New Guidance Clarifies SGLT2 Inhibitor Use in Diabetes

Liam Davenport

July 27, 2018

Guidance on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes mellitus (T2DM) has been published by a group of UK experts to provide clarity over their use.

These drugs selectively inhibit glucose reabsorption in the kidney and are recommended for consideration for glucose-lowering therapy in patients who have not achieved glucose control with metformin. They have been available in the UK for 5 years, but there are conflicting messages over their efficacy and safety.

Researchers, including Prof John Wilding, head of the Department of Obesity and Endocrinology at the University of Liverpool, therefore conducted a review to summarise the available evidence and to offer guidance to clinicians. The study was funded by Napp Pharmaceuticals who make one of the SGLT2 inhibitors used in the UK.

Risks and Benefits

The guidance, which was published online by Diabetes Therapy on 23rd July, also includes a risk/benefit tool to identify patients most suitable for treatment with SGLT2 inhibitors.

In a news release, co-author Dr Kevin Fernando, a GP from North Berwick Health Centre near Edinburgh, said that "managing patients with type 2 diabetes is complex and can be challenging, particularly for clinicians working in primary care who are faced with many competing clinical priorities."

He added: "We felt it was important to help provide everyday, usable tools that will help healthcare professionals ensure their patients receive optimal care for their type 2 diabetes."

However, a leading UK expert who was not involved in the guidance - and did not want to be named - questioned its utility. While saying that it is "well written", up-to-date, "puts the pros and cons of the drug class into context" and addresses the known safety issues, he told Medscape Medical News that it looks only at SGLT2 inhibitors "and provides no balance with other possible oral agents."

He also raises concerns over how the guidance was funded.

He says that, while the authors "are very highly regarded in their field", he believes that "the funding issue and industry support is going to raise eyebrows and the review will, therefore, have little utility in clinical practice."

Reviewing Evidence

To address "misconceptions" over the efficacy, safety and place of SGLT2 inhibitors the Improving Diabetes Steering Committee, comprising experts from primary and secondary care, reviewed the available evidence.

The authors note that several studies, including a systematic review and meta-analysis, have shown that the drugs are associated with significant reductions in HbA1c levels when compared with placebo, with the greatest reductions seen with canagliflozin 300mg monotherapy.

In addition, they note that SGLT2 inhibitors are associated with weight loss, largely due to reductions in visceral fat, and that there is a growing body of evidence to suggest they are linked to reductions in serious cardiovascular complications and progression of kidney disease.

However, the authors point out that the drugs are also associated with an increased risk of genital infections, and that they should be used with caution in patients at high risk of lower limb amputations (LLAs).

There may also be an increased risk of bone fractures with SGLT2 inhibitor use, particularly early on in treatment, although dates are inconsistent and meaningful differences in bone mineral density have not been shown.

In addition, there is an association between SGLT2 inhibitors and diabetic ketoacidosis (DKA), with the Medicines and Healthcare Products Regulatory Agency (MHRA) recommending that patients be checked for raised ketone levels when symptoms are present, even if blood glucose levels are near normal.

The drugs should also be suspended immediately in patients with acute illness or who have planned surgical procedures, during which the type 2 diabetes sick day rules apply.

To summarise the evidence, the authors created a benefit/risk tool using a traffic light system corresponding to low-risk situations in which the use of SGLT2 inhibitors is supported, moderate-risk situations in which the drugs should be used with caution, and high-risk situations.

The aim, the authors say, is to offer "a quick reference guide concerning the specific areas covered in this review."

They add: "The tool aims to provide clarity regarding common areas of confusion in clinical practice associated with the risk of LLAs and bone fractures, late and early use of SGLT2 [inhibitor] treatments within the T2DM pathway, and risk of DKA."

However, the expert we consulted doubted how useful the tool will be in clinical practice.

He said: "The problem is that the figure is wordy, difficult to wade through and could actually be off-putting to busy clinicians."

Moreover, he pointed out that the information is already contained in the licence and already published guidelines.

He concluded that, in contrast, the latest draft of the American Diabetes Association/European Association for the Study of Diabetes guidelines "look extremely good, logical, easy to follow and give a good overview as to when SGLT-2 inhibitors should be used and when best to avoid."

The Improving Diabetes Steering Committee is supported by an educational grant from Napp Pharmaceuticals Limited, which also funded the medical writing assistance.

Prof Wilding has received funding for providing educational sessions and/or attending advisory boards from Astellas, AstraZeneca, Biologix, Boehringer Ingelheim, Janssen, Lilly, Merck, Napp Pharmaceuticals, Novo Nordisk, Orexigen, Sanofi and Takeda. He has received travel grants to attend conferences from AstraZeneca, Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi. He has institutional research grant support or funding for clinical trials from AstraZeneca, Boehringer Ingelheim, Janssen, Novo Nordisk, Sanofi and Takeda. Other authors also report numerous funding disclosures.

Diabetes Therapy 2018. doi: 10.1007/s13300-018-0471-8 .

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