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Ketone Monitoring Approaches for DKA Risk Mitigation in People with T1D on Adjunctive SGLT2 Inhibitors (KARMA)

Award Number: U01DK143384
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/11/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Ketone Monitoring Approaches for DKA Risk Mitigation in People with T1D on Adjunctive SGLT2 Inhibitors (KARMA) - People with type 1 diabetes (T1D) are at increased risk of cardiovascular disease (CVD), heart failure (HF) and chronic kidney disease (CKD). SGLT2 inhibitors have been shown to decrease risk of CVD, HF, and to slow the progression of CKD in people with Type 2 diabetes. However, the FDA has not approved the use of SGLT2 inhibitors as adjunctive treatments for T1D because of a ~6-fold increase in the risk of diabetic ketoacidosis (DKA). In trials of SGLT2 inhibitors in people with T1D, self-monitored plasma beta-hydroxybutyrate (BOHB) levels were predictive of DKA but this type of monitoring did not prevent ketoacidosis. Recent advances have enabled continuous monitoring of BOHB levels in interstitial fluid – raising the possibility that continuous ketone monitoring (CKM) could effectively mitigate the increased risk of DKA in SGLT2 inhibitor treated patients with T1D. The overarching goal of this proposal is to develop and test a pragmatic risk mitigation strategy using CKM that will enable safer use of SGLT2 inhibitors in patients with T1D. To accomplish this, we will recruit and study a cohort of 75 patients with T1D to address 3 Specific Aims. In Aim 1a we will determine how adjunctive SGLT2 inhibitor use affects the development of hyperglycemia, ketosis and ketoacidosis during insulin withdrawal testing (IWT) in a highly controlled, inpatient setting in people with T1D on insulin monotherapy to that on insulin + adjunctive therapy with an SGLT2 inhibitor. In Aim 1b we will assess insulin, carbohydrate and fluid requirements to reverse ketosis during these conditions to refine recovery protocols that reverse elevated ketones during these conditions. We hypothesize that adjunctive SGLT2 inhibitor use will increase the rate of development and maximal levels of ketosis and ketoacidosis while blunting increases in glucose during an insulin withdrawal test. In Aim 2a we will test the effectiveness of a CKM enabled DKA risk mitigation strategy that accounts for the increased risk for ketosis and ketoacidosis with SGLT2 inhibitors. We will use a sequential, 2-phase study design to compare the number and severity of CKM-assessed ketone events that occur during a generalized DKA risk mitigation plan vs. a personalized DKA plan implemented for people with T1D on SGLT2 inhibitors. In Aim 2b we will actively update ‘decision tree algorithms’ for broad risk mitigation to incorporate new learnings obtained during the conduct of the study using an adaptive design. We hypothesize that a strategy accounting for the physiological effects of SGLT2 inhibitors on the development and resolution of ketosis will be more effective at reducing the number and severity of ketosis events. In Aim 3 we will explore intrinsic and extrinsic factors associated with ketone levels and responses to SGLT2 inhibition among people with T1D in both free living conditions and during IWT by conducting secondary analyses of data generated in Aims 1 and 2 to determine possible predictors of the number and severity of ketone events and responses to SGLT2 inhibition. The results of this study will lead to an improved risk mitigation strategy that will enable persons with T1D to safely use SGLT2 inhibitors to decrease risk for CVD, HF and CKD, thus improving long-term outcomes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	ADVENTIST HEALTH SYSTEM/SUNBELT INC	601 E ROLLINS ST	ORLANDO	FL	32803	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/20/2026	NEW	$0
2026	2025	ADVENTIST HEALTH SYSTEM/SUNBELT INC	601 E ROLLINS ST	ORLANDO	FL	32803	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	4/1/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $2,477,577 )
2025	2025	ADVENTIST HEALTH SYSTEM/SUNBELT INC	601 E ROLLINS ST	ORLANDO	FL	32803	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/11/2025	NEW	$2,477,577
														Subtotal = $2,477,577

Grand Total All Awards = $2,477,577

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Ketone Monitoring Approaches for DKA Risk Mitigation in People with T1D on Adjunctive SGLT2 Inhibitors (KARMA)

Award Number: U01DK143384

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/11/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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