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Review
. 2023 Mar 20:58:101882.
doi: 10.1016/j.eclinm.2023.101882. eCollection 2023 Apr.

Pharmacotherapy of obesity: an update on the available medications and drugs under investigation

Marlene Chakhtoura  1 , Rachelle Haber  1 , Malak Ghezzawi  1 , Caline Rhayem  1 , Raya Tcheroyan  2 , Christos S Mantzoros  3
Affiliations
Review

Pharmacotherapy of obesity: an update on the available medications and drugs under investigation

Marlene Chakhtoura et al. EClinicalMedicine. .

Abstract

Obesity is an epidemic and a public health threat. Medical weight management remains one of the options for the treatment of excess weight and recent advances have revolutionized how we treat, and more importantly how we will be treating obesity in the near future. Metreleptin and Setmelanotide are currently indicated for rare obesity syndromes, and 5 other medications (orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide) are approved for non-syndromic obesity. Tirzepatide is about to be approved, and other drugs, with exciting novel mechanisms of action primarily based on incretins, are currently being investigated in different phases of clinical trials. The majority of these compounds act centrally, to reduce appetite and increase satiety, and secondarily, in the gastrointestinal tract to slow gastric emptying. All anti-obesity medications improve weight and metabolic parameters, with variable potency and effects depending on the specific drug. The currently available data do not support a reduction in hard cardiovascular outcomes, but it is almost certain that such data are forthcoming in the very near future. The choice of the anti-obesity medication needs to take into consideration the patient's clinical and biochemical profile, co-morbidities, and drug contra-indications, as well as expected degree of weight loss and improvements in cardio-renal and metabolic risk. It also remains to be seen whether precision medicine may offer personalized solutions to individuals with obesity, and whether it may represent the future of medical weight management along with the development of novel, very potent, anti-obesity medications currently in the pipeline.

Funding: None.

Keywords: Anti-obesity medications; Obesity; Weight management.

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Conflict of interest statement

C.S.M. has been a shareholder of and reports grants through his institution from Merck, grants through his Institution and personal consulting fees from Coherus Inc. and AltrixBio, he reports grants through his institution and personal consulting fees from Novo Nordisk, reports personal consulting fees and support with research reagents from Ansh Inc., reports personal consulting fees from Genfit, Lumos, Amgen, Corcept, Intercept, Astra Zeneca, 89bio and Regeneron, reports support (educational activity meals at and through his institution) from Amarin, Novo Nordisk and travel support and fees from TMIOA, Elsevier, the California Walnut Commission, College Internationale Researche Servier and the Cardio Metabolic Health Conference. None is related to the work presented herein. All other authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Site of action of FDA approved anti-obesity medications. (1): parietal cortex, (2) hippocampus, (3) hypothalamus, (4) insula, (5) putamen, (6) dorsal anterior cingulate, (7) superior frontal cortex, (8) nucleus accumbens, (9) orbitofrontal cortex, (10) superior parietal cortex. For GLP-1 receptor agonists and naltrexone/bupropion, the central sites of action are derived from animal studies and brain functional MRI studies in humans; For phentermine/topiramate, the central sites of action are derived from animal studies. Animal studies showed that GLP-1 agonists act on the hypothalamus and the nucleus of the solitary tract. GLP-1 agonists act also on the parietal cortex, insula, putamen, and orbitofrontal cortex in response of food images, as demonstrated in functional MRI studies., Naltrexone/bupropion acts on the hypothalamus, superior parietal cortex, posterior insula, dorsal anterior cingulate, hippocampus. There are inconsistent data on its role in the superior frontal cortex, the amygdala and nucleus accumbens.,, , Phentermine acts on the hypothalamus. Topiramate acts on the hypothalamus and the hippocampus, as shown in animal models and the nucleus accumbens, in a proof-of-concept study for the treatment of alcohol dependence, not for weight management. GLP-1, glucagon-like peptide-1; HCl, hydrochloric acid. This figure was created using BioRender (https://biorender.com/).
Fig. 2
Fig. 2
Mean percent (%) weight change reported in the main phase 3 and extension trials of the FDA approved anti-obesity medications. Orlistat: XENDOS trial (years 1 and 4). Phentermine/topiramate: CONQUER and SEQUEL trials. Naltrexone/bupropion: COR-I and COR-II trials. Liraglutide: SCALE Obesity, SCALE Obesity and Prediabetes Extension, and SCALE maintenance trials. Semaglutide: STEP 1 and STEP 4 trial. All trials are listed in order as seen in the figure from left to right. The grey color represents placebo arms; the red color represents intervention arms. aThe mean weight change in the orlistat group is in kg not in percent (stripped bar charts). bUnder expedited consideration for FDA approval.
Fig. 3
Fig. 3
Suggested algorithm for the selection of anti-obesity medications, taking into consideration the availability of drug safety, contra-indications, and preliminary efficacy data for a specific patient profile.a CVD, cardiovascular disease; DM, diabetes mellitus; HTN, hypertension; MTC, medullary thyroid cancer; NAFLD, non-alcoholic fatty liver disease. aWith the exception of data in patients with NAFLD, Orlistat was not investigated in patients with CVD, mental diseases and sleep apnea. However, given its safety profile, Orlistat can be considered in these conditions. None of the drugs is approved for use during pregnancy. Additional contra-indications for specific medications are described in Table 1. bAge >65 years: Liraglutide and Phentermine/Topiramate trials included 7% of participants ≥65 years. For Semaglutide, SUSTAIN trials in patients with diabetes mellitus showed that efficacy is preserved regardless of age. The COR program included only 2% of participants from the elderly population, and the XENDOS included none. cCVD includes patient with previous history of CVD and those at high risk for CVD. The suggestion for the use of GLP-1 receptors agonist is based on the availability of indirect evidence on cardiovascular risk reduction in patients with diabetes mellitus, LEADER trial for liraglutide and SUSTAIN trial for semaglutide. There was no signal of increased CVD in patient with obesity on liraglutide. The suggestion for the use of Liragluide and Semaglutide in patients with obesity and DM is based on the fact that GLP-1 receptor agonists are anti-diabetic medications. dDepression: For Phentermine/topiramate, NB and liraglutide, the FDA includes “Suicidal Behavior and Ideation” under “Warning and Precautions” and recommend to monitor patients for depression and suicidal thoughts, and to stop the drug in case of symptoms development.,,eMTC: personal or family history of MTC, a contra-indication for Liraglutide and Semaglutide. fSmall trials on Orlistat, Liraglutide and Semaglutide showed improvement in steatosis, but none of them showed improvement in liver fibrosis; only post-hoc data are available on NB. gThe FDA leaflet of Phentermine states the following under contra-indications “History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension). The FDA leaflet of NB states that uncontrolled hypertension is a contra-indication. For liraglutide and semaglutide, increased heart rate is considered under “Warning and Precautions” in the FDA leaflets, with a suggestion to monitor as the clinical implication of the increase in heart rate by few beats per minutes is not known.,
Fig. 4
Fig. 4
Site of action of drugs under development for treatment of obesity. (1) parietal cortex, (2) hypothalamus, (3) insula, (4) putamen, (5) nucleus accumbens, (6) striatum, (7) orbitofrontal cortex, (8) hindbrain, (9) mesolimbic area. GLP-1/glucagon dual agonists, GIP/GLP-1 dual agonists, Y2R, amylin receptor agonists, methylphenidate, oxytocin, and leptin sensitizers act centrally to reduce food intake. Few drugs act solely peripherally: SGLT-2 inhibitors on the kidney; Gladribin on liver and muscle; Vitamin E on adipose tissue. GIP, Gastric inhibitory polypeptide; GLP-1, Glucagon receptor agonist; SGLT2, Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors; Y2R, Y2-receptor. Tesofensine is not included in the figure as we did not identify any related ongoing study. This figure was created using BioRender (https://biorender.com/).
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