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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 [
]. 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 [
], 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 [
]. 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 [
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 [
]. 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 [
], 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 [
]. 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 [
]. 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 [
]. 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 [
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 [
]. 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 [
]. Exceptionally, semaglutide results in a more significant weight loss reaching 15 % of baseline weight, when combined with behavioral and lifestyle modifications [
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 [
]. 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 [
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.
]. 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 [
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 [
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 [
]. 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 [
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 [
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.
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.
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.
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.
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 [
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 [
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.
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.
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.
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 [
]. 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 [
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.
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.
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.
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.
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.
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.
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.
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 [
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.
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.
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.
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 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 [
]. 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 [
]. 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 [
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 [
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.
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.
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 [
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.
]. 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 [
]. 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 [
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 [
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.
]. 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 [
Clinical recommendations to manage gastrointestinal adverse events in patients treated with GLP-1 receptor agonists: a multidisciplinary expert consensus.
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 [
]. 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
Age ≥ 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
Completed
December 2022
TZP in T2D and overweight/obese
SURMOUNT-2 (NCT04657003)
Phase 3
TZP 10 mg/week TZP 15 mg/ week Placebo/week
72 weeks
900
Age ≥ 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 recruiting
April 2023
TZP after a lifestyle weight loss program
SURMOUNT-3 (NCT04657016)
Phase 3
TZP/week (Unknown dose) Placebo/week
72 weeks
800
Age ≥ 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 recruiting
May 2023
TZP for maintenance of weight loss
SURMOUNT-4 (NCT04660643)
Phase 3
TZP/week (Unknown dose) Placebo/week 88 weeks
750
Age ≥ 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 recruiting
May 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
15,000
BMI ≥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
Recruiting
October 2027
TZP for overweight/obese and CKD
TREASURE-CKD (NCT05536804)
Phase 2
TZP (Unknown dose) Placebo
52 weeks
140
Age ≥ 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 T2D
Primary -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 recruiting
November 2025
TZP in OSA
SURMOUNT-OSA (NCT05412004)
Phase 3
TZP/week up to a maximum tolerated dose Placebo/week
52 weeks
414
Age ≥ 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
BMI 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 recruiting
January 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
261
Age ≥ 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
Age ≥ 18 years, histologically diagnosed NASH and Fibrosis 2 or 3, BMI ≥27 and ≤50 kg/m2, with or without T2D
Primary -% 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 recruiting
February 2024
TZP in heart failure and obesity
SUMMIT (NCT04847557)
Phase 3
TZP (Unknown dose) Placebo
52 weeks
700
Age ≥ 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/m2
Primary -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
]. 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 [
]. 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 [
]. 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 [
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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
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.
References
How some effects of modernization fuel non-communicable diseases in Africa.
American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity.
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.
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.
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).
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.
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.
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.
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.
Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study.
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.
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.
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.
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.
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.
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.
Clinical recommendations to manage gastrointestinal adverse events in patients treated with GLP-1 receptor agonists: a multidisciplinary expert consensus.
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