Academic Journal
Effectiveness and Safety of Setmelanotide in a Patient With a Heterozygous PCSK1 Deficiency.
| Title: | Effectiveness and Safety of Setmelanotide in a Patient With a Heterozygous PCSK1 Deficiency. |
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| Authors: | Lytvyak E; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada., Rattol A; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada., Grunvald E; School of Medicine, University of California San Diego, La Jolla, California, USA. |
| Source: | Obesity (Silver Spring, Md.) [Obesity (Silver Spring)] 2026 Sep; Vol. 34 Suppl 2, pp. 70-74. Date of Electronic Publication: 2026 May 01. |
| Publication Type: | Journal Article; Case Reports |
| Language: | English |
| Journal Info: | Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 101264860 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1930-739X (Electronic) Linking ISSN: 19307381 NLM ISO Abbreviation: Obesity (Silver Spring) Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2013- : Malden, MA : John Wiley & Sons Original Publication: Silver Spring, MD : NAASO, the Obesity Society, c2006- |
| MeSH Terms: | Proprotein Convertase 1*/genetics , Proprotein Convertase 1*/deficiency , Receptor, Melanocortin, Type 4*/agonists , alpha-MSH*/analogs & derivatives , alpha-MSH*/therapeutic use , alpha-MSH*/adverse effects , Obesity*/drug therapy , Obesity*/genetics , Anti-Obesity Agents*/therapeutic use , Anti-Obesity Agents*/adverse effects, Weight Loss/drug effects ; Hyperpigmentation/chemically induced ; Humans ; Female ; Adult ; Heterozygote ; Mutation ; Treatment Outcome |
| Abstract: | Setmelanotide, a melanocortin 4 receptor (MC4R) agonist, is a promising pharmacological treatment option for people with rare monogenic obesity conditions affecting the leptin-melanocortin signaling pathway, including proprotein convertase subtilisin/kexin type 1 (PCSK1) gene mutations. It has been studied in people with homozygous mutations causing a complete deficiency of PCSK1. We report the first case of a 40-year-old female with a heterozygous PCSK1 N221D (c.661 A>G) variant mutation leading to severe early-onset treatment-resistant obesity with previous suboptimal response to bariatric surgery and conventional obesity medications, who achieved a total weight loss of 11.8% with setmelanotide treatment over the course of 3 months. Although her mutation confers a loss of 10% to 30% enzymatic function in in vitro studies, setmelanotide was highly effective in treating her obesity. It is also the first reported case of a cutaneous adverse effect of setmelanotide in the form of severe skin hyperpigmentation in a patient with a pathogenic PCSK1 variant. This case underscores the effectiveness and safety of setmelanotide in a heterozygous PCSK1 mutation. (© 2026 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.) |
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| Contributed Indexing: | Keywords: c.661A>G (p.Asn221Asp) variant; effectiveness; heterozygous PCSK1 deficiency; obesity; safety; setmelanotide; weight loss |
| Substance Nomenclature: | EC 3.4.21.93 (Proprotein Convertase 1) EC 3.4.21.93 (PCSK1 protein, human) 0 (Receptor, Melanocortin, Type 4) 0 (setmelanotide) 581-05-5 (alpha-MSH) 0 (Anti-Obesity Agents) 0 (MC4R protein, human) |
| Entry Date(s): | Date Created: 20260502 Date Completed: 20260902 Latest Revision: 20260904 |
| Update Code: | 20260904 |
| PubMed Central ID: | PMC13535729 |
| DOI: | 10.1002/oby.70213 |
| PMID: | 42068058 |
| Database: | MEDLINE |
| ISSN: | 1930-739X |
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| DOI: | 10.1002/oby.70213 |