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

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 9200299 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-5233 (Electronic) Linking ISSN: 09405429 NLM ISO Abbreviation: Acta Diabetol Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin : Springer International, c1991-

Diabetes Mellitus, Type 2*/drug therapy ; Metformin*/therapeutic use ; Muscular Atrophy, Spinal*/drug therapy ; Non-alcoholic Fatty Liver Disease*; Adult ; Child ; Humans ; Male ; Young Adult ; Glucagon-Like Peptide 1/analogs & derivatives ; Glucagon-Like Peptide-1 Receptor ; Hypoglycemic Agents/therapeutic use ; Hypoglycemic Agents/pharmacology ; Liraglutide/therapeutic use ; Liraglutide/pharmacology ; Obesity

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.
(© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

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Keywords: Childhood obesity; Early-onset severe obesity; Hepatic nuclear factor 1 alpha (HNF1α MODY); MC4R gene mutation; Spinal muscular atrophy (SMA) type 3

89750-14-1 (Glucagon-Like Peptide 1)
0 (Glucagon-Like Peptide-1 Receptor)
0 (Hypoglycemic Agents)
839I73S42A (Liraglutide)
9100L32L2N (Metformin)

Date Created: 20230510 Date Completed: 20230626 Latest Revision: 20230626

20240628

10.1007/s00592-023-02109-9

37160786