AstraZeneca said that the decision is not motivated by safety concerns, but that an increased risk of diabetic ketoacidosis may cause ‘confusion’ among clinicians using the drug to treat other indications
In a shock, yet low-key announcement, the sodium–glucose co-transporter-2 (SGLT-2) inhibitor dapagliflozin (Forxiga; AstraZeneca) has been withdrawn from the market in all EU countries for the indication of type 1 diabetes.
This includes withdrawal in the UK, which was part of the EU when dapagliflozin was approved for type 1 diabetes in 2019 but, following Brexit, is no longer.
AstraZeneca said that the decision is not motivated by safety concerns, but pointed nevertheless to an increased risk of diabetic ketoacidosis (DKA) associated with SGLT-2 inhibitors in those with type 1 diabetes, which it said may cause ‘confusion’ among physicians using the drug to treat numerous other indications for which this agent is now approved.
DKA is a potentially dangerous side effect resulting from the build-up of ketones in the blood, and is normally accompanied by very high glucose levels. DKA is flagged as a potential side effect in type 2 diabetes, but is more common in those with type 1 diabetes. It can also occur as ‘euglycaemic’ DKA—ketosis, but with relatively normal glucose levels, which is therefore harder for patients to detect. Euglycaemic DKA is thought to be more of a risk in people with type 1 diabetes than in those with type 2 diabetes.
One charity believes that concerns around safety are the underlying factor for the withdrawal of dapagliflozin for type 1 diabetes in Europe, and has suggested that AstraZeneca may not want to risk income from more lucrative indications—such as type 2 diabetes, which has a much larger patient population—because of potential concerns from doctors, who may be deterred from prescribing the drug due to the risk of DKA.
Juvenile Diabetes Research Foundation (JDRF) International, a leading global type 1 diabetes charity, called on AstraZeneca in a statement to ‘explain to people affected by type 1 diabetes why the drug has been withdrawn’.
It added that dapagliflozin is the ‘only other drug besides insulin’ to be licensed in Europe for the treatment of type 1 diabetes, and represents a ‘major advancement since the discovery of insulin 100 years ago’.
Karen Addington, UK Chief Executive of JDRF International, said that it is ‘appalling’ that the drug has been withdrawn, as ‘many people with type 1 are finding it an effective and useful tool to help manage their glucose levels’.
SGLT-2 inhibitors never approved for type 1 diabetes in the US
Dapagliflozin and other drugs from the SGLT-2 inhibitor class had already been approved for the treatment of type 2 diabetes for a number of years when dapagliflozin was approved in early 2019 for the treatment of adults with type 1 diabetes. The drug was approved for this indication after meeting certain criteria of the European Medicines Agency (EMA), which at that time included the UK in its remit, based on data from the DEPICT series of phase-3 trials.
SGLT-2 inhibitors have also recently shown benefits in other indications, such as heart failure and chronic kidney disease (CKD)—even in the absence of diabetes—leaving some to label them a new class of wonder drugs.
Following the 2019 EU approval for type 1 diabetes, dapagliflozin was subsequently recommended for this use on the NHS in England and Wales, and was accompanied by NICE Guidance, which has now had to be withdrawn.
Of note, dapagliflozin was never approved for use in type 1 diabetes in the US (where it is known as Farxiga), where the US Food and Drug Administration (FDA) turned it down in July 2019.
An advisory panel for the FDA also later turned down another SGLT-2 inhibitor for type 1 diabetes—empagliflozin (Jardiance; Boehringer Ingelheim)—in November 2019, as reported by Medscape Medical News.
Discontinuation ‘not due to any safety concern’, says AstraZeneca
The announcement to discontinue dapagliflozin for the indication of type 1 diabetes in certain adults just over 2 years after its approval in the EU comes as a big surprise, especially as it was made with little fanfare just last month.
In the UK, AstraZeneca sent a letter to healthcare professionals on 2 November 2021 stating that, from 25 October, dapagliflozin 5 mg was no longer authorised for the treatment of type 1 diabetes and should no longer be used in this patient population.
However, it underlined that other indications for dapagliflozin 5 mg and 10 mg were not affected by this licensing change, and the drug remains available for adults with type 2 diabetes, as well as for the management of symptomatic chronic heart failure with reduced ejection fraction (HFrEF) and CKD.
In the letter, sent by Tom Keith-Roach, Country President of AstraZeneca UK, the company asserts that the removal of the type 1 diabetes indication from dapagliflozin is ‘not due to any safety concern’ with the drug for ‘any indication, including type 1 diabetes’.
It nevertheless goes on to highlight that DKA is a known common side effect of dapagliflozin in type 1 diabetes and, following the announcement, ‘additional risk minimization measures … will no longer be available.’
In a separate statement, AstraZeneca said that the decision to remove the indication was made voluntarily and had been agreed with the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain and the equivalent body in Northern Ireland.
‘It follows discussions regarding product information changes needed post-approval for dapagliflozin 5 mg specific to type 1 diabetes,’ the company said, ‘which might cause confusion’ among physicians treating patients with type 2 diabetes, chronic HFrEF, or CKD.
AstraZeneca told Medscape Medical News that similar communications about the withdrawal were issued to healthcare agencies and professionals in all countries of the EU.
‘Disappointing’ for patients
The announcement has been met with disappointment in some quarters and outrage in others, and questions have been raised as to the explanation given by AstraZeneca for the drug’s withdrawal.
‘Although only a small number of people with type 1 diabetes have been using dapagliflozin, we know that those who have been using it will have been benefiting from tighter control of their condition,’, Simon O’Neill, Director of Health Intelligence and Professional Liaison at Diabetes UK, told Medscape Medical News.
‘It’s disappointing that these people will now need to go back to the drawing board and will have to work with their clinical team to find other ways of better managing their condition.’
O’Neill said that it was ‘disappointing that AstraZeneca and the MHRA were unable to find a workable solution to allow people living with type 1 diabetes to continue using the drug safely without leading to confusion for clinicians or people living with type 2 diabetes, who also use it.’
Sanjoy Dutta, Vice President of Research at JDRF International, added that the news is ‘devastating’.
‘The impending negative impact of removing a drug like dapagliflozin from any market can be detrimental in the potential for other national medical ruling boards to have confidence in approving it for their citizens,’ he added.
‘We stand with our type 1 diabetes communities across the globe in demanding an explanation to clarify this removal.’
Motives behind the withdrawal
A clue as to the real motives behind the withdrawal can be found in an announcement, just last week, by the MHRA.
‘The decision by the marketing authorisation holder to voluntarily withdraw the indication in type 1 diabetes followed commercial considerations due to a specific European-wide regulatory requirement for this authorisation,’ it said.
‘The decision was not driven by any new safety concerns, such as the already known increased risk of diabetic ketoacidosis in type 1 diabetes compared with type 2 diabetes.’
This article originally appeared on Medscape, part of the Medscape Professional Network.
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