Advertisement
Review Article| Volume 92, P170-192, March 2019

Download started.

Ok

Pharmacotherapy of obesity: Available medications and drugs under investigation

Published:October 31, 2018DOI:https://doi.org/10.1016/j.metabol.2018.10.010

      Highlights

      • Obesity is a chronic, multifactorial disease, initially managed with lifestyle modifications
      • Upon failure an FDA approved medication can be started based on patient comorbidities
      • Many novel anti-obesity agents are currently in clinical trials
      • Bariatric surgery studies highlight the role of gut-derived hormones in weight loss
      • Agents referring to gastrointestinal hormones will more likely reach the market

      Abstract

      Obesity is a chronic disease with a continuously rising prevalence that currently affects more than half a billion people worldwide. Energy balance and appetite are highly regulated via central and peripheral mechanisms, and weight loss triggers a homeostatic response leading to weight regain. Lifestyle and behavioral modifications are the cornerstones of obesity management; however, they often fail to achieve or sustain long-term weight loss. Pharmacotherapy added onto lifestyle modifications results in an additional, albeit limited, weight reduction. Regardless, this weight reduction of 5–10% conveys multiple cardiovascular and metabolic benefits. In this review, evidence on the food and drug administration (FDA)-approved medications, i.e., orlistat, lorcaserin, phentermine/topiramate, liraglutide and naltrexone/bupropion, is summarized. Furthermore, anti-obesity agents in the pipeline for potential future therapeutic use are presented.

      Abbreviations:

      Ach (acetylcholine), ACTH (adrenocorticotropic hormone), ADHD (attention-deficit hyperactivity disorder), AgRP (agouti-related peptide), AHI (apnea hypopnea index), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), ARC (arcuate nucleus), AVP (arginine-vasopressin), BAT (brown adipose tissue), BDNF (brain-derived neurotrophic factor), BED (binge eating disorder), BID (twice daily), BMI (body mass index), BOTOX (botulinum toxin), BW (body weight), CART (cocaine- and amphetamine-regulated transcript), CB1 (cannabinoid receptor type 1), CNS (central nervous system), CR (controlled release), CV (cardiovascular), CVD (cardiovascular disease), DA (dopamine), DBP (diastolic blood pressure), DIO (diet-induced obesity), FDA (Food and Drug Administration), eGFR (estimated glomerular filtration rate), FGF (fibroblast growth factor), fMRI (functional magnetic resonance imaging), GABA (gamma-aminobutyric acid), GCG R (glucagon receptor), GI (gastrointestinal), GIP R (gastric inhibitory peptide receptor), GLP (Glucagon-like peptide), HbA1c (glycosylated hemoglobin), HCl (hydrochloric), HDL-C (high density lipoprotein-cholesterol), HR (heart rate), HT R (hydroxytryptamin receptor), K (potassium), LDL-C (low density lipoprotein-cholesterol), MC (melanocortin), MC4R (melanocortin 4 receptor), MSH (melanocyte-stimulating hormone), NA (not available), Na (sodium), NAFLD (nonalcoholic fatty liver disease), Nal-Bup (naltrexone-bupropion), NE (norepinephrine), NPY (neuropeptide Y), NS (non-significant), NTS (nucleus of the solitary tract), OSA (obstructive sleep apnea), PCOS (polycystic ovary syndrome), PDE (phosphodiesterase), Phen-Top (phentermine/topiramate), POMC (proopiomelanocortin), PP (pancreatic polypeptide), PVN (paraventricular nucleus), PWS (Prader Willi syndrome), PYY (peptide YY), QD (once daily), RCT (randomized controlled trial), rhGH (recombinant human growth hormone), SBP (systolic blood pressure), sc (subcutaneous), SE (serotonin), SGLT (sodium-glucose cotransporter), TC (total cholesterol), T2D (type 2 diabetes), TC (total cholesterol), TG (triglyceride), TID (three times daily), TNF (tumor necrosis factor), TRH (Thyrotropin-releasing, ventromedial nucleus), WC (waist circumference), XR (extended release), y (year)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Metabolism - Clinical and Experimental
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • O'Rahilly S.
        • Farooqi I.S.
        Human obesity: a heritable neurobehavioral disorder that is highly sensitive to environmental conditions.
        Diabetes. 2008; 57: 2905-2910
        • Broskey N.T.
        • et al.
        Skeletal muscle ceramides and daily fat oxidation in obesity and diabetes.
        Metabolism. 2018; 82: 118-123
        • Bray G.A.
        • et al.
        Management of obesity.
        Lancet. 2016; 387: 1947-1956
        • Hales C.M.
        • et al.
        Differences in obesity prevalence by demographic characteristics and urbanization level among adults in the United States, 2013-2016.
        JAMA. 2018; 319: 2419-2429
        • Heymsfield S.B.
        • Wadden T.A.
        Mechanisms, pathophysiology, and management of obesity.
        N Engl J Med. 2017; 376: 254-266
        • CDC
        Ten leading causes of death and injury.
        (2016 June 15, 2018]; Available from:)
        • Narayanaswami V.
        • Dwoskin L.P.
        Obesity: current and potential pharmacotherapeutics and targets.
        Pharmacol Ther. 2017; 170: 116-147
        • Jakobsen G.S.
        • et al.
        Association of Bariatric Surgery vs medical obesity treatment with long-term medical complications and obesity-related comorbidities.
        JAMA. 2018; 319: 291-301
        • Alford S.
        • et al.
        Obesity as a risk factor for Alzheimer's disease: weighing the evidence.
        Obes Rev. 2018; 19: 269-280
        • Borrell L.N.
        • Samuel L.
        Body mass index categories and mortality risk in US adults: the effect of overweight and obesity on advancing death.
        Am J Public Health. 2014; 104: 512-519
        • Klatsky A.L.
        • et al.
        Body mass index and mortality in a very large cohort: is it really healthier to be overweight?.
        Perm J. 2017; 21
        • Huh J.H.
        • et al.
        Obesity is more closely related with hepatic steatosis and fibrosis measured by transient elastography than metabolic health status.
        Metabolism. 2017; 66: 23-31
        • Boutari C.
        • Mantzoros C.S.
        Inflammation: a key player linking obesity with malignancies.
        Metabolism. 2018; 81: A3-A6
        • Koren D.
        • Taveras E.M.
        Association of sleep disturbances with obesity, insulin resistance and the metabolic syndrome.
        Metabolism. 2018; 84: 67-75
        • Grover S.A.
        • et al.
        Years of life lost and healthy life-years lost from diabetes and cardiovascular disease in overweight and obese people: a modelling study.
        Lancet Diabetes Endocrinol. 2015; 3: 114-122
        • Kitahara C.M.
        • et al.
        Association between class III obesity (BMI of 40-59 kg/m2) and mortality: a pooled analysis of 20 prospective studies.
        PLoS Med. 2014; 11e1001673
        • WHO
        Obesity and overweight.
        (2017 25 June, 2018]; Available from:)
        • Dee A.
        • et al.
        The direct and indirect costs of both overweight and obesity: a systematic review.
        BMC Res Notes. 2014; 7: 242
      1. Prevalence of obesity among adults in the United States in 2012 and 2030.
        (2018 25 June, 2018]; Available from:)
        • Rock C.L.
        • et al.
        Effects of diet composition on weight loss, metabolic factors and biomarkers in a 1-year weight loss intervention in obese women examined by baseline insulin resistance status.
        Metabolism. 2016; 65: 1605-1613
        • Patel D.
        Pharmacotherapy for the management of obesity.
        Metabolism. 2015; 64: 1376-1385
        • Chao A.M.
        • Wadden T.A.
        • Berkowitz R.I.
        The safety of pharmacologic treatment for pediatric obesity.
        Expert Opin Drug Saf. 2018; 17: 379-385
        • Mendes N.F.
        • et al.
        TGF-beta1 down-regulation in the mediobasal hypothalamus attenuates hypothalamic inflammation and protects against diet-induced obesity.
        Metabolism. 2018; 85: 171-182
        • Wood J.
        • et al.
        BDNF mimetic alleviates body weight gain in obese mice by enhancing mitochondrial biogenesis in skeletal muscle.
        Metabolism. 2018; 87: 113-122
        • Leon S.
        • et al.
        Sex-biased physiological roles of NPFF1R, the canonical receptor of RFRP-3, in food intake and metabolic homeostasis revealed by its congenital ablation in mice.
        Metabolism. 2018; 87: 87-97
        • Adams J.M.
        • et al.
        Liraglutide modulates appetite and body weight through glucagon-like peptide 1 receptor-expressing glutamatergic neurons.
        Diabetes. 2018; 67: 1538-1548
        • Farr O.M.
        • Li C.S.
        • Mantzoros C.S.
        Central nervous system regulation of eating: insights from human brain imaging.
        Metabolism. 2016; 65: 699-713
        • Saunders K.H.
        • et al.
        Obesity pharmacotherapy.
        Med Clin North Am. 2018; 102: 135-148
        • Rothman R.B.
        • Baumann M.H.
        Appetite suppressants, cardiac valve disease and combination pharmacotherapy.
        Am J Ther. 2009; 16: 354-364
        • Masson J.
        • et al.
        Neurotransmitter transporters in the central nervous system.
        Pharmacol Rev. 1999; 51: 439-464
        • Velazquez A.
        • Apovian C.M.
        Updates on obesity pharmacotherapy.
        Ann N Y Acad Sci. 2018; 1411: 106-119
        • Kalyanasundar B.
        • et al.
        D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell.
        J Neurophysiol. 2015; 114: 585-607
      2. Hightlights of prescribing information—adipex. 2017
        • Onakpoya I.J.
        • Heneghan C.J.
        • Aronson J.K.
        Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review.
        BMC Med. 2016; 14: 191
        • Daneschvar H.L.
        • Aronson M.D.
        • Smetana G.W.
        FDA-approved anti-obesity drugs in the United States.
        Am J Med. 2016; 129 ([e1–6]): 879
        • Kim K.K.
        • et al.
        Effects on weight reduction and safety of short-term phentermine administration in Korean obese people.
        Yonsei Med J. 2006; 47: 614-625
        • Cercato C.
        • et al.
        A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects.
        Int J Obes (Lond). 2009; 33: 857-865
        • Munro J.F.
        • et al.
        Comparison of continuous and intermittent anorectic therapy in obesity.
        Br Med J. 1968; 1: 352-354
        • Aronne L.J.
        • et al.
        Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults.
        Obesity (Silver Spring). 2013; 21: 2163-2171
        • Kang J.G.
        • et al.
        Randomized controlled trial to investigate the effects of a newly developed formulation of phentermine diffuse-controlled release for obesity.
        Diabetes Obes Metab. 2010; 12: 876-882
        • Moldovan C.P.
        • et al.
        Effects of a meal replacement system alone or in combination with phentermine on weight loss and food cravings.
        Obesity (Silver Spring). 2016; 24: 2344-2350
        • Li Z.
        • et al.
        Meta-analysis: pharmacologic treatment of obesity.
        Ann Intern Med. 2005; 142: 532-546
        • Thomas E.A.
        • et al.
        Greater hunger and less restraint predict weight loss success with phentermine treatment.
        Obesity (Silver Spring). 2016; 24: 37-43
        • Suplicy H.
        • et al.
        A comparative study of five centrally acting drugs on the pharmacological treatment of obesity.
        Int J Obes (Lond). 2014; 38: 1097-1103
        • Valle-Jones J.C.
        • et al.
        A comparative study of phentermine and diethylpropion in the treatment of obese patients in general practice.
        Pharmatherapeutica. 1983; 3: 300-304
        • Heck A.M.
        • Yanovski J.A.
        • Calis K.A.
        Orlistat, a new lipase inhibitor for the management of obesity.
        Pharmacotherapy. 2000; 20: 270-279
        • Torgerson J.S.
        • et al.
        XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.
        Diabetes Care. 2004; 27: 155-161
        • Patel D.K.
        • Stanford F.C.
        Safety and tolerability of new-generation anti-obesity medications: a narrative review.
        Postgrad Med. 2018; 130: 173-182
        • Rossner S.
        • et al.
        Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European orlistat obesity study group.
        Obes Res. 2000; 8: 49-61
        • Weir M.A.
        • et al.
        Orlistat and acute kidney injury: an analysis of 953 patients.
        Arch Intern Med. 2011; 171: 703-704
        • Dossabhoy N.R.
        • et al.
        Orlistat-induced oxalate nephropathy may be dose-independent and present as a late manifestation.
        J La State Med Soc. 2013; 165: 283-285
        • Buysschaert B.
        • et al.
        Weight loss at a high cost: orlistat-induced late-onset severe kidney disease.
        Diabetes Metab. 2016; 42: 62-64
        • Perazella M.A.
        Crystal-induced acute renal failure.
        Am J Med. 1999; 106: 459-465
        • Humayun Y.
        • et al.
        Acute oxalate nephropathy associated with orlistat.
        J Nephropathol. 2016; 5: 79-83
        • Grandone A.
        • et al.
        New treatment modalities for obesity.
        Best Pract Res Clin Endocrinol Metab. 2018; 32: 535-549
        • Smith S.R.
        • et al.
        Orlistat 60 mg reduces visceral adipose tissue: a 24-week randomized, placebo-controlled, multicenter trial.
        Obesity (Silver Spring). 2011; 19: 1796-1803
        • Aldekhail N.M.
        • et al.
        Effect of orlistat on glycaemic control in overweight and obese patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.
        Obes Rev. 2015; 16: 1071-1080
        • Sahebkar A.
        • et al.
        Effects of orlistat on blood pressure: a systematic review and meta-analysis of 27 randomized controlled clinical trials.
        J Am Soc Hypertens. 2018; 12: 80-96
        • Siebenhofer A.
        • et al.
        Long-term effects of weight-reducing drugs in people with hypertension.
        Cochrane Database Syst Rev. 2016; 3CD007654
        • Bryson A.
        • de la Motte S.
        • Dunk C.
        Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers.
        Br J Clin Pharmacol. 2009; 67: 309-315
        • Kopelman P.
        • et al.
        Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical).
        Obesity (Silver Spring). 2010; 18: 108-115
        • Kopelman P.
        • et al.
        Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients.
        Int J Obes (Lond). 2007; 31: 494-499
        • Martin C.K.
        • et al.
        Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure.
        J Clin Endocrinol Metab. 2011; 96: 837-845
        • Smith S.R.
        • et al.
        Lorcaserin (APD356), a selective 5-HT(2C) agonist, reduces body weight in obese men and women.
        Obesity (Silver Spring). 2009; 17: 494-503
        • Farr O.M.
        • et al.
        Lorcaserin administration decreases activation of brain centers in response to food cues and these emotion- and salience-related changes correlate with weight loss effects: a 4-week-long randomized, placebo-controlled, Double-Blind Clinical Trial.
        Diabetes. 2016; 65: 2943-2953
        • Chao A.M.
        • et al.
        A randomized controlled trial of lorcaserin and lifestyle counselling for weight loss maintenance: Changes in emotion- and stress-related eating, food cravings and appetite.
        Clin Obes. 2018; https://doi.org/10.1111/cob.12279
        • Taylor J.R.
        • Dietrich E.
        • Powell J.
        Lorcaserin for weight management.
        Diabetes Metab Syndr Obes. 2013; 6: 209-216
        • Fidler M.C.
        • et al.
        A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial.
        J Clin Endocrinol Metab. 2011; 96: 3067-3077
        • O'Neil P.M.
        • et al.
        Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study.
        Obesity (Silver Spring). 2012; 20: 1426-1436
        • Smith S.R.
        • et al.
        Multicenter, placebo-controlled trial of lorcaserin for weight management.
        N Engl J Med. 2010; 363: 245-256
        • Bohula E.A.
        • et al.
        Design and rationale for the cardiovascular and metabolic effects of Lorcaserin in overweight and obese patients-thrombolysis in myocardial infarction 61 (CAMELLIA-TIMI 61) trial.
        Am Heart J. 2018; 202: 39-48
        • Bohula E.A.
        • et al.
        Cardiovascular safety of Lorcaserin in overweight or obese patients.
        N Engl J Med. 2018; 379: 1107-1117
        • Nguyen C.T.
        • et al.
        Lorcaserin in obese and overweight patients taking prohibited serotonergic agents: a retrospective analysis.
        Clin Ther. 2016; 38: 1498-1509
        • Chan E.W.
        • et al.
        Efficacy and safety of lorcaserin in obese adults: a meta-analysis of 1-year randomized controlled trials (RCTs) and narrative review on short-term RCTs.
        Obes Rev. 2013; 14: 383-392
        • Smith S.R.
        • et al.
        Coadministration of lorcaserin and phentermine for weight management: a 12-week, randomized, pilot safety study.
        Obesity (Silver Spring). 2017; 25: 857-865
        • Rebello C.J.
        • et al.
        Effect of lorcaserin alone and in combination with phentermine on food cravings after 12-week treatment: a randomized substudy.
        Obesity (Silver Spring). 2018; 26: 332-339
        • Meeting., E.a.M.D.A.C
        QNEXA (phentermine/topiramate) clinical briefing document.
        2012
        • Allison D.B.
        • et al.
        Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP).
        Obesity (Silver Spring). 2012; 20: 330-342
        • Gadde K.M.
        • et al.
        Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.
        Lancet. 2011; 377: 1341-1352
        • Daudon M.
        • et al.
        Drug-induced kidney stones and crystalline nephropathy: pathophysiology, Prevention and Treatment.
        Drugs. 2018; 78: 163-201
        • Fujioka K.
        Safety and tolerability of medications approved for chronic weight management.
        Obesity (Silver Spring). 2015; 23: S7-11
        • Garvey W.T.
        • et al.
        Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study.
        Am J Clin Nutr. 2012; 95: 297-308
        • Garvey W.T.
        • et al.
        Weight-loss therapy in type 2 diabetes: effects of phentermine and topiramate extended release.
        Diabetes Care. 2014; 37: 3309-3316
        • Khera R.
        • et al.
        Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis.
        JAMA. 2016; 315: 2424-2434
        • Winslow D.H.
        • et al.
        A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults.
        Sleep. 2012; 35: 1529-1539
        • Guerdjikova A.I.
        • et al.
        Combination phentermine-topiramate extended release for the treatment of binge eating disorder: an open-label, Prospective Study.
        Innov Clin Neurosci. 2018; 15: 17-21
        • Upadhyay J.
        • et al.
        Pharmacotherapy of type 2 diabetes: an update.
        Metabolism. 2018; 78: 13-42
        • van Can J.
        • et al.
        Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults.
        Int J Obes (Lond). 2014; 38: 784-793
        • Farr O.M.
        • et al.
        Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: a randomized, placebo-controlled, crossover study.
        Metabolism. 2016; 65: 945-953
        • Ten Kulve J.S.
        • et al.
        Liraglutide reduces CNS activation in response to visual food cues only after short-term treatment in patients with type 2 diabetes.
        Diabetes Care. 2016; 39: 214-221
        • Schlogl H.
        • et al.
        Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity.
        Diabetes Care. 2013; 36: 1933-1940
        • Knudsen L.B.
        • et al.
        Long-acting glucagon-like peptide-1 receptor agonists have direct access to and effects on pro-opiomelanocortin/cocaine- and amphetamine-stimulated transcript neurons in the mouse hypothalamus.
        J Diabetes Investig. 2016; 7: 56-63
        • Secher A.
        • et al.
        The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss.
        J Clin Invest. 2014; 124: 4473-4488
        • Geloneze B.
        • de Lima-Junior J.C.
        • Velloso L.A.
        Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the brain-adipocyte Axis.
        Drugs. 2017; 77: 493-503
        • Dickson S.L.
        • et al.
        The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors.
        J Neurosci. 2012; 32: 4812-4820
        • Farr O.M.
        • et al.
        GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial.
        Diabetologia. 2016; 59: 954-965
        • Pi-Sunyer X.
        • et al.
        A randomized, controlled trial of 3.0 mg of Liraglutide in weight management.
        N Engl J Med. 2015; 373: 11-22
        • Lean M.E.
        • et al.
        Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults.
        Int J Obes (Lond). 2014; 38: 689-697
        • Monami M.
        • et al.
        Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from randomized controlled trials.
        Diabetes Obes Metab. 2017; 19: 1233-1241
        • Bahtiyar G.
        • Pujals-Kury J.
        • Sacerdote A.
        Cardiovascular effects of different GLP-1 receptor agonists in patients with type 2 diabetes.
        Curr Diab Rep. 2018; 18: 92
        • Steinberg W.M.
        • et al.
        Impact of liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity and Normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from the SCALE clinical development Program.
        Diabetes Care. 2017; 40: 839-848
        • Matveyenko A.V.
        • et al.
        Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin.
        Diabetes. 2009; 58: 1604-1615
        • Butler A.E.
        • et al.
        Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors.
        Diabetes. 2013; 62: 2595-2604
        • Koehler J.A.
        • et al.
        GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7.
        Cell Metab. 2015; 21: 379-391
        • Elashoff M.
        • et al.
        Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.
        Gastroenterology. 2011; 141: 150-156
        • Htoo P.T.
        • et al.
        Effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on colorectal cancer incidence and its precursors.
        Eur J Clin Pharmacol. 2016; 72: 1013-1023
        • Hegedus L.
        • et al.
        No evidence of increase in calcitonin concentrations or development of C-cell malignancy in response to Liraglutide for up to 5 years in the LEADER trial.
        Diabetes Care. 2018; 41: 620-622
        • Nauck M.A.
        • et al.
        Neoplasms reported with liraglutide or placebo in people with type 2 diabetes: results from the LEADER randomized trial.
        Diabetes Care. 2018; 41: 1663-1671
        • O'Neil P.M.
        • et al.
        Neuropsychiatric safety with liraglutide 3.0 mg for weight management: results from randomized controlled phase 2 and 3a trials.
        Diabetes Obes Metab. 2017; 19: 1529-1536
        • Davies M.J.
        • et al.
        Efficacy of Liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial.
        JAMA. 2015; 314: 687-699
        • Wadden T.A.
        • et al.
        Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE maintenance randomized study.
        Int J Obes (Lond). 2013; 37: 1443-1451
        • Fujioka K.
        • et al.
        Early weight loss with liraglutide 3.0 mg predicts 1-year weight loss and is associated with improvements in clinical markers.
        Obesity (Silver Spring). 2016; 24: 2278-2288
        • Khera R.
        • et al.
        Effects of weight-loss medications on cardiometabolic risk profiles: a systematic review and network meta-analysis.
        Gastroenterology. 2018; 154 ([e7]): 1309-1319
        • le Roux C.W.
        • et al.
        3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial.
        Lancet. 2017; 389: 1399-1409
        • Marso S.P.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2016; 375: 311-322
        • Mann J.F.E.
        • et al.
        Liraglutide and renal outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 839-848
        • Sharma A.
        • et al.
        Liraglutide and weight loss among patients with advanced heart failure and a reduced ejection fraction: Insights from the FIGHT trial.
        ESC Heart Fail. 2018; https://doi.org/10.1002/ehf2.12334
        • Iepsen E.W.
        • et al.
        Patients with obesity caused by melanocortin-4 receptor mutations can be treated with a glucagon-like Peptide-1 receptor agonist.
        Cell Metab. 2018; 28 ([e3]): 23-32
        • Blackman A.
        • et al.
        Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial.
        Int J Obes (Lond). 2016; 40: 1310-1319
        • Wang F.F.
        • et al.
        Pharmacologic therapy to induce weight loss in women who have obesity/overweight with polycystic ovary syndrome: a systematic review and network meta-analysis.
        Obes Rev. 2018; 19: 1424-1445
        • Greig S.L.
        • Keating G.M.
        Naltrexone ER/bupropion ER: a review in obesity management.
        Drugs. 2015; 75: 1269-1280
        • Dutia R.
        • et al.
        Beta-endorphin antagonizes the effects of alpha-MSH on food intake and body weight.
        Endocrinology. 2012; 153: 4246-4255
        • Wang G.J.
        • et al.
        Effect of combined naltrexone and bupropion therapy on the brain's reactivity to food cues.
        Int J Obes (Lond). 2014; 38: 682-688
        • Greenway F.L.
        • et al.
        Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet. 2010; 376: 595-605
        • Apovian C.M.
        • et al.
        A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II).
        Obesity (Silver Spring). 2013; 21: 935-943
        • Hollander P.
        • et al.
        Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes.
        Diabetes Care. 2013; 36: 4022-4029
        • Wadden T.A.
        • et al.
        Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial.
        Obesity (Silver Spring). 2011; 19: 110-120
        • Halseth A.
        • et al.
        Method-of-use study of naltrexone sustained release (SR)/bupropion SR on body weight in individuals with obesity.
        Obesity (Silver Spring). 2017; 25: 338-345
        • Kolotkin R.L.
        • et al.
        Patient-reported quality of life in a randomized placebo-controlled trial of naltrexone/bupropion for obesity.
        Clin Obes. 2015; 5: 237-244
        • Nissen S.E.
        • et al.
        Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: a randomized clinical trial.
        JAMA. 2016; 315: 990-1004
        • Rosenstock J.
        • et al.
        Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes.
        Diabetes Care. 2010; 33: 1173-1175
        • Basolo A.
        • et al.
        Exenatide has a pronounced effect on energy intake but not energy expenditure in non-diabetic subjects with obesity: a randomized, double-blind, placebo-controlled trial.
        Metabolism. 2018; 85: 116-125
        • Su N.
        • et al.
        Exenatide in obese or overweight patients without diabetes: a systematic review and meta-analyses of randomized controlled trials.
        Int J Cardiol. 2016; 219: 293-300
        • Vilsboll T.
        • et al.
        Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials.
        BMJ. 2012; 344: d7771
        • Zaccardi F.
        • et al.
        Benefits and harms of once-weekly glucagon-like Peptide-1 receptor agonist treatments: a systematic review and network meta-analysis.
        Ann Intern Med. 2016; 164: 102-113
        • Blundell J.
        • et al.
        Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity.
        Diabetes Obes Metab. 2017; 19: 1242-1251
        • Ahren B.
        • et al.
        Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials.
        Diabetes Obes Metab. 2018; 20: 2210-2219
        • Shi F.H.
        • et al.
        Efficacy and safety of once-weekly Semaglutide for the treatment of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.
        Front Pharmacol. 2018; 9: 576
        • Andreadis P.
        • et al.
        Semaglutide for type 2 diabetes mellitus: a systematic review and meta-analysis.
        Diabetes Obes Metab. 2018; 20: 2255-2263
        • O'Neil P.M.
        • et al.
        Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial.
        Lancet. 2018; 392: 637-649
        • Rena G.
        • Hardie D.G.
        • Pearson E.R.
        The mechanisms of action of metformin.
        Diabetologia. 2017; 60: 1577-1585
        • Li M.
        • et al.
        Molecular mechanisms of metformin for diabetes and cancer treatment.
        Front Physiol. 2018; 9: 1039
        • Domecq J.P.
        • et al.
        Clinical review: drugs commonly associated with weight change: a systematic review and meta-analysis.
        J Clin Endocrinol Metab. 2015; 100: 363-370
        • Golay A.
        Metformin and body weight.
        Int J Obes (Lond). 2008; 32: 61-72
        • Bjorkhem-Bergman L.
        • Asplund A.B.
        • Lindh J.D.
        Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis.
        J Psychopharmacol. 2011; 25: 299-305
        • Elmaraezy A.
        • et al.
        Effect of metformin on maternal and neonatal outcomes in pregnant obese non-diabetic women: a meta-analysis.
        Int J Reprod Biomed (Yazd). 2017; 15: 461-470
        • Mogul H.
        • Freeman R.
        • Nguyen K.
        Metformin-sustained weight loss and reduced android fat tissue at 12 months in EMPOWIR (enhance the metabolic profile of women with insulin resistance): a double blind, placebo-controlled, randomized trial of NORMOGLYCEMIC women with midlife weight gain.
        Endocr Pract. 2016; 22: 575-586
        • O'Connor E.A.
        • et al.
        Screening for obesity and intervention for weight Management in Children and Adolescents: evidence report and systematic review for the US preventive services task force.
        JAMA. 2017; 317: 2427-2444
        • Mishriky B.M.
        • et al.
        Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: a systematic review and meta-analysis.
        Diabetes Metab. 2018; 44: 112-120
        • Vallianou N.G.
        • Geladari E.
        • Kazazis C.E.
        SGLT-2 inhibitors: their pleiotropic properties.
        Diabetes Metab Syndr. 2017; 11: 311-315
        • Neff L.M.
        • et al.
        Network meta-analysis of lorcaserin and oral hypoglycaemics for patients with type 2 diabetes mellitus and obesity.
        Clin Obes. 2017; 7: 337-346
        • Sasaki T.
        • Sugawara M.
        • Fukuda M.
        Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: The components of weight loss in Japanese patients with type 2 diabetes mellitus) study.
        J Diabetes Investig. 2018; https://doi.org/10.1111/jdi.12851
        • Cai X.
        • et al.
        The association between the dosage of SGLT2 inhibitor and weight reduction in type 2 diabetes patients: a meta-analysis.
        Obesity (Silver Spring). 2018; 26: 70-80
        • Bolinder J.
        • et al.
        Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.
        J Clin Endocrinol Metab. 2012; 97: 1020-1031
        • Thomas M.C.
        • Cherney D.Z.I.
        The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure.
        Diabetologia. 2018; 61: 2098-2107
        • Hollander P.
        • et al.
        Coadministration of canagliflozin and phentermine for weight management in overweight and obese individuals without diabetes: a randomized clinical trial.
        Diabetes Care. 2017; 40: 632-639
        • Lundkvist P.
        • et al.
        Dapagliflozin once-daily and exenatide once-weekly dual therapy: a 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes.
        Diabetes Obes Metab. 2017; 19: 49-60
        • Dawwas G.K.
        • Smith S.M.
        • Park H.
        Cardiovascular outcomes of sodium glucose cotransporter-2 inhibitors in patients with type 2 diabetes.
        Diabetes Obes Metab. 2018; https://doi.org/10.1111/dom.13477
        • Heerspink H.J.L.
        • et al.
        Renoprotective effects of sodium-glucose cotransporter-2 inhibitors.
        Kidney Int. 2018; 94: 26-39
        • Radholm K.
        • et al.
        Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS Program (Canagliflozin cardiovascular assessment study).
        Circulation. 2018; 138: 458-468
        • Mahaffey K.W.
        • et al.
        Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin cardiovascular assessment study).
        Circulation. 2018; 137: 323-334
        • Cherney D.Z.I.
        • et al.
        Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial.
        Lancet Diabetes Endocrinol. 2017; 5: 610-621
        • Fitchett D.
        • et al.
        Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME(R) trial.
        Eur Heart J. 2018; 39: 363-370
        • Baptist G.
        The cardiovascular benefits associated with the use of sodium-glucose cotransporter 2 inhibitors - real-world data.
        Eur Endocrinol. 2018; 14: 17-23
        • Suissa S.
        Mortality reduction in EMPA-REG OUTCOME trial: beyond the antidiabetes effect.
        Diabetes Care. 2018; 41: 219-223
        • Neuen B.L.
        • et al.
        Cardiovascular and renal outcomes with Canagliflozin according to baseline kidney function: data from the CANVAS Program.
        Circulation. 2018; 138: 1537-1550
        • Inzucchi S.E.
        • et al.
        Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial.
        Diabetes Care. 2018; 41: e4-e5
        • Yamashita H.
        • et al.
        A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver.
        Proc Natl Acad Sci U S A. 2001; 98: 9116-9121
        • Ferre P.
        • Foufelle F.
        Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c.
        Diabetes Obes Metab. 2010; 12: 83-92
        • Kuchay M.S.
        • et al.
        Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial).
        Diabetes Care. 2018; 41: 1801-1808
        • FDA
        Highlights of prescribing information — canagliflozin.
        (2016 10/12/2018]; Available from:)
        • FDA
        Highlights of prescribing information — dapagliflozin.
        2014
        • FDA
        Highlights of prescribing information — empagliflozin.
        2016
        • FDA
        Highlights of prescribing information — ertugliflozin.
        2017
        • Goncalves E.
        • Bell D.S.H.
        Combination treatment of SGLT2 inhibitors and GLP-1 receptor agonists: symbiotic effects on metabolism and Cardiorenal risk.
        Diabetes Ther. 2018; 9: 919-926
        • Jeong J.K.
        • Kim J.G.
        • Lee B.J.
        Participation of the central melanocortin system in metabolic regulation and energy homeostasis.
        Cell Mol Life Sci. 2014; 71: 3799-3809
        • McMinn J.E.
        • et al.
        Effect of intracerebroventricular alpha-MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression.
        Am J Physiol Regul Integr Comp Physiol. 2000; 279: R695-R703
        • Kievit P.
        • et al.
        Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques.
        Diabetes. 2013; 62: 490-497
        • Koegler F.H.
        • et al.
        Central melanocortin receptors mediate changes in food intake in the rhesus macaque.
        Endocrinology. 2001; 142: 2586-2592
        • Cowley M.A.
        • et al.
        Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat.
        Neuron. 1999; 24: 155-163
        • Ayers K.L.
        • et al.
        Melanocortin-4 receptor pathway dysfunction in obesity: patient stratification aimed at MC4R agonist treatment.
        J Clin Endocrinol Metab. 2018; 103: 2601-2612
        • Ma L.
        • et al.
        Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians.
        Diabetes. 2004; 53: 2696-2699
        • Collet T.H.
        • et al.
        Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.
        Mol Metab. 2017; 6: 1321-1329
        • Kuhnen P.
        • et al.
        Proopiomelanocortin deficiency treated with a Melanocortin-4 receptor agonist.
        N Engl J Med. 2016; 375: 240-246
        • Clement K.
        • et al.
        MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency.
        Nat Med. 2018; 24: 551-555
        • Srivastava G.
        • Apovian C.
        Future pharmacotherapy for obesity: new anti-obesity drugs on the horizon.
        Curr Obes Rep. 2018; 7: 147-161
        • Krishna R.
        • et al.
        Potent and selective agonism of the melanocortin receptor 4 with MK-0493 does not induce weight loss in obese human subjects: energy intake predicts lack of weight loss efficacy.
        Clin Pharmacol Ther. 2009; 86: 659-666
        • Chen K.Y.
        • et al.
        RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals.
        J Clin Endocrinol Metab. 2015; 100: 1639-1645
        • Hansen H.H.
        • et al.
        Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat.
        Pharmacol Biochem Behav. 2013; 110: 265-271
        • van de Giessen E.
        • et al.
        Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats.
        Eur Neuropsychopharmacol. 2012; 22: 290-299
        • Sjodin A.
        • et al.
        The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men.
        Int J Obes (Lond). 2010; 34: 1634-1643
        • Gilbert J.A.
        • et al.
        The effect of tesofensine on appetite sensations.
        Obesity (Silver Spring). 2012; 20: 553-561
        • Astrup A.
        • et al.
        Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.
        Lancet. 2008; 372: 1906-1913
      3. Tesofensine monotherapy for treatment of obesity.
        (2018 2018, June 6]; Available from:)
        • Volkow N.D.
        • et al.
        Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain.
        Am J Psychiatry. 2004; 161: 1173-1180
        • Arnsten A.F.
        The emerging neurobiology of attention deficit hyperactivity disorder: the key role of the prefrontal association cortex.
        J Pediatr. 2009; 154: I-S43
        • Berridge K.C.
        • Robinson T.E.
        What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?.
        Brain Res Brain Res Rev. 1998; 28: 309-369
        • Golinko B.E.
        Side effects of dextroamphetamine and methylphenidate in hyperactive children--a brief review.
        Prog Neuropsychopharmacol Biol Psychiatry. 1984; 8: 1-8
        • Albayrak O.
        • et al.
        Successful methylphenidate treatment of early onset extreme obesity in a child with a melanocortin-4 receptor gene mutation and attention deficit/hyperactivity disorder.
        Eur J Pharmacol. 2011; 660: 165-170
        • Elfers C.T.
        • Roth C.L.
        Effects of methylphenidate on weight gain and food intake in hypothalamic obesity.
        Front Endocrinol (Lausanne). 2011; 2: 78
        • Sahin S.
        • et al.
        Effect of methylphenidate treatment on appetite and levels of leptin, ghrelin, adiponectin, and brain-derived neurotrophic factor in children and adolescents with attention deficit and hyperactivity disorder.
        Int J Psychiatry Clin Pract. 2014; 18: 280-287
        • Poulton A.
        • et al.
        Weight loss on stimulant medication: how does it affect body composition and bone metabolism? - a prospective longitudinal study.
        Int J Pediatr Endocrinol. 2012; 2012: 30
        • Levy L.D.
        • Fleming J.P.
        • Klar D.
        Treatment of refractory obesity in severely obese adults following management of newly diagnosed attention deficit hyperactivity disorder.
        Int J Obes (Lond). 2009; 33: 326-334
        • Goldfield G.S.
        • Lorello C.
        • Doucet E.
        Methylphenidate reduces energy intake and dietary fat intake in adults: a mechanism of reduced reinforcing value of food?.
        Am J Clin Nutr. 2007; 86: 308-315
        • Leddy J.J.
        • et al.
        Influence of methylphenidate on eating in obese men.
        Obes Res. 2004; 12: 224-232
        • Lorello C.
        • Goldfield G.S.
        • Doucet E.
        Methylphenidate hydrochloride increases energy expenditure in healthy adults.
        Obesity (Silver Spring). 2008; 16: 470-472
        • Farr O.M.
        • et al.
        The effects of methylphenidate on cerebral activations to salient stimuli in healthy adults.
        Exp Clin Psychopharmacol. 2014; 22: 154-165
        • Storebo O.J.
        • et al.
        Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies.
        Cochrane Database Syst Rev. 2018; 5CD012069
        • Richey J.M.
        • Woolcott O.
        Re-visiting the endocannabinoid system and its therapeutic potential in obesity and associated diseases.
        Curr Diab Rep. 2017; 17: 99
        • Scheen A.J.
        • et al.
        Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study.
        Lancet. 2006; 368: 1660-1672
        • Van Gaal L.F.
        • et al.
        Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe study.
        Eur Heart J. 2008; 29: 1761-1771
        • Van Gaal L.F.
        • et al.
        Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study.
        Lancet. 2005; 365: 1389-1397
        • Moreira F.A.
        • Crippa J.A.
        The psychiatric side-effects of rimonabant.
        Rev Bras Psiquiatr. 2009; 31: 145-153
        • Cluny N.L.
        • et al.
        A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents.
        Br J Pharmacol. 2010; 161: 629-642
        • Argueta D.A.
        • Dipatrizio N.V.
        Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity.
        Physiol Behav. 2017; 171: 32-39
        • Randall P.A.
        • et al.
        The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior.
        Pharmacol Biochem Behav. 2010; 97: 179-184
        • Ma H.
        • et al.
        Peripheral CB1 receptor neutral antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice.
        Front Pharmacol. 2018; 9: 156
        • Tam J.
        • et al.
        Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance.
        Cell Metab. 2012; 16: 167-179
        • Marathe C.S.
        • et al.
        Glucagon-like peptides 1 and 2 in health and disease: a review.
        Peptides. 2013; 44: 75-86
        • le Roux C.W.
        • Bloom S.R.
        Peptide YY, appetite and food intake.
        Proc Nutr Soc. 2005; 64: 213-216
        • Capozzi M.E.
        • et al.
        Targeting the incretin/glucagon system with Triagonists to treat diabetes.
        Endocr Rev. 2018; 39: 719-738
        • Day J.W.
        • et al.
        Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents.
        Biopolymers. 2012; 98: 443-450
        • Evers A.
        • et al.
        Dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists specifically optimized for multidose formulations.
        J Med Chem. 2018; 61: 5580-5593
        • Pocai A.
        Action and therapeutic potential of oxyntomodulin.
        Mol Metab. 2014; 3: 241-251
        • Will S.
        • et al.
        Gut check on diabesity: leveraging gut mechanisms for the treatment of type 2 diabetes and obesity.
        Curr Opin Pharmacol. 2017; 37: 10-15
        • Holst J.J.
        • et al.
        Mechanisms in bariatric surgery: gut hormones, diabetes resolution, and weight loss.
        Surg Obes Relat Dis. 2018; 14: 708-714
        • Cohen M.A.
        • et al.
        Oxyntomodulin suppresses appetite and reduces food intake in humans.
        J Clin Endocrinol Metab. 2003; 88: 4696-4701
        • Wynne K.
        • et al.
        Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial.
        Diabetes. 2005; 54: 2390-2395
        • Wynne K.
        • et al.
        Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial.
        Int J Obes (Lond). 2006; 30: 1729-1736
        • Tan T.
        • et al.
        The effect of a subcutaneous infusion of GLP-1, OXM, and PYY on energy intake and expenditure in obese volunteers.
        J Clin Endocrinol Metab. 2017; 102: 2364-2372
        • Ambery P.
        • et al.
        MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study.
        Lancet. 2018; 391: 2607-2618
        • Ambery P.D.
        • et al.
        MEDI0382, a GLP-1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, phase 1 study.
        Br J Clin Pharmacol. 2018; 84: 2325-2335
        • Ghofrani H.A.
        • Osterloh I.H.
        • Grimminger F.
        Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.
        Nat Rev Drug Discov. 2006; 5: 689-702
        • Li S.
        • et al.
        Sildenafil induces browning of subcutaneous white adipose tissue in overweight adults.
        Metabolism. 2018; 78: 106-117
        • Jansson P.A.
        • et al.
        Tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes.
        Diabetologia. 2010; 53: 2205-2208
        • Kim F.
        • et al.
        Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance.
        Arterioscler Thromb Vasc Biol. 2008; 28: 1982-1988
        • Xu Z.R.
        • et al.
        The effectiveness of leucine on muscle protein synthesis, lean body mass and leg lean mass accretion in older people: a systematic review and meta-analysis.
        Br J Nutr. 2015; 113: 25-34
        • Fu L.
        • et al.
        Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism.
        Diabetes Metab Syndr Obes. 2015; 8: 227-239
        • Lawson E.A.
        The effects of oxytocin on eating behaviour and metabolism in humans.
        Nat Rev Endocrinol. 2017; 13: 700-709
        • Ott V.
        • et al.
        Oxytocin reduces reward-driven food intake in humans.
        Diabetes. 2013; 62: 3418-3425
        • Thienel M.
        • et al.
        Oxytocin's inhibitory effect on food intake is stronger in obese than normal-weight men.
        Int J Obes (Lond). 2016; 40: 1707-1714
        • Lawson E.A.
        • et al.
        Oxytocin reduces caloric intake in men.
        Obesity (Silver Spring). 2015; 23: 950-956
        • van der Klaauw A.A.
        • et al.
        Oxytocin administration suppresses hypothalamic activation in response to visual food cues.
        Sci Rep. 2017; 7: 4266
        • Plessow F.
        • et al.
        Effects of intranasal oxytocin on the blood oxygenation level-dependent signal in food motivation and cognitive control pathways in overweight and obese men.
        Neuropsychopharmacology. 2018; 43: 638-645
        • Spetter M.S.
        • et al.
        Oxytocin curbs calorie intake via food-specific increases in the activity of brain areas that process reward and establish cognitive control.
        Sci Rep. 2018; 8: 2736
        • Hsu E.A.
        • et al.
        Oxytocin and naltrexone successfully treat hypothalamic obesity in a boy post-Craniopharyngioma resection.
        J Clin Endocrinol Metab. 2018; 103: 370-375
        • Zhang H.
        • et al.
        Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models.
        PLoS One. 2013; 8e61477
        • Hieronymus L.
        • Griffin S.
        Role of amylin in type 1 and type 2 diabetes.
        Diabetes Educ. 2015; 41: 47S-56S
        • Meneghini L.F.
        • et al.
        Weight beneficial treatments for type 2 diabetes.
        J Clin Endocrinol Metab. 2011; 96: 3337-3353
        • Riddle M.
        • et al.
        Pramlintide improved glycemic control and reduced weight in patients with type 2 diabetes using basal insulin.
        Diabetes Care. 2007; 30: 2794-2799
        • Hollander P.A.
        • et al.
        Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial.
        Diabetes Care. 2003; 26: 784-790
        • Boyle C.N.
        • Lutz T.A.
        • Le Foll C.
        Amylin - its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity.
        Mol Metab. 2018; 8: 203-210
        • Smith S.R.
        • et al.
        Pramlintide treatment reduces 24-h caloric intake and meal sizes and improves control of eating in obese subjects: a 6-wk translational research study.
        Am J Physiol Endocrinol Metab. 2007; 293: E620-E627
        • Aronne L.
        • et al.
        Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study.
        J Clin Endocrinol Metab. 2007; 92: 2977-2983
        • De Silva A.
        • Bloom S.R.
        Gut hormones and appetite control: a focus on PYY and GLP-1 as therapeutic targets in obesity.
        Gut Liver. 2012; 6: 10-20
        • Ballantyne G.H.
        Peptide YY(1-36) and peptide YY(3-36): part I. distribution, release and actions.
        Obes Surg. 2006; 16: 651-658
        • Ueno H.
        • et al.
        The role of PYY in feeding regulation.
        Regul Pept. 2008; 145: 12-16
        • Goldstone A.P.
        • et al.
        Link between increased satiety gut hormones and reduced food reward after gastric bypass surgery for obesity.
        J Clin Endocrinol Metab. 2016; 101: 599-609
        • Sloth B.
        • et al.
        Effect of subcutaneous injections of PYY1-36 and PYY3-36 on appetite, ad libitum energy intake, and plasma free fatty acid concentration in obese males.
        Am J Physiol Endocrinol Metab. 2007; 293: E604-E609
        • Field B.C.
        • et al.
        PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans.
        Diabetes. 2010; 59: 1635-1639
        • Steinert R.E.
        • et al.
        Oral administration of glucagon-like peptide 1 or peptide YY 3-36 affects food intake in healthy male subjects.
        Am J Clin Nutr. 2010; 92: 810-817
        • Ma J.
        • Vella A.
        What has bariatric surgery taught us about the role of the upper gastrointestinal tract in the regulation of postprandial glucose metabolism?.
        Front Endocrinol (Lausanne). 2018; 9: 324
        • Karras S.
        • et al.
        The effects of incretins on energy homeostasis: physiology and implications for the treatment of type 2 diabetes mellitus and obesity.
        Curr Vasc Pharmacol. 2012; 10: 781-791
        • Choi I.Y.
        • Lee J.S.
        • Kim J.K.
        • Park Y.J.
        • Jung S.Y.
        • Kim Y.H.
        Potent body weight loss and efficacy in a NASH animal model by a novel long-acting GLP-1/Glucagon/GIP triple-agonist (HM15211).
        American Diabetes Association's 77th Scientific Session, San Diego, CA USA2017
        • Gavrieli A.
        • Mantzoros C.S.
        Novel molecules regulating energy homeostasis: physiology and regulation by macronutrient intake and weight loss.
        Endocrinol Metab (Seoul). 2016; 31: 361-372
        • Thompson W.C.
        • et al.
        PF-05231023, a long-acting FGF21 analogue, decreases body weight by reduction of food intake in non-human primates.
        J Pharmacokinet Pharmacodyn. 2016; 43: 411-425
        • Talukdar S.
        • et al.
        A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human Primates and type 2 diabetic subjects.
        Cell Metab. 2016; 23: 427-440
        • Gaich G.
        • et al.
        The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes.
        Cell Metab. 2013; 18: 333-340
        • Imran M.
        • Najmi A.K.
        • Tabrez S.
        Mirabegron for overactive bladder: a novel, first-in-class beta3-agonist therapy.
        Urol J. 2013; 10: 935-940
        • Iwen K.A.
        • et al.
        Cold-induced Brown adipose tissue activity alters plasma fatty acids and improves glucose metabolism in men.
        J Clin Endocrinol Metab. 2017; 102: 4226-4234
        • Poekes L.
        • Lanthier N.
        • Leclercq I.A.
        Brown adipose tissue: a potential target in the fight against obesity and the metabolic syndrome.
        Clin Sci (Lond). 2015; 129: 933-949
        • Din M U.
        • et al.
        Postprandial oxidative metabolism of human brown fat indicates thermogenesis.
        Cell Metab. 2018; 28 ([e3]): 207-216
        • Cypess A.M.
        • et al.
        Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist.
        Cell Metab. 2015; 21: 33-38
        • Richard J.E.
        • et al.
        CNS beta3-adrenergic receptor activation regulates feeding behavior, white fat browning, and body weight.
        Am J Physiol Endocrinol Metab. 2017; 313: E344-E358
        • Marlatt K.L.
        • Chen K.Y.
        • Ravussin E.
        Is activation of human brown adipose tissue a viable target for weight management?.
        Am J Physiol Regul Integr Comp Physiol. 2018; 315: R479-R483
        • Azegami T.
        • et al.
        Nanogel-based nasal ghrelin vaccine prevents obesity.
        Mucosal Immunol. 2017; 10: 1351-1360
        • Walters W.A.
        • Xu Z.
        • Knight R.
        Meta-analyses of human gut microbes associated with obesity and IBD.
        FEBS Lett. 2014; 588: 4223-4233
        • Huo L.
        • Lyons J.
        • Magliano D.J.
        Infectious and environmental influences on the obesity epidemic.
        Curr Obes Rep. 2016; 5: 375-382
        • Coulter A.A.
        • Rebello C.J.
        • Greenway F.L.
        Centrally acting agents for obesity: past, present, and future.
        Drugs. 2018; 78: 1113-1132
        • Gadde K.M.
        • et al.
        Obesity: pathophysiology and management.
        J Am Coll Cardiol. 2018; 71: 69-84
        • Fruhbeck G.
        • et al.
        Novel protective role of kallistatin in obesity by limiting adipose tissue low grade inflammation and oxidative stress.
        Metabolism. 2018; 87: 123-135
        • Sumithran P.
        • et al.
        Long-term persistence of hormonal adaptations to weight loss.
        N Engl J Med. 2011; 365: 1597-1604
      4. Obesity (Silver Spring). 2014; 22: 5-13
        • Zhang Y.
        • et al.
        Nanomedicine for obesity treatment.
        Sci China Life Sci. 2018; 61: 373-379
        • Xanthopoulos M.S.
        • Berkowitz R.I.
        • Tapia I.E.
        Effects of obesity therapies on sleep disorders.
        Metabolism. 2018; 84: 109-117
        • Kang J.H.
        • Le Q.A.
        Effectiveness of bariatric surgical procedures: a systematic review and network meta-analysis of randomized controlled trials.
        Medicine (Baltimore). 2017; 96e8632
        • Polyzos S.A.
        • et al.
        Nonalcoholic fatty liver disease: is it time for combination treatment and a diabetes-like approach?.
        Hepatology. 2018; 68: 389
        • Abbasi J.
        Oral GLP-1 analog for type 2 diabetes on the horizon.
        JAMA. 2018; 320: 539