What's new in the drug treatment of obesity?

Ali Al-SHALEEL, Jad BISSAR, Barbara HERSANT, MD PHD.

Place of MAO (Anti-Obesity Drugs)

INTRODUCTION 

Obesity is recognized as a major pandemic of the 21st century.e century, contributing to rising morbidity, mortality and the burden of healthcare costs. 
Overweight and obesity are defined by theWorld Health Organizationé(WHO) as a BMI of 25-29.9 kg/m2 and a BMI ≥ 30 kg/m2respectively. 
Predictive models now suggest that prevalence will rise to one in two adults by 2030. 
Worldwide, one adult in five now suffers from obesity. 
The Global Burden of Disease study reports that overweight and obesity are the fourth leading risk of death worldwide, and more than 4.7 million adults die each year as a result of being overweight or obese. 
Obesity is a major risk factor in the development of cardiovascular disease (CVD), type 2 diabetes (T2DM), musculoskeletal disorders and several cancers. 
Associations between obesity, central obesity (increased * waist circumference, particularly intra-abdominal / visceral fat) and risks of cardiometabolic diseases as well as obstructive sleep apnea, asthma and non-alcoholic fatty liver disease (NAFLD) are well established. 
Cytokines secreted by visceral adipocytes, including interleukin-6, tumor necrosis factor-alpha, resistin and plasminogen activation inhibitor-1, have been implicated in the pathogenesis of these diseases, in part by promoting local and systemic states of inflammation and thrombosis. 
A reduction in body weight of 5 to 10 % significantly reduces inflammatory and chronic prothrombotic manufacturers, as well as the incidence of disease. 

Place of MAO (Anti-Obesity Drugs)

PRINCIPLES OF PHARMACOTHERAPY FOR OBESITY.

As with other chronic diseases, the initial management of overweight and obesity focuses on sustainable changes in nutrition, physical activity and behavior that have been shown to reduce weight and cardiometabolic risk. 
However, lifestyle interventions that include calorie restriction and/or portion control alone are insufficient to maintain long-term weight loss in most patients, with one-third to two-thirds of the weight lost regained within one year of the end of treatment and >95 % of weight regained within 5 years. 
For patients who have failed to achieve clinically significant weight loss, defined as ≥ 5 % of baseline weight [16] after 6 months of lifestyle interventions, professional organizations such as The Obesity Society, l'Endocrine Society and theAmerican Association of Clinical Endocrinologistsrecommend MAO (Anti-Obesity Drugs) for people with a BMI ≥ 30 kg/m2 or a BMI ≥ 27 kg/m2 with comorbidities. 
For healthcare professionalsé that use pharmacothérapie for weight management, the following basic principles can be kept in mindés in mind: 
Lifetime treatment: because obesity is a chronic disease, drug therapy should be prescribed with the intention of lifelong use and as part of a comprehensive management plan that includes nutrition, physical activity and behavioral counseling.
Stopping an AOM often leads to weight regain. 
MAOs affect pathophysiological pathways leading to obesity: Current pharmacotherapy for obesity targets the underlying neurohormonal disturbances that cause weight gain and prevent sustained weight loss.
Hormonal changes in response to diet-induced weight loss, such as a reduction in the anorectic hormone leptin and an increase in the orexigenic hormone ghrelin, create a physiological environment conducive to the body's return to its previously established higher body weight set point.
Additional adaptive responses to diet-induced weight loss affecting energy expenditure, including reduced basal metabolic rate, also compromise weight loss maintenance. 
The bénéficient in both weight and co-morbiditiesés : the objectives of obesity treatment are primary, secondary and tertiary prevention, i.e. preventing the development or exacerbation of obesity and its complications. For example, improvements in cardiometabolic risk factors and a reduction in the risk of diabetes have been systematically reported in phase 3 trials for MAOs. 
Expect a hétérogénéité in the réponse to weight loss: Phase 3 trials have consistently demonstrated that AOMs deliver significantly greater weight loss than placebo when combined with lifestyle modifications.
The average efficacy of these studies ranges from 5 to 10 % of total body weight loss.
However, as with any medical treatment, significant inter-individual variability in response has been reported, including the possibility of zero weight loss (non-responders) to weight loss of 20 % or more. 

HISTORY OF ANTI-OBESITY DRUGS 

The development of MAOs dates back to the 1940s, before the standard FDA rules and regulations with which we are familiar today. 
Drug approval in the 1940s required only proof of efficacy beyond placebo.
Weighing benefits against risks in controlled investigations was not a requirement until the Kefauver-Harris amendment was passed in 1962. 
Approval of the first MAO, deoxyephedrine, in 1947led to the development of a number of amphetamine derivatives for weight loss, all of which have since been withdrawn from the market because of this modification. 
Since the FDA's adoption of stricter regulations and evidence of clinical efficacy, only a few of the recently approved MAOs have been withdrawn from the US market for safety reasons. 

Méanti-ob drugsésité récently remindedés by the FDA.

Table I. FDA-approved drugs for weight management.

Orlistat (Xenical®)

Orlistat (brand name Xenical®) is approved for the treatment of obesity in adults and adolescents (aged 12 to 16).
It promotes weight loss by inhibiting gastrointestinal lipases, thus reducing fat absorption from the gastrointestinal tract. 
On average, 120 mg Orlistat taken three times a day will reduce fat absorption by 30%.
Orlistat has been shown to be more effective in inhibiting fat digestion in solid foods, as opposed to liquids.
Orlistat at a lower dose of 60 mg 3 times a day (trade name Alli) is approved for over-the-counter use in the United States. 
Safety and side effects
The gastrointestinal side effects of Orlistat, including greasy / oily stools, fecal urgency, oily stains, increased defecation, fecal incontinence, flatulence with discharge and oily evacuation, are the main reasons for discontinuing treatment. 
These symptoms are usually mild to moderate and decrease in frequency with prolonged use of the drug. 
Administration of Orlistat with psyllium mucilloid reduced the incidence of gastrointestinal side effects to 29 % with psyllium versus 71 % without psyllium. 
Orlistat may reduce the absorption of fat-soluble vitamins A, D, E and K, which can be mitigated by the separate administration of vitamin supplements. 
 

Phentermine/topiramate (Qsymia®) 

The extended-release, single-tablet combination phentermine + topiramate (trade name Qsymia®) was approved by the FDA in 2012 as a long-term treatment for obesity in adults with a BMI ≥ 30 kg/m2 or a BMI ≥ 27 kg/m2 with at least one weight-related comorbidity. 
Phentermine is thought to promote weight loss by increasing noradrenaline release and decreasing its uptake in the hypothalamic nuclei, leading to a reduction in food intake. 
It also acts as an adrenergic agonist, activating the sympathetic nervous system. 
Phentermine/topiramate is available in 4 doses: 3.75/23 mg (initial dose), 7.5/46 mg (lowest treatment dose), 11.25/69 mg or 15/92 mg (maximum treatment dose) per day. 
Safety and side effects 
Phentermine-topiramate is not recommended for patients with a significant cardiac history, such as coronary heart disease and uncontrolled hypertension. 
However, in people without coronary artery disease and with well-controlled hypertension, it is considered safe to use this drug with regular blood pressure monitoring. 
Exposure to phentermine/topiramate carries an increased risk of cleft lip and palate in infants exposed to the drug combination during the first trimester of pregnancy.
Women of childbearing age should undergo a pregnancy test before starting the drug, and use contraception while taking it. 
Clinicians who prescribe phentermine-topiramate and pharmacists who dispense it should register for a stratégie d'éassessment and atténuation (REMS)This includes education on dosing information, monitoring during treatment and side effects. This drug is also contraindicated in patients with hyperthyroidism, glaucoma and in patients who have taken monoamine oxidase inhibitors (MAOI) within 14 days. 
Topiramate may increase the risk of acidosis and kidney stones, so it should be used with caution in patients with a history of stones. 
 

Bupropion/naltrexone (Contrave®) 

The combined tablet of bupropion and naltrexone (trade name Contrave®) was approved by the FDA for weight loss in September 2014. 
The bupropion is a dopamine and noradrenaline reuptake inhibitor that promotes activation of central melanocortin pathways.
Naltrexone is an opioid receptor antagonist that reduces the auto-inhibitory feedback loop of mu-opioid receptors on bupropion-activated hypothalamic anorectic neurons, enabling sustained weight loss. 
The bupropion/naltrexone tablets containing 90 mg bupropion HCl extended-release hydrochloride and 8 mg naltrexone HCl.
The recommended initial dose is 1 tablet per day, increasing by 1 tablet each week until a total dose of 2 tablets twice daily is reached (total daily dose : bupropion 360 mg/naltrexone 32 mg). 
Safety and side effects 
The most common side effects of bupropion/naltrexone include nausea/vomiting, constipation, headache, dizziness, insomnia and dry mouth. 
Drug interactions include MAO inhibitors (use during or within 14 days of administration), opioids and opioid agonists (including partial agonists) which are inactive in the presence of naltrexone, and the abrupt discontinuation of alcohol, benzodiazepines, barbiturates or anti-epileptic drugs which may increase the risk of convulsions.
Bupropion/naltrexone should be avoided in patients with uncontrolled hypertension, a history of seizures, a history of bulimia or anorexia nervosa, and in those taking narcotics for pain control. 
The FDA recommends monitoring patients for worsening or emergence of suicidal thoughts or behavior. Women of childbearing potential should undergo a pregnancy test before starting the drug and use contraception while taking it. 

Liraglutide 3.0 (Saxenda®) 

Liraglutide 3.0 mg (trade name Saxenda®) was approved by the FDA in December 2014 for obesity in adults and has proven effective in adolescents aged 12 to <18. 
Liraglutide is a glucagon-like peptide-1 (GLP-1) analog that activates the GLP-1 receptor. 
In animal studies, peripheral administration of liraglutide results in uptake in specific appetite-regulating brain regions, including the hypothalamus and brainstem. 
A short-term study (5 weeks) in obese, non-diabetic subjects demonstrated that liraglutide 3.0 mg/d suppressed acute food intake, subjective hunger and delayed gastric emptying. 
Energy expenditure in subjects treated with liraglutide 3.0 mg /d decreased, associated with weight loss , which may reflect a metabolic adaptation to weight loss. 
Safety and side effects 
Gastrointestinal symptoms, such as nausea, vomiting and abdominal pain, were the most common reason subjects withdrew from the SCALE tests. 
In a secondary analysis of these trials, treatment with liraglutide 3.0 resulted in a dose-independent, reversible increase in amylase/lipase activity (7 % for amylase and 31 % for lipase). 
Thirteen subjects (0.4 %) in the liraglutide 3.0 group versus one (0.1 %) with placebo developed pancreatitis, but almost half of them also showed signs of gallstones. 
Although liraglutide treatment showed improvements in blood pressure and lipid levels, it was found to increase heart rate by an average of 2 beats/min in diabetes. 
Animal studies with liraglutide showing an association with medullary thyroid cancer led to FDA labeling warnings. 
Although the relevance of this observation to humans has not been determined, a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN 2) is considered a contraindication to treatment with this drug . 
Women of childbearing age should undergo a pregnancy test before starting the drug, and use contraception while taking it. 

 

Setmelanotide (Imcivree®) 

Setmelanotide (trade name Imcivree®) is a melanocortin-4 receptor (MC4R) agonist that was approved by the FDA in November 2020 for the treatment of monogenic obesity due to deficiency of pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) in people aged 6 years or older. 
Binding of leptin to its receptor causes intracellular cleavage of the POMC peptide by PCSK1 into alpha-melanocyte stimulating hormone (aMSH), which is the endogenous agonist of MC4R. 
Deficiencies in this pathway manifest clinically as hyperphagia, impaired pubertal development, obesity and insulin resistance in homozygous or compound heterozygous individuals for deleterious mutations in POMC also presenting with adrenal insufficiency and hypopigmentation.
Setmelanotide is administered as a once-daily subcutaneous injection starting at 2 mg per day in patients aged 12 and over, and 1 mg per day in patients aged 6 to under 12. 
The dose can be titrated up to a maximum of 3 mg per day, depending on tolerance and efficacy. 
Safety and side effects 
The most frequent adverse reactions were injection-site reactions, hyperpigmentation and nausea. 
No clinically significant changes in heart rate or blood pressure were observed.
Spontaneous penile erections occurred in men. 
Although the manufacturer warns against suicidal ideation and depression, the Phase 3 trial reported one case of suicidal ideation not present at baseline, and no treatment-related worsening of depression.

 

Semaglutide 2.4 (Wegovy®) 

The Sémaglutide 2.4 mg (trade name Wegovy®) was approved by the FDA for the treatment of obesity in adults in June 2021. 
Semaglutide is a long-acting GLP-1 analog administered by weekly subcutaneous injection in doses of 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg and 2.4 mg. 
It promotes weight loss through multiple mechanisms, including the slowing of gastric emptying, thus reducing hunger and energy intake, in addition to direct anorectic effects on the brain leading to increased satiety. 
Safety and side effects 
The most frequent adverse events in the Phase 3 RCTs of semaglutide 2.4 mg were nausea, diarrhea, vomiting and constipation. In the STEP 1 trial, these gastrointestinal side effects occurred more frequently in people receiving semaglutide compared with placebo (74.2 % vs. 47.9 %). 
However, most of them were mild to moderate in severity. 
Serious adverse events occurred in 9.8 % of those receiving semaglutide versus 6.4 % of those on placebo. 
Serious adverse events included severe gastrointestinal disorders (1.4 % with semaglutide vs. 0 % with placebo), hepatobiliary disorders (1.3 % with semaglutide vs. 0,2 % with placebo), gallbladder disorders (2.6 % with semaglutide vs. 1.2 % with placebo) and mild acute pancreatitis (0.2 % with semaglutide vs. 0 % with placebo). 
In all RCTs, participants experienced an average increase in heart rate of 1 to 4 beats per minute (bpm); 26 % of those on semaglutide versus 16 % of those on placebo had an increase in heart rate of 20 bpm or more. 
Among T2DM patients, hypoglycemia occurred in 6.2 % of semaglutide-treated patients versus 2.5 % of placebo-treated patients. 
Like liraglutide, semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 syndrome. 
In rodents, semaglutide caused thyroid C-cell tumors, but no human cases have been linked to the use of semaglutide. 
Women of childbearing age should undergo a pregnancy test before starting the drug, and use contraception while taking it. 
Semaglutide 2.4 mg should be discontinued at least 2 months before conception, in accordance with the manufacturer's recommendations. 

 

Gelesis 100 (Plenity®) 

Gelesis 100 (Plenity®) is the first FDA-approved AOM for overweight adults (BMI 25-40 kg/m2) with or without comorbidities. 
Gelesis 100 is a hydrogel matrix composed of modified cellulose cross-linked with citric acid. 
Its mechanism of action is to absorb water to occupy around a quarter of the average stomach volume, promoting fullness. 
Because it achieves its primary objective through a mechanical mode of action, it is considered a device rather than a drug, and has no systemic effect. 
One dose consists of three oral capsules (2.25 g/dose) ingested with 500 mL of water 20-30 minutes before breakfast and lunch. 
Safety and side effects 
Side effects due to Gelesis 100 are usually gastrointestinal, including abdominal distension, infrequent bowel movements or dyspepsia. 
There were no significant differences between groups in serum vitamin levels.
Gelesis 100 is contraindicated during pregnancy or in people allergic to cellulose, citric acid, sodium stearyl fumarate, gelatin or titanium oxide. 
It should be avoided in patients with anatomical esophageal anomalies, suspected strictures or postoperative complications affecting gastrointestinal transit and motility. 
The manufacturer recommends caution in patients with active gastrointestinal reflux disease. 
The impact of Gelesis 100 on the absorption of other drugs has only been studied with metformin. 
Concomitant administration of Gelesis 100 with fasting metformin reduced the median area under the curve (AUC) of metformin, but had no effect on the AUC of metformin when administered with a meal. 
It is recommended that Gelesis 100 be taken with meals, unlike other drugs, which must be taken on an empty stomach. 

 

FUTURE DIRECTIONS FOR WEIGHT-LOSS DRUGS 

Medical providers, policy-makers and the pharmaceutical industry are increasingly recognizing the need for safe and effective pharmacotherapy for overweight and obese patients. 
A number of MAOs are currently at various stages of development. 
Dual gastrointestinal peptide modulators of GLP-1 and glucagon-dependent insulinotropic polypeptide (GIP) receptors, such as tirzepatide and the cotadutidehave Phase 2 results demonstrating effective weight loss in specific populations. 
The bimagrumab is a new first-in-class MAO which is a monoclonal antibody against activin type 2 receptors on skeletal myoblasts. 
Its Phase 2 trial focused on the single endpoint of fat mass loss rather than total body weight loss. 
With the advent of highly efficient MAOs such as the semaglutide 2.4 mg and new agents specifically targeting fat lossPharmacotherapy is likely to become more acceptable to society and the medical community for treating obesity as a disease. 

 

CARE OF THE OBÉSITÉ IN FRANCE 

Affecting 17.2% [15.2-19.3] of the 18-74 year-old population in 2015 in France, obesity is a real public health issue. 
As in the rest of the developed world, treatment consists first and foremost in modifying dietary habits and engaging in physical activity. 
This management must be active and multidisciplinary, with regular follow-up lasting at least 2 years, with the objective of achieving a weight loss of 5 % in 6 months. 
In the event of failure, GLP1 analogue drug treatment may be proposed for obese patients with a BMI ≥ 35 kg/m2. 
However, this drug prescription may be proposed from the outset for patients whose obesity compromises their autonomy or causes severe impairment of organ function, and for whom lifestyle changes are limited. 
In the event of failure of well-managed drug therapy, and as a last resort, surgical management may be proposed to patients with a BMI>40 or those with a BMI>35 and comorbidities. 
Regardless of the technique used, this is an effective treatment, with a weight loss of between 20 and 40 % that is maintained over the long term, but is nonetheless cumbersome and invasive. 
Of the above-mentioned drugs, only three have marketing authorization in France for the treatment of obesity, always in association with a moderately hypocaloric diet and increased physical activity: Orlistat (Xenical®), liraglutide (Saxenda®) and semaglutide (Wegovy®). 
Of these three drugs, only semaglutide (Wegovy®) is reimbursed by the French health insurance system, à Following a positive report from the HAS in late December 2022. 
Orlistat (Xenical®) is indicated for the treatment of obesity(BMI≥ 30 kg/m2), or overweight (BMI ≥ 28 kg/m2) associated with risk factors.
It should be discontinued after 12 weeks if patients have not lost at least 5 % of the initial weight measured at the start of drug treatment.
Liraglutide (Saxenda®) has marketing authorization for an indication similar to that of Wegovy (semaglutide), but non-refundable. 
Wegovy® (semaglutide) is indicated in the event of failure of nutritional management (weight loss of 5 % in 6 months) in adults aged 35. It is covered by the French health insurance system. 
However, this favourable opinion from the HAS remains conditional on the re-evaluation of Wegovy® (semaglutide) within a maximum of 2 years on the basis of réResults of the SELECT Phase III studyThe results of this study will be available in the first quarter of 2024. 

 

FOCUS ON SÉMAGLUTIDE (WEGOVY®) 

The only drug currently reimbursed, its initial prescription is réservée à to the professionals and structures involvedés in the management of obesity at recourse levels 2 and 3, namely : 
The obesity specialist (nutritionist), working in partnership with other professionals involved in obesity, SSR specialized in "gastroenterology, endocrinology, diabetology, nutrition", 
Specialized obesity centers (CSO) or university hospitals (CHU). 
This medication takes the form of an injectable solution in a multi-dose pre-filled pen. 
It is administered subcutaneously to the skin.èweekly (once a week). 
Maintenance dosage is 2.4 mg per week.
The latter is reached gradually by increasing the dosage in successive stages, each stage lasting 1 month: 
  • Stage 1: 0.25 mg / week
  • Stage 2: 0.5mg / week
  • Stage 3: 1mg / week
  • Stage 4: 1.7mg / week
  • Stage 5: Standard dosage 2.4mg / week 
This measure is primarily intended to reduce the occurrence of gastrointestinal symptoms. In the event of significant gastrointestinal symptoms, it is advisable to consider delaying the dose increase or reducing to the previous dose until symptoms improve. 
What should I do if I miss a dose? Take the missed dose if it is less than 5 days old, then resume treatment on the scheduled day. If forgotten for more than 5 days, do not take the missed dose, but resume treatment on the scheduled day. 

 

Warning about special situations 

Patients with type 2 diabetes When initiating treatment with semaglutide, a reduction in the dose of insulin or concomitantly administered insulin secretagogues (such as hypoglycemic sulfonamides) should be considered to reduce the risk of hypoglycemia. 
Renal failure patients No dose adjustment is necessary in patients with mild to moderate renal impairment. 
Experience with semaglutide in patients with severe renal impairment is limited. 
Semaglutide is not recommended for patients with severe or end-stage renal disease (eGFR <30 mL/min/1.73 m2). 
Patients with hépatiques : No dose adjustment is required in patients with mild to moderate hepatic impairment. Experience with semaglutide in patients with severe hepatic impairment is limited. 
Semaglutide is not recommended for patients with severe hepatic impairment, and should be used with caution in patients with mild to moderate hepatic impairment. 
Pediatric population and elderly subjects (≥ 65 years) : Not shown.

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