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

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ClinicalTrials.gov Identifier: NCT05402579
Recruitment Status : Recruiting
First Posted : June 2, 2022
Last Update Posted : July 11, 2023
Sponsor:
Collaborators:
Unity Health Toronto
University Health Network, Toronto
Sault Area Hospital
Information provided by (Responsible Party):
Mount Sinai Hospital, Canada

Study Description
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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
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
Diabetes Type 2 DKA Diabetic Ketoacidosis Genetic: Genomic analysis

Study Design
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Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Case-Control
Time Perspective: Other
Official Title: Diabetic Ketoacidosis From New SGLT2i: Can Genomics Estimate Risk (DaNGER)
Actual Study Start Date : July 29, 2022
Estimated Primary Completion Date : June 6, 2024
Estimated Study Completion Date : June 6, 2024

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort 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)


Outcome Measures
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Primary Outcome Measures :
  1. Identification of genomic variants associated with an increased risk of SGLT2 inhibitor-associated DKA [ Time Frame: 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.


Biospecimen Retention:   None Retained
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)

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Cases: Patients with type 2 diabetes mellitus who were hospitalized with SGLT2 inhibitor-associated DKA will be eligible for inclusion in our study.

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.

Criteria

Inclusion Criteria:

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

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

Exclusion Criteria:

A participant will be ineligible for participation in this study if he or she satisfies any one or more of the following criteria:

  1. Diagnosis of type 1 diabetes mellitus.
  2. Unable to spit 10mL into a vial.
  3. A first degree relative has already been recruited into the study.

Our study will not include children or pregnant women because SGLT2 inhibitors are not approved for use in either patient population.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05402579


Contacts
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Contact: Michael Fralick, MD, PhD 4165864800 mike.fralick@sinaihealth.ca

Locations
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Canada, Ontario
St. Joseph's Health Centre (Unity Health Toronto) Recruiting
Toronto, Ontario, Canada
Contact: Michael Fralick       mike.fralick@sinaihealth.ca   
Toronto General Hospital (University Health Network) Recruiting
Toronto, Ontario, Canada
Contact: Michael Fralick       mike.fralick@sinaihealth.ca   
Sponsors and Collaborators
Mount Sinai Hospital, Canada
Unity Health Toronto
University Health Network, Toronto
Sault Area Hospital
More Information
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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
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Responsible Party: Mount Sinai Hospital, Canada
ClinicalTrials.gov Identifier: NCT05402579    
Other Study ID Numbers: CTO 3737
First Posted: June 2, 2022    Key Record Dates
Last Update Posted: July 11, 2023
Last Verified: July 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Mount Sinai Hospital, Canada:
DKA
SGLT2i
Diabetes Type 2
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Ketosis
Acidosis
Diabetic Ketoacidosis
Diabetes Mellitus
 Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Acid-Base Imbalance
Diabetes Complications