Page 17 - IMO-2-2

Innovative Medicines & Omics Pharmacotherapy of obesity

serious risks include the development of antibodies against concerns about melanocytic tumors. Sexual dysfunction,
this medicine, which could reduce its effectiveness. Some such as persistent erection in males, results from MC4R
people may experience hypoglycemia, particularly when activation affecting sexual brain processing. Obese patients
combined with other diabetes medications. Furthermore, treated with setmelanotide are also at an increased risk
there are concerns about the potential for liver enzyme of suffering from depression. The administration of this
elevations and the possibility of lymphoma in rare cases, medication to neonates and infants is contraindicated due
especially in patients with underlying conditions like to the presence of benzyl alcohol, which could trigger fatal
lipodystrophy. reactions such as gasping syndrome.
Metreleptin is contraindicated in individuals with a Setmelanotide is contraindicated during pregnancy
known hypersensitivity to the drug or its components. due to potential risks to the fetus, such as benzyl alcohol-
It should not be used in patients with endogenous leptin induced gasping syndrome. Weight loss while pregnant
production, as it may not be effective or appropriate. is not recommended. Furthermore, this medicine is not
Metreleptin is also contraindicated in patients with recommended with breastfeeding, as it may be excreted
uncontrolled active infections, especially those with a in milk. Due to limited safety data, it is not suitable for
history of lymphoma or other cancers, as it may increase children under 6 or elderly patients over 65. Moreover,
the risk of malignancy. In addition, it should not be used it is contraindicated in patients with moderate-to-severe
during pregnancy unless the benefits outweigh the risks. 72 renal impairment or end-stage renal disease, and not
recommended for those with hepatic impairment. 73
11.6. Setmelanotide
Setmelanotide is an octapeptide that focuses on 11.7. Semaglutide
melanocortin receptors, and specifically in MC4R, Semaglutide is an antidiabetic medication used for the
MC3R, and MC1R, in the hypothalamus. This peptide treatment of Type 2 diabetes and an anti-obesity medication
boosts MC4R signaling, which plays an important role in used for long-term weight management. It is a peptide
controlling satiety and appetite and as a result, it decreases similar to the GLP-1 hormone, with a modification to its
hyperphagia and contributes to weight loss. This medicine side chain. It is available as both a subcutaneous injection
has been clinically proven to promote weight loss in and an oral medication, with doses given as 0.25 mg, 0.5 mg,
individuals with deficiencies in POMC and LEPR with and 1 mg through subcutaneous injection once weekly,
noteworthy outcomes. Furthermore, the drug’s metabolism and 3 mg, 7 mg, and 14 mg orally once daily. The FDA has
yields peptides and amino acids with approximately 39% also approved semaglutide in June 2021 for the long-term
excreted unaltered in the urine. Setmelanotide is indicated management of weight using higher subcutaneous doses
for chronic weight management (weight loss and weight of 1.7 and 2.4 mg once weekly. Specifically, clinical trials
maintenance for at least one year) in people six years and on the semaglutide treatment effect in people with obesity
older with obesity due to three rare genetic conditions: have documented that semaglutide is effective for obesity
POMC deficiency, proprotein subtilisin/kexin Type 1 management. 74
(PCSK1) deficiency, and LEPR deficiency confirmed by
genetic testing demonstrating variants in POMC, PCSK1, The dose of semaglutide for obesity is usually initiated
and LEPR genes, which are considered pathogenic (causing at a low dose and titrated upward to minimize adverse
disease), likely pathogenic, or of uncertain significance. effects. The exact dosing and titration schedule depend
on the formulation used (e.g., Ozempic and Wegovy)
Setmelanotide is administered as a subcutaneous and the patient’s response to treatment. The general
injection. The typical starting dose is 1 mg once daily, dosing schedule, which is specifically approved for weight
which may be increased gradually based on clinical management, is 0.25 mg injection once a week from week
response and tolerability, up to a maximum of 2 mg daily. 1 to 4, 0.5 mg injection once a week from week 5 to 8, 1 mg
The exact dose may vary depending on individual patient injection once a week from week 9 to 12, 1.7 mg injection
needs and physician recommendations. once a week from week 13 to 16, and 2.4 mg injection once
Hypersensitivity at the injection site, including blistering, a week at week 17 and beyond (with the latter being the
burning, hives, and skin discoloration, constitutes one of maintenance dose). 75
the most frequent side effects observed with setmelanotide.
Other undesirable effects comprise sexual dysfunction, 11.7.1. Mechanism of action of liraglutide and
skin hyperpigmentation, depression, and suicidal ideation. semaglutide
MC4R receptor stimulation on melanocytes leads to GLP-1 is an incretin hormone produced by enteroendocrine
hyperpigmentation, which is reversible but may raise L-cells and α-cells in both the pancreas and the central

Volume 2 Issue 2 (2025) 11 doi: 10.36922/imo.8316