Many patients with type 1 diabetes could reap substantial cardiometabolic benefits from SGLT2 inhibitors if safeguards are put in place to mitigate the risk of diabetic ketoacidosis, Australian endocrinologists say.
The overcautious approach by drug regulators and industry to use of SGLT2 inhibitors in T1D means that patients are missing out on what may be an almost ideal insulin adjunct therapy that would meet the goals of reduced hyperglycaemia, weight reduction, delay in progression of diabetes-related complications, cardiorenal protection and mortality reduction, according to Dr Jennifer Snaith and Dr Jerry Greenfield of the Garvan Institute, Sydney.
In a perspective article in the MJA they argue that the concerns about the risk of DKA with SGLT2 inhibitors in patients with T1D could be addressed by careful patient selection protocols and the use of low dose therapy.
They say that SGLT2 inhibitors are a logical therapeutic choice for people with T1D, because of their high risk of cardiovascular disease, even among those with on-target glycaemia. People with T1D have Individuals with type 1 diabetes have greater insulin-resistance compared with their peers without diabetes and display metabolic syndrome features, they note
“This issue is under-recognised but potentially targetable with repurposed medications intended for type 2 diabetes used adjunctively with insulin, such as SGLT2 inhibitors,” they write.
However although the metabolic benefits of SGLT2 inhibitors have been demonstrated in three RCTs in people with T1D, this has not been enough to overcome the concerns of regulators such as the FDA, who have called for more data to confirm the efficacy or the safety of the drugs in the setting of T1D.
Similarly the European Medicines Agency (EMA) abruptly reversed its approval of dapagliflozin for use in T1D in 2021, despite early real-world evidence from registry data showing no increase in DKA risk.
In their article, Dr Snaith and Dr Greenfield say that because of the relatively small number of patients with T1D compared to those with T2D, it is unlikely that major randomised controlled trials will be done to provide further data to satisfy regulators of the safety and efficacy of SGLT2 inhibitors in T1D.
Nevertheless, they assert that off-label prescription of low dose SGLT2 inhibitors in T1D is prevalent, and can be supported by the careful selection of patients based on personalised assessment of their cardiovascular risk and DKA risk.
“Combined with type 1 diabetes-specific cardiovascular risk estimator tools that compute risk based on multiple inputs (age, diabetes duration, blood pressure, glycaemia, albuminuria), there is opportunity to select ideal risk–benefit candidates,” they write.
“This may provide a compromise solution without current access to hard cardiovascular outcome data in type 1 diabetes. Equally, groups at greatest risk of DKA could be avoided, including women aged 25–44years, captured by registry data reporting …”
They suggest that with the compelling and robust evidence for cardiorenal protection in type 2 diabetes, the absence of very large randomised controlled trials is an insufficient reason to exclude the use of SGLT2 inhibitors for metabolic benefit in type 1 diabetes.
“Without backing from both industry and regulators and a creative approach to research development and resource consumption, this ground-breaking drug class will remain a lost opportunity to close the mortality gap in type 1 diabetes,” they conclude.