loss versus 2.4% for placebo (treatment difference 12.4%), and one-third of the semaglutide group lost ≥20% body weight versus 1.7% with placebo.
- Tirzepatide, a GIP/GLP-1 dual receptor agonist, in SURMOUNT-1 (n = 2,539 individuals with obesity without T2D, 72 weeks) produced 20.9% weight loss at 15 mg versus 3.1% for placebo (treatment difference 17.8%); more than half of participants on 10 mg or 15 mg lost ≥20% body weight versus 3.1% with placebo. It was FDA approved for T2D but not yet for chronic weight management at the time of the review.
- Cagrilintide, an amylin analogue, in a phase II trial (n = 706) produced 10.6% weight loss at 4.5 mg weekly versus 8.4% with liraglutide 3.0 mg and 2.8% with placebo at 26 weeks. In a phase Ib trial (n = 95), semaglutide 2.4 mg plus cagrilintide 2.4 mg produced 17.1% weight loss versus 9.8% with semaglutide alone at 20 weeks.
- Other pipeline agents include BI456906 (GCG/GLP-1 dual agonist), which in a phase I study produced 8.8–13.7% weight reduction with biweekly dosing versus 0.1% for placebo; LY3437943 (GIP/GCG/GLP-1 triple agonist), which in a phase I study of 45 adults produced 2.9 kg and 3.5 kg weight reduction at day 8 for the 4.5 mg and 6 mg doses, maintained at day 43; and danuglipron, an oral small-molecule GLP-1 RA, which in a phase I study of 98 participants with T2D produced −4.4 kg at day 28 with 70 mg twice daily versus −1.8 kg for placebo.
Methods
- Narrative review of the biology and pharmacological application of GLP-1 receptor agonists and nascent nutrient-stimulated hormone-based therapeutics for obesity.
- Synthesizes results from phase III trials (SCALE, STEP, SURMOUNT-1) and earlier-phase studies, with tables of hormone targets and trial outcomes and a pipeline figure.
- No systematic search, meta-analysis, or new primary data collection is described.
Limitations
- The paper states that clinical management of patients receiving these agents is beyond the scope of the review.
- Evident from the text: it is a narrative review without a described systematic search or quality appraisal, and many discussed agents are investigational, in early-phase trials, or ongoing, so efficacy and safety conclusions are provisional.
- Table 1 notes that leptin and adiponectin are not included because they are secreted in adipose tissue.
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Integrity signals
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Cites
Statistics
Claims the paper makes
0 of 71 cited sources checked · 0 supported · 0 flagged
- Premisecitation
Appetitive brain areas such as the striatum, insula, and orbitofrontal cortex that are commonly activated by viewing rewarding and energy-dense food pictures are significantly reduced by GLP-1 RA.
“Appetitive brain areas such as the striatum, insula, and orbitofrontal cortex that are commonly activated by viewing rewarding and energy-dense food pictures (13) are also significantly reduced by GLP-1 RA (14).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
In STEP 8, weekly semaglutide 2.4 mg was superior to daily liraglutide 3.0 mg, with a treatment difference of -9.4% body weight.
“The more recently published STEP 8 trial demonstrates the superiority of weekly semaglutide 2.4 mg versus daily liraglutide 3.0 mg (treatment difference -9.4% body weight) (37).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] source
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- Premisecitation
In a phase I study, danuglipron 70 mg twice daily produced a change in body weight of -4.4 kg at day 28 compared with -1.8 kg for placebo.
“A change in body weight of -4.4 kg at day 28 was reported with danuglipron 70 mg twice daily (compared with -1.8 kg for placebo), a dose level with a lower incidence of nausea and vomiting compared to other formulations.”
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- Premisecitation
In SCALE TEENS, liraglutide 3.0 mg daily produced a placebo-subtracted weight reduction of 5% in adolescents with obesity over 56 weeks.
“The liraglutidetreated group demonstrated a placebo-subtracted weight reduction of 5% (29).”
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- Premisecitation
In STEP 3, estimated mean weight change from baseline was 16% with semaglutide versus 5.7% with placebo, a mean difference of 10.3%.
“Estimated mean weight change from baseline was 16% with semaglutide versus 5.7% with placebo (mean difference of 10.3%) (35).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] source
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- Premisecitation
In STEP 1, one-third of the semaglutide group lost ≥20% body weight versus only 1.7% in the placebo group.
“Furthermore, one-third of the semaglutide group lost ≥20% body weight versus only 1.7% achieving this target in the placebo group (33).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] source
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- Premisecitation
GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released from specialized entero-endocrine cells in the intestinal mucosa in response to nutrient intake.
“Among the gut peptides are GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), incretin hormones released from specialized entero-endocrine cells in the intestinal mucosa stimulated by nutrient intake (5).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] source
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- Premisecitation
Excess weight loss for older antiobesity agents compared to placebo at 1 year ranges from 2.6 kg to 8.8 kg.
“Excess weight loss for these agents compared to placebo at 1 year ranges from 2.6 kg to 8.8 kg (3).”
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- Interpretationcitation
Weight regain data from STEP 4 and the STEP 1 extension study, where participants discontinue active medication, strongly suggest that pharmacological treatment must be sustained to combat adaptive physiological forces that hinder long-term weight reduction.
“The weight regain data seen in STEP 4 (36) and the STEP 1 extension study (38), where participants discontinue active medication, strongly suggest that pharmacological treatment must be sustained to combat the adaptive physiological forces that hinder long-term weight reduction (39).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
The first four STEP trials demonstrate a significant biological effect of a sustained-release GLP-1 RA on subsequent weight reduction over 68 weeks.
“The first four STEP trials demonstrate the significant biological effect of a sustained-release GLP-1 RA on subsequent weight reduction over 68 weeks.”
Quote in the paperSubstantial claim - Premisecitation
In STEP 2, participants with T2D randomized to semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo lost 9.6%, 7.0%, and 3.4% body weight, respectively.
“In the STEP 2 trial (individuals with T2D), participants randomized to semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo lost 9.6%, 7.0%, and 3.4% body weight, respectively (34).”
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- Premisecitation
Native GLP-1 requires structural modification to resist rapid proteolytic degradation by dipeptidyl peptidase 4 (DPP-4).
“Pharmacological application of native GLP-1 requires modification to its structure to resist rapid proteolytic degradation by dipeptidyl peptidase 4 (DPP-4), a ubiquitous enzyme that is found in multiple organ beds.”
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- Premisecitation
Oral administration of GLP-1 RAs results in low bioavailability owing to poor absorption coupled with rapid degradation by proteolytic enzymes.
“Oral administration results in low bioavailability owing to poor absorption coupled with rapid degradation by proteolytic enzymes (40).”
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- Premisecitation
Amylin is a pancreatic islet cell hormone cosecreted with insulin from beta cells in response to nutrient intake.
“Amylin is a pancreatic islet cell hormone, cosecreted with insulin from beta cells in response to nutrient intake (44,45).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Weight reduction occurs when GLP-1 RA biological actions are translated into reduced food intake, diminished food cravings and prospective food consumption, and increased satiety.
“Subsequently, weight reduction occurs when these biological actions are translated into reduced food intake, diminished food cravings and prospective food consumption, and increased satiety (15)(16)(17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (15)(16)(17)
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- Interpretationreasoning
Novel hormone-based pharmacotherapies present a mechanistic-based and increasingly effective paradigm for the treatment of obesity.
“Novel hormone-based pharmacotherapies that leverage entero-endocrine and endopancreatic peptides are in various phases of development and present a mechanistic-based and increasingly effective paradigm for the treatment of obesity.”
Quote in the paperSubstantial claim - Premisecitation
GIP is thought to potentially decrease food intake through action in the hypothalamus.
“GIP is thought to potentially decrease food intake through action in the hypothalamus (61).”
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- Premisecitation
Side effects of cagrilintide include nausea, diarrhea, constipation, fatigue, and injection-site reactions.
“Side effects of cagrilintide include nausea, diarrhea, constipation, fatigue, and injection-site reactions (52).”
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- Premisecitation
Cagrilintide, an amylin receptor agonist, when combined with semaglutide, resulted in 17.1% weight reduction versus 9.8% with semaglutide alone in a phase Ib trial.
“Cagrilintide, an amylin receptor agonist, when combined with semaglutide, resulted in 17.1% weight reduction versus 9.8% with semaglutide alone in a phase Ib trial.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] source
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- Premisecitation
Entero-endocrine and endo-pancreatic hormones work in concert impacting food intake, weight regulation, and glycemic homeostasis.
“Entero-endocrine and endo-pancreatic hormones work in concert impacting food intake, weight regulation, and glycemic homeostasis.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
GIP receptors have been identified in adipose tissue, bone, and the brain.
“In addition to GIP's actions in the pancreatic beta cell, GIP receptors have been identified in adipose tissue, bone, and the brain (58).”
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- Interpretationreasoning
A triagonist formulation may have greater efficacy due to additive effects.
“Thus, a triagonist formulation may have greater efficacy due to additive effects.”
Quote in the paperSubstantial claim - Premisereasoning
Novel hormone-based pharmacotherapies that leverage entero-endocrine and endopancreatic peptides are in various phases of development.
“Novel hormone-based pharmacotherapies that leverage entero-endocrine and endopancreatic peptides are in various phases of development and present a mechanistic-based and increasingly effective paradigm for the treatment of obesity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Figure 1
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- Interpretationreasoning
Combining or coformulating entero-endocrine and endo-pancreatic peptides as dual or triple receptor agonists can target the multifaceted pathophysiology of obesity.
“by combining or coformulating entero-endocrine and endo-pancreatic peptides as dual or triple receptor agonists, we can target the multifaceted pathophysiology of obesity”
Quote in the paperSubstantial claim - Premisecitation
In SURMOUNT-1, more than half of participants randomized to tirzepatide 10 mg or 15 mg lost ≥20% body weight versus 3.1% in the placebo group.
“Additionally, more than half of the participants randomized to tirzepatide 10 mg or 15 mg lost ≥20% body weight versus 3.1% achieving this target in the placebo group.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [69] source
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- Study design and conductcitation
In a phase I randomized double-blind placebo-controlled study, 45 adult participants received a single injection of placebo or ascending dose of LY3437943.
“In the phase I randomized double-blind placebo-controlled study, 45 adult participants received a single injection of placebo or ascending dose of LY3437943 (78).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [78]
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- Interpretationreasoning
Targeting the multifaceted pathophysiology of obesity by combining these peptides results in reregulation of physiology and resetting of the defended fat mass set point.
“resulting in reregulation of physiology and resetting of the defended fat mass set point”
Quote in the paperNot a substantial claim- Rests on an assumption: Obesity involves a defended fat mass set point that can be reset by restoring hormone balance.
- Premisecitation
In a phase II trial, participants who received cagrilintide 4.5 mg weekly lost 10.6% weight versus 8.4% in the liraglutide group and 2.8% in the placebo group.
“The participants who received the highest dose of cagrilintide (4.5 mg weekly) lost 10.6% weight versus 8.4% in the liraglutide group and 2.8% in the placebo group (52).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] source
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- Premisecitation
Liraglutide produces average placebo-subtracted weight reduction of 5.2%.
“producing average placebo-subtracted weight reduction of 5.2% and 12.5%, respectively.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] source
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- Premisecitation
In a phase Ib trial, after 20 weeks, the group that received semaglutide 2.4 mg plus cagrilintide 2.4 mg weekly lost 17.1% weight, whereas the group that received semaglutide 2.4 mg monotherapy lost 9.8% weight.
“After 20 weeks, which included a 16-week dose titration, the group that received the combination of semaglutide 2.4 mg plus cagrilintide 2.4 mg weekly lost 17.1% weight, whereas the group that received monotherapy with semaglutide 2.4 mg weekly lost 9.8% weight (53).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] source
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- May combine two claims. 31
- Classified as probably not a substantial claim. 6
- The quote only partly states this claim. 1
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PremisecitationSemaglutide is a GLP-1 RA designed for once-weekly subcutaneous administration with a half-life of 183 h.
“Semaglutide represents the next generation of GLP-1 RAs that are further chemically modified and designed for once-weekly SC administration with a longer half-life (183 h) (30,31).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationCoformulating semaglutide with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) facilitates transcellular absorption through the gastric membrane and helps prevent degradation of semaglutide in the stomach.
“Coformulating semaglutide with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) facilitates transcellular absorption through the gastric membrane and helps prevent degradation of semaglutide in the stomach (41).”
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Interpretationnone givenThe most common gastrointestinal side effects of GLP-1 RA agents are likely caused by direct interactions with central nervous system GLP-1 receptors, including in the area postrema, and mainly occur at initiation of treatment during dose escalation.
“These are likely caused by direct interactions with central nervous system GLP-1 receptors, including in the area postrema, and mainly occur at initiation of treatment during dose escalation.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationGLP-1 has diverse actions including reduction of blood pressure, inflammation, and coagulation, as well as promotion of natriuresis and diuresis.
“Other diverse pleomorphic actions of GLP-1, inclusive of the cardiovascular system, have also been described; these include reduction of blood pressure, inflammation, and coagulation, as well as promotion of natriuresis and diuresis (7,8).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIntention-to-treat 1-year placebo-subtracted weight reduction with liraglutide 3.0 mg was 5.2%, 4%, 3.4%, and 6.1% for SCALE, SCALE Diabetes, SCALE IBT, and SCALE Maintenance, respectively.
“Intention-to-treat 1-year placebo-subtracted weight reduction was 5.2%, 4%, 3.4%, and 6.1% for SCALE, SCALE Diabetes, SCALE IBT, and SCALE Maintenance, respectively.”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationGLP-1 inhibits glucagon secretion, reduces gastric emptying, and causes early acute reduction in appetite and food intake when infused intravenously.
“In addition to promoting a glucose-dependent increase in insulin secretion, GLP-1 inhibits glucagon secretion, reduces gastric emptying, and causes early acute reduction in appetite and food intake when infused intravenously (6).”
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PremisecitationIn STEP 3, compared to STEP 1, individuals in the placebo group lost more weight with the addition of intensive behavioral therapy, but mean weight reduction in the semaglutide group was only 1% greater than in STEP 1.
“Compared to the STEP 1 trial, individuals in the STEP 3 placebo group lost more weight with the addition of IBT; however, mean weight reduction in the semaglutide group was only 1% greater than that observed in STEP 1.”
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PremisecitationDanuglipron was generally safe and well tolerated and demonstrated dose-responsive reductions in glycemic indices in a phase I study.
“The drug was generally safe and well tolerated and demonstrated dose-responsive reductions in glycemic indices.”
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Interpretationnone givenGLP-1 RA gastrointestinal side effects wane with time and do not contribute to the durable weight effects demonstrated by these agents.
“These gastrointestinal side effects wane with time and do not contribute to the durable weight effects demonstrated by these agents.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationLiraglutide has reduced susceptibility to DPP-4 and is dosed subcutaneously once daily with a half-life of approximately 11-15 h.
“As a result of molecular modifications of the structure, liraglutide has reduced susceptibility to DPP-4 and is dosed subcutaneously (SC) once daily with a half-life of approximately 11-15 h (22,23).”
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- cites [23]
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PremisecitationIn STEP 4, during the 48 weeks after randomization, participants who remained on semaglutide lost an additional 7.9% body weight whereas the placebo group gained 6.9% body weight.
“During the subsequent 48 weeks, participants who remained on semaglutide lost an additional 7.9% body weight whereas the placebo group gained 6.9% body weight (36).”
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PremisecitationIn STEP 1, individuals randomized to semaglutide 2.4 mg achieved an average weight reduction of 14.9% compared to 2.4% for placebo, a treatment difference of 12.4%.
“In STEP 1, individuals randomized to semaglutide achieved an average weight reduction of 14.9% compared to 2.4% for placebo (treatment difference of 12.4%).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] source
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PremisecitationObesity is a disease of energy regulation with complex underlying pathophysiology in which the energy homeostasis system defends an elevated fat mass set point.
“This is driven, in part, by the understanding of obesity as a disease (1) of energy regulation with complex underlying pathophysiology whereby the energy homeostasis system defends an elevated fat mass set point (2).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationGlucagon receptor has been localized to the brain and pancreas, as well as the heart, kidney, liver, and adipose tissue, suggesting pleiotropic effects in the body.
“Glucagon receptor has been localized to the brain and pancreas, as well as the heart, kidney, liver, and adipose tissue (76), suggesting pleiotropic effects in the body.”
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Interpretationnone givenGLP-1, GIP, and glucagon each impact food intake and satiety through disparate mechanisms, playing complementary roles in maintaining the body's defended fat mass set point.
“GLP-1, GIP, and glucagon each impact food intake and satiety through disparate mechanisms, playing complementary roles in maintaining the body's defended fat mass set point.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataSURMOUNT-1 demonstrates the impact of dual GIP/GLP-1 receptor agonism as a potential new treatment modality for obesity, demonstrating weight reduction not previously demonstrated in phase III obesity treatment trials.
“The SURMOUNT-1 trial demonstrates the impact of dual GIP/GLP-1 receptor agonism as a potential new treatment modality for obesity, demonstrating weight reduction that has not been previously demonstrated in phase III obesity treatment trials.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningCombining the hormones may be an approach that targets the many intertwined mechanisms of obesity.
“Combining the hormones may be an approach that targets the many intertwined mechanisms of obesity.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe most common side effects of LY3437943 were gastrointestinal and mild to moderate in severity.
“The most common side effects were gastrointestinal and were mild to moderate in severity.”
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PremisecitationGIP is a 42-amino-acid nutrient-stimulated hormone secreted from entero-endocrine cells in response to nutrient intake and works in concert with GLP-1, resulting in glucose-dependent insulin secretion.
“GIP is a 42-amino-acid nutrient-stimulated hormone that is secreted from entero-endocrine cells in response to nutrient intake (54) and works in concert with GLP-1, resulting in glucosedependent insulin secretion.”
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PremisecitationTirzepatide is a long-acting, weekly injectable, single-molecule GIP/GLP-1 receptor agonist with a half-life of ∼117 h.
“Tirzepatide is a long-acting, weekly (62), injectable, single-molecule GIP/GLP-1 receptor agonist with a half-life of ∼117 h (63).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationAmylin acts on appetitive/energy-regulating neurons in the hypothalamus impacting food intake, dopaminergic neurons in the ventral tegmental area impacting reward and motivation, and chemoreceptive neurons in the area postrema/nucleus tractus solitarius.
“Amylin acts on (a) appetitive/energy-regulating neurons in the hypothalamus impacting food intake, (b) dopaminergic neurons in the ventral tegmental area impacting reward and motivation, and (c) chemoreceptive neurons in the area postrema/nucleus tractus solitarius (51).”
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationGlucagon is a 29-amino-acid peptide secreted from alpha cells of the pancreatic islets that stimulates glycogenolysis and gluconeogenesis.
“Glucagon is a 29-amino-acid peptide, secreted from the alpha cells of the pancreatic islets, which stimulates glycogenolysis (70) and gluconeogenesis (71,72).”
Quote in the paperNot a substantial claim0 of 3 sources checkedThe quote only partly states this claim.
InterpretationreasoningLY3437943 is currently in phase II clinical development.
“Based on these results, currently, LY34379943 is in phase II undergoing further clinical development.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn a phase I study of BI456906, individuals with obesity who received biweekly dosing exhibited a lower withdrawal rate and a weight reduction of 8.8-13.7% compared to 0.1% weight reduction in the placebo group.
“Individuals who received biweekly dosing exhibited a lower withdrawal rate and a weight reduction of 8.8-13.7%compared to 0.1% weight reduction in the placebo group (77).”
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InterpretationreasoningResetting the defended fat mass set point leads to sustained weight reduction and improved metabolic and overall health.
“with ensuing sustained weight reduction and improved metabolic and overall health.”
Quote in the paperNot a substantial claim- Rests on an assumption: Obesity involves a defended fat mass set point that can be reset by restoring hormone balance.
May combine two claims.
PremisecitationGIP-stimulated insulin secretion is significantly blunted in individuals with T2D, but responsiveness can be restored by mitigating hyperglycemia.
“It remained in the shadow of GLP-1, partly because GIP-stimulated insulin secretion is significantly blunted in individuals with T2D (56); notably, responsiveness can be restored by mitigating hyperglycemia (57).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThe two highest doses of LY3437943, 4.5 mg and 6 mg, resulted in weight reduction of 2.9 kg and 3.5 kg at day 8 post dose, respectively, with weight reduction maintained at day 43.
“The two highest doses of LY3437943, 4.5 mg and 6 mg, resulted in weight reduction of 2.9 kg and 3.5 kg at day 8 post dose, respectively, with weight reduction maintained at day 43.”
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PremisecitationAmylin suppresses postprandial glucagon and delays gastric emptying.
“It suppresses postprandial glucagon and delays gastric emptying (46).”
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InterpretationcitationIn GIP/GLP-1 dual agonism, GLP-1 quells the potential glucagon-stimulatory effects of GIP and also (re)sensitizes beta cells to GIP's incretin effects, while potentially enhancing GIP's beneficial effects on weight regulation mechanisms.
“In the setting of GIP/GLP-1 receptor agonist (dual agonism), GLP-1 quells the potential glucagon-stimulatory effects of GIP (64) and also (re)sensitizes beta cells to GIP's incretin effects (57), all while potentially enhancing GIP's beneficial effects on weight regulation mechanisms.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationTirzepatide, a novel single-molecule GIP/GLP-1 receptor agonist, demonstrated average placebo-subtracted weight reduction of 17.8% with more than half of individuals losing ≥20% body weight.
“Tirzepatide, a novel single-molecule GIP/GLP-1 receptor agonist, demonstrated average placebo-subtracted weight reduction of 17.8% with more than half of individuals losing ≥20% body weight.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [68] source
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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenA multitude of novel multi-hormone therapeutics are in the pipeline.
“A multitude of novel multi-hormone therapeutics are in the pipeline (Figure 1).”
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PremisecitationSemaglutide has demonstrated average placebo-subtracted weight reduction of 12.5%, with one-third of individuals losing ≥20% body weight.
“semaglutide has demonstrated average placebo-subtracted weight reduction of 12.5%, with one-third of individuals losing ≥20% body weight.”
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PremisecitationIn SURMOUNT-1, participants randomized to tirzepatide 15 mg lost 20.9% of their body weight, whereas the placebo group lost 3.1%, a treatment difference of 17.8%.
“The participants who were randomized to the highest dose of tirzepatide (15 mg) lost 20.9% of their body weight, whereas the placebo group lost 3.1% (treatment difference of 17.8%) (Table 2).”
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PremisecitationPreclinical studies demonstrate that glucagon levels increase following protein ingestion, that inhibiting glucagon action results in increased food intake, and that glucagon potentially has an effect on thermogenesis via increasing brown adipose tissue oxygen consumption.
“Preclinical studies demonstrate that glucagon levels increase following protein ingestion (73), that inhibiting glucagon (action) results in increased food intake (74), and that glucagon potentially has an effect on thermogenesis via increasing brown adipose tissue oxygen consumption (75).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [73] source
Not checked in the free run.
- cites [74]
Not checked in the free run.
- cites [75]
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S4 (based).
InterpretationreasoningAiming to restore the balance of these hormones may also help reset the defended fat mass set point by altering complementary central (neural) energy-homeostasis pathways.
“Aiming to restore the balance of these hormones may also help reset the defended fat mass set point by altering complementary central (neural) energy-homeostasis pathways.”
Quote in the paperNot a substantial claim- Rests on an assumption: Obesity involves a defended fat mass set point that can be reset by restoring hormone balance.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRecently, a GIP/GLP-1/glucagon triple analogue (LY3437943) completed phase I studies.
“Recently, a GIP/GLP-1/ glucagon triple analogue (LY3437943) completed phase I studies.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [78]
Not checked in the free run.
The paper relies on this without support.
Semaglutide 2.4 mg is approved by the FDA and EMA for chronic weight management.
“The FDA's and EMA's approval of semaglutide 2.4 mg for chronic weight management”
The paper relies on this without support.
Liraglutide 3.0 mg is approved in multiple countries for chronic weight management.
“Liraglutide 3.0 mg is also approved in multiple countries for chronic weight management”
The paper relies on this without support.
Two oral GLP-1 RAs are under investigation for obesity treatment.
“two oral GLP-1 RAs are under investigation for obesity treatment.”
The paper relies on this without support.
Obesity involves a defended fat mass set point that can be reset by restoring hormone balance.
“resetting of the defended fat mass set point”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Newer GLP-1 receptor agonists including liraglutide, semaglutide, and tirzepatide have demonstrated better effectiveness, health benefits, and safety.
“have shown greater effectiveness, health benefits, and safety profiles (7; 8).”
From Regional trends and disparities in newer <scp>GLP1</scp> receptor agonist initiation among real‐world adult patients eligible for obesity treatment (2025) · cites this paper as [7]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
BI456906 has inconsistent identifiers
MinorTable 1 names the glucagon/GLP-1 dual receptor agonist BI1456906, while the discussion names it BI456906.
“BI1456906 (GCG/GLP-1 dual RA)”
“BI456906 GCG/GLP-1 dual RA”
AMG133 is assigned different receptor targets
MinorTable 1 describes AMG133 as a GIP/glucagon dual receptor agonist, whereas Figure 1 describes it as a GIP receptor antagonist/GLP-1 receptor agonist.
“AMG133 (GIP/GCG dual RA)”
“AMG133 GIP Receptor Antagonist/ GLP-1 RA”
Triple-agonist identifier changes in the phase II statement
MinorThe compound tested in the described phase I study is identified as LY3437943, but the statement about its subsequent phase II development calls it LY34379943.
“Recently, a GIP/GLP-1/ glucagon triple analogue (LY3437943) completed phase I studies.”
“Based on these results, currently, LY34379943 is in phase II undergoing further clinical development.”
SCALE placebo-subtracted weight loss differs between text and table
MinorThe text reports 5.2% for SCALE, while Table 2 reports 5.4%. The table's treatment and placebo values, 8.0% and 2.6%, also differ by 5.4 percentage points.
“Intention-to-treat 1-year placebo-subtracted weight reduction was 5.2%, 4%, 3.4%, and 6.1% for SCALE, SCALE Diabetes, SCALE IBT, and SCALE Maintenance, respectively.”
“Placebo-subtracted weight loss (%) 5.4 4.0 3.4 6.1”
The citation lists haven’t been fetched yet
References 87 · Cited by 158
Research works printed but not linked: 51
- 10.1001/jama.2016.7602 · DOI · Paper page
- 10.1098/rstb.2006.1856 · DOI
- 10.1016/S2213-8587(16)30263-7 · DOI · Paper page
- 10.1210/jc.86.9.4382 · DOI
- 10.1172/JCI78371 · DOI · Paper page
- 10.1172/jci.insight.133429 · DOI · Paper page
- 10.1111/dom.12932 · DOI · Paper page
- 10.1038/s41366-019-0348-6 · DOI · Paper page
- 10.1007/s12325-021-01710-0 · DOI · Paper page
- 10.2337/cd19-0100 · DOI · Paper page
- 10.1016/j.mcna.2021.06.005 · DOI · Paper page
- 10.3389/fendo.2019.00155 · DOI · Paper page
- 10.1016/j.diabres.2011.12.015 · DOI
- 10.1001/jama.2015.9676 · DOI · Paper page
- 10.1016/S0140-6736(17)30069-7 · DOI · Paper page
- 10.1021/acs.jmedchem.5b00726 · DOI · Paper page
- 10.1056/NEJMoa2032183 · DOI · Paper page
- 10.1016/S0140-6736(21)00213-0 · DOI · Paper page
- 10.1001/jama.2021.23619 · DOI · Paper page
- 10.1038/s41591-022-02026-4 · DOI · Paper page
- Aronne LJ, 2021, Obesity, 29, S9, 10.1002/oby.23092 · DOI · Paper page
- Kim HS, 2021, Int. J. Mol. Sci., 22, ijms22189936
- 10.1089/dia.2019.0185 · DOI · Paper page
- 10.2337/dc19-0749 · DOI · Paper page
- 10.1038/s41591-021-01391-w · DOI · Paper page
- 10.2337/diab.39.6.752 · DOI · Paper page
- 10.1210/jc.2009-2133 · DOI
- 10.1016/j.cmet.2015.10.012 · DOI
- 10.1007/s00018-011-0905-1 · DOI
- 10.1038/npp.2013.66 · DOI
- 10.1038/npp.2014.180 · DOI
- 10.1016/S0140-6736(21)01751-7 · DOI · Paper page
- 10.1016/S0140-6736(21)00845-X · DOI · Paper page
- 10.3390/life12010029 · DOI
- 10.1210/endo.133.6.8243312 · DOI · Paper page
- 10.1523/JNEUROSCI.4920-04.2005 · DOI · Paper page
- 10.1016/S0140-6736(21)01324-6 · DOI · Paper page
- 10.1016/S0140-6736(21)02188-7 · DOI · Paper page
- 10.1016/S0140-6736(21)01443-4 · DOI · Paper page
- 10.1016/S0021-9258(19)52762-4 · DOI
- 10.1172/JCI106297 · DOI · Paper page
- 10.1056/NEJM197112232852603 · DOI
- 10.1126/science.7134979 · DOI
- 10.1016/0024-3205(82)90614-2 · DOI
- 10.1038/nrendo.2015.51 · DOI · Paper page
- Arrubla J., 2021, Obesity, 29, 231
- 10.3389/fphys.2018.00900 · DOI
- 10.1016/j.molmet.2017.11.009 · DOI · Paper page
- 10.1038/s41366-019-0386-0 · DOI
- 10.1016/j.tem.2015.09.010 · DOI
- 10.2337/diabetes.53.12.3091 · DOI
- Authors
- Jastreboff, A. M., & Kushner, R. F.
- Affiliations
- Yale University (US)
- Northwestern University (US)
- Venue
- Annual Review of Medicine
- Publisher
- Annual Reviews
- Published
- 2023-01-27
- Volume
- 74
- Issue
- 1
- Pages
- 125-139
- ISSN
- 0066-4219 (ISSN-L)
- 1545-326X
- OpenAlex
- W4318262708
- Semantic Scholar
- 8955de4bdfd21a4b65f200b2a5d8b7c2977008c0
- Cited by
- 158
- References
- 87
- Citations by year
- 2026: 24 · 2025: 68 · 2024: 51 · 2023: 15
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Annual Review of Medicine (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099039, R01DK117651)
- Topics
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- obesity treatment, GLP-1 receptor agonists, glucagon-like peptide-1, enteroendocrine hormones, endocrine pancreas, neurobiology of obesity, anti-obesity drugs
- MeSH terms
- Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Obesity, Treatment Outcome, Glucagon-Like Peptide 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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