Glucagon-like peptide-1 analog therapy in rare genetic diseases: monogenic obesity, monogenic diabetes, and spinal muscular atrophy

• Published in: Acta diabetologica Vol. 60; no. 8; pp. 1099 - 1108
• Main Authors: Zaitoon, Hussein, Lubetzky, Ronit, Amir, Achiya Z., Moran-Lev, Hadar, Sagi, Liora, Yacobi-Bach, Michal, Borger, Ophir, Chorna, Efrat, Lebenthal, Yael, Brener, Avivit
• Format: Journal Article
• Language: English
• Published: Milan Springer Milan 01.08.2023; Springer Nature B.V
• Subjects: Age; Antihypertensives; Body mass index; Body weight gain; Comorbidity; Diabetes; Diabetes mellitus; Fatty liver; Genetic analysis; Genetic disorders; Glucagon; Glucagon-like peptide 1; Hypercholesterolemia; Internal Medicine; Literature reviews; Liver diseases; Medicine; Medicine & Public Health; Metabolic Diseases; Metformin; Mutation; Neuromuscular diseases; Obesity; Original Article; Peptides; Spinal muscular atrophy; Statins; Early-onset severe obesity; Childhood obesity; MC4R gene mutation; Hepatic nuclear factor 1 alpha (HNF1α MODY); Spinal muscular atrophy (SMA) type 3
• DOI: 10.1007/s00592-023-02109-9
• ISSN: 1432-5233; 0940-5429

Aim Implementing genetic analyses have unraveled rare alterations causing early-onset obesity and complications, in whom treatment is challenging. We aimed to report on the effects of adjuvant off-label therapy with liraglutide, glucagon-like peptide-1 analogue (GLP-1a), in rare genetic diagnoses. Methods Case scenarios and review of the literature. Results Case 1: Nine-year-old boy with early-onset severe obesity and nonalcoholic fatty liver disease (NAFLD) due to a homozygous mutation in the MC4R gene deteriorated under lifestyle change and metformin therapy [at 10.5 years: body mass index (BMI) 51.2kg/m 2 , 226% of the 95th percentile, fat percentage (FP) 65% and muscle-to-fat ratio (MFR) z-score of −2.41]. One year of liraglutide treatment halted progressive weight gain [BMI 50.3kg/m 2 , 212% of the 95th percentile, 63.7% FP and MFR z-score of −2.34], with biochemical improvement. Case 2: Twelve-year-old boy with obesity presented with diabetes and progressive NAFLD. Exome analysis revealed two heterozygous mutations compatible with monogenic diabetes ( HNF1A ) and familial hypercholesterolemia ( LDLR ). Lifestyle modifications resulted in clinical and laboratory improvement (BMI 87th percentile, 32.8% FP, MFR z-score of −1.63, HbA1c 5.5%) without the expected recovery in liver transaminases. Liraglutide treatment augmented the improvement in weight status (BMI 68th percentile, 22.6% FP, MFR z-score of −1.13) with normalization of liver transaminases. Case 3: Nineteen-year-old male with spinal muscular atrophy type 3 presented with sarcopenic obesity and comorbidities. Treatment strategy included dietary counseling and multiple drug therapies (metformin, anti-hypertensive and statins). Liraglutide therapy led to a gradual recovery of metabolic complications allowing tapering-down other medications. Conclusions Considering the pleiotropic effects of GLP1-a beyond BMI reduction, this treatment modality may serve as a game changer in challenging cases.