Type 1 Diabetes Prevention: a systematic review of studies testing disease-modifying therapies and features linked to treatment response

Background Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Efforts to prevent T1D have focused on modulating immune responses and supporting beta cell health; however, heterogeneity in disease progression and responses to therapies have made these efforts difficult to translate to clinical practice, highlighting the need for precision medicine approaches to T1D prevention. Methods To understand the current state of knowledge regarding precision approaches to T1D prevention, we performed a systematic review of randomized-controlled trials from the past 25 years testing disease-modifying therapies in T1D and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. Results We identified 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss in individuals at disease onset. Seventeen agents tested, mostly immunotherapies, showed benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employed precision analyses to assess features linked to treatment response. Age, measures of beta cell function and immune phenotypes were most frequently tested. However, analyses were typically not prespecified, with inconsistent methods reporting, and tended to report positive findings. Conclusions While the quality of prevention and intervention trials was overall high, low quality of precision analyses made it difficult to draw meaningful conclusions that inform clinical practice. Thus, prespecified precision analyses should be incorporated into the design of future studies and reported in full to facilitate precision medicine approaches to T1D prevention. Plain Language Summary Type 1 diabetes (T1D) results from the destruction of insulin-producing cells in the pancreas, necessitating lifelong insulin dependence. T1D prevention remains an elusive goal, largely due to immense variability in disease progression. Agents tested to date in clinical trials work in a subset of individuals, highlighting the need for precision medicine approaches to prevention. We systematically reviewed clinical trials of disease-modifying therapy in T1D. While age, measures of beta cell function, and immune phenotypes were most commonly identified as factors that influenced treatment response, the overall quality of these studies was low. This review reveals an important need to proactively design clinical trials with well-defined analyses to ensure that results can be interpreted and applied to clinical practice. ### Competing Interest Statement EKS has received compensation for educational lectures from Medscape, ADA, and MJH Life Sciences and as a consultant for DRI Healthcare. CEM reported serving on advisory boards for Provention Bio, Isla Technologies, MaiCell Technologies, Avotres, DiogenyX, and Neurodon; receiving in-kind research support from Bristol Myers Squibb and Nimbus Pharmaceuticals; and receiving investigator-initiated grants from Lilly Pharmaceuticals and Astellas Pharmaceuticals. LAD reports research support to institution from Dompe, Lilly, Mannkind, Provention, Zealand and consulting relationships with Abata and Vertex. RAO had a UK MRC Confidence in concept grant to develop a T1D GRS biochip with Randox Ltd, and has ongoing research funding from Randox R & D. No other authors report any relevant conflicts of interest. ### Funding Statement JF: DiabDocs K12 1K12DK133995-01, The Leona M. and Harry B. Helmsley Charitable Trust Grant 2307-06126. KG: The Leona M. and Harry B. Helmsley Charitable Trust and Sanford Health. RAO: RAO had a UK MRC confidence in concept award to develop a type 1 diabetes GRS biochip with Randox R&D and has ongoing research funding from Randox; and has research funding from a Diabetes UK Harry Keen Fellowship (16/0005529), National Institute of Diabetes and Digestive and Kidney Diseases grants (NIH R01 DK121843-01 and U01DK127382-01), JDRF (3-SRA-2019-827-S-B, 2-SRA-2022-1261-S-B, 2-SRA-2002-1259-S-B, 3-SRA-2022-1241-S-B, and 2-SRA-2022-1258-M-B), and The Larry M and Leona B Helmsley Charitable Trust; and is supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the National Institutes for Health Research or the Department of Health and Social Care. LAD: NIH for TrialNet U01DK106993/6163-1082-00-BO, DiabDocs K12 program 1K12DK133995-01, CTSI UL1TR001108-01, CEM: R01DK093954, R01DK127236, U01DK127786, R01DK127308, and UC4DK104166, U54DK118638, P30 P30 DK097512), a US Department of Veterans Affairs Merit Award (I01BX001733), grants from the JDRF (3-IND-2022-1235-I-X) and Helmsley Charitable Trust (2207-05392), and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, and the George and Frances Ball Foundation. HI: K23DK129799; RJ: NIH R03-DK127472 and The Leona M. and Harry B. Helmsley Charitable Trust (2103-05094); SAL: NIH NIAID R01 AI141952 (PI), NIH NCI R01 CA231226 (Other support), NIH NIAID 1 R01HL149676 (Other support), NIH NIDDK 1UC4DK117483 (subaward), JDRF 3-SRA-2019-851-M-B; SOG: NIH R01 DK121843-01; SR: R01 DK122586, THE LEONA M AND HARRY B HELMSLEY CHARITABLE TRUST 2204-05134; JW: JDRF 2-SRA-2022-1282-M-X, 3-SRA-2022-1095-M-B, 4-SRA-2022-1246-M-N, 3-SRA-2023-1374-M-N.; MR: NIH NIDDK R01DK124395 and R01DK121843; R01DK121929A1, R01DK133881, U01DK127786, U01 DK127382 (EKS). Effort from this grant (to EKS, HI, JF) is also supported by Grant 2021258 from the Doris Duke Charitable Foundation through the COVID-19 Fund to Retain Clinical Scientists collaborative grant program and was made possible through the support of Grant 62288 from the John Templeton Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All studies reviewed were identified via publically available databases (PubMed and Embase). Article review data supporting the findings of this study are available upon reasonable request from the corresponding author.