Objective
The main objective of this study is to assess glucose levels and incidence of diabetes ketoacidosis (DKA) with sotagliflozin compared to placebo in adults with type 1 diabetes with adjunct ketone sensor use and education about strategies to minimise risk of DKA.
Background Rationale
A significant proportion of people with type 1 diabetes are still unable to consistently meet recommended blood glucose, even when using advanced diabetes technologies such as continuous glucose monitoring and automated insulin delivery systems. This increases long-term risk of diabetes-related complications, such as heart and kidney disease. SGLTi therapy has been demonstrated to significantly improve blood glucose levels, weight management and reduce complications in people with type 2 diabetes, with similar data seen in people with type 1 diabetes.
However, the use of SGLTi in people with type 1 diabetes is associated with a significant risk of DKA, which is a life-threatening complication, and may occur in the absence of high blood glucose levels, making it hard to recognize and treat. This is why SGLTi therapy in general has failed to receive approval for commercial therapeutic use in the United States of America (FDA; Food and Drug Administration) and Australia (TGA; Therapeutic Goods Administration) in people with type 1 diabetes.
If risk mitigation strategies can be put in place to shift the risk-benefit balance in favour of benefit, SGLTi therapy may become a viable therapy in people with type 1 diabetes. We believe that this may be achieved through close monitoring of ketone levels via a newly available technology; continuous ketone monitoring (CKM), in conjunction with education about strategies for management of ketosis+/-hyperglycaemia to prompt early action.
Description of Project
Sodium-glucose co-transporter inhibitors (SGLTi) are a new class of drugs that lower blood sugar (ie. blood glucose) levels by preventing the kidneys from reabsorbing glucose and the extra glucose leaves the body through urine. These SGLTi drugs have the potential to substantially benefit blood glucose control, weight management and reduce development of complications in people with type 1 diabetes, including but not limited to significant reductions in heart and kidney disease. However, SGLTi use has been associated with a significantly increased risk of diabetes ketoacidosis (DKA) which is a life-threatening complication involving excess production of 'ketones', a metabolic by-product which is usually associated with high blood glucose levels.
SGLTi use increases the risk of DKA up to 16-fold and importantly, DKA may occur in the absence of high blood sugar in people with type 1 diabetes using SGLTi, meaning that they may not realise that DKA is occurring. Therefore, SGLT inhibitors in general have failed to receive approval in the United States of America (FDA; Food and Drug Administration) and Australia (TGA; Therapeutic Goods Administration) for use to manage glucose control and complications in people with type 1 diabetes due to this unacceptable increase in DKA incidence.
This study will assess if glucose levels improve with sotagliflozin (an SGLTi which is approved and commercially available for type 2 diabetes) compared to placebo in adults with type 1 diabetes, and at the same time will seek to determine if the incidence/risk of DKA is mitigated by used of a new device called a continuous ketone monitor (CKM) in conjunction with education about hyperglycemia/ketosis management. The CKM is analogous and similar in appearance to commercially available and widely used devices called continuous glucose monitors (CGM), which measure a person's glucose levels every 5 minutes and alarms if levels are too high or too low. The CKM measures ketones continuously, and similarly will alarm if levels are approaching a dangerously high level. This risk mitigation strategy may balance the increased risk of DKA by giving people with type 1 diabetes pre-warning that their ketone levels are rising, allowing them to act before DKA sets in.
Sixty adults with type 1 diabetes will be recruited across five clinical sites in Australia, and will be allocated to a placebo for three months and an SGLTi for three months, in conjunction with provision of the CKM device and education about hyperglycemia/ketosis management. The key outcomes will include whether blood glucose control improves and whether risk of DKA is still increased with SGLTi when used in conjunction with the CKM.
Anticipated Outcome
We hypothesise that SGLTi will result in improved glucose levels compared to placebo in people with type 1 diabetes, and this will occur with no increase in incidence of diabetes ketoacidosis when used in conjunction with continuous ketone monitoring and appropriate education about ketone management.
Relevance to T1D
This study has been designed to assess if SGLT inhibitors (e.g. sotagliflozin) can be used in people with type 1 diabetes to improve glucose levels, and to assess if the use of CKM can mitigate risk of DKA. This is the first step towards exploring the possibility of SGLTi therapy in people with type 1 diabetes, so that these people can receive the significant benefits of SGLTi on glucose levels, weight management and reduction in heart and kidney complications, without the simultaneous increased risk of DKA.