Future directions in obesity pharmacotherapy

  • Nick Finer
    Corresponding author: Global Medical Affairs Management – VTC3, Novo Nordisk A/S, Vandtårnsvej, 114 DK-2860, Søborg, Denmark
    Hon. Clinical Professor National Centre for Cardiovascular Prevention and Outcomes, UCL Institute of Cardiovascular Science, Nomura House, 1 St Martin's le Grand, London EC1A 4NP, UK
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      • Obesity pharmacotherapy is needed to meet clinical needs currently unmet
      • Existing anti-obesity medications do not meet double-digit weight loss that is often required especially in those with severe obesity
      • Many new druggable targets have been identified as knowledge on body weight control increases
      • GLP-1 and GLP-1/GIP compounds offer weight losses ≥ 15% and are well advanced in clinical trials
      • Regulatory approval pathways need updating to meet current concepts of obesity as a chronic disease
      • Treatment guidelines will need to evolve as more anti-obesity medications become available


      There is a growing unmet need for more effective treatment of obesity and its complications. While current anti-obesity medications are effective and offer real clinical benefits over diet and lifestyle interventions, they cannot meet the levels of efficacy and reduction of hard endpoint outcomes seen with bariatric surgery. As knowledge on the control of body weight unravels, the complexity of this physiology opens the opportunity to new druggable targets. Currently, gut peptide analogues such as semaglutide, a glucagon like peptide-1 (GLP-1) receptor agonist, and the dual agonist GLP-1 and gastric inhibitory polypeptide (GIP) tirzepatide are the furthest advanced in clinical development and seem likely to meet current regulatory requirements within the next year or so. However, current regulatory requirements are out of step with the efficacy of new compounds and concepts relating to obesity and its complications. Many other drugs in early development will target different pathways of energy balance, raising the possibility of drug combinations to maximise efficacy as for other chronic disease such as hypertension and diabetes. This will allow more complex and personalised guidelines to evolve.


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        • Fildes A
        • Charlton J
        • Rudisill C
        • Littlejohns P
        • Prevost AT
        • Gulliford MC.
        Probability of an Obese Person Attaining Normal Body Weight: Cohort Study Using Electronic Health Records.
        Am J Public Health. 2015; 105: e54-e59
        • Sharma S
        • Wharton S
        • Forhan M
        • Kuk JL.
        Influence of weight discrimination on weight loss goals and self-selected weight loss interventions.
        Clin Obes. 2011; 1: 153-160
        • Heo KS
        • Fujiwara K
        • Abe J.
        Glucagon-like peptide-1 and its cardiovascular effects.
        Curr Atheroscler Rep. 2012; 14: 422-428
        • Knudsen LB
        • Lau J.
        The Discovery and Development of Liraglutide and Semaglutide.
        Front Endocrinol (Lausanne). 2019; 10: 155
        • Carbone LJ
        • Angus PW
        • Yeomans ND.
        Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis.
        J Gastroenterol Hepatol. 2016; 31: 23-31
        • Lv X
        • Dong Y
        • Hu L
        • Lu F
        • Zhou C
        • Qin S.
        Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): A systematic review.
        Endocrinol Diabetes Metab. 2020; 3 (e00163)
        • Erbil D
        • Eren CY
        • Demirel C
        • Kucuker MU
        • Solaroglu I
        • Eser HY.
        GLP-1′s role in neuroprotection: a systematic review.
        Brain Inj. 2019; 33: 734-819
        • Saxon DR
        • Rasouli N
        • Eckel RH.
        Pharmacological Prevention of Cardiovascular Outcomes in Diabetes Mellitus: Established and Emerging Agents.
        Drugs. 2018; 78: 203-214
        • Reimer KC
        • Wree A
        • Roderburg C
        • Tacke F.
        New drugs for NAFLD: lessons from basic models to the clinic.
        Hepatol Int. 2020; 14: 8-23
        • Htike ZZ
        • Zaccardi F
        • Papamargaritis D
        • Webb DR
        • Khunti K
        • Davies MJ.
        Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis.
        Diabetes Obes Metab. 2017; 19: 524-536
        • Lin CH
        • Shao L
        • Zhang YM
        • Tu YJ
        • Zhang Y
        • Tomlinson B
        • et al.
        An evaluation of liraglutide including its efficacy and safety for the treatment of obesity.
        Expert Opin Pharmacother. 2020; 21: 275-285
        • Lau J
        • Bloch P
        • Schaffer L
        • Pettersson I
        • Spetzler J
        • Kofoed J
        • et al.
        Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.
        J Med Chem. 2015; 58: 7370-7380
        • Blundell J
        • Finlayson G
        • Axelsen M
        • Flint A
        • Gibbons C
        • Kvist T
        • 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
        • Gabery S
        • Salinas CG
        • Paulsen SJ
        • Ahnfelt-Ronne J
        • Alanentalo T
        • Baquero AF
        • et al.
        Semaglutide lowers body weight in rodents via distributed neural pathways.
        JCI Insight. 2020; 5
        • Aroda VR
        • Ahmann A
        • Cariou B
        • Chow F
        • Davies MJ
        • Jodar E
        • et al.
        Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1-7 trials.
        Diabetes Metab. 2019; 45: 409-418
        • Thethi TK
        • Pratley R
        • Meier JJ.
        Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme.
        Diabetes Obes Metab. 2020; 22: 1263-1277
        • Kushner RF
        • Calanna S
        • Davies M
        • Dicker D
        • Garvey WT
        • Goldman B
        • et al.
        Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5.
        Obesity (Silver Spring). 2020; 28: 1050-1061
        • O'Neil PM
        • Birkenfeld AL
        • McGowan B
        • Mosenzon O
        • Pedersen SD
        • Wharton S
        • 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.
        The Lancet. 2018; 392: 637-649
        • Wilding JPH
        • Batterham RL
        • Calanna S
        • Davies M
        • Van Gaal LF
        • Lingvay I
        • et al.
        Once-Weekly Semaglutide in Adults with Overweight or Obesity.
        N Engl J Med. 2021; 384: 989
        • Wadden TA
        • Bailey TS
        • Billings LK
        • Davies M
        • Frias JP
        • Koroleva A
        • et al.
        Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial.
        JAMA. 2021;
        • Rubino D
        • Abrahamsson N
        • Davies M
        • Hesse D
        • Greenway FL
        • Jensen C
        • et al.
        Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.
        JAMA. 2021;
        • Davies M
        • Faerch L
        • Jeppesen OK
        • Pakseresht A
        • Pedersen SD
        • Perreault L
        • et al.
        Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial.
        Lancet. 2021; 397: 971-984
        • Ryan DH
        • Lingvay I
        • Colhoun HM
        • Deanfield J
        • Emerson SS
        • Kahn SE
        • et al.
        Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design.
        Am Heart J. 2020; 229: 61-69
        • Sonne N
        • Karsdal MA
        • Henriksen K.
        Mono and dual agonists of the amylin, calcitonin, and CGRP receptors and their potential in metabolic diseases.
        Molecular Metabolism. 2020; 101109
        • Hay DL
        • Chen S
        • Lutz TA
        • Parkes DG
        • Roth JD.
        Amylin: Pharmacology, Physiology, and Clinical Potential.
        Pharmacol Rev. 2015; 67: 564-600
        • Boyle CN
        • Lutz TA
        • 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
        • Lutz TA
        • Del Prete E
        • Scharrer E.
        Reduction of food intake in rats by intraperitoneal injection of low doses of amylin.
        Physiol Behav. 1994; 55: 891-895
        • Dunican KC
        • Adams NM
        • Desilets AR.
        The role of pramlintide for weight loss.
        Ann Pharmacother. 2010; 44: 538-545
        • Lau DCW
        • McFarlane J
        • Erichsen L
        • Francisco AM
        • le Roux CW
        • McGowan B
        • et al.
        Efficacy and Safety of AM833 for Weight Loss: A Dose-finding Trial in Adults With Overweight/Obesity.
        Obesity Week; On line. 2020; (Line)
        • Astrup A
        • Madsbad S
        • Breum L
        • Jensen TJ
        • Kroustrup JP
        • Larsen TM.
        Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.
        The Lancet. 2008; 372: 1906-1913
        • The Lancet Editors
        Expression of concern—Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.
        The Lancet. 2013; 381: 1167
      1. Saniona. Accessed 6/4/21.

      2. Wexler M. Accessed 10/4/2021.

      3. Novo Nordisk. Accessed 1/11/2020.

        • Baggio LL
        • Drucker DJ.
        Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease.
        Molecular Metabolism. 2020; 101090
        • Willard FS
        • Douros JD
        • Gabe MB
        • Showalter AD
        • Wainscott DB
        • Suter TM
        • et al.
        Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.
        JCI Insight. 2020; 5
        • Frias JP
        • Nauck MA
        • Van J
        • Kutner ME
        • Cui X
        • Benson C
        • et al.
        Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial.
        The Lancet. 2018; 392: 2180-2193
      4. Eli Lilly and Company. Accessed 6/4/21.

        • Bagger JI
        • Holst JJ
        • Hartmann B
        • Andersen B
        • Knop FK
        • Vilsboll T.
        Effect of Oxyntomodulin, Glucagon, GLP-1, and Combined Glucagon +GLP-1 Infusion on Food Intake, Appetite, and Resting Energy Expenditure.
        J Clin Endocrinol Metab. 2015; 100: 4541-4552
        • Brandt SJ
        • Gotz A
        • Tschop MH
        • Muller TD.
        Gut hormone polyagonists for the treatment of type 2 diabetes.
        Peptides. 2018; 100: 190-201
      5. Eli Lilly and Company. Accessed 6/4/21.

        • Gydesen S
        • Andreassen KV
        • Hjuler ST
        • Christensen JM
        • Karsdal MA
        • Henriksen K.
        KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight.
        Am J Physiol Endocrinol Metab. 2016; 310: E821-E827
        • Wells G
        • Chernoff J
        • Gilligan JP
        • Krause DS.
        Does salmon calcitonin cause cancer? A review and meta-analysis.
        Osteoporos Int. 2016; 27: 13-19
        • Karra E
        • Chandarana K
        • Batterham RL.
        The role of peptide YY in appetite regulation and obesity.
        J Physiol. 2009; 587: 19-25
        • Batterham RL
        • ffytche DH
        • Rosenthal JM
        • Zelaya FO
        • Barker GJ
        • Withers DJ
        • et al.
        PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans.
        Nature. 2007; 450: 106-109
        • Le Roux CW
        • Aylwin SJB
        • Batterham RL
        • Borg CM
        • Coyle F
        • Prasad V
        • et al.
        Gut Hormone Profiles Following Bariatric Surgery Favor an Anorectic State, Facilitate Weight Loss, and Improve Metabolic Parameters.
        Ann Surg. 2006; 243: 108-114
        • Pucci A
        • Cheung WH
        • Jones J
        • Kingett H
        • Doyle J
        • Adamo M
        • et al.
        A case of anorexia with extreme weight loss after a sleeve gastrectomy due to excessive PYY secretion. Improvement of symptoms with octreotide therapy.
        British Journal of Surgery. 2015; 102: 12-13
        • Tsai VWW
        • Husaini Y
        • Sainsbury A
        • Brown DA
        • Breit SN.
        The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases.
        Cell Metab. 2018; 28: 353-368
        • Villanueva MT.
        Obesity: GDF15 tells the brain to lose weight.
        Nat Rev Drug Discov. 2017; 16: 827
        • Tsai VW
        • Macia L
        • Feinle-Bisset C
        • Manandhar R
        • Astrup A
        • Raben A
        • et al.
        Serum Levels of Human MIC-1/GDF15 Vary in a Diurnal Pattern, Do Not Display a Profile Suggestive of a Satiety Factor and Are Related to BMI.
        PLoS One. 2015; 10 (e0133362)
        • Ouyang J
        • Isnard S
        • Lin J
        • Fombuena B
        • Peng X
        • Chen Y
        • et al.
        GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin.
        Front Endocrinol (Lausanne). 2020; : 11
        • Dushay J
        • Chui PC
        • Gopalakrishnan GS
        • Varela-Rey M
        • Crawley M
        • Fisher FM
        • et al.
        Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease.
        Gastroenterology. 2010; 139: 456-463
        • Liu X
        • Zhang P
        • Martin RC
        • Cui G
        • Wang G
        • Tan Y
        • et al.
        Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice.
        Am J Cancer Res. 2016; 6: 1011-1025
        • Ritchie M
        • Hanouneh IA
        • Noureddin M
        • Rolph T
        • Alkhouri N.
        Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)?.
        Expert Opin Investig Drugs. 2020; 29: 197-204
        • Yashiro H
        • Hamagami K
        • Hiyoshi H
        • Sugama J
        • Tsuchimori K
        • Yamaguchi F
        • et al.
        SCO-792, an enteropeptidase inhibitor, improves disease status of diabetes and obesity in mice.
        Diabetes, Obesity and Metabolism. 2019; 21: 2228-2239
        • Colman E.
        Food and Drug Administration's Obesity Drug Guidance Document: a short history.
        Circulation. 2012; 125: 2156-2164
        • European Medicines Agency
        Guideline on clinical evaluation of medicinal products used in weight managment.
        European Medicines Agency, London, UK2016: 2-10
        • Garber AJ.
        Treat-to-target trials: uses, interpretation and review of concepts.
        Diabetes Obes Metab. 2014; 16: 193-205
      6. US Food and Drugs Administration. ICH HARMONISED GUIDELINE. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials. In: USE ICFHOTRFPFH, editor. USA2017.

      7. European Medicines Agency. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials. In: Committee for Human Mediciinal Products, editor. London, UK2017.

        • Wharton S
        • Astrup A
        • Endahl L
        • Lean MEJ
        • Satylganova A
        • Skovgaard D
        • et al.
        Estimating and interpreting treatment effects in clinical trials for weight management: implications of estimands, intercurrent events and missing data.
        International Journal of Obesity. 2020; (in press)
        • Finer N
        • Ryan DH
        • Renz CL
        • Hewkin AC.
        Prediction of response to sibutramine therapy in obese non-diabetic and diabetic patients.
        Diabetes Obes Metab. 2006; 8: 206-213
        • Hamer M
        • O'Donovan G.
        Sarcopenic obesity, weight loss, and mortality: the English Longitudinal Study of Ageing.
        Am J Clin Nutr. 2017; 106: 125-129
        • Cruz-Jentoft AJ
        • Bahat G
        • Bauer J
        • Boirie Y
        • Bruyere O
        • Cederholm T
        • et al.
        Sarcopenia: revised European consensus on definition and diagnosis.
        Age Ageing. 2019; 48: 16-31
        • Kalarchian MA
        • Marcus MD.
        Psychosocial Concerns Following Bariatric Surgery: Current Status.
        Curr Obes Rep. 2019; 8: 1-9
        • Singh AK
        • Singh R.
        Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs.
        Expert Rev Clin Pharmacol. 2020; 13: 53-64
        • Specialised Commissioning Team
        Clinical Commissioning Policy: Metreleptin for congenital leptin deficiency (all ages).
        London: NHS England;. 2018; : 1-15