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Background: Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes., Methods: This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m 2 or higher and glycated haemoglobin (HbA 1c ) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003., Findings: Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m 2 (SD 6·6), and HbA 1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12·8% (SE 0·6) and -14·7% (0·5), respectively, and -3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of -9·6% percentage points (95% CI -11·1 to -8·1) with tirzepatide 10 mg and -11·6% percentage points (-13·0 to -10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79-83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator., Interpretation: In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests WTG has served as a consultant on advisory boards for Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck, and as a site principal investigator for multicentred clinical trials sponsored by his university and funded by Novo Nordisk, Eli Lilly and Company, Epitomee, Neurovalens, and Pfizer. JPF has received research funding (paid to his institution) from Akero, AstraZeneca, Boehringer Ingelheim, 89bio, Eli Lilly and Company, Intercept, IONIS, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, and Sanofi; has received consulting fees from Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly and Company, Merck, Novo Nordisk, Pfizer, and Sanofi; has received speaker bureau honoraria from Eli Lilly and Company and travel support for attending meetings from Eli Lilly and Company, Novo Nordisk, Pfizer, and Sanofi; has served on advisory boards for Altimmune, Becton Dickenson, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly and Company, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, and Sanofi; and has served on the board of directors for T1D Exchange. AMJ reports grants or contracts (through her institution) from Novo Nordisk, Eli Lilly and Company, Rhythm Pharmaceutical, and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases; consults for Amgen and Scholar Rock; has received honoraria or travel support from Eli Lilly and Company, Novo Nordisk, and WeightWatchers, and stock options from Intellihealth; and serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly and Company, Intellihealth, Novo Nordisk, Rhythm Pharmaceuticals, Structure Therapeutics, Terns Pharmaceutics, and WeightWatchers. CWlR reports grants from the Irish Research Council, Science Foundation Ireland, Anabio, and the Health Research Board. He serves on advisory boards and speakers’ panels of Novo Nordisk, Herbalife, GI Dynamics, Eli Lilly and Company, Johnson & Johnson, Glia, Irish Life Health, and Boehringer Ingelheim; is a member of the Irish Society for Nutrition and Metabolism outside the area of work commented on here; was the chief medical officer and director of the Medical Device Division of Keyron in 2021 (both unremunerated positions); is a previous investor in Keyron; was gifted stock holdings and divested all stock holdings in Keyron in September, 2021; continues to provide scientific advice to Keyron for no remuneration; and provides obesity clinical care in the Beyond BMI clinic and is a shareholder. NS has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; a grant from Roche Diagnostics; and personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly and Company, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, outside of the submitted work. SZ, HM, NNA, MCB, IB, and XMZ are employees and shareholders of Eli Lilly and Company., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses., Methods: In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18-75 years with type 2 diabetes, glycated haemoglobin (HbA 1c ) of 7·0-10·5% (53·0-91·3 mmol/mol), and BMI of 25-50 kg/m 2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (≥1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA 1c and BMI, to receive once-weekly injections of placebo, 1·5 mg dulaglutide, or retatrutide maintenance doses of 0·5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA 1c from baseline to 24 weeks, and secondary endpoints included change in HbA 1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785., Findings: Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56·2 years [SD 9·7], mean duration of diabetes 8·1 years [7·0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1·5 mg dulaglutide group, and 47 in the retatrutide 0·5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0·5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA 1c with retatrutide were -0·43% (SE 0·20; -4·68 mmol/mol [2·15]) for the 0·5 mg group, -1·39% (0·14; -15·24 mmol/mol [1·56]) for the 4 mg escalation group, -1·30% (0·22; -14·20 mmol/mol [2·44]) for the 4 mg group, -1·99% (0·15; -21·78 mmol/mol [1·60]) for the 8 mg slow escalation group, -1·88% (0·21; -20·52 mmol/mol [2·34]) for the 8 mg fast escalation group, and -2·02% (0·11; -22·07 mmol/mol [1·21]) for the 12 mg escalation group, versus -0·01% (0·21; -0·12 mmol/mol [2·27]) for the placebo group and -1·41% (0·12; -15·40 mmol/mol [1·29]) for the 1·5 mg dulaglutide group. HbA 1c reductions with retatrutide were significantly greater (p<0·0001) than placebo in all but the 0·5 mg group and greater than 1·5 mg dulaglutide in the 8 mg slow escalation group (p=0·0019) and 12 mg escalation group (p=0·0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3·19% (SE 0·61) for the 0·5 mg group, 7·92% (1·28) for the 4 mg escalation group, 10·37% (1·56) for the 4 mg group, 16·81% (1·59) for the 8 mg slow escalation group, 16·34% (1·65) for the 8 mg fast escalation group, and 16·94% (1·30) for the 12 mg escalation group, versus 3·00% (0·86) with placebo and 2·02% (0·72) with 1·5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0·0017 for the 4 mg escalation group and p<0·0001 for others) and 1·5 mg dulaglutide (all p<0·0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0·5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1·5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study., Interpretation: In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests JR has received grants and research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Merck, Oramed, Novartis, Novo Nordisk, Pfizer, and Sanofi; served on scientific advisory boards and received honorarium or consulting fees from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly and Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Terns Pharma, and Zealand; received honorarium for lectures or educational events from Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, and Sanofi; and received support for attending meetings or travel from Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, and Sanofi. AMJ has received grants and contracts (paid to their institution) from Novo Nordisk, Eli Lilly and Company, Rhythm Pharmaceutical, and the US National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases; consults for Amgen and Scholar Rock; has received honoraria or travel expenses from Eli Lilly and Company, Novo Nordisk, and WeightWatchers; has stock options from Intellihealth; and serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly and Company, Intellihealth, Novo Nordisk, Rhythm Pharmaceuticals, Structure Therapeutics, Terns Pharmaceuticals, and WeightWatchers. JF reports research funding from Akero, AstraZeneca, Boehringer Ingelheim, 89bio, Eli Lilly and Company, Intercept, IONIS, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, and Sanofi; consulting fees from Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly and Company, Merck, Novo Nordisk, Pfizer, and Sanofi; speaker bureau fees from Eli Lilly and Company; support for attending meetings or travel from Eli Lilly and Company, Novo Nordisk, Pfizer, and Sanofi; participation on advisory boards and consulting for Altimmune, Becton Dickenson, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly and Company, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, and Sanofi; and is on the Board of Directors of T1D Exchange. YD, JL, SG, MKT, MLH, AH, ZM, and TC are employees and shareholders of Eli Lilly and Company. MKT also reports roles as Industry Chair, Steering Committee for Accelerating Medicines Partnership-Type 2 Diabetes and Steering Committee Member for Accelerating Medicines Partnership-Common Metabolic Diseases., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Context: The neural regulation of appetite and energy homeostasis significantly overlaps with the neurobiology of stress. Frequent exposure to repeated acute stressors may cause increased allostatic load and subsequent dysregulation of the cortico-limbic striatal system leading to inefficient integration of postprandial homeostatic and hedonic signals. It is therefore important to understand the neural mechanisms by which stress generates alterations in appetite that may drive weight gain., Objective: To determine glucocorticoid effects on metabolic, neural and behavioral factors that may underlie the association between glucocorticoids, appetite and obesity risk., Methods: A randomized double-blind cross-over design of overnight infusion of hydrocortisone or saline followed by a fasting morning perfusion magnetic resonance imaging to assess regional cerebral blood flow (CBF) was completed. Visual Analog Scale (VAS) hunger, cortisol and metabolic hormones were also measured., Results: Hydrocortisone relative to saline significantly decreased whole brain voxel based CBF responses in the hypothalamus and related cortico-striatal-limbic regions. Hydrocortisone significantly increased hunger VAS pre-scan, insulin, glucose and leptin, but not other metabolic hormones versus saline CBF groups. Hydrocortisone related increases in hunger were predicted by less reduction of CBF (hydrocortisone minus saline) in the medial OFC, medial brainstem and thalamus, left primary sensory cortex and right superior and medial temporal gyrus. Hunger ratings were also positively associated with plasma insulin on hydrocortisone but not saline day., Conclusions: Increased glucocorticoids at levels akin to those experienced during psychological stress, result in increased fasting hunger and decreased regional cerebral blood flow in a distinct brain network of prefrontal, emotional, reward, motivation, sensory and homeostatic regions that underlie control of food intake., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background: Preclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD)., Methods: Non-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin)., Results: Thirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ± 1.2 vs. 9.1 ± 1.2; p = 0.39), self-reported euphoria (4.4 ± 0.8 vs. 4.1 ± 0.8; p = 0.21), or wanting of cocaine (5.6 ± 0.9 vs. 5.4 ± 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001)., Conclusions: We did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Although tobacco-smoking is associated with relatively leaner body mass and smoking cessation with weight gain, the brain mechanisms underlying these relationships are not well understood. Smokers compared to non-smokers have shown diminished neural responses to non-tobacco rewarding stimuli (e.g., monetary rewards), but brain responses to favorite-food cues have not been investigated relative to smoking status. We hypothesized that smokers would exhibit diminished neural responses compared to non-smokers in response to favorite-food cues in motivation-reward and emotion-regulating regions of the brain., Methods: Twenty-three smokers and 23 non-smokers matched based on body mass index (BMI), age, and gender listened to personalized favorite-food cue, stress, and neutral-relaxing audiotapes during fMRI., Results: During favorite-food cue exposure, smokers versus non-smokers exhibited diminished activations in the caudate, putamen, insula, and thalamus. Neural responses during stress and neutral-relaxing conditions were similar across groups. Subjective food-craving ratings were similar across groups., Conclusions: The relatively diminished neural responses to favorite-food cues in smokers may contribute to lower BMI., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Stress is associated with obesity, and the neurobiology of stress overlaps significantly with that of appetite and energy regulation. This review will discuss stress, allostasis, the neurobiology of stress and its overlap with neural regulation of appetite, and energy homeostasis. Stress is a key risk factor in the development of addiction and in addiction relapse. High levels of stress changes eating patterns and augments consumption of highly palatable (HP) foods, which in turn increases incentive salience of HP foods and allostatic load. The neurobiological mechanisms by which stress affects reward pathways to potentiate motivation and consumption of HP foods as well as addictive drugs is discussed. With enhanced incentive salience of HP foods and overconsumption of these foods, there are adaptations in stress and reward circuits that promote stress-related and HP food-related motivation as well as concomitant metabolic adaptations, including alterations in glucose metabolism, insulin sensitivity, and other hormones related to energy homeostasis. These metabolic changes in turn might also affect dopaminergic activity to influence food motivation and intake of HP foods. An integrative heuristic model is proposed, wherein repeated high levels of stress alter the biology of stress and appetite/energy regulation, with both components directly affecting neural mechanisms contributing to stress-induced and food cue-induced HP food motivation and engagement in overeating of such foods to enhance risk of weight gain and obesity. Future directions in research are identified to increase understanding of the mechanisms by which stress might increase risk of weight gain and obesity., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)