Evaluating Safe Ketone Thresholds To Minimise Ketosis in People With Type 1 Diabetes Using Dapagliflozin (KETO-TRACK)

The Evaluation of Two Response Thresholds to Continuous Ketone Monitoring Information Minimising Ketosis in People With Type 1 Diabetes Treated With Dapagliflozin

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a type of medicine that help the kidneys get rid of extra sugar in the blood through urine. In people with type 2 diabetes (T2D), these medications help lower blood sugar levels, help people lose weight and improve heart and kidney health.

SGLT2 inhibitors are mainly used in T2D, however some studies show they might also help people with type 1 diabetes (T1D). The same health benefits observed in people with T2D the investigators anticipate may help those with T1D. Currently, there is a safety concern that people with T1D using these medicines can raise the risk of diabetic ketoacidosis (DKA). DKA occurs when the body doesn't have enough insulin (a hormone made in the pancreas that helps your body use sugar (glucose) for energy), it starts to break down fats as a source of energy. This breakdown of fats produces ketones. Very high levels of ketones in the blood can make the blood acidic (toxic) and lead to DKA. If not treated in time, this can make the person living with T1D very ill and can be life-threatening. Because of this risk, health agencies like the FDA in the U.S., and the TGA in Australia have not approved use of SGLT2 inhibitors for people with T1D.

Still, some experts believe SGLT2 inhibitors may safely be used alongside insulin in T1D if DKA risk is carefully managed. This might be possible with early detection and treatment of rising ketone levels. One approach is using continuous ketone monitors, which track ketone levels in real time and can alert users early. People would also need proper education on what to do if ketone levels start rising.

To date, there's no official agreement on the exact ketone level that should trigger action. Some suggest action when ketone levels reach 1.0 or 1.5 mmol/L. A lower limit like 1.0 mmol/L may be safer, but it could also lead to too many alarms and extra stress, or unnecessary eating to bring ketones down.

Therefore, the aim of this study is to assess if initiating responses to elevated ketone levels at a threshold of 1.0 mmol/L, compared to a threshold of 1.5 mmol/L, will reduce the risk of DKA in people with T1D using Dapagliflozin.

The investigators will recruit 115 adults with T1D and provide Dapagliflozin (SGLT2 inhibitor) and continuous glucose and ketone monitoring (DGK) devices. Participants will be randomly assigned to two groups. Group 1 will wear a DGK with alarms set at ketone level of 1.0 mmol/L and receive education about taking action when ketone levels are ≥1.0 mmol/L. Group 2 will wear a DGK with alarms set at ketone level of 1.5 mmol/L and receive education about taking action when ketone levels are ≥1.5 mmol/L. Participants will be assessed for time spent with critically high ketone levels, incidence of DKA, glucose and person reported outcomes.

Findings from this study will provide real life data and clinical evidence to help guide safe use of SGLT2 inhibitors in people with T1D by informing protocols for monitoring and managing associated DKA risks.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: FORXIGA

Detailed Description

Sodium glucose cotransporter 2 (SGLT2) is responsible for approximately 90% of glucose re-absorption in the renal proximal tubules, so SGLT2 inhibition results in significant excretion of glucose in the urine. SGLT2 inhibition may play a key role in the prevention and management of the cardiovascular-kidney-metabolic (CKM) syndrome as this class of agent has been shown to benefit glucose levels (reducing HbA1c, and glycaemic variability without increasing severe or total hypoglycaemia), reduce heart failure, improve weight control, reduce cardiovascular mortality, and provide reno-protection in people with diabetes thereby addressing some of the fundamental issues contributing to the syndrome. While most data pertain to agents which inhibit SGLT2 in people with T2D, SGLT2 inhibition also has the potential to substantially benefit glucose control, weight management, and reduce complication development including that of the CKM syndrome in people with T1D. Dapagliflozin is a SGLT2 inhibitor. Data available in adults with T1D indicate that Dapagliflozin improves glucose control without increasing hypoglycaemia and reduces glycaemic variability. In addition, there are improvements in body weight and blood pressure. There is also substantial evidence in people with T2D that Dapagliflozin lowers mortality from cardiovascular causes and hospitalisations for heart failure. In terms of reno-protective effects, Dapagliflozin was demonstrated to slow down decline in renal function, reduce rates of renal failure and death from renal causes in T2D.These cardiorenal benefits may extend to people with T1D.

While SGLT2 inhibitors as adjunctive therapy to insulin may benefit people with T1D, in general their use has been associated with a significantly increased risk of diabetic ketoacidosis (DKA) which may occur in the absence of hyperglycaemia. DKA represents a life-threatening acute emergency of T1D, which occurs when insulin deficiency leads to lipolysis and accumulation of ketones, resulting in metabolic acidosis. It requires prompt identification and action, and delays in management are associated with an increase in mortality. For example, the pooled analysis of DEPICT-1 and DEPICT-2 participants showed that over 52 weeks of treatment, the incidence of adjudicated DKA was numerically higher with Dapagliflozin 5 mg/day or 10 mg/day than with placebo (4.0% and 3.5% vs. 1.1%). Therefore, SGLT2 inhibitors in general have failed to receive approval in the USA (FDA) and Australia (TGA) for use to control glucose levels in people with T1D due to an unacceptable increase in DKA. It is possible that SGLT2 inhibitor therapy may be viable in people with T1D if an intervention is able to shift the risk-benefit balance in favour of benefit e.g. if the risk of DKA could be recognized and addressed in a timely manner. The early recognition of impending DKA is of critical importance. However, symptoms of ketosis which include nausea, vomiting, fatigue, loss of appetite, malaise, weakness, and tachypnoea appear late and those associated with dehydration may be absent in the setting of normoglycaemia. Therefore, timely ketone measurement represents a cornerstone of management allowing therapeutic measures to be initiated.

A continuous ketone sensor (CKS) would address many of the shortcomings associated with current standard-of-care blood ketone testing using a handheld meter. Ketones can be quantified in interstitial fluid using a similar approach to that taken with widely commercially used continuous glucose monitor (CGM), using an enzymatic reaction. While feasibility of CKS devices has previously been demonstrated, the optimum thresholds for alerts, balancing the burden of alarms vs. timely intervention, have yet to be determined. Preliminary at home CKS data provided by Abbott indicate free-living people with T1D who are not using SGLTi spend <1% of the time with ketone levels >1.0mmol/L. Ketone levels in free-living with T1D using SGLT2 inhibitors remains unknown. To provide insights into appropriate ketone thresholds for alerts a literature search was undertaken in May 2024.

Studies included were published between January 2000 and April 2024 involving those aged ≥16 years of age which described capillary β-OHB levels in relation to suspected DKA and which reported sensitivity, specificity, negative predictive value, or positive predictive value. Eight of the 11 studies provided capillary β-OHB levels that excluded DKA; these ranged from 0.7 to ≥3.0 mmol/L 13-23 and the most recommended cut-off level was 1.0 mmol/L (n=3) followed by 1.5 mmol/L (n=2). The β-OHB cut-offs for the diagnosis of DKA ranged from 1.8 mmol/L to 3.5 mmol/L, with 3.0 mmol/L being most proposed by five of the studies. The investigators therefore concluded that capillary β-OHB cut off values of <1.0 mmol/L and <1.5 mmol/L exclude DKA. The investigators also conclude that a capillary β-OHB level ≥3.0 mmol/L exhibited high sensitivity and specificity in detecting DKA with levels between 1.5 mmol/L and 3.0 mmol/L representing a transition range with increasing risk.

The investigators propose that to pre-empt DKA in people with T1D using SGLTi that responses to CKS data could be initiated at levels of either 1.0mmol/L or 1.5mmol/L with alerts aligned accordingly. The lower alert may provide an additional safety margin though could come at the cost of a greater number of alarms and carbohydrates eaten that may not have necessarily been required. The investigators also suggest that there may be high DKA-risk subgroups (female sex, lower baseline body mass index (BMI), β-hydroxybutyrate levels pre-treatment, use of an insulin pump, and lower insulin requirements at baseline with dose reductions required post SGLT inhibitor commencement to avoid hypoglycaemia) who may benefit from the lower alarm thresholds facilitating earlier intervention. Finally, the risk for DKA may vary according to illness, fasting and high intensity exercise requiring alerts to be adjusted according to circumstances. However, data are required to inform protocols.

• Study Type: Interventional
• Enrollment (Estimated): 115
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Prof. David O'Neal; Phone Number: +61 3 9231 2757; Email: DTRG-t1research@unimelb.edu.au

Study Locations

• Australia
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital Melbourne
      • Contact: Dr Yee Wen Kong; Phone Number: +61 3 9231 2757; Email: DTRG-t1research@unimelb.edu.au
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
      • Contact: Prof Elif Ekinci; Phone Number: +61 3 9496 2160; Email: elif.ekinci@unimelb.edu.au
      • Contact: Adele Manzoney; Phone Number: +61 3 9496 2160
    • Melbourne, Victoria, Australia, 3004
      • Baker Heart and Diabetes Institute
      • Contact: Prof David O'Neal; Phone Number: +61 3 9231 2757; Email: dno@unimelb.edu.au
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital
      • Contact: Prof Spiros Fourlanos; Phone Number: +61 3 9342 7365; Email: diabetesendo@mh.org.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged between 24 and 85 years of age inclusive (66% 24Y to 65Y; and 33% >65Y to 85Y)
• Diagnosed with T1D (made on clinical criteria) for at least 1 year
• Insulin regimen either on MDI or insulin pump with at least 40% in one mode
• Minimum total daily insulin dose 0.4 Units per kg / day (can be on insulin pump or MDI);
• HbA1c <10% (86mmol/ mol)
• Minimum daily carbohydrate intake of 100g
• Willing to adhere to the study protocol
• Ability to perform high-intensity exercise (specific to the exercise sub-study)

Exclusion Criteria:

• Pregnancy or planned pregnancy
• eGFR <30ml/min/1.73m2
• History of DKA in the last 12 months
• Use of low carbohydrate diet (<100g/day)
• Diabetic gastroparesis
• Tape allergy
• Heavy alcohol use (15 standard drinks per week or binge drinking)
• Use of SGLT inhibitor in the last month
• Medications increasing the risk of DKA e.g. steroids, anorectic agents (eg phentermine, naltrexone HCl/bupropion HCl, and GLP 1 agonists).
• Major medical or psychiatric illness that in the opinion of the investigator would interfere with protocol adherence or impact participant safety.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dual glucose and ketone (DGK) sensor threshold 1.0mmol/L; The DGK will be set with threshold alarms activated at 1.0mmol/L for participant response to ketosis	Drug: FORXIGA; All participants will take FORXIGA (Dapagliflozin) orally at a dose of 10mg/day for 12 weeks
Active Comparator: Dual glucose and ketone (DGK) sensor threshold 1.5mmol/L; The DGK will be set with threshold alarms activated at 1.5mmol/L for participant response to ketosis	Drug: FORXIGA; All participants will take FORXIGA (Dapagliflozin) orally at a dose of 10mg/day for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent time spent with interstitial ketones ≥3.0mmol/L (Main Study)	Percent of time spent with interstitial ketone levels ≥3.0mmol/L on dual glucose / ketone monitoring device during 12-weeks of taking Dapagliflozin	Commencement to end of study (12 weeks)
Percent of time spent with interstitial ketones ≥3.0mmol/L during exercise (Exercise Study)	Percent of time spent with interstitial ketones ≥3.0mmol/L on dual glucose / ketone monitoring device from start of exercise to 12 hours post-commencement of exercise	Weeks 4 to12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of time with ketone levels in different ranges	Percent time with interstitial ketone levels of: >0.6 mmol/L; >1.0 mmol/L; >1.5mmol/L	Commencement to end of study (12 weeks)
Mean interstitial ketone levels	Average if ketone levels measured by dual glucose / ketone monitor device over 12 weeks	Commencement to end of study (12 weeks)
Incidence of diabetic ketoacidosis (DKA)	Number of DKA events	Commencement to end of study (12 weeks)
Change in HbA1c	Difference in HbA1c (mmol/mol) between baseline and study end	Week 0 and Week 12 from study commencement
CGM metrics	Standardised consensus CGM metrics (% times in prespecified ranges, mean glucose, and CV) over 12 weeks	Commencement to end of study (12 weeks)
Change in weight	Change in weight (kg) from baseline to study end	Week 0 and Week 12 from study commencement
Change in BMI	Change in BMI (kg/m2) from baseline to study end	Week 0 and Week 12 from study commencement
Change in treatment satisfaction using Diabetes Medication System Rating Questionnaire - Short form	Change in questionnaire scores from baseline to study end. Questionnaire contains 20 items. Items are scored on a scale from 0 to 3-4. Higher scores mean better outcome	Week 0 and Week 12 from study commencement
Change in Gold score	Change in questionnaire scores from baseline to study end. Questionnaire contains 1 item. Item is scored on a scale from 1 to 7. Higher scores mean worse outcome	Week 0 and Week 12 from study commencement
Change in Pittsburgh Sleep Quality Index	Change in questionnaire scores from baseline to study end. Questionnaire contains 19 items. Items are scored on a scale from 0 to 3. Higher scores mean worse outcome	Week 0 and Week 12 from study commencement
Change in PROMIS Fatigue - Short form	Change in questionnaire scores from baseline to study end. Questionnaire contains 4 items. Items are scored on a scale from 1 to 5. Higher scores mean worse outcome	Week 0 and Week 12 from study commencement
Change in EQ-5D-5L	Change in questionnaire scores from baseline to study end. Questionnaire contains 6 items. Items are scored on a scale from 1 to 5. Higher scores mean worse outcome	Week 0 and Week 12 from study commencement
Change in Problem Areas in Diabetes - Short form	Change in questionnaire scores from baseline to study end. Questionnaire contains 5 items. Items are scored on a scale from 0 to 4. Higher scores mean worse outcome	Week 0 and Week 12 from study commencement
Change in WHO-5 Well-being index	Change in questionnaire scores from baseline to study end. Questionnaire contains 5 items. Items are scored on a scale from 0 to 5. Higher scores mean better outcome	Week 0 and Week 12 from study commencement
Change in Hypoglycaemia Fear Survey - Short Form	Change in questionnaire scores from baseline to study end. Questionnaire contains 11items. Items are scored on a scale from 0 to 4. Higher scores mean worse outcome	Week 0 and Week 12 from study commencement
Treatment satisfaction with ketone sensor using Study specific questions regarding treatment satisfaction	Questionnaire contains 10 items. Items are scored on a scale from 1 to 5. Higher scores mean better outcome	Week 12 from study commencement (study end)
Ketone sensor usability with System Usability Scale	Questionnaire contains 10 items. Items are scored on a scale from 1-5. Higher scores mean better outcome	Week 12 from study commencement (study end)
Treatment satisfaction and ketone sensor usability with User Experience Questionnaire	Change in questionnaire scores from baseline to study end. Questionnaire contains 26 items. Items are scored on a scale from 1 to 7. Higher scores mean better outcome	Week 12 from study commencement (study end)
Lived experience of a using DGK system during Dapagliflozin treatment	Thematic analysis of interviews exploring lived experience of a using DGK system during Dapagliflozin treatment	Week 12 from study commencement (study end)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent time of sensor wear	Percentage of time dual glucose/ketone sensor is worn during the 12 weeks of the study	Commencement to end of study (12 weeks)
Incidence of sensor- related skin infections	Number of skin infections at site of sensor insertion	Commencement to end of study (12 weeks)
Mean duration of sensor survival before replacement	Number of days dual glucose/ketone sensor is working for before needing replacement	Commencement to end of study (12 weeks)
Difference between blood and interstitial ketones values	Difference between ketone readings from the dual ketone/glucose sensor (study sensor) and fingerprick blood ketone test (standard of care)	Commencement to end of study (12 weeks)

Collaborators and Investigators

• Sponsor: St Vincent's Hospital Melbourne
• Collaborators: Melbourne Health; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Austin Health; University of Melbourne; Baker Heart and Diabetes Institute

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): February 1, 2028

Study Registration Dates

• First Submitted: November 2, 2025
• First Submitted That Met QC Criteria: November 4, 2025
• First Posted (Estimated): November 6, 2025

Study Record Updates

• Last Update Posted (Estimated): November 6, 2025
• Last Update Submitted That Met QC Criteria: November 4, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Dapagliflozin; Type 1 Diabetes; SGLT2 inhibitor; Ketosis; Dual Glucose and Ketone Monitor
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Acid-Base Imbalance; Acidosis; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 1; Ketosis; dapagliflozin
• Other Study ID Numbers: 235/25; 1U01DK143330-01 (U.S. NIH Grant/Contract)

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