Diabetic Ketoacidosis From New SGLT2i: Can Genomics Estimate Risk

Diabetes Type 2 Clinical Trial

— DaNGER  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05402579
• Other study ID #: CTO 3737
• Status: Recruiting
• Start date: July 29, 2022
• Est. completion date: June 6, 2024

Study information

• Verified date: July 2023
• Source: Mount Sinai Hospital, Canada
• Contact: Michael Fralick, MD, PhD
• Phone: 4165864800
• Email: mike.fralick[@]sinaihealth.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: June 6, 2024
• Est. primary completion date: June 6, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acidosis
• Diabetes Mellitus, Type 2
• Diabetes Type 2
• Diabetic Ketoacidosis
• Ketosis

Intervention

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)

Locations

Country	Name	City	State
Canada	St. Joseph's Health Centre (Unity Health Toronto)	Toronto	Ontario
Canada	Toronto General Hospital (University Health Network)	Toronto	Ontario

Sponsors (4)

Lead Sponsor	Collaborator
Mount Sinai Hospital, Canada	Sault Area Hospital, Unity Health Toronto, University Health Network, Toronto

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identification of genomic variants associated with an increased risk of SGLT2 inhibitor-associated DKA	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.	One year