UK NICE Elevates SGLT2 Inhibitors in Diabetes Guidance

Miriam E. Tucker

May 26, 2017

The UK National Institute of Health and Care Excellence (NICE) has revised its 2015 type 2 diabetes guidelines to feature the sodium-glucose cotransporter 2 (SGLT2) inhibitor class more prominently as a treatment option, while adding a warning about diabetic ketoacidosis (DKA) with the agents.

The May 2017 revisions — presented in a new algorithm — represent a small but important change to the December 2015 guidelines, then the first major revision in 6 years.

The December 2015 guidelines listed SGLT2 inhibitors as "reasonable options for second- and third-line therapy," following the September 2015 publication of the landmark EMPA-REG trial, which showed a reduction in cardiovascular death with the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) compared with placebo in type 2 diabetes patients at high cardiovascular risk.

But the way the old guideline was worded prompted one expert at the time to call the recommendation "a little bit guarded."

Now the SGLT2 inhibitors are listed much more prominently as second-line therapy options, along with dipeptidyl peptidase-4 (DPP-4) inhibitors, pioglitazone, or sulfonylureas to be used on treatment intensification when HbA1c rises above 7.5% on metformin. They are also listed prominently for use in triple therapy once HbA1c rises above 7.5% on dual therapy.

In addition, SGLT2 inhibitors can be considered as a first-line therapy option if metformin is contraindicated or cannot be tolerated and "a sulfonylurea or pioglitazone is not appropriate."

At the same time, a new footnote has been added regarding reports of DKA in people taking any of the three currently available SGLT2 inhibitors — canagliflozin (Invokana, Invokamet, Janssen), dapagliflozin (Farxiga, Xigduo XR, AstraZeneca), or empagliflozin — and to test ketones in people taking these agents who show symptoms of DKA, even those with normoglycemia.

This information has also been included in the products' EU labels since February 2016.

Asked to comment, Simon Heller, MD, professor of clinical diabetes and honorary consultant physician, University of Sheffield, United Kingdom, told Medscape Medical News, "Now the SGLT2 inhibitors have been elevated to a reasonable option in the earliest stage."

But he added it's "interesting" to see all three [SGLT2 inhibitors] listed when only empagliflozin has major trial data to back it up thus far. And he pointed out that the drug's cardiovascular mortality benefit isn't mentioned in the NICE algorithm because the indication isn't on the UK label as it is on the US label.

And the recent warning about canagliflozin and amputations isn't mentioned either, even though that is on the EU label. "You can't expect NICE to pick up every potential bad thing and side effect and contraindication," he commented.

"This Is Guidance, but...You Can Use Judgment"

Also mostly left out of the algorithm are the glucagonlike peptide-1 (GLP-1) receptor agonists — except for use in very limited circumstances and then with strict "stopping rules" — and NPH insulin, rather than basal analogs, is advised as first-line insulin therapy for type 2 patients who require insulin.

Dr Heller told Medscape Medical News that practitioners are still free to use whatever agents they feel are appropriate for a given patient.

"I think you'd find that GLP-1 analogs are used more at an early stage in some individuals, particularly those who are very overweight. There are reasons you wouldn't want to use sulfonylureas early. This is guidance, but I think you can use judgment, so that's what you do."

And as for NPH insulin, "I think if somebody has hypoglycemia, particularly at night, it would be entirely reasonable to use an insulin analog. . . . A specialist wouldn't get pushback on using glargine."

He acknowledged, though, that "most people would use NPH first-line because it's cheaper, and primary-care budgets are scrutinized."

In general, he said, while NICE does try to encourage the less-expensive agents such as NPH insulin and sulfonylureas, it doesn't mandate their use.

"You are given options. . . . I think it would be unfair to say the UK forces use of sulfonylureas because they're the cheapest. The guidance doesn't say that."

How Helpful Are the Guidelines to Nonspecialists?

What does concern Dr Heller about the guidelines, though, is that "they're not really guidelines. They say consider all these options."

"Most people with type 2 diabetes are seen by primary-care physicians. If you're not particularly knowledgeable in diabetes, it's not clear which one to choose."

And thus, he cautioned, providers shouldn't rely solely on this guidance in managing type 2 diabetes patients.

"Alone it's not sufficient. . . . You really have to supplement it with experience in managing diabetes, however you want to do that. Whether you do it by reading journals, working with experienced colleagues, or attending meetings and courses — that has to be an essential component, as does talking to your patients and learning what they want."

Dr Heller has consulted for Novo Nordisk, Eli Lilly, and Boehringer Ingelheim and is a speaker for AstraZeneca and Roche.

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