Evaluating Safe Ketone Thresholds To Minimise Ketosis in People With Type 1 Diabetes Using Dapagliflozin

NCT ID: NCT07225465

Last Updated: 2025-11-06

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 115 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-02-28
• Study Completion Date: 2028-02-29

Brief Summary

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.

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.

Conditions

Type 1 Diabetes Mellitus

Keywords

Ketosis; Dapagliflozin; Type 1 Diabetes; Dual Glucose and Ketone Monitor; SGLT2 inhibitor

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

FORXIGA

Intervention Type: DRUG

All participants will take FORXIGA (Dapagliflozin) orally at a dose of 10mg/day for 12 weeks

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

Group Type: ACTIVE_COMPARATOR

FORXIGA

Intervention Type: DRUG

All participants will take FORXIGA (Dapagliflozin) orally at a dose of 10mg/day for 12 weeks

Interventions

FORXIGA

All participants will take FORXIGA (Dapagliflozin) orally at a dose of 10mg/day for 12 weeks

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 24 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Baker Heart and Diabetes Institute

OTHER

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Melbourne

OTHER

Sponsor Role: collaborator

Melbourne Health

OTHER

Sponsor Role: collaborator

Austin Health

OTHER_GOV

Sponsor Role: collaborator

St Vincent's Hospital Melbourne

OTHER

Sponsor Role: lead

Responsible Party

David O'Neal

Coordinating Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

St Vincent's Hospital Melbourne

Fitzroy, Victoria, Australia

Austin Health

Heidelberg, Victoria, Australia

Baker Heart and Diabetes Institute

Melbourne, Victoria, Australia

The Royal Melbourne Hospital

Parkville, Victoria, Australia

Countries

Australia

Central Contacts

Prof. David O'Neal

Role: CONTACT

Phone: +61 3 9231 2757

Email: DTRG-t1research@unimelb.edu.au

Facility Contacts

Dr Yee Wen Kong

Role: primary

Prof Elif Ekinci

Role: primary

Adele Manzoney

Role: backup

Prof David O'Neal

Role: primary

Prof Spiros Fourlanos

Role: primary

Other Identifiers

1U01DK143330-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

235/25

Identifier Type: -

Identifier Source: org_study_id