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

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Abstract

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/m2, 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/m2, 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.

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Data availability

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Acknowledgements

The authors are grateful to the patients and their families for their consent to share their unique vignettes, to the multidisciplinary team of dedicated health-care professionals caring for these patients, and to Esther Eshkol for editorial assistance.

Funding

None.

Author information

Authors and Affiliations

  1. Pediatric Endocrinology and Diabetes Unit, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, 6 Weizmann St, 64239-06, Tel Aviv, Israel

    Hussein Zaitoon, Ophir Borger, Efrat Chorna, Yael Lebenthal & Avivit Brener

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ronit Lubetzky, Achiya Z. Amir, Hadar Moran-Lev, Liora Sagi, Yael Lebenthal & Avivit Brener

  3. Department of Pediatrics, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Ronit Lubetzky

  4. Pediatric Gastroenterology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Achiya Z. Amir & Hadar Moran-Lev

  5. Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Liora Sagi

  6. The Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Michal Yacobi-Bach

  7. Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Michal Yacobi-Bach

  8. The Nutrition and Dietetics Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Ophir Borger

  9. Social Services, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Efrat Chorna

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  1. Hussein Zaitoon
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Contributions

YL and AB helped in conceptualization; HZ, RL, AA, HM-L, LS, MY-B, OB, EC, YL, and AB helped in data curation; HZ, RL, AA, HM-L, LS, MY-B, OB, EC, YL, and AB worked in investigation; HZ and AB helped in writing—original draft; and HZ, RL, AA, HM-L, LS, MY-B, OB, EC, YL, and AB helped in writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Avivit Brener.

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Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

The institutional ethics committee after careful consideration and deliberation in each case approved the off-label use of liraglutide.

Informed consent

The patients and their parents gave their informed consent to publish their case.

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Zaitoon, H., Lubetzky, R., Amir, A.Z. et al. Glucagon-like peptide-1 analog therapy in rare genetic diseases: monogenic obesity, monogenic diabetes, and spinal muscular atrophy. Acta Diabetol 60, 1099–1108 (2023). https://doi.org/10.1007/s00592-023-02109-9

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