Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework.
Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients w...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0300708&type=printable |
| _version_ | 1797242862069350400 |
|---|---|
| author | Alan J M Brnabic Sarah E Curtis Joseph A Johnston Albert Lo Anthony J Zagar Ilya Lipkovich Zbigniew Kadziola Megan H Murray Timothy Ryan |
| author_facet | Alan J M Brnabic Sarah E Curtis Joseph A Johnston Albert Lo Anthony J Zagar Ilya Lipkovich Zbigniew Kadziola Megan H Murray Timothy Ryan |
| author_sort | Alan J M Brnabic |
| collection | DOAJ |
| description | Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies-which was statistically significant for the comparison with teriflunomide-this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis. |
| first_indexed | 2024-04-24T18:45:57Z |
| format | Article |
| id | doaj.art-0d5a1ab4d7554a9784f75d42f490719a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-24T18:45:57Z |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0d5a1ab4d7554a9784f75d42f490719a2024-03-27T05:32:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-01193e030070810.1371/journal.pone.0300708Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework.Alan J M BrnabicSarah E CurtisJoseph A JohnstonAlbert LoAnthony J ZagarIlya LipkovichZbigniew KadziolaMegan H MurrayTimothy RyanResearchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies-which was statistically significant for the comparison with teriflunomide-this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0300708&type=printable |
| spellingShingle | Alan J M Brnabic Sarah E Curtis Joseph A Johnston Albert Lo Anthony J Zagar Ilya Lipkovich Zbigniew Kadziola Megan H Murray Timothy Ryan Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework. PLoS ONE |
| title | Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework. |
| title_full | Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework. |
| title_fullStr | Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework. |
| title_full_unstemmed | Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework. |
| title_short | Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework. |
| title_sort | incidence of type 2 diabetes cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease modifying therapies retrospective cohort study using a frequentist model averaging statistical framework |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0300708&type=printable |
| work_keys_str_mv | AT alanjmbrnabic incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework AT sarahecurtis incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework AT josephajohnston incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework AT albertlo incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework AT anthonyjzagar incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework AT ilyalipkovich incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework AT zbigniewkadziola incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework AT meganhmurray incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework AT timothyryan incidenceoftype2diabetescardiovasculardiseaseandchronickidneydiseaseinpatientswithmultiplesclerosisinitiatingdiseasemodifyingtherapiesretrospectivecohortstudyusingafrequentistmodelaveragingstatisticalframework |