Dapagliflozin During Exercise for the PrevenTion of Hypoglycaemia

There are approximately 400,000 people in the UK who are living with type 1 diabetes (T1DM), of whom 29,000 are children.

People with T1DM experience on average 2 episodes of symptomatic hypoglycaemia per week , and exercise (especially aerobic) increases this risk . Strategies to prevent hypoglycaemia during and after exercise include increasing glucose consumption and reducing insulin dose, however overcompensation may result in worsening of blood glucose control.

Dysregulated glucagon secretion, manifested as a reduced counter-regulatory response during hypoglycaemia, is a key feature in T1DM, occurring soon after diagnosis.

Anecdotal evidence suggests that SGLT-2 (sodium/glucose cotransporter-2) inhibitors (SGLT2i) such as dapagliflozin prevent exercise-induced hypoglycaemia in T1DM. SGLT2is promote glucose excretion without causing hypoglycaemia.Paradoxically, given their mode of action, they increase plasma glucose and stimulate glucagon secretion. Studies in diabetic rats indicate that the physiological counter-regulatory response is suppressed in insulin-treated diabetes, a defect that can be corrected by somatostatin antagonists.

The DEPTH trial will test the novel hypothesis that hypoglycaemia results from hypersecretion of somatostatin, and that this defect can be corrected by SGLT2i. As these medications are already in clinical use, our findings may be rapidly translated into practice. Understanding these key processes has the potential to generate novel therapeutic strategies to improve glycaemic control, thereby facilitating a more active lifestyle in people with T1DM.

PART A Study visit 1 (30min, day 1): 1. Observations documented in CRF: resting heart rate and blood pressure 2. CGM sensor inserted. 3. Insulin dose reduced by approximately 15%. 4. Participants instructed to return on day 3 (study visit 2) fasted (no breakfast), and to refrain from exercising until then. 5. If they experience a hypoglycaemic episode within 24h of visit 2 then it will be postponed by 2 days. The medical research team will review the participant's insulin dose and make any required changes. If following this a second hypoglycaemia event occurs, then the participant will be withdrawn from the trial.

Study visit 2 (5 hours, day 3): 1. Observations documented in CRF: resting heart rate and blood pressure 2. Euglycaemic clamp for up to 1.5h to maintain blood glucose at 5mmol/L (90mg/dL) 3. Exercise challenge 4. If a participant fails to reach hypoglycaemia (defined as \<3.3mmol/L, 60mg/dL) during the exercise challenge, then the study visit will be repeated after at least 2 days of washout/rest. If they again fail to reach hypoglycaemia then they will be withdrawn from the trial. 5. If the exercise challenge is completed with a hypoglycaemia episode, then the participant will proceed to Part B.

Following visit 2, participants will be allocated to a treatment group using an adaptive randomisation scheme. This will be used to balance the groups' baseline characteristics (age, sex \& fitness level) in this relatively small pilot trial.

PART B Study visit 3 (30 minutes, day 8): 1. Observations documented in CRF: resting heart rate and blood pressure 2. CGM sensor inserted (if required). 3. Participants informed which arm of the study they have been randomised to, and supplied with their prescription of dapagliflozin. Participants in arm B1 will take the single dose when they attend study visit 4. Participants in arm B2 will begin taking their regular dose of dapagliflozin immediately. 4. Participants instructed to return on day 10 (study visit 4) fasted (no breakfast), and to refrain from exercising until then. 5. If they experience a hypoglycaemic episode within 24h of visit 4 then the exercise challenge will be postponed by 2 days. The medical research team will review the participant's insulin dose and make any required changes. If following this a second hypoglycaemia event occurs, then the participant will be withdrawn from the trial.

Study visit 4 (5 hours; day 10): 1. Observations documented in CRF: resting heart rate and blood pressure 2. (Arm B1): single dose of dapagliflozin taken when they arrive at the department unless they have experienced a hypoglycaemia event earlier in the morning. (Arm B2): compliance with dapagliflozin regimen and adverse events recorded in the CRF by the medical research team. 3. Euglycaemic clamp for up to 1.5h to maintain blood glucose at 5mmol/L (90mg/dL) 4. Exercise challenge 5. Participants in Arm B2 will be instructed to take one final dose of dapagliflozin the following day. All participants will be instructed to return to their pre-trial insulin dose after 48h 6. Arrangements made for end of study visit (either at CRU or home-visit).

Study visit 5 (30min; day 12-20): 1. End of study visit (either at CRU or home-visit) 2. CGM sensor removed and data downloaded. CGM system returned to CRU. 3. (Arm B1): adverse events recorded. (Arm B2): compliance with dapagliflozin regimen, adverse events recorded and any unused dapagliflozin returned (document drug accountability).

Telephone follow-up (15min; 19-27 days after study visit 5): 1. Documentation of any adverse events occurred following the discontinuation of dapagliflozin. 2. Participant informed about end of study

Eligibility Criteria:
Inclusion criteria:

1. Age 18-74
2. T1DM diagnosed at least 12 months prior to screening test
3. On insulin pump or multiple daily injections
4. HbA1c \<10% (86 mmol/L)
5. Engage in some form of regular exercise
6. Have experienced at least one episode of exercise-induced hypoglycaemia
7. Adequate treatment of celiac disease if it exists.
8. Willing and able to give informed consent for participation in the trial
9. In the Investigator's opinion is able and willing to comply with all trial requirements
10. Will allow their General Practitioner to be notified of participation in the trial.

Exclusion criteria:

1. History of seizures or coma associated with hypoglycaemia in the past 2 years.
2. Active diabetic retinopathy ( including proliferative diabetic retinopathy or vitreous haemorrhage in the past 6 months).
3. Pregnant, breastfeeding, planning to become pregnant or not using adequate contraception methods (females only) during the course of the study
4. History of ischemic heart disease ( unless has had successful reperfusion), stroke/TIA, ventricular rhythm disturbances or thromboembolic disease.
5. A history of hypotension if currently on antihypertensive therapy
6. An episode of diabetic ketoacidosis in the previous 1 month
7. Currently on loop diuretics
8. On beta-blocker medication
9. A history of heart failure (NYHA Class 3 or 4)
10. A history of rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption
11. Renal impairment ( eGFR\<60 ml/min/1.73m2)
12. Untreated Graves disease
13. ECG or stress test findings indicating active ischemia or a condition that would compromise the participant's safety
14. Major psychiatric disease including diagnosed eating disorders, history of drug or alcohol abuse.
15. Known or suspected allergy to trial medication
16. Oral or injectable steroid treatment 30 days prior to the start or at any time during the trial period
17. Known malignancy or any other condition or circumstances which, in the opinion of the investigator, would affect the patient's ability to participate in the protocol.
18. Receipt of any investigational trial drug within 3 months prior to participation in the current trial.