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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetic Ketoacidosis; Diabetes Type 2; DKA
• Intervention / Treatment: Genetic: Genomic analysis

• Study Type: Observational
• Enrollment (Actual): 63

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • St. Joseph's Health Centre (Unity Health Toronto)
    • Toronto, Ontario, Canada
      • Toronto General Hospital (University Health Network)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• 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.

Description

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.
4. Had an alcohol binge before admission
5. Had prolonged fasting (>48 hours) prior to hospital admission
6. Recently stopped their insulin (within the past 7 days prior to hospital admission)

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cases; Patients with type 2 diabetes mellitus who were hospitalized with SGLT2 inhibitor-associated DKA (60 cases).	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 (1000 controls via CLSA).	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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: University Health Network, Toronto; Unity Health Toronto; Sault Area Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2022
• Primary Completion (Actual): January 20, 2025
• Study Completion (Actual): January 20, 2025

Study Registration Dates

• First Submitted: May 30, 2022
• First Submitted That Met QC Criteria: May 30, 2022
• First Posted (Actual): June 2, 2022

Study Record Updates

• Last Update Posted (Estimated): December 4, 2025
• Last Update Submitted That Met QC Criteria: November 26, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: DKA; SGLT2i; Diabetes Type 2
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Complications; Acid-Base Imbalance; Acidosis; Nutritional and Metabolic Diseases; Ketosis; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis
• Other Study ID Numbers: CTO 3737

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No