Advertisement
Editorial| Volume 142, 155531, May 2023

Advances in physiology, design and development of novel medications changing the landscape of obesity pharmacotherapy

      As the word has been celebrating innovations and technological achievements during the last few decades, there has also been a noticeable increase in various non-communicable diseases, attributed, at least in part, to modernization and globalization [
      How some effects of modernization fuel non-communicable diseases in Africa.
      ,
      • Fox A.
      • Feng W.
      • Asal V.
      What is driving global obesity trends? Globalization or "modernization"?.
      ]. In an era of increased sedentary lifestyle and unhealthy diet, obesity has been spreading steadily [
      Prevalence of obesity | World Obesity Federation.
      ]. Initially, this modern era pandemic of metabolic diseases due to obesity remained, and to a large extent still remains, largely overlooked, due to the slower pace and longer periods needed for the development of comorbidities [
      • Alford S.
      • Patel D.
      • Perakakis N.
      • Mantzoros C.S.
      Obesity as a risk factor for Alzheimer's disease: weighing the evidence: obesity as a risk factor for Alzheimer's disease.
      ,
      • Pedersen S.D.
      Metabolic complications of obesity.
      ], as compared for example to COVID-19, Ebola, influenza and other epidemics of communicable diseases [
      The Lancet Gastroenterology H
      Obesity: another ongoing pandemic.
      ]. Overweight and obesity affect one third to two thirds of children and adults in the US, Europe and other regions [
      Organization WHO
      WHO European regional obesity report 2022.
      , ], and the numbers are still rising. Approximately 80 % of patients with excess weight have metabolically unhealthy obesity, and the numbers of those afflicted by obesity induced comorbidities are definitively higher if one also considers individuals who have a normal body mass index (BMI), but central distribution of fat and an unhealthy metabolic profile, and thus are at a high risk of complications [
      • Raji A.
      • Gerhard-Herman M.D.
      • Warren M.
      • Silverman S.G.
      • Raptopoulos V.
      • Mantzoros C.S.
      • et al.
      Insulin resistance and vascular dysfunction in nondiabetic Asian Indians.
      ,
      • Mathew H.
      • Farr O.M.
      • Mantzoros C.S.
      Metabolic health and weight: understanding metabolically unhealthy normal weight or metabolically healthy obese patients.
      ]. This is the time to act to address the obesity epidemic by preventing and/or treating excess weight, and thus reducing the associated morbidity and mortality [
      • Ryan D.H.
      • Yockey S.R.
      Weight loss and improvement in comorbidity: differences at 5%, 10%, 15%, and over.
      ].

      Abbreviations:

      Food and Drug Administration (FDA), Tirzepatide (TZP), Glucose-dependent insulinotropic polypeptide (GIP), Glucagon-like peptide 1 (GLP-1), Type 2 diabetes mellitus (T2D), Hemoglobin A1c (HbA1c), Body mass index (BMI), Sodium-glucose Cotransporter-2 (SGLT2)

      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

      1. How some effects of modernization fuel non-communicable diseases in Africa.
        (Available from) ([accessed February 2023])
        • Fox A.
        • Feng W.
        • Asal V.
        What is driving global obesity trends? Globalization or "modernization"?.
        Glob Health. 2019; 15: 32
      2. Prevalence of obesity | World Obesity Federation.
        (Available from) ([accessed February 2023])
        • Alford S.
        • Patel D.
        • Perakakis N.
        • Mantzoros C.S.
        Obesity as a risk factor for Alzheimer's disease: weighing the evidence: obesity as a risk factor for Alzheimer's disease.
        Obes Rev. 2018; 19: 269-280
        • Pedersen S.D.
        Metabolic complications of obesity.
        Best Pract Res Clin Endocrinol Metab. 2013; 27: 179-193
        • The Lancet Gastroenterology H
        Obesity: another ongoing pandemic.
        J Gastroenterol Hepatol. 2021; 6: 411
        • Organization WHO
        WHO European regional obesity report 2022.
        World Health Organization. Regional Office for Europe, 2022
      3. WHO report highlights the dangers of obesity.
        (Available from) ([accessed February 2023])
        • Raji A.
        • Gerhard-Herman M.D.
        • Warren M.
        • Silverman S.G.
        • Raptopoulos V.
        • Mantzoros C.S.
        • et al.
        Insulin resistance and vascular dysfunction in nondiabetic Asian Indians.
        J Clin Endocrinol Metab. 2004; 89: 3965-3972
        • Mathew H.
        • Farr O.M.
        • Mantzoros C.S.
        Metabolic health and weight: understanding metabolically unhealthy normal weight or metabolically healthy obese patients.
        Metab Clin Exp. 2016; 65: 73-80
        • Ryan D.H.
        • Yockey S.R.
        Weight loss and improvement in comorbidity: differences at 5%, 10%, 15%, and over.
        Curr Obes Rep. 2017; 6: 187-194
        • Angelidi A.M.
        • Belanger M.J.
        • Kokkinos A.
        • Koliaki C.C.
        • Mantzoros C.S.
        Novel noninvasive approaches to the treatment of obesity: from pharmacotherapy to gene therapy.
        Endocr Rev. 2022; 43: 507-557
        • Chakhtoura M.
        • El Haber R.
        • Ghezzawi M.
        • Rhayem C.
        • Tcheroyan R.
        • Mantzoros C.
        Pharmacotherapy of obesity: an update on the available medications and drugs under investigation.
        eClinicalMedicine. 2023; (Accepted)
        • Zhang Y.
        • Proenca R.
        • Maffel M.
        • Barone M.
        • Leopold L.
        • Friedman J.M.
        Positional cloning of the mouse obese gene and its human homologue.
        Nature. 1994; 372 (London): 425-432
        • Mantzoros C.S.
        • Magkos F.
        • Brinkoetter M.
        • Sienkiewicz E.
        • Dardeno T.A.
        • Kim S.-Y.
        • et al.
        Leptin in human physiology and pathophysiology.
        Am J Physiol Endocrinol. 2011; 301: E567-E584
        • Dardeno T.A.
        • Chou S.H.
        • Moon H.-S.
        • Chamberland J.P.
        • Fiorenza C.G.
        • Mantzoros C.S.
        Leptin in human physiology and therapeutics.
        Front Neuroendocrinol. 2010; 31: 377-393
        • Mantzoros C.S.
        The role of leptin in human obesity and disease: a review of current evidence.
        Ann Intern Med. 1999; 130: 671-680
        • Chan J.L.
        • Heist K.
        • DePaoli A.M.
        • Veldhuis J.D.
        • Mantzoros C.S.
        The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men.
        J Clin Investig. 2003; 111: 1409-1421
        • Kelesidis T.
        • Kelesidis I.
        • Chou S.
        • Mantzoros C.S.
        Narrative review: the role of leptin in human physiology: emerging clinical applications.
        Ann Intern Med. 2010; 152: 93-100
        • Le Roux C.W.
        • Vincent R.P.
        • Ashrafian H.
        Mechanisms of disease: the role of gastrointestinal hormones in appetite and obesity.
        Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 268-277
        • Camilleri M.
        Peripheral mechanisms in appetite regulation.
        Gastroenterology. 2015; 148 (New York, NY 1943): 1219-1233
        • Kokkinos A.
        • Tsilingiris D.
        • le Roux C.W.
        • Rubino F.
        • Mantzoros C.S.
        Will medications that mimic gut hormones or target their receptors eventually replace bariatric surgery?.
        Metab Clin Exp. 2019; 100153960
        • Chan J.L.
        • Mun E.C.
        • Stoyneva V.
        • Mantzoros C.S.
        • Goldfine A.B.
        Peptide YY levels are elevated after gastric bypass surgery.
        Obesity. 2006; 14 (Silver Spring, Md): 194-198
        • Farhadipour M.
        • Depoortere I.
        The function of gastrointestinal hormones in obesity—implications for the regulation of energy intake.
        Nutrients. 2021; 13: 1839
        • Holscher C.
        Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models.
        Neuropharmacology. 2018; 136: 251-259
        • Chowdhury S.
        • Goswami S.
        GLP1 agonists beyond glycemic control—redefining their role.
        Int J Diabetes Dev Ctries. 2020; 40: 461-463
        • Perakakis N.
        • Farr O.M.
        • Mantzoros C.S.
        Leptin in leanness and obesity: JACC state-of-the-art review.
        J Clin Investig. 2021; 77: 745-760
        • Rodgers R.J.
        • Tschöp M.H.
        • Wilding J.P.H.
        Anti-obesity drugs: past, present and future.
        Dis Model Mech. 2012; 5: 621-626
        • Colman E.
        Food and drug administration's obesity drug guidance document a short history.
        Circulation. 2012; 125 (New York, NY): 2156-2164
        • Apovian C.M.
        • Aronne L.J.
        • Bessesen D.H.
        • McDonnell M.E.
        • Murad M.H.
        • Pagotto U.
        • et al.
        Pharmacological management of obesity: an endocrine society clinical practice guideline.
        J Clin Endocrinol Metab. 2015; 100: 342-362
        • Wilding J.P.H.
        • Batterham R.L.
        • Calanna S.
        • Davies M.
        • Van Gaal L.F.
        • Lingvay I.
        • et al.
        Once-weekly semaglutide in adults with overweight or obesity.
        N Engl J Med. 2021; 384: 989-1002
        • Garvey W.T.
        • Mechanick J.I.
        • Brett E.M.
        • Garber A.J.
        • Hurley D.L.
        • Jastreboff A.M.
        • et al.
        American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity.
        Endocr Pract. 2016; 22: 1-203
        • Enright C.
        • Thomas E.
        • Saxon D.R.
        An updated approach to antiobesity pharmacotherapy: moving beyond the 5% weight loss goal.
        JES. 2023; 7bvac195
        • Gregg E.
        • Jakicic J.
        • Blackburn G.
        • Bloomquist P.
        • Bray G.
        • Clark J.
        • et al.
        Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial.
        Lancet Diabetes Endocrinol. 2016; 4: 913-921
        • Yeh H.C.
        • Bantle J.P.
        • Cassidy-Begay M.
        • Blackburn G.
        • Bray G.A.
        • Byers T.
        • et al.
        Intensive weight loss intervention and cancer risk in adults with type 2 diabetes: analysis of the look AHEAD randomized clinical trial.
        Obesity. 2020; 28 (Silver Spring, Md): 1678-1686
        • Stroud A.M.
        • Dewey E.N.
        • Husain F.A.
        • Fischer J.M.
        • Courcoulas A.P.
        • Flum D.R.
        • et al.
        Association between weight loss and serum biomarkers with risk of incident cancer in the longitudinal assessment of bariatric surgery cohort.
        Surg Obes Relat Dis. 2020; 16: 1086-1094
        • Bass J.
        • Tschöp M.H.
        • Beutler L.R.
        Dual gut hormone receptor agonists for diabetes and obesity.
        J Clin Invest. 2023; 133
        • Sun B.
        • Willard F.S.
        • Feng D.
        • Alsina-Fernandez J.
        • Chen Q.
        • Vieth M.
        • et al.
        Structural determinants of dual incretin receptor agonism by tirzepatide.
        Proc Natl Acad Sci. 2022; 119e2116506119-e
        • Nauck M.
        • D'Allesio D.
        Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading gylcaemic control and body weight reduction.
        Cardiovasc Diabetol. 2022; 21: 169
      4. Mounjaro™ (tirzepatide) injection.
        (Available from) ([accessed February 2023])
        • Samms R.J.
        • Coghlan M.P.
        • Sloop K.W.
        How may GIP enhance the therapeutic efficacy of GLP-1?.
        Trends Endocrinol Metab. 2020; 31: 410-421
        • McIntosh C.H.S.
        • Widenmaier S.
        • Kim S.J.
        Chapter 15 glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP).
        in: Vitam Horm. 80. Elsevier Science & Technology, 2009: 409-471
        • Thondam S.K.
        • Cuthbertson D.J.
        • Wilding J.P.H.
        The influence of Glucose-dependent Insulinotropic Polypeptide (GIP) on human adipose tissue and fat metabolism: implications for obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).
        Peptides. 2020; 125 (New York, NY:1980)170208
        • Baggio L.L.
        • Drucker D.J.
        Biology of incretins: GLP-1 and GIP.
        Gastroenterology. 2007; 132 (New York, NY 1943): 2131-2157
        • Farr O.M.
        • Tsoukas M.A.
        • Triantafyllou G.
        • Dincer F.
        • Filippaios A.
        • Ko B.-J.
        • 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.
        Metab Clin Exp. 2016; 65: 945-953
        • Farr O.M.
        • Upadhyay J.J.
        • Rutagengwa C.C.
        • DiPrisco B.B.
        • Ranta Z.Z.
        • Adra A.A.
        • et al.
        Longer-term liraglutide administration at the highest dose approved for obesity increases reward-related orbitofrontal cortex activations to food cues: implications for plateauing weight loss in response to anti-obesity therapies.
        Diabetes Obes Metab. 2019; 21: 2459-2464
        • Farr O.M.
        • Sofopoulos M.
        • Tsoukas M.A.
        • Dincer F.
        • Thakkar B.
        • Sahin-Efe A.
        • 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
        • Gabery S.
        • Salinas C.G.
        • Paulsen S.J.
        • Ahnfelt-Rønne J.
        • Alanentalo T.
        • Baquero A.F.
        • et al.
        Semaglutide lowers body weight in rodents via distributed neural pathways.
        JCI Insight. 2020; 5
        • Daousi C.
        • Wilding J.P.H.
        • Aditya S.
        • Durham B.H.
        • Cleator J.
        • Pinkney J.H.
        • et al.
        Effects of peripheral administration of synthetic human glucose-dependent insulinotropic peptide (GIP) on energy expenditure and subjective appetite sensations in healthy normal weight subjects and obese patients with type 2 diabetes.
        Clin Endocrinol (Oxf). 2009; 71: 195-201
        • Bergmann N.C.
        • Lund A.
        • Gasbjerg LrS
        • Meessen E.C.E.
        • Andersen M.M.
        • Bergmann S.
        • et al.
        Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study.
        Diabetologia. 2019; 62: 665-675
        • Rosenstock J.
        • Wysham C.
        • Frías J.P.
        • Kaneko S.
        • Lee C.J.
        • Fernández Landó L.
        • et al.
        Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial.
        Lancet. 2021; 398 (British edition): 143-155
        • Frías J.P.
        • Davies M.J.
        • Rosenstock J.
        • Pérez Manghi F.C.
        • Fernández Landó L.
        • Bergman B.K.
        • et al.
        Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes.
        N Engl J Med. 2021; 385: 503-515
        • Ludvik B.
        • Giorgino F.
        • Jódar E.
        • Frias J.P.
        • Fernández Landó L.
        • Brown K.
        • et al.
        Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial.
        Lancet. 2021; 398 (British edition): 583-598
        • Del Prato S.
        • Pavo I.
        • Weerakkody G.J.
        • Yang Z.
        • Aizenberg D.
        • Wynne A.G.
        • et al.
        Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.
        Lancet. 2021; 398 (British edition): 1811-1824
        • Dahl D.
        • Onishi Y.
        • Norwood P.
        • Huh R.
        • Bray R.
        • Patel H.
        • et al.
        Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial.
        JAMA. 2022; 327: 534-545
        • Permana H.
        • Yanto T.A.
        • Hariyanto T.I.
        Efficacy and safety of tirzepatide as novel treatment for type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials.
        Diabetes Metab Syndr Clin Res Rev. 2022; 16102640
        • Jastreboff A.M.
        • Aronne L.J.
        • Ahmad N.N.
        • Wharton S.
        • Connery L.
        • Alves B.
        • Kiyosue A.
        • Zhang S.
        • Liu B.
        • Bunck M.C.
        • Stefanski A.
        SURMOUNT-1 investigators. Tirzepatide once weekly for the treatment of obesity.
        N Engl J Med. 2022; 387: 205-216
        • van Rijswijk A.N.
        • van Olst N.
        • Schats W.
        • van der Peet D.
        • van de Laar A.
        What is weight loss after bariatric surgery expressed in percentage total weight loss (%TWL)?A systematic review.
        Obes Surg. 2021; 31: 3833-3847
      5. FDA grants fast track designation to Tirzepatide for obesity, associated comorbidities pharmacy times.
        (Available from) ([accessed February 2023])
        • Gastaldelli A.
        • Cusi K.
        • Fernández Landó L.
        • Bray R.
        • Brouwers B.
        • Rodríguez A.
        Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial.
        Lancet Diabetes Endocrinol. 2022; 10: 393-406
        • Lilly E Companycollab
        A study of tirzepatide (LY3298176) on the reduction on morbidity and mortality in adults with obesity.
        (Available from) ([accessed February 2023])
      6. A study of tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes (SURPASS-CVOT).
        • Sattar N.
        • McGuire D.K.
        • Pavo I.
        • Weerakkody G.J.
        • Nishiyama H.
        • Wiese R.J.
        • et al.
        Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis.
        Nat Med. 2022; 28: 591-598
        • Patoulias D.
        • Papadopoulos C.
        • Fragakis N.
        • Doumas M.
        Updated meta-analysis assessing the cardiovascular efficacy of tirzepatide.
        Am J Card. 2022; 181: 139-140
        • Mishra R.
        • Raj R.
        • Elshimy G.
        • Zapata I.
        • Kannan L.
        • Majety P.
        • et al.
        Adverse events related to tirzepatide.
        J Endocr Soc. 2023; https://doi.org/10.1210/jendso/bvad016
        • Alkhezi O.S.
        • Alahmed A.A.
        • Alfayez O.M.
        • Alzuman O.A.
        • Almutairi A.R.
        • Almohammed O.A.
        Comparative effectiveness of glucagon-like peptide-1 receptor agonists for the management of obesity in adults without diabetes: a network meta-analysis of randomized clinical trials.
        Obes Rev. 2022; e13543-e
        • Gorgojo-Martínez J.J.
        • Mezquita-Raya P.
        • Carretero-Gómez J.
        • Castro A.
        • Cebrián-Cuenca A.
        • de Torres-Sánchez A.
        • et al.
        Clinical recommendations to manage gastrointestinal adverse events in patients treated with GLP-1 receptor agonists: a multidisciplinary expert consensus.
        J Clin Med. 2022; 12: 145
        • Wharton S.
        • Davies M.
        • Dicker D.
        • Lingvay I.
        • Mosenzon O.
        • Rubino D.M.
        • et al.
        Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice.
        Postgrad Med. 2022; 134: 14-19
        • Roux C.W.
        • Zhang S.
        • Aronne L.J.
        • Kushner R.F.
        • Chao A.M.
        • Machineni S.
        • et al.
        Tirzepatide for the treatment of obesity: rationale and design of the SURMOUNT clinical development program.
        Obesity. 2023; 31 (Silver Spring, Md): 96-110
        • Müller T.D.
        • Blüher M.
        • Tschöp M.H.
        • DiMarchi R.D.
        Anti-obesity drug discovery: advances and challenges.
        Nat Rev Drug Discov. 2022; 21: 201-223
        • Jimenez-Munoz C.M.
        • López M.
        • Albericio F.
        • Makowski K.
        Targeting energy expenditure—drugs for obesity treatment.
        Pharmaceuticals. 2021; 14 (Basel, Switzerland): 435
        • Lilly E Companycollab
        A study of tirzepatide (LY3298176) in participants with obesity or overweight.
        ([accessed February 2023])
        • Meier J.J.
        Efficacy of semaglutide in a subcutaneous and an oral formulation.
        Front Endocrinol. 2021; 12 (Lausanne)645617
        • Nordisk N.
        Research study to investigate how well Semaglutide tablets taken once daily work in people who Are overweight or living with obesity (OASIS 1).
        (Available from) ([accessed February 2023])
        • Salas X.R.
        Closing obesity care gaps and achieving health equity for people living with obesity.
        Eur J Intern Med. 2021; 91: 1-2
        • Tsai A.G.
        • Histon T.
        • Kyle T.K.
        • Rubenstein N.
        • Donahoo W.T.
        Evidence of a gap in understanding obesity among physicians.
        Obes Sci Pract. 2018; 4: 46-51
        • Heymsfield S.
        • Aronne L.J.
        • Eneli I.
        • Kumar R.B.
        • Michalsky M.
        • Walker E.
        • et al.
        Clinical perspectives on obesity treatment: challenges, gaps, and promising opportunities.
        NAM Perspect. 2018; https://doi.org/10.31478/201809b