Diabetic Ketoacidosis From New SGLT2i: Can Genomics Estimate Risk

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.

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Key information

Conditions

Diabetes Type 2 Acid-Base Imbalance Acidosis DKA Diabetes Complications Diabetes Mellitus Diabetes Mellitus, Type 2 Diabetic Ketoacidosis Endocrine System Diseases Glucose Metabolism Disorders Ketosis Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–100 year

Sex eligibility

All sexes

Study type

Observational

Primary location

St. Joseph's Health Centre (Unity Health Toronto), Toronto, Ontario, Canada

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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).

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:

Diagnosis of type 1 diabetes mellitus.
Unable to spit 10mL into a vial.
A first degree relative has already been recruited into the study.
Had an alcohol binge before admission
Had prolonged fasting (>48 hours) prior to hospital admission
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.

Treatment and study plan

Genomic analysis

Genetic

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)

Primary outcomes

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.

Sponsors and collaborators

Lead sponsor

Mount Sinai Hospital, Canada

Other

Collaborators

Sault Area Hospital
Unity Health Toronto
University Health Network, Toronto

Registry information

Official study title

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

Acronym: DaNGER

Important dates

Study start: 2022
Primary completion: 2025
Study completion: 2025
First posted: Jun 2, 2022
Registry last updated: Dec 4, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Published trials that share one or more normalized conditions with this study.

Completed