DaNGER: Diabetic Ketoacidosis From New SGLT2i: Can Genomics Estimate Risk

Sponsor

Mount Sinai Hospital, Canada (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05402579

Collaborator

Unity Health Toronto (Other), University Health Network, Toronto (Other), Sault Area Hospital (Other)

200

Enrollment

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Sodium glucose co-transporter 2 (SGLT2) inhibitors have revolutionized care for people living with type 2 diabetes mellitus (T2DM). They reduce a person's risk of heart failure, renal failure, myocardial infarction, stroke, cardiovascular mortality, and potentially all-cause mortality. Remarkably, some of these benefits also extend to people who do not have T2DM. While the benefits of SGLT2 inhibitors are impressive, there is one life-threatening side effect associated with their use: diabetic ketoacidosis (DKA). The ability to predict which patients are at highest risk of DKA is needed to sufficiently mitigate this risk. Moreover, considering the impressive benefits of SGLT2 inhibitors, identifying patients at the lowest risk of SGLT2 inhibitor-associated DKA is also important so that providers do not overestimate risk in those who stand to benefit most.

Advances in genomic technologies and related analyses have provided unprecedented opportunities to bring genomics-driven precision medicine initiatives to the forefront of clinical research. Leading these developments has been the progress made by genome-wide association studies (GWAS) due to decreasing genotyping costs, and consequently, the ability to routinely study large numbers of patients. These approaches allow for systematic screening of the genome in an unbiased manner and have accelerated the discovery of genetic variants and novel biological processes that contribute to the development of adverse treatment outcomes.

By using innovative approaches, which harness large cohorts of population controls, sample size limitations that are associated with rare adverse drug reactions such as SGLT2 inhibitor-associated DKA can be overcome. The DANGER study represents a highly innovative new direction wherein partnership among basic science researchers and computational biologists will lead to the application of genomic techniques to identify genetic variants that may be associated with SGLT2 inhibitor-associated DKA.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Type 2 DKA Diabetic Ketoacidosis	Genetic: Genomic analysis

Study Design

Study Type:

Observational

Anticipated Enrollment :

200 participants

Observational Model:

Case-Control

Time Perspective:

Other

Official Title:

Diabetic Ketoacidosis From New SGLT2i: Can Genomics Estimate Risk (DaNGER)

Anticipated Study Start Date :

Jun 6, 2022

Anticipated Primary Completion Date :

Jun 6, 2024

Anticipated Study Completion Date :

Jun 6, 2024

Arms and Interventions

Arm	Intervention/Treatment
Cases Patients with type 2 diabetes mellitus who were hospitalized with SGLT2 inhibitor-associated DKA	Genetic: Genomic analysis Genetic samples will be collected using a DNA saliva collection kit (Oragene: OG-510) and will be sent for genome-wide genotyping to The Centre for Applied Genomics in The Hospital for Sick Children (SickKids)
Controls There are two sources for controls. [1] Patients hospitalized at one of the participating hospitals who were on an SGLT2i and do not have DKA. [2] Population controls using publicly available data from the Canadian Longitudinal Study on Aging (CLSA) database.	Genetic: Genomic analysis Genetic samples will be collected using a DNA saliva collection kit (Oragene: OG-510) and will be sent for genome-wide genotyping to The Centre for Applied Genomics in The Hospital for Sick Children (SickKids)

Arm

Intervention/Treatment

Cases

Patients with type 2 diabetes mellitus who were hospitalized with SGLT2 inhibitor-associated DKA

Genetic: Genomic analysis

Genetic samples will be collected using a DNA saliva collection kit (Oragene: OG-510) and will be sent for genome-wide genotyping to The Centre for Applied Genomics in The Hospital for Sick Children (SickKids)

Controls

There are two sources for controls. [1] Patients hospitalized at one of the participating hospitals who were on an SGLT2i and do not have DKA. [2] Population controls using publicly available data from the Canadian Longitudinal Study on Aging (CLSA) database.

Genetic: Genomic analysis

Outcome Measures

Primary Outcome Measures

Identification of genomic variants associated with an increased risk of SGLT2 inhibitor-associated DKA [One year]
Genetic ancestry will be calculated using principal component analyses and outliers will be removed. GWAS will be performed with SAIGE, including genetic ancestry and the relevant clinical/demographic variables as covariates, to identify genetic variants associated with SGLT2 inhibitor-associated DKA.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 100 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

To be considered eligible for participation in this study, a participant must meet each of the following criteria:

Be 18 years or older and have a diagnosis of type 2 diabetes mellitus.
Have been admitted to hospital with SGLT2 inhibitor-associated DKA (cases) or admitted to hospital on an SGLT2 inhibitor and not have DKA (controls).
Be able to provide written consent (or, if patient is unable, have a substitute decision maker [SDM] available).