Effectiveness and Safety of Setmelanotide in a Patient With a Heterozygous PCSK1 Deficiency.
Setmelanotide may aid weight loss in patients with heterozygous PCSK1 mutations, but skin hyperpigmentation is a potential side effect.
Where it sits
this study against the rest of the setmelanotide corpusSummary and findings
A 40-year-old female with a heterozygous PCSK1 N221D mutation and severe obesity achieved an 11.8% weight loss over 3 months with setmelanotide. This case also reported severe skin hyperpigmentation as an adverse effect. The study highlights setmelanotide's potential in treating obesity linked to PCSK1 mutations.
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.
Background
Setmelanotide is a melanocortin 4 receptor agonist used to treat rare monogenic obesity conditions. It targets the leptin-melanocortin signaling pathway, which is often disrupted in individuals with PCSK1 gene mutations. Previous studies have focused on homozygous mutations, but this study explores its effectiveness in a heterozygous mutation.
Methods
This study is a single case report involving a 40-year-old female with a heterozygous PCSK1 N221D mutation. The patient had severe early-onset obesity resistant to bariatric surgery and conventional treatments. Setmelanotide was administered, and outcomes were observed over a 3-month period.
Results
The patient experienced an 11.8% reduction in total body weight over 3 months of setmelanotide treatment. A notable adverse effect was severe skin hyperpigmentation. The mutation was associated with a 10% to 30% loss of enzymatic function in vitro.
Interpretation
This case suggests that setmelanotide may be effective in treating obesity associated with heterozygous PCSK1 mutations, expanding its potential use beyond homozygous cases. However, the clinical significance of the weight loss should be interpreted cautiously due to the small sample size and lack of a control group. The adverse effect of skin hyperpigmentation warrants further investigation.
Key findings
- 11.8% total weight loss over 3 months
- 40-year-old female with heterozygous PCSK1 N221D mutation
- Severe skin hyperpigmentation as an adverse effect
- First case report of setmelanotide in heterozygous PCSK1 mutation
Limitations
- Single case report
- No control group
- Short 3-month follow-up
- Limited to heterozygous PCSK1 mutation