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Review
. 2021 Sep 30;30(3):196-208.
doi: 10.7570/jomes21033.

Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?

Donna H Ryan  1
Affiliations
Review

Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?

Donna H Ryan. J Obes Metab Syndr. .

Abstract

There is a new generation of antiobesity drugs in development or just arriving on the scene. First, setmelanotide has been approved for three of the ultrarare genetic conditions that cause obesity-pro-opiomelanocortin deficiency, proprotein convertase subtilisin and kexin type 1 (an important enzyme in the melanocortin pathway) and leptin receptor deficiency. Setmelanotide marks the first in a personalized medicine approach to obesity. Second, semaglutide 2.4 mg once weekly has been submitted to regulators in the United States and the European Union for approval for patients with obesity (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and at least one weight related comorbidity. This drug has been studied in five phase 3 clinical trials, four discussed herein: semaglutide produces roughly twice as much weight loss as we have seen in older antiobesity medications. Semaglutide is already in use for treatment of diabetes and, as a glucagon-like peptide 1 (GLP-1) receptor analog, is part of a class of drugs used widely in diabetes. Tirzepatide, a glucose-insulin peptide and GLP-1 dual agonist is in phase 3 study for obesity management, and bimagrumab is a new agent in phase 2 with a unique mechanism of action; they are generating much interest. The purpose of this narrative review is lay the groundwork for a discussion of the clinical impact of these new medications on the clinical practice of obesity. Further, these developments shall be used to launch a speculation of what is likely to be their impact on the future of obesity pharmacotherapy.

Keywords: Anti-obesity agents; Anti-obesity drugs; Bimagrumab; Semaglutide; Setmelanotide; Tirzepatide; Weight loss agents.

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Figures

Figure. 1
Figure. 1
Chemical structure of setmelanotide, semaglutide, tirzepatide and bimagrumab. (A) Setmelanotide. Adapted from Wikimedia Commons contributors. (B) Semaglutide. Adapted from Echemi. (C) Tirzepatide. Adapted from Echemi. (D) Bimagrumab. Adapted from RCSB Protein Data Bank.
Figure. 2
Figure. 2
(A) Setmelanotide and pro-opiomelanocortin (POMC) deficiency. Weight loss percentages from baseline for nine participants at week 52 are shown. There were 10 patients enrolled (nine with POMC deficiency and one with proprotein convertase subtilisin/kexin type 1 [PCSK1] deficiency). The patient with PCSK1 deficiency dropped out following the drug withdrawal placebo phase of the clinical trial, when hyperphagia reoccurred and the patient experienced suicidal ideation. Nine patients completed the trial and of those, eight achieved the primary endpoint (≥ 10% weight loss). (B) Setmelanotide in leptin receptor (LEPR) deficiency. Weight loss percentages from baseline for seven participants at week 52 are shown. There were 11 patients enrolled. One patient died in an auto accident. Five patients achieved the primary endpoint (≥ 10% weight loss). Not shown are data from two patients who did not lose at least 5% during the initial open-label period. Data from Clément et al.
Figure. 3
Figure. 3
Observed mean weight loss with semaglutide 2.4 mg weekly compared to placebo over 68 weeks of treatment. Error bars are standard error. Line graph shows participants in the full analysis set from randomization to last contact with trial site. CI, confidence interval. Adapted from Wilding et al. N Engl J Med 2021;384:989-1002 with permission.
Figure. 4
Figure. 4
Mean weight loss from baseline to week 68 for semaglutide or placebo in Semaglutide Treatment Effect in People with obesity (STEP) trials 1–4. Results are shown for treatment policy estimand. This is like an intention-to-treat analysis where all assigned participants are considered, and missing data are accounted for with statistical measures of multiple imputation for the primary estimand. STEP 1: modified from Wilding et al. N Engl J Med 2021;384:989-1002. STEP 2: modified from Davies et al. Lancet 2021;397:971-84. STEP 3: modified from: Wadden et al. JAMA 2021;325:1403-13. STEP 4: modified from: Rubino D et al. JAMA 2021; 325:1414-25.
Figure. 5
Figure. 5
Categorical weight loss for semaglutide and placebo in Semaglutide Treatment Effect in People with obesity (STEP) trials 1–4. Note that in STEP 2, the achievement of higher categories of weight loss was less in the semaglutide 2.4 mg treated participants, compared to STEP 1 and STEP 3. Note the greater achievement in weight loss categories in the placebo group in STEP 3. In STEP 3 in the presence of a more intensive behavioral intervention resulted in greater efficacy in the placebo group but in the semaglutide treatment group the categorical weight losses were less than in STEP 1 and STEP 3. (A) STEP 1: adapted from Wilding et al. N Engl J Med 2021;384:989- 1002 with permission. (B) STEP 2: modified from Davies et al. Lancet 2021;397:971-84. (C) STEP 3: modified from Wadden et al. JAMA 2021;325:1403-13. (D) STEP 4: modified from Rubino D et al. JAMA 2021;325:1414-25.
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