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Matthias Blüher MD Mohini Aras MD Louis J. Aronne MD Rachel L. Batterham MD Francesco Giorgino MD Linong Ji MD Kirsi H. Pietiläinen MD Oliver Schnell MD Elena Tonchevska MSc John P.H. Wilding MD 《Diabetes, obesity & metabolism》2023,25(8):2058-2072
Obesity is a chronic, progressive and relapsing disease with a rising global prevalence associated with increased morbidity and mortality and reduced quality of life. Treatment of obesity requires a comprehensive medical approach that includes behavioural interventions, pharmacotherapy and bariatric surgery. The degree of weight loss with all approaches is highly heterogeneous, and long-term weight maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy and raising numerous safety concerns. Therefore, there is a need for the development of highly efficacious and safe new agents. Recent insights into the complex pathophysiology of obesity have increased our understanding of intervenable targets for pharmacotherapies to treat obesity and improve weight-related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia and hypertension. As a result, novel potent therapies have emerged, such as semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) recently approved for the treatment of obesity. Semaglutide 2.4 mg once weekly significantly reduces body weight by approximately 15%, with simultaneous improvement in cardiometabolic risk factors and physical functioning in people with obesity. Tirzepatide, the first dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA, has recently demonstrated that body weight reduction exceeding 20% in people with obesity and coupled with improved cardiometabolic measures is feasible. Thus, these novel agents promise to narrow the gap between the weight-loss effects of behaviour interventions, previous pharmacotherapies, and bariatric surgery. In this narrative review, we highlight established and emerging therapeutic treatments for long-term obesity management and position them in a framework according to their weight loss effects. 相似文献
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Neuropsychiatric safety with liraglutide 3.0 mg for weight management: Results from randomized controlled phase 2 and 3a trials 下载免费PDF全文
Patrick M. O'Neil PhD Vanita R. Aroda MD Arne Astrup MD DMSc Robert Kushner MD David C. W. Lau MD PhD Thomas A. Wadden PhD Jason Brett MD Ana‐Paula Cancino MD MSc John P. H. Wilding DM FRCP 《Diabetes, obesity & metabolism》2017,19(11):1529-1536
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Signe Foghsgaard MD Louise Vedtofte MSc Emilie S. Andersen MD Emilie Bahne MD Camilla Andreasen MD Anne L. Sørensen MSc Julie L. Forman MSc Elisabeth R. Mathiesen MD Jens A. Svare MD Tine D. Clausen MD Peter Damm MD Jens J. Holst MD Filip K. Knop MD Tina Vilsbøll MD 《Diabetes, obesity & metabolism》2024,26(1):201-214
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Efficacy and safety of liraglutide 3.0 mg for weight management are similar across races: subgroup analysis across the SCALE and phase II randomized trials 下载免费PDF全文
J. Ard A. Cannon C. E. Lewis H. Lofton T. Vang Skjøth B. Stevenin X. Pi‐Sunyer 《Diabetes, obesity & metabolism》2016,18(4):430-435
The efficacy and safety of liraglutide 3.0 mg versus placebo, as adjunct to diet and exercise, was evaluated in racial subgroups. This post hoc analysis of pooled data from five double‐blind randomized, placebo‐controlled trials was conducted in 5325 adults with either a body mass index (BMI) ≥27 kg/m2 plus ≥1 comorbidity or a BMI ≥30 kg/m2. Statistical interaction tests evaluated possible treatment effect differences between racial subgroups: white (4496, 84.4%), black/African‐American (550, 10.3%), Asian (168, 3.2%) and other (111, 2.1%). Effects of liraglutide 3.0 mg on weight loss, associated metabolic effects and safety profile were generally consistent across racial subgroups. All achieved statistically significant mean weight loss at end‐of‐treatment with liraglutide 3.0 mg versus placebo: white 7.7% versus 2.3%, black/African‐American 6.3% versus 1.4%, Asian 6.3% versus 2.5%, other 7.3% versus 0.49%. Treatment effects on weight and cardiovascular risk markers generally showed no dependence on race (interaction test p > 0.05). Adverse events were similar across racial subgroups. 相似文献
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Michael A. Nauck MD Daniel R. Quast MD Jakob Wefers PhD Andreas F. H. Pfeiffer MD 《Diabetes, obesity & metabolism》2021,23(Z3):5-29
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to “isoglycaemic” intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and—in the long run—body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs. 相似文献
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Mohamed Suliman MD Adam Buckley MD Alia Al Tikriti MBA Tricia Tan MD Carel W. le Roux MD Nader Lessan MD Maha Barakat MD 《Diabetes, obesity & metabolism》2019,21(6):1498-1501
In this study we prospectively collected data on the use of liraglutide 3 mg in obese Arab patients. As part of routine care, 2092 patients were dispensed liraglutide 3 mg. Median age was 38 years and 77% were women. Median baseline weight was 95 kg and body mass index was 36.6 kg/m2. Of the patients, 188 (9%) had previous bariatric surgery. Seven hundred and eighty-seven patients were treated for ≥16 weeks and their median (interquartile range) weight loss was 6.0 (2.4-9.4) kg, equivalent to 6.4% (2.6%-9.7%) of baseline weight (P < 0.0001, n = 787). Of those treated for ≥16 weeks, 474 (60%) achieved a weight loss of >5% of baseline weight while 182 (23%) achieved >10% weight loss. There was no difference in percentage weight loss between postbariatric surgery (n = 76) and non-surgical patients (n = 711). As a result of adverse events, mainly gastrointestinal symptoms, 140 (6.7%) of the patients stopped treatment. One patient developed acute pancreatitis in the context of gallstone disease but made an uneventful recovery. Liraglutide 3 mg was well tolerated and resulted in weight loss in routine clinical care similar to that seen in randomized controlled trials. 相似文献
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Henriette H. Nerild MD Andreas Brønden MD Ida M. Gether MD Pernille H. Hellmann MD Mille Baekdal MD Matthew P. Gillum PhD Jens S. Svenningsen Bolette Hartmann PhD Naveen Rathor MD Hanna Angelene Kudiyanur Muniraju MSc Jens F. Rehfeld MD Jens J. Holst MD Tina Vilsbøll MD David P. Sonne MD Filip K. Knop MD 《Diabetes, obesity & metabolism》2023,25(6):1632-1637
Aim
Liraglutide treatment is associated with gallbladder-related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon-like peptide 2 (GLP-2), are known to regulate gallbladder motility and may be implicated in gallbladder-related disorders associated with liraglutide treatment.Materials and Methods
In a double-blind, 12-week trial, 52 participants [50% male, age 47.6 ± 10.0 years, body mass index 32.6 ± 3.4 kg/m2 (mean ± standard deviation)] with obesity were randomized 1:1 to once-daily subcutaneous liraglutide (escalated from 0.6 mg to 3.0 mg once-daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12 weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP-2.Results
Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC)0-240 min 24.8 vs. 48.0 min × ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12 weeks of treatment [AUC0-240 min 33.7 vs. 48.5 ng/ml × min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP-2 responses (AUC0-240 min 3650 vs. 4894 min × pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12 weeks [AUC0-240 min 3760 vs. 4882 min × pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC0-240 min 762 vs. 670 min × pmol/L; TR 1.14 (0.97; 1.33)] and following 12 weeks of treatment [AUC0-240 min 873 vs. 628 min × pmol/L; TR 1.39 (1.12; 1.73)].Conclusion
Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP-2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide. 相似文献9.
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Natasha Chidekel Bergmann MD Melanie J. Davies MD Ildiko Lingvay MD Filip K. Knop MD 《Diabetes, obesity & metabolism》2023,25(1):18-35
Obesity is a chronic, relapsing disease associated with multiple complications and a substantial morbidity, mortality and health care burden. Pharmacological treatments for obesity provide a valuable adjunct to lifestyle intervention, which often achieves only limited weight loss that is difficult to maintain. The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial programme is evaluating once-weekly subcutaneous semaglutide 2.4 mg (a glucagon-like peptide-1 analogue) in people with overweight or obesity. Across STEP 1, 3, 4 and 8, semaglutide 2.4 mg was associated with mean weight losses of 14.9%-17.4% in individuals with overweight or obesity without type 2 diabetes from baseline to week 68; 69%-79% of participants achieved ≥10% weight loss with semaglutide 2.4 mg (vs. 12%-27% with placebo) and 51%-64% achieved ≥15% weight loss (vs. 5%-13% with placebo). In STEP 5, mean weight loss was −15.2% with semaglutide 2.4 mg versus −2.6% with placebo from baseline to week 104. In STEP 2 (individuals with overweight or obesity, and type 2 diabetes), mean weight loss was −9.6% with semaglutide 2.4 mg versus −3.4% with placebo from baseline to week 68. Improvements in cardiometabolic risk factors, including high blood pressure, atherogenic lipids and benefits on physical function and quality of life were seen with semaglutide 2.4 mg. The safety profile of semaglutide 2.4 mg was consistent across trials, primarily gastrointestinal adverse events. The magnitude of weight loss reported in the STEP trials offers the potential for clinically relevant improvement for individuals with obesity-related diseases. 相似文献
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Subodh Verma MD Udi Fainberg MD Mansoor Husain MD Søren Rasmussen PhD Lars Rydén MD Maria Sejersten Ripa MD John B. Buse MD 《Diabetes, obesity & metabolism》2021,23(7):1677-1680
In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the “established CV disease” (CVD) and “CV risk factor” subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P-interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum. 相似文献
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John P. H. Wilding D.M Rachel L. Batterham MBBS Melanie Davies M.D Luc F. Van Gaal M.D Kristian Kandler M.D Katerina Konakli PhD Ildiko Lingvay M.D Barbara M. McGowan M.D Tugce Kalayci Oral MD Julio Rosenstock M.D Thomas A. Wadden Ph.D Sean Wharton M.D Koutaro Yokote M.D Robert F. Kushner M.D STEP Study Group 《Diabetes, obesity & metabolism》2022,24(8):1553-1564
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Switching from sitagliptin to liraglutide to manage patients with type 2 diabetes in the UK: A long‐term cost‐effectiveness analysis 下载免费PDF全文
Anthony H. Barnett MD Simon Arnoldini PhD Barnaby Hunt MSc Gowri Subramanian MBChB Christina Stentoft Hoxer BSc 《Diabetes, obesity & metabolism》2018,20(8):1921-1927
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David C. Klonoff MD Stephanie Bassock MS Ella Engels MS Marie Frederiksen MS Matthew Marber MS Marianne Qvist MS Thomas Sparre MD PhD Søren Snitker MD 《Diabetes, obesity & metabolism》2021,23(11):2590-2594
Subcutaneous semaglutide, at a 2.4 mg once-weekly maintenance dose, is approved in the United States for weight management in individuals with a body mass index (BMI) of 30 kg/m2 or higher, or with a BMI of 27 kg/m2 or higher and at least one obesity-related co-morbidity. To investigate the usability of the semaglutide pen-injector in individuals who met these criteria, we report post hoc analysis of the summative (human factors validation) usability testing and safety analysis involving patients with type 2 diabetes (an obesity-related co-morbidity) with the same pen-injector, limited to the 26 out of 30 patients with a BMI of 27 kg/m2 or higher (11 pen-injector–naïve, 15 pen-injector–experienced) and 15 non-pharmacist healthcare professionals (HCPs). Participants performed two simulated injections into an injection pad. No potentially serious use errors occurred. Mean subjective ease-of-use rating on a seven-point scale, where 1 = difficult and 7 = easy, was 6.9 for the second injection in all three groups. These results suggest that the semaglutide pen-injector is easy to use and not associated with serious use errors when used by pen-injector–naïve or pen-injector–experienced patients meeting the requirement for weight management with semaglutide treatment, and by non-pharmacist HCPs. 相似文献
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Preeshila Behary PhD Haya Alessimii PhD Alexander D. Miras PhD George Tharakan PhD Kleopatra Alexiadou PhD Madhawi M. Aldhwayan PhD Sanjay Purkayastha MD Krishna Moorthy MD Ahmed R. Ahmed PhD Stephen R. Bloom FRS Tricia M. Tan PhD 《Diabetes, obesity & metabolism》2023,25(6):1731-1739