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Editorial| Volume 142, 155531, May 2023

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

      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

      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.
      ].
      Progress in our understanding of the underlying mechanisms and thus the development of appropriate preventive and therapeutic approaches for weight management has been slowly advancing over the past several decades [
      • 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.
      ]. We have long been suspecting that genetic predisposition interplays with lifestyle, especially lack of physical activity and unhealthy diet, to cause an imbalance of energy intake/consumption, and as a result an increasing amount of energy stored overtime as fat, leading to obesity [
      • 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.
      ,
      • 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.
      ]. The discovery of leptin, almost thirty years ago [
      • Zhang Y.
      • Proenca R.
      • Maffel M.
      • Barone M.
      • Leopold L.
      • Friedman J.M.
      Positional cloning of the mouse obese gene and its human homologue.
      ], opened the black box of molecules secreted by the adipose tissue, the gastrointestinal tract and other organs in the periphery, as well as the discovery of variants in several genes that predispose to obesity. These findings have altered our understanding and ostracized the prevailing idea that obesity is mainly the result of lack of will and self-control. Moreover, scientific innovations in the above fields leading to advancements in medicine appear to start offering tangible benefits by tackling the obesity challenge, much more effectively as time progresses, since novel discoveries and a more detailed understanding of the mechanisms that lead to obesity are being translated into new medications with increasing efficacy.
      Obesity pharmacotherapy started with the discovery of leptin and its role as a “thermostat” informing the brain of the amount of energy stored in the adipose tissue [
      • Zhang Y.
      • Proenca R.
      • Maffel M.
      • Barone M.
      • Leopold L.
      • Friedman J.M.
      Positional cloning of the mouse obese gene and its human homologue.
      ,
      • Mantzoros C.S.
      • Magkos F.
      • Brinkoetter M.
      • Sienkiewicz E.
      • Dardeno T.A.
      • Kim S.-Y.
      • et al.
      Leptin in human physiology and pathophysiology.
      ,
      • Dardeno T.A.
      • Chou S.H.
      • Moon H.-S.
      • Chamberland J.P.
      • Fiorenza C.G.
      • Mantzoros C.S.
      Leptin in human physiology and therapeutics.
      ,
      • Mantzoros C.S.
      The role of leptin in human obesity and disease: a review of current evidence.
      ,
      • 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.
      ,
      • Kelesidis T.
      • Kelesidis I.
      • Chou S.
      • Mantzoros C.S.
      Narrative review: the role of leptin in human physiology: emerging clinical applications.
      ]. Leptin has paved the way for the investigation, and thus the better understanding of the role of hormones secreted by peripheral organs, providing feedback to the brain, and therefore altering the activity of hunger and satiety centers that control food intake [
      • Le Roux C.W.
      • Vincent R.P.
      • Ashrafian H.
      Mechanisms of disease: the role of gastrointestinal hormones in appetite and obesity.
      ,
      • Camilleri M.
      Peripheral mechanisms in appetite regulation.
      ]. Among these molecules, central is the role of incretins - the gut hormones secreted in response to nutrient intake to regulate metabolism - not only in metabolizing food, but also in regulating the amount of food intake [
      • Le Roux C.W.
      • Vincent R.P.
      • Ashrafian H.
      Mechanisms of disease: the role of gastrointestinal hormones in appetite and obesity.
      ,
      • 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?.
      ,
      • Chan J.L.
      • Mun E.C.
      • Stoyneva V.
      • Mantzoros C.S.
      • Goldfine A.B.
      Peptide YY levels are elevated after gastric bypass surgery.
      ,
      • Farhadipour M.
      • Depoortere I.
      The function of gastrointestinal hormones in obesity—implications for the regulation of energy intake.
      ]. In the last few decades, gastro-intestinal hormones have been the focus of innovations in the field of diabetes and weight management, and more recently evidence has emerged on their potential role in neurologic, cardiovascular, renal, liver and metabolic disorders [
      • 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.
      ,
      • Holscher C.
      Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models.
      ,
      • Chowdhury S.
      • Goswami S.
      GLP1 agonists beyond glycemic control—redefining their role.
      ,
      • Perakakis N.
      • Farr O.M.
      • Mantzoros C.S.
      Leptin in leanness and obesity: JACC state-of-the-art review.
      ].
      The history of invention and commercialization of weight loss medications, unlike the history of development of medications for other disease states such as hypertension for example, has initially been marked by drug failures and withdrawals, mainly due to cardiac and psychiatric adverse effects [
      • Rodgers R.J.
      • Tschöp M.H.
      • Wilding J.P.H.
      Anti-obesity drugs: past, present and future.
      ]. Therefore, the Food and Drug Administration (FDA) issued a new guidance for the development of obesity drugs, emphasizing the importance of safety data for drug approval [
      • Colman E.
      Food and drug administration's obesity drug guidance document a short history.
      ]. The current FDA-approved weight reducing medications result in a significant weight loss of 6–10 %, in combination with lifestyle modifications [
      • 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.
      ]. Exceptionally, semaglutide results in a more significant weight loss reaching 15 % of baseline weight, when combined with behavioral and lifestyle modifications [
      • 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.
      ]. While various cardio-metabolic risk factors improve with a weight loss of at least 5 % [
      • 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.
      ], a 2–3 fold higher weight loss may be needed to alter hard outcomes including not only cardiovascular but also renal, liver, metabolic, neurological as well as malignancy outcomes [
      • Enright C.
      • Thomas E.
      • Saxon D.R.
      An updated approach to antiobesity pharmacotherapy: moving beyond the 5% weight loss goal.
      ]. A post-hoc 10-year follow up of the landmark Look AHEAD trial showed that a mean weight loss of 15 % during the first year was associated with a 21 % reduction in the risk of cardiovascular disease [
      • 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.
      ]. Weight loss to a similar extent may be needed to achieve a significant reduction in obesity-related cancers [
      • 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.
      ,
      • 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.
      ]. Fortunately, the landscape of obesity pharmacotherapy started moving into a new era with the discovery of Tirzepatide (TZP), the use of which in trials has resulted in an even more substantial weight reduction and improvement of diabetes which could hopefully lead to improved morbidity and survival of patients with obesity. We predict that, in the next few years, many more specific and safer drugs, leveraging this newfound knowledge of neuroendocrine mechanisms, will become available and will reduce excess body weight and the complications of metabolically unhealthy obesity even more significantly. We expect to see in the coming years unimolecular drugs, that will have the components and efficacy of three or more hormones in one, and which could act on several receptors involved in metabolic pathways to improve outcomes [
      • Bass J.
      • Tschöp M.H.
      • Beutler L.R.
      Dual gut hormone receptor agonists for diabetes and obesity.
      ].
      TZP is the first dual unimolecular agonist binding and activating two receptors i.e. the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). The molecule is characterized by an “imbalanced agonism”, with a high affinity to GIP receptors and a weak affinity to GLP-1 receptors which, in combination with the differential expression of the respective receptors, leads to a balanced final effect [
      • 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.
      ]. It has 39 amino acids, some of which are shared with GIP and/or GLP-1 and, others are unique [
      • 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.
      ] (Fig. 1). It is manufactured by Eli Lilly, and is administered as a weekly subcutaneous injection [
      • 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.
      , ]. In the gastro-intestinal tract, GIP and GLP-1 receptors exist on the pancreas, increasing nutrient-induced insulin secretion, while their effects on glucagon secretion is different and depends on the glycemic state [
      • Samms R.J.
      • Coghlan M.P.
      • Sloop K.W.
      How may GIP enhance the therapeutic efficacy of GLP-1?.
      ]. GLP-1 reduces gastric emptying, while GIP does not affect gastric motility, although it may reduce gastric secretions [
      • McIntosh C.H.S.
      • Widenmaier S.
      • Kim S.J.
      Chapter 15 glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP).
      ]. GIP may induce subcutaneous adipogenesis and may increase blood flow to adipose tissue, resulting in the expansion of the subcutaneous fat; it may thus affect the secretion and circulating levels of adipokines and pro-inflammatory cytokines [
      • 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).
      ]. GLP-1 reduces hunger and increases satiety by acting on the hypothalamus and the nucleus of the solitary tract, and by altering the neural activity in other areas of the central nervous system, including the reward system (putamen, insula, etc.), as well as to a lesser degree the executive function (orbitofrontal cortex), as shown in functional MRI studies in humans treated with liraglutide [
      • Baggio L.L.
      • Drucker D.J.
      Biology of incretins: GLP-1 and GIP.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ]. Conversely, the exact sites of any anorexigenic effect of GIP on the brain have not been yet confirmed in humans [
      • Samms R.J.
      • Coghlan M.P.
      • Sloop K.W.
      How may GIP enhance the therapeutic efficacy of GLP-1?.
      ,
      • 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.
      ,
      • 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.
      ], and related clinical studies are ongoing. It has been proposed that GIP seems to enhance the satiating effect of GLP1, directly or indirectly, by expanding the GLP1 tolerance window, through an anti-emetic effect in the brainstem [
      • Samms R.J.
      • Coghlan M.P.
      • Sloop K.W.
      How may GIP enhance the therapeutic efficacy of GLP-1?.
      ] (Fig. 1).
      Fig. 1
      Fig. 1Illustartion of the molecular structure of tirzepatide and mechanisms of action of dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1) agonists
      For Tirzepatide structure, circles represent amino acids (AA). The blue color represents AA homologous with GIP, the yellow color represents AA homologous with GLP-1, the green color represents AA homologous with both GIP and GLP-1, the grey color represents AA unique to tirzepatide
      * GIP effect on gastric secretion is derived from animal data; ** GIP effect on appetite is controversial in humans and needs to be studied further; GLP1 acts on the following central nervous system areas: (a) hypothalamus, (b) nucleus of tractus solitarius, (c) orbitofrontal cortex, (d) reward system; ƚ GIP decreases diastolic blood pressure, while the effect of GLP-1 on blood pressure is inconsistent in published studies; ǂ Effect on bone markers is inconsistent. Some studies showed no change in bone markers for both GIP and GLP-1. Other studies showed that GIP and GLP-1 increase bone formation markers and GIP reduces bone resorption markers.
      The SURPASS phase 3 trials program evaluated the efficacy of TZP in patients with type 2 diabetes mellitus (T2D) on glycemic parameters, compared to various medications [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ]. Five randomised controlled trials included middle age men and women, with T2D, of 4–13 years duration, a mean baseline Hemoglobin A1c (HbA1c) around 8 %, and a mean baseline body mass index (BMI) of 32–34 kg/m2 [
      • 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.
      ]. There was a dose response effect on the achieved HbA1c at study completion, with the highest reduction being with TZP 15 mg/week, and a significant difference of 2 % compared to placebo, 1–1.5 % compared to long acting insulin and 0.5 % compared to semaglutide [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ]. The potent effect of TZP on glycemic control led to its FDA approval for the treatment of T2D in 2022 [
      • 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.
      ]. Beyond glycemic parameters, TZP showed a significant drop in blood pressure and lipid parameters [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ].
      In patients with T2D, TZP resulted in a significant dose dependent weight loss (Fig. 2). At a dose of 15 mg/week, TZP allowed for the majority (71–88 %) of the enrolled individuals to achieve 5 % weight loss, while one third achieved 15 % weight loss upon study completion [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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.
      ]. In the SURMOUNT-1 trial, patients with obesity and without T2D (mean baseline BMI 37–38 kg/m2) experienced a larger weight loss [
      • 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.
      ]. The mean percent weight loss was 15 %, 19.5 % and 20.9 %, in the 5, 10 and 15 mg/week TZP groups, respectively, while it was only 3 % in the placebo group, with all groups receiving lifestyle modification instructions on diet and exercise, through counseling sessions delivered by a dietician or a health care professional [
      • 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.
      ]. Almost all individuals (85–91 %) across all arms achieved a 5 % weight loss. One third of the individuals receiving TZP 10 or 15 mg/week achieved 25 % weight loss at one year [
      • 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.
      ], a drastic drop in weight that is not too far from weight loss following bariatric procedures [
      • 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.
      ]. There was no significant difference in the effect on weight between TZP 10 and 15 mg/week, that could be just related to lack of power, as the SURMOUNT-1 trial aimed to compare the high doses to placebo [
      • 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.
      ]. In light of these results, TZP was granted by the FDA a Fast Track designation to treat adults with obesity [
      FDA grants fast track designation to Tirzepatide for obesity, associated comorbidities pharmacy times.
      ].
      Fig. 2
      Fig. 2Change in weight (kg) in response to Tirzepatide versus comparator in SURPASS and SURMOUNT-1 trials
      All studies describe the weight change in Kg, except for SURMOUNT-1 that reports percent change in weight; Comparator is * Placebo in SURPASS-1, SURPASS-5 and SURMOUNT-1, ƚ Semaglutide (1 mg/week) in SURPASS-2, ǂ Insulin Degludec in SURPASS 3, ȴ Insulin Glargine in SURPASS-4.
      Given the known effect of GIP on adipose tissue, TZP seems to be an attractive option in patients with fatty liver disease. The SURPASS-3 sub-trial investigated the effect of TZP on liver fat content (LFC), measured by MRI [
      • 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.
      ,
      • 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.
      ]. There was a significant drop in the LFC in TZP groups, with a trend for larger decrements with the intermediate and high doses [
      • 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.
      ]. Interestingly, 40–48 % of individuals in the TZP 10 and 15 mg/week reached a LFC of <6 % (which corresponds to <5 % macroscopic liver fat content on histology), while only 20 % did so with TZP 5 mg/week and insulin degludec arms [
      • 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.
      ].
      While awaiting the results of the ongoing TZP cardiovascular outcome trial [
      • Lilly E Companycollab
      A study of tirzepatide (LY3298176) on the reduction on morbidity and mortality in adults with obesity.
      ,
      A study of tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes (SURPASS-CVOT).
      ], pooled data from the available trials are reassuring [
      • 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.
      ,
      • Patoulias D.
      • Papadopoulos C.
      • Fragakis N.
      • Doumas M.
      Updated meta-analysis assessing the cardiovascular efficacy of tirzepatide.
      ]. A meta-analysis on the cardiovascular safety of TZP in patients with T2D included a total of 7 trials (one phase 2 and 6 phase 3 trials) with an intervention duration of at least 26 weeks [
      • 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.
      ]. There was no increase in major adverse cardiovascular events nor all-cause death, in TZP groups (all doses combined) compared to all comparators combined (placebo, semaglutide or basal insulins). Such findings were consistent across genders, age categories (<65 years or ≥65 years), baseline HbA1c, race, country and the presence or absence of concomitant Sodium-glucose Cotransporter-2 (SGLT2) inhibitor [
      • 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.
      ].
      The safety profile of TZP seems to be similar to GLP-1 receptor agonist, with a high rate of gastrointestinal side effects, occurring in around 40 % of participants; nausea and diarrhea being the most frequent [
      • Mishra R.
      • Raj R.
      • Elshimy G.
      • Zapata I.
      • Kannan L.
      • Majety P.
      • et al.
      Adverse events related to tirzepatide.
      ,
      • 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.
      ]. There is possibly a higher rate of adverse event with a high dose (15 mg/week), compared to a low dose (5 mg/week) [
      • Mishra R.
      • Raj R.
      • Elshimy G.
      • Zapata I.
      • Kannan L.
      • Majety P.
      • et al.
      Adverse events related to tirzepatide.
      ]. As suggested for patients starting GLP-1 agonists, education on potential gastro-intestinal adverse events, dietary changes (avoiding high fat and spicy food, and appropriate hydration), slower dose escalation, lowering the dose and the use of over the counter medications, as needed, may help reduce patient symptomatology [
      • 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.
      ,
      • 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.
      ].
      We believe that we are just at the beginning. The global SURMOUNT phase 3 trials program investigates the safety and efficacy of weekly TZP on various surrogate and hard outcomes, in patients with obesity with or without other co-morbidities such as T2D, renal, liver and cardio-vascular diseases [
      • 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.
      ]. These trials are expected to be completed in the coming few years and will definitively enlighten our decisions in terms of weight management options available to us (Table 1).
      Table 1Overview of ongoing trials on tirzepatide in adult patients with obesity
      We identified one phase 2 trial on patients with Wolfram Syndrome Type 1.
      identified on Clinicaltrials.gov (as of February 5, 2023).
      Trial name

      (NCT number)

      Phase
      Study arms
      All interventions are subcutaneous injections.


      Duration
      Sample sizeMain inclusion criteriaOutcomesStatusCompletion date
      TZP in Chinese overweight/obese



      SURMOUNT-CN

      (NCT05024032)



      Phase 3
      TZP dose 1/week

      TZP dose 2/week

      (Unknown dose)

      Placebo/week



      52 weeks
      210Age ≥ 18 years, BMI ≥28 kg/m2, or ≥24 kg/m2 with at least one of the following comorbidities: HT, dyslipidemia, OSA, CVD, ≥1 unsuccessful dietary effort to lose weight



      (Excluding T2D)
      Primary

      -% change in body weight

      -% of participants achieving ≥5 % weight loss

      Secondary

      -Change in weight, waist circumference, BMI, HbA1C, BP, lipid profile, free fatty acids, fasting glucose and insulin, quality of life

      -% of participants achieving ≥10 and 15 % weight loss
      CompletedDecember 2022
      TZP in T2D and overweight/obese



      SURMOUNT-2

      (NCT04657003)



      Phase 3
      TZP 10 mg/week

      TZP 15 mg/ week

      Placebo/week



      72 weeks
      900Age ≥ 18 years, T2D, ≥27 kg/m2, ≥1 unsuccessful dietary effort to lose weight.Primary

      -% change in body weight

      -% of participants achieving ≥5 % weight loss

      Secondary

      -Change in weight, waist circumference, BMI, HbA1C, BP, lipid profile, free fatty acids, fasting glucose and insulin, quality of life

      -% of participants achieving ≥10 and 15 % weight loss

      -Steady state area under the curve
      Active not recruitingApril 2023
      TZP after a lifestyle weight loss program



      SURMOUNT-3

      (NCT04657016)



      Phase 3
      TZP/week

      (Unknown dose)

      Placebo/week



      72 weeks
      800Age ≥ 18 years, BMI ≥ 30 or ≥27 kg/m2 with at least one weight-related complication (HT, dyslipidemia, OSA, or CVD), ≥1 unsuccessful dietary effort to lose weight



      (Excluding T2D)
      Primary

      -% change in body weight

      -% of participants achieving ≥5 % weight loss

      Secondary

      -Change in weight, waist circumference, BMI, HbA1C, BP, lipid profile, free fatty acids, fasting glucose and insulin, quality of life

      -% of participants maintaining ≥80 % weight loss, achieving ≥10 and 15 % weight loss
      Active not recruitingMay 2023
      TZP for maintenance of weight loss



      SURMOUNT-4

      (NCT04660643)



      Phase 3
      TZP/week

      (Unknown dose)

      Placebo/week

      88 weeks
      750Age ≥ 18 years, BMI ≥ 30 or ≥27 kg/m2 with at least one weight-related complication (HT, dyslipidemia, OSA, or CVD), ≥1 unsuccessful dietary effort to lose weight



      (Excluding T2D)
      Primary

      -% change in body weight

      Secondary

      -Change in weight, waist circumference, BMI, HbA1C, BP, lipid profile, free fatty acids, fasting glucose and insulin, quality of life, physical function

      -% of participants maintaining ≥80 % of their weight loss, achieving ≥5, 10 %, 15 % weight loss

      -Time to first occurrence of returning to >95 % baseline weight of those who lost >5 %
      Active not recruitingMay 2023
      TZP for reduction in morbidity and mortality in obesity



      SURMOUNT-MMO

      (NCT05556512)



      Phase 3
      TZP/week up to maximal tolerated dose

      Placebo



      60 months
      15,000BMI ≥27 kg/m2 with age ≥ 40 years of age with established CVD or without established CVD but have the presence of cardiovascular risk factors



      (Excluding T1D and T2D)
      Primary

      -Time to first occurrence of any component event of composite (all-cause death, nonfatal MI, nonfatal stroke, coronary revascularization, or heart failure events)

      Secondary

      -Time to onset of T2D or renal disease or death, occurrence of any component event of MACE-3 (CV death, nonfatal MI or nonfatal stroke)

      -Time to occurrence of all-cause death

      -Time to first occurrence of CV death, MI, stroke, coronary revascularization, heart failure events, hospitalization for unstable angina or hospitalization or urgent visit, any component event of a composite renal endpoint

      -eGFR slope

      -% change in body weight

      -% of participants achieving HbA1c <5.7 %

      -Change in BP, quality of life, physical function
      RecruitingOctober 2027
      TZP for overweight/obese and CKD



      TREASURE-CKD

      (NCT05536804)



      Phase 2
      TZP

      (Unknown dose)

      Placebo



      52 weeks
      140Age ≥ 18 years, BMI ≥27 kg/m2 with CKD (≥30 to ≤60 ml/min/1.73 m2), on angiotensin-converting enzyme or angiotensin II receptor blockers with or without T2DPrimary

      -Change in kidney oxygenation

      Secondary

      -Change in kidney oxygenation in T2D and without T2D

      -% change in body weight, renal sinus fat content, renal fat content, renal blood flow, urine Albumin-to-Creatinine ratio

      -Change in apparent diffusion coefficient, GFR Iohexol clearance, 24-h urinary albumin excretion
      Not yet recruitingNovember 2025
      TZP in OSA



      SURMOUNT-OSA

      (NCT05412004)



      Phase 3
      TZP/week up to a maximum tolerated dose

      Placebo/week



      52 weeks
      414Age ≥ 18 years, BMI ≥30 kg/m2, AHI ≥ 15, history of at least 1 self-reported unsuccessful dietary effort to lose body weight, on PAP or unable or unwilling to put PAP



      (Excluding T2D)
      Primary

      -% change in AHI

      Secondary

      -Hierarchical combination of FOSQ 10 Score, FOSQ vigilance domain score, and FOSQ activity level domain score

      -Change in AHI, blood pressure, CRP, sleep apnea-specific hypoxic burden

      -% change in body weight

      -% of participants with >50 % reduction in AHI, or AHI <5 or with AHI 5–14 with Epworth Sleepiness Scale ≤10
      RecruitingFebruary 2024
      TZP for overweight/obese



      (NCT04311411)



      Phase 1
      TZP

      (Unknown dose)

      Liraglutide

      (Unknown dose)

      Placebo



      6 weeks
      111BMI 27–50 kg/m2, with a stable weight for at least one month



      (Excluding T2D)
      Primary

      -Change in energy intake (kilocalories/day)

      Secondary

      -Change in blood oxygenation level dependent functional MRI activation to images of high-fat foods during the fasting state in the brain reward areas

      -Change in fasting and postprandial appetite visual analog scale
      Active, not recruitingJanuary 2023
      TZP in Japanese with obesity



      SURMOUNT-J (NCT04844918)



      Phase 3
      TZP/week Regimen A

      (Unknown dose)

      TZP/week Regimen B

      (Unknown dose)

      Placebo



      72 weeks
      261Age ≥ 20 years, BMI ≥27–35 kg/m2 with at least 2 obesity-related health problems or ≥35 kg/m2 with at least 1 obesity-related health problems (IGT, hyperlipidemia, NAFLD), ≥1 self-reported unsuccessful dietary effort to lose body weight



      (Excluding T2D)
      Primary

      -% of participants who achieve ≥5 % body weight reduction

      -% change in body weight

      Secondary

      -% of participants who have improvement in obesity-related health problems, or improvement in IGT, or hyperlipidemia, or NAFLD, achieve ≥10 % and 15 % body weight reduction, achieve VAT <100 cm2

      -Change in weight, BMI, oral glucose tolerance test, fasting glucose and insulin, lipid profile, hepatic fat fraction, body weight, VAT, SAT, waist circumference, HbA1c, BP, quality of life
      Active, not recruitingJune 2023
      TZP for NASH



      SYNERGY-NASH

      (NCT04166773)



      Phase 2
      TZP 5 mg/week

      TZP 10 mg/week

      TZP 15 mg/week

      Placebo



      52 weeks
      196Age ≥ 18 years, histologically diagnosed NASH and Fibrosis 2 or 3, BMI ≥27 and ≤50 kg/m2, with or without T2DPrimary

      -% of participants who have absence of NASH with no worsening of fibrosis on liver histology

      Secondary

      -% of participants with ≥1-point increase in fibrosis, ≥1-point decrease in fibrosis, ≥2-point decrease in NAFLD activity score

      -Changes in LFC by MRI-proton density fat fraction, body weight
      Active not recruitingFebruary 2024
      TZP in heart failure and obesity



      SUMMIT

      (NCT04847557)



      Phase 3
      TZP

      (Unknown dose)

      Placebo



      52 weeks
      700Age ≥ 40 years, stable HF and HF medications, LVEF ≥50 %, elevated pro-BNP or structural heart disease or elevated left ventricular filling pressure, 6MWD 100-425 m, KCCQCS score ≤ 80, GFR < 70 ml/min, BMI ≥30 kg/m2Primary

      -Hierarchical composite of all-cause mortality, heart failure events, 6MWD, and KCCQCS score

      -Change in exercise capacity as measured by 6MWD

      Secondary

      -% change in body weight loss

      -Change in 6MWD, KCCQCS score

      -Time to first occurrence of HF events or CV death, HF events or all-cause death, HF events; Time to recurrent events of HF, HF or CV death

      -% of participants with NYHA class change
      RecruitingJuly 2024
      Abbreviations: AHI: Apnea Hypopnea index; BNP: Blood natriuretic peptide; BP: Blood pressure; BMI: Body Mass Index; CKD: Chronic kidney disease; CVD: Cardiovascular disease; FOSQ: Functional Outcomes of Sleep Questionnaire; GFR: Glomerular filtration Rate; HF: Heart failure; HT: Hypertension; IGT: Impaired glucose tolerance; KCCQCS: Kansas City Cardiomyopathy Questionnaire Clinical Summary; LFC: Liver fat content; LVEF: Left ventricular ejection fraction; MI: Myocardial infarct; MACE-3: Major adverse cardiovascular events; NAFLD: Non-alcoholic fatty liver disease; NAS: NAFLD activity score; NASH: Non-alcoholic steatohepatitis; NYHA: New York Heart Association; OSA: Obstructive sleep apnea; PAP: Positive Airway Pressure; SAT: Subcutaneous Adipose tissue; T2D: Type 2 diabetes mellitus; T1D: Type 1 diabetes mellitus; TZP: Tirzepatide; VAT: Visceral Adipose Tissue; 6MWD: 6-min walk distance.
      1 We identified one phase 2 trial on patients with Wolfram Syndrome Type 1.
      2 All interventions are subcutaneous injections.
      The pipeline of potential anti-obesity medications is still expanding, with some medications reducing caloric intake [
      • 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.
      ,
      • Müller T.D.
      • Blüher M.
      • Tschöp M.H.
      • DiMarchi R.D.
      Anti-obesity drug discovery: advances and challenges.
      ], and others affecting thermogenesis and energy expenditure [
      • Jimenez-Munoz C.M.
      • López M.
      • Albericio F.
      • Makowski K.
      Targeting energy expenditure—drugs for obesity treatment.
      ]. Several drugs are currently under investigation, leveraging mostly the gastrointestinal tract secreted hormones and targeting the reward and hunger/satiety centers in the hypothalamus, nucleus of the solitary tract and other brain areas, that have been shown to be important in energy homeostasis [
      • Lilly E Companycollab
      A study of tirzepatide (LY3298176) in participants with obesity or overweight.
      ]. These drugs include GIP/GLP1 dual agonists, GLP1/glucagon dual agonists, GIP/GLP1/glucagon tri-agonists, Y2R agonists, dopamine reuptake inhibitor, amylin receptor agonist, oxytocin, leptin sensitizers and others. The mechanisms through which glucagon agonists affect body weight is still unknown, and the GLP1/glucagon dual agonists might be working mostly through GLP-1 agonism [
      • Bass J.
      • Tschöp M.H.
      • Beutler L.R.
      Dual gut hormone receptor agonists for diabetes and obesity.
      ,
      • Lilly E Companycollab
      A study of tirzepatide (LY3298176) in participants with obesity or overweight.
      ]. Interestingly, given that glucagon receptors are expressed in the liver, GLP1/glucagon dual agonists may have a particular beneficial effect in individuals with fatty liver [
      • Bass J.
      • Tschöp M.H.
      • Beutler L.R.
      Dual gut hormone receptor agonists for diabetes and obesity.
      ].
      The major challenges with the currently available potent weight loss medications are related to their gastro-intestinal side effects and their administration mode since they are injectable [
      • Bass J.
      • Tschöp M.H.
      • Beutler L.R.
      Dual gut hormone receptor agonists for diabetes and obesity.
      ]. Trials in patients with T2D and obesity showed that oral semaglutide leads to less weight loss, compared to the subcutaneous preparation, which may be explained by the much lower bioavailability of the former [
      • Meier J.J.
      Efficacy of semaglutide in a subcutaneous and an oral formulation.
      ]. Increasing the dose might overcome the limitations of the oral preparation and yield a higher weight loss; although this is now being investigated, cost of goods, given the lower absorption rate and bioavailability, may prove to be a prohibitive factor [
      • 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).
      ]. Weight regain upon treatment cessation is another hurdle on patients and physicians, and the most appropriate approaches to tackle it are still unknown, although it remains possible that longer duration and more significant weight loss may decrease overtime the obesity induced inflammation centrally, and thus make longer term weight loss achievable [
      • Bass J.
      • Tschöp M.H.
      • Beutler L.R.
      Dual gut hormone receptor agonists for diabetes and obesity.
      ]. Increasing the armamentarium of obesity pharmacotherapy allows to tailor treatment options and to match them to the patient's profile and risk factors, with the hope of reaching drugs that allow a significant and a sustainable weight loss, with minimal short- and long-term adverse events.
      Despite the revolutionary progress in obesity management, the breakthrough in drug development and the wealth of evidence on the benefits of various interventions, there are still several treatment barriers that contribute to the “health inequity” of patients with obesity [
      • Salas X.R.
      Closing obesity care gaps and achieving health equity for people living with obesity.
      ]. These include cultural factors and lack of patient awareness of weight problems, limited health care providers knowledge and competency in the delivery of appropriate care, weight bias and stigma, in addition to costs and lack of coverage for obesity treatments [
      • Tsai A.G.
      • Histon T.
      • Kyle T.K.
      • Rubenstein N.
      • Donahoo W.T.
      Evidence of a gap in understanding obesity among physicians.
      ,
      • 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.
      ].
      This is far from being a happy end of the story, however; the reality is that significant challenges remain. Since many insurance companies, governments and international organizations do not consider obesity as a disease, and the relevant treatments are not universally covered by the public or private health insurance systems. We tend to consider innovations as the breakthroughs in terms of scientific advancements and product developments. Our societies call for yet another form of innovation at many levels. At the society level, innovation is needed to accept obesity and its comorbidities as a disease. At the government and international organizations level, innovation is needed to accept that, in addition to prevention, one needs to not only advance by creating novel drugs for obesity and metabolic disorders, but also in compensating for drugs for these diseases. At the level of insurance companies, innovation is needed in terms of creating novel criteria to screen effective medications and start covering medications that are necessary for improving obesity associated morbidity and mortality. However, we need to stress the fact that societies need to compensate fairly and invest generously on new drugs in order to make them accessible to the community.
      Action is thus needed to close the obesity care gap. Innovation in social policy is crucial to make treatments accessible to the community and help people live healthier and longer lives. This calls for a multi-level approach. Educating healthcare providers and patients and increasing their awareness of the harms associated with weight excess and the safe approaches to lose weight is a must. At the society and public health level, strategies to reduce weight bias and stigma should be implemented. Governments and insurance companies must recognize obesity as a disease, and therefore cover and invest in not only the development of novel medications but also in weight reduction interventions.
      These are exciting times in the obesity and metabolism field since recent developments and what is coming in the not so distant future promises to really help persons with obesity live longer and healthier lives.

      Declaration of competing interest

      C.S.M. reports grants from Merck, AltrixBio, Coherus Biosciences, Novo Nordisk, and Boehringer Ingellheim through his institution, personal fees and non-financial support from Ansh, AltrixBio, Coherus Biosciences, and Novo Nordisk, and personal fees from 89Bio, Lumos, Amgen, Madrigal, GENFIT, Corcept, Intercept, Regeneron, CardioMetabolic Health Conference, The Metabolic Institute of America and Amgen. MC has nothing to report.
      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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