Dapagliflozin withdrawn for type 1 diabetes
Just over two years after its approval in the UK and EU as the first new treatment for type 1 diabetes since the discovery of insulin, the use of dapagliflozin is no longer authorised in this population group. Dr Susan Aldridge reports.
In September 2019, dapagliflozin became the first adjunct therapy to be prescribed to people with type 1 in the UK and the EU - widely seen as perhaps the most significant development in the treatment of type 1 diabetes since the discovery of insulin 100 years ago (although it has not been approved as an adjunct therapy for type 1 in the USA). Little more than two years later, on 25 October 2021, the authorisation for prescribing the sodium-glucose cotransporter-2 (SGLT-2) inhibitor dapagliflozin 5 mg in type 1 diabetes was withdrawn by its manufacturer, AstraZeneca.
The withdrawal of the indication for dapagliflozin’s use in people with type 1 diabetes is a particularly bitter blow considering the extent of unmet clinical need in this patient population. According to the Type 1 Diabetes Exchange Registry in the USA, glycaemic targets are not being met – despite optimal insulin therapy and the use of new technology like insulin pumps and continuous glucose monitoring. Mean HbA1c is 8.3% with prevailing risks of hypoglycaemia and diabetic ketoacidosis (DKA), as well as a growing problem of overweight and obesity. Similar findings have been reported from Europe. Furthermore, people with type 1 diabetes have a reduced life expectancy – for instance, a woman diagnosed with the condition before the age of 10 years will lose 17 years of life, compared with a woman without diabetes. All of which suggests that insulin alone is sometimes insufficient to manage hyperglycaemia.
SGLT-2 inhibitors are also known to confer significant benefits above and beyond their glucose-lowering properties, and are seen as playing an increasingly important role in reducing the risk of cardiorenal complications in people with diabetes. This change to dapagliflozin’s indication could, therefore, effectively deny those benefits to people with type 1 diabetes.
One other drug of this type – sotagliflozin (actually a dual inhibitor of SGLT-1 and 2) - is also currently approved for use as an adjunct to insulin in type 1 diabetes in the EU and the UK, and has been recommended by the UK’s National Institute for Health and Care Excellence (NICE). However, although there is currently no sign that sotagliflozin is also to be withdrawn as a treatment for type 1 diabetes, the drug has not yet been marketed as such.
Balancing benefits and risks
Dapagliflozin, and the other SGLT-2 inhibitors, lower glucose by stopping the kidneys from reabsorbing excess glucose, making them excrete it into the urine instead - a process which also causes weight loss. It was first licensed for use in type 2 diabetes, where it is helpful in managing type 2 diabetes and cardiovascular risk. And it is important to point out that dapagliflozin’s use in type 2 diabetes continues. It is also still licensed as a treatment for symptomatic chronic heart failure with reduced ejection fraction and for the treatment of chronic kidney disease.
In two Phase 3 clinical trials, covering 548 patients with type 1 diabetes, dapagliflozin was found to have beneficial effects on glycaemic control – without increasing hypoglycaemia – and on glucose variability, weight and blood pressure. Accordingly, the European Medicines Agency (EMA) gave dapagliflozin a favourable opinion for licensing. Dapagliflozin was licensed in the UK and the EU for both hyperglycaemia and weight loss in people with a BMI over 27, in cases where even optimal insulin therapy does not provide adequate glucose control. The EMA decision was welcomed by people with type 1 diabetes and authorities such as the Federal Joint Committee in Germany and by NICE in the UK. NICE made it available on the NHS as an adjunct therapy in July 2019.
The BMI restriction on the dapagliflozin indication exists because these individuals will likely be on a higher insulin dose (dosage per kg), which should help protect them from diabetic ketoacidosis (DKA), a potential side effect of dapagliflozin use in type 1 diabetes. They also have more to gain as they are at higher risk of cardiorenal complications than those of lower weight – put simply, the risk-benefit ratio of dapagliflozin shifts in their favour.
Why has the type 1 diabetes indication been removed?
It is the concerns around DKA that have led to the withdrawal of dapagliflozin. In trials, DKA was shown to be quite common, affecting one in 100 patients. DKA on SGLT-2 inhibitors can be particularly problematic, as it may occur when blood glucose is in range, making it harder to detect. Individuals with type 1 on dapagliflozin are required to do regular blood glucose and ketone monitoring to guard against the condition. However, AstraZeneca say the withdrawal is not about any new safety or efficacy concerns or any new data on DKA relating to the use of SGLT-2 inhibitors in people with type 1 diabetes.
So the question arises – shouldn’t people with type 1 diabetes have been able to continue to use dapagliflozin safely and enjoy the potential long-term health benefits, so long as they and their diabetes team continue to monitor carefully for the occurrence of DKA? The critical issue here seems to have been the requirement by the Medicines and Health Regulatory Agency (MHRA) in Great Britain and the EMA in the EU and Northern Ireland that a black triangle warning be placed alongside the drug name. The black triangle is actually quite commonly used with new drugs and just signals a requirement for ongoing monitoring of side effects, like DKA with dapagliflozin.
Responding to concerns raised by patient advocacy groups as to its reasons for the withdrawal, AstraZeneca said that the black triangle was poorly understood, even among prescribers, with the most common misconception being that it indicated a lack of safety data or a new safety concern. Given this, it seems AstraZeneca thought that patients and physicians alike might have perceived there to be new safety concerns over dapagliflozin and become reluctance to prescribe or take it, even in its other indications – such as for type 2 diabetes, for which the licence has not been withdrawn.
Simon O’Neill, Director of Health Intelligence and Professional Liaison at Diabetes UK, said: “As there is no new safety concern to people living with type 1 diabetes using this medication, Diabetes UK is disappointed that AstraZeneca and the MHRA did not find a solution that allowed people living with type 1 diabetes to continue using dapagliflozin safely.” The charity has been in discussion with the MHRA over clarifying the reasons for the withdrawal. The Juvenile Diabetes Research Foundation (JDRF) has also voiced concern over the decision.
Commenting on the withdrawal, Chantal Mathieu Vice-President of EASD and Professor of Medicine at the University of Leuven, Belgium, told Horizons: “This is disappointing news for people living with type 1 diabetes. Increasingly SGLT-2 inhibitors are seen as essential drugs for protecting against cardiorenal complications in people with diabetes. The WHO has even just added SGLT-2 inhibitors to their Essential Medicines List. Denying people with type 1 diabetes such essential medication, over what would appear to be a technicality, could be considered unethical.”
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Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.