Precision treatment of beta-cell monogenic diabetes: a systematic review
Authors: Naylor Rochelle N. , Patel Kashyap A. , Kettunen Jarno L. T. , Männistö Jonna M. E. , Støy Julie , Beltrand Jacques , Polak Michel ,   ADA/EASD PMDI, Tobias Deirdre K. , Merino Jordi , Ahmad Abrar , Aiken Catherine , Benham Jamie L. , Bodhini Dhanasekaran , Clark Amy L. , Colclough Kevin , Corcoy Rosa , Cromer Sara J. , Duan Daisy , Felton Jamie L. , Francis Ellen C. , Gillard Pieter , Gingras Véronique , Gaillard Romy , Haider Eram , Hughes Alice , Ikle Jennifer M. , Jacobsen Laura M. , Kahkoska Anna R. , Kreienkamp Raymond J. , Lim Lee-Ling , Massey Robert , Mclennan Niamh-Maire , Miller Rachel G. , Morieri Mario Luca , Most Jasper , Ozkan Bige , Patel Kashyap Amratlal , Pilla Scott J. , Prystupa Katsiaryna , Raghavan Sridharan , Rooney Mary R. , Schön Martin , Semnani-Azad Zhila , Sevilla-Gonzalez Magdalena , Svalastoga Pernille , Takele Wubet Worku , Tam Claudia Ha-ting , Thuesen Anne Cathrine B. , Tosur Mustafa , Wallace Amelia S. , Wang Caroline C. , Wong Jessie J. , Yamamoto Jennifer M. , Young Katherine , Amouyal Chloé , Andersen Mette K. , Bonham Maxine P. , Chen Mingling , Cheng Feifei , Chikowore Tinashe , Chivers Sian C. , Clemmensen Christoffer , Dabelea Dana , Dawed Adem Y. , Deutsch Aaron J. , Dickens Laura T. , DiMeglio Linda A. , Dudenhöffer-Pfeifer Monika , Evans-Molina Carmella , Fernández-Balsells María Mercè , Fitipaldi Hugo , Fitzpatrick Stephanie L. , Gitelman Stephen E. , Goodarzi Mark O. , Grieger Jessica A. , Guasch-Ferré Marta , Habibi Nahal , Hansen Torben , Huang Chuiguo , Harris-Kawano Arianna , Ismail Heba M. , Hoag Benjamin , Johnson Randi K. , Jones Angus G. , Koivula Robert W. , Leong Aaron , Leung Gloria K. W. , Libman Ingrid M. , Liu Kai , Long S. Alice , Lowe William L. , Morton Robert W. , Motala Ayesha A. , Onengut-Gumuscu Suna , Pankow James S. , Pathirana Maleesa , Pazmino Sofia , Perez Dianna , Petrie John R. , Powe Camille E. , Quinteros Alejandra , Jain Rashmi , Ray Debashree , Ried-Larsen Mathias , Saeed Zeb , Santhakumar Vanessa , Kanbour Sarah , Sarkar Sudipa , Monaco Gabriela S. F. , Scholtens Denise M. , Selvin Elizabeth , Sheu Wayne Huey-Herng , Speake Cate , Stanislawski Maggie A. , Steenackers Nele , Steck Andrea K. , Stefan Norbert , Støy Julie , Taylor Rachael , Tye Sok Cin , Ukke Gebresilasea Gendisha , Urazbayeva Marzhan , Van der Schueren Bart , Vatier Camille , Wentworth John M. , Hannah Wesley , White Sara L. , Yu Gechang , Zhang Yingchai , Zhou Shao J. , Beltrand Jacques , Polak Michel , Aukrust Ingvild , de Franco Elisa , Flanagan Sarah E. , Maloney Kristin A. , McGovern Andrew , Molnes Janne , Nakabuye Mariam , Njølstad Pål Rasmus , Pomares-Millan Hugo , Provenzano Michele , Saint-Martin Cécile , Zhang Cuilin , Zhu Yeyi , Auh Sungyoung , de Souza Russell , Fawcett Andrea J. , Gruber Chandra , Mekonnen Eskedar Getie , Mixter Emily , Sherifali Diana , Eckel Robert H. , Nolan John J. , Philipson Louis H. , Brown Rebecca J. , Billings Liana K. , Boyle Kristen , Costacou Tina , Dennis John M. , Florez Jose C. , Gloyn Anna L. , Gomez Maria F. , Gottlieb Peter A. , Greeley Siri Atma W. , Griffin Kurt , Hattersley Andrew T. , Hirsch Irl B. , Hivert Marie-France , Hood Korey K. , Josefson Jami L. , Kwak Soo Heon , Laffel Lori M. , Lim Siew S. , Loos Ruth J. F. , Ma Ronald C. W. , Mathieu Chantal , Mathioudakis Nestoras , Meigs James B. , Misra Shivani , Mohan Viswanathan , Murphy Rinki , Oram Richard , Owen Katharine R. , Ozanne Susan E. , Pearson Ewan R. , Perng Wei , Pollin Toni I. , Pop-Busui Rodica , Pratley Richard E. , Redman Leanne M. , Redondo Maria J. , Reynolds Rebecca M. , Semple Robert K. , Sherr Jennifer L. , Sims Emily K. , Sweeting Arianne , Tuomi Tiinamaija , Udler Miriam S. , Vesco Kimberly K. , Vilsbøll Tina , Wagner Robert , Rich Stephen S. , Franks Paul W. , Vilsbøll Tina , Greeley Siri A. W. , Hattersley Andrew T. , Tuomi Tiinamaija 
Published: July 2024

Background

Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes.

Methods

The search of PubMed, MEDLINE, and Embase for individual and group level data for glycemic outcomes using inclusion (English, original articles written after 1992) and exclusion (VUS, multiple diabetes types, absent/aggregated treatment effect measures) criteria. The risk of bias was assessed using NHLBI study-quality assessment tools. Data extracted from Covidence were summarized and presented as descriptive statistics in tables and text.

Results

There are 146 studies included, with only six being experimental studies. For GCK-related hyperglycemia, the six studies (35 individuals) assessing therapy discontinuation show no HbA1c deterioration. A randomized trial (18 individuals per group) shows that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes. Cohort and case studies support SU’s effectiveness in lowering HbA1c. Two cross-over trials (each with 15–16 individuals) suggest glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes is limited. Most reported patients with HNF1B-diabetes (N = 293) and MD (N = 233) are on insulin without treatment studies. Limited data support oral agents after relapse in 6q24-TND and for thiamine improving glycemic control and reducing/eliminating insulin requirement in SLC19A2-diabetes.

Conclusion

There is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes.