UK NICE Backtracks on Some of its Type 2 Diabetes Guidance

December 02, 2015

The UK drug watchdog, the National Institute of Health and Care Excellence (NICE), has backtracked somewhat on many of its original proposals for its new clinical-practice guidelines on the treatment of type 2 diabetes in adults, following 9 months of complaints from experts and diabetes organizations.

"One-half to two-thirds [of the original objections] have now been listened to and changes made, which is great," diabetes expert Anthony H Barnett, MD, from University of Birmingham and the Heart of England NHS Foundation Trust in Birmingham, United Kingdom, told Medscape Medical News.

Dr Barnett and many other diabetes specialists had been vocal in their opposition to the draft guidelines, originally issued for a period of consultation in February. This is the first update to the treatment of type 2 diabetes in the UK in 6 years.

In particular, Dr Barnett is pleased that NICE has changed some of its advice from the original draft guidelines regarding which oral therapies to recommend if patients cannot tolerate metformin and for second-line "step-up" treatment after metformin alone is no longer sufficient to control blood glucose.

However, there are still parts of the guidelines that he says are questionable, including: the recommendation that NPH (human insulin) be the first-line basal insulin of choice in type 2 diabetes and the "stopping" rules for use of injectable GLP-1 agonists.

But most important — and despite NICE saying it is adopting "an individualized approach to diabetes care that is tailored to the needs and circumstances of adults with type 2 diabetes" — Dr Barnett argues that the advice given regarding the HbA1c level at which to intensify therapy encourages a "waiting-for-failure" approach.

Diabetes UK also has reservations and says the new guidance may be "putting unnecessary obstacles in the way of people with type 2 diabetes getting best care." It is concerned that, even with solid evidence, NICE is still continuing to wait far too long before making changes to the guidelines that could benefit patients.

In a statement, Chris Askew, chief executive of Diabetes UK, said: "There are many things we welcome from these new guidelines, but we are calling on NICE to commit to ongoing updates so that people with type 2 diabetes can benefit from latest advances in medication and diabetes care. Diabetes treatment is an ever-changing field, so it is important for recommendations to be updated regularly to reflect new evidence."

Original Guidance Criticized

The original draft guidance for the treatment of type 2 diabetes was first issued 10 months ago.

But immediately the proposals came under fire from diabetes experts, who took to social media to stress that the resulting recommendations would be ignored, at best, or at worst could harm patient care. Some expressed their criticisms in an editorial published in the British Journal of Diabetes and Vascular Disease.

A major complaint was that repaglinide was recommended as the principal alternative to metformin for first-line treatment of type 2 diabetes in patients who cannot tolerate or take metformin because of contraindications.

"This was illogical, given the risks of hypoglycemia and weight gain with repaglinide, the lack of outcome data, and the fact that it has to be taken three times per day, 15 minutes before meals," Dr Barnett noted.

Also lamented was the recommendation for a number of older drugs as second-line therapy after metformin, which seemed to be based on "headline" cost, which didn't take into account the overall healthcare costs associated with side effects of these agents, he argued. These include higher risks of hypoglycemia (with sulfonylureas and repaglinide) and concerns specifically with pioglitazone relating to weight gain, fluid retention, heart failure, fractures, and even possibly increased risk of bladder cancer.

Following a period of public consultation, NICE revised the draft guidelines in August but did not significantly alter the advice that had drawn the most criticism, prompting doctors to again complain, this time in a letter published online August 4 in Lancet Diabetes & Endocrinology.

Important Changes Made Regarding Early Intensification of Therapy

But in the 3 months since then, NICE does appear to have had a change of heart, at least regarding some of its initial recommendations.

In the new guidance, published December 2, it has removed repaglinide from the treatment algorithm — although advice on the use of this agent is retained in a footnote — and given instead the recommendation that modified-release metformin can be tried if standard-release cannot be tolerated as first-line treatment of type 2 diabetes.

Alternatively, dipeptidyl peptidase-4 (DPP-4) inhibitors, pioglitazone, or sulfonylureas are listed as first-line alternatives to metformin when the latter cannot be tolerated or is contraindicated.

And for second-line treatment where metformin alone is insufficient to control blood glucose levels, NICE now recommends that doctors can choose between DPP-4 inhibitors, sulfonylureas, and pioglitazone, with an extra caution regarding the known side effects of the last.

These represent "some very welcome improvements; they have concentrated on the early intensification steps," says Dr Barnett.

Also, the sodium-glucose cotransporter-2 (SGLT-2) inhibitors, another newer class of oral antidiabetes drugs that were previously completely overlooked in the draft guidance, are now listed as reasonable options for second- and third-line therapy.

However the NICE advice on SGLT-2 inhibitors is still "a little bit guarded," says Dr Barnett, and this is in spite of the very impressive recent results with one SGLT-2 inhibitor, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), in the landmark EMPA-REG trial, the first cardiovascular-outcomes trial to have shown a reduction in deaths with a therapy for the treatment of type 2 diabetes.

But Still Some Complaints: "Waiting for Failure"

However, there are still some bones of contention in the new guidelines.

The recommendations still do not leave enough room for individualization of therapy for type 2 diabetes, says Dr Barnett, in stark contrast to the American Diabetes Association/European Association for the Study of Diabetes position statement on the management of hyperglycemia in type 2 diabetes.

NICE recommends that if HbA1c levels are not adequately controlled by a single drug and rise to 7.5% or higher and after reinforcing lifestyle advice and adherence to therapy, then "support the person to aim for an HbA1c level of 7.0% and intensify drug treatment."

But this represents a "waiting-for-failure" approach for some patients — for example, those who are younger and more recently diagnosed with diabetes — Dr Barnett stresses.

In such patients, waiting for 7.5% "is much too late and, in my opinion, represents bad advice," he asserts. "Individualization must be just that — agreeing on individual HbA1c targets "and not waiting to intensify until control has been lost."

And "I don't think it is coincidence that 7.5% is the same as the [UK Quality and Outcomes Framework] QOF target for HbA1c attainment that GPs are given for type 2 diabetes [ie, they are financially rewarded for getting a patient to below 7.5%] — but this is an audit standard and not reflecting best practice."

Dr Barnett says he can predict a scenario where a less specialized GP "might "tick the box" at an HbA1c of 7.4% in a 50-year-old uncomplicated, recently diagnosed diabetic patient," when in reality they require a much lower HbA1c target and intensification must be enacted well before that 7.5% recommended by NICE.

On the other hand, a 7.5%-intensification recommendation may be "totally inappropriate" for some other patients — for example, "an elderly person living alone who perhaps has angina and other comorbidities." Here, a more appropriate target, particularly if treatment involves a drug that can cause hypoglycemia, might be higher than HbA1c 7.5%

The recommendation on intensification remains the "biggest problem" with the new guidance, says Dr Barnett: "They need to talk more about individualization rather than talking about a specific number."

Also he is also critical of the decision to retain NPH as the first-line choice for basal insulin when type 2 diabetes patients require insulin.

NICE is "not sufficiently convinced that the case is proven for the more expensive insulins, and this is disappointing," he asserts, noting that type 2 diabetes patients have to wait for significant hypoglycemic episodes before they can be considered for basal insulin other than NPH.

And finally, Dr Barnett is critical of the "stopping" rules for use of injectable glucagonlike peptide-1 (GLP-1) agonists in type 2 diabetes patients.

To be able to continue taking injectable GLP-1 agonists for longer than 6 months, type 2 diabetes patients who are using them must show both a minimum 1% drop in HbA1c and a 3% weight loss, something that is "paradoxical," he asserts, as many patients will drop HbA1c by 1% but not get the full 3% weight loss, whereas others may get very considerable weight loss but may not quite get to the 1%-HbA1c reduction.

"In both instances we would consider this a success for the treatment, but NICE would have us stop the drug."

GPs Rely on Guidelines and Won't Be Au Fait With Latest Evidence

Diabetes UK says that while diabetes specialists tend to be up-to-date and change their practices accordingly, the "vast majority" of people with type 2 diabetes "will be seen by generalist clinicians who often rely heavily on the guidelines, may not be up to speed with the application of new evidence, and may be reluctant to go beyond out-of-date existing guidelines.

"The concern is that this could lead to many patients waiting unnecessarily to get access to tried-and-tested newer therapies."

The charity is calling on NICE to put in place a regular review process that looks at emerging evidence and fully incorporates it into existing guidelines "on an ongoing basis so patients are not left waiting 5 years or more for an update."

Dr Barnett reports honoraria and lecture fees from AstraZeneca, MSD, Boehringer Ingelheim, Takeda, Novartis, Janssen, Eli Lilly, Sanofi, and Novo Nordisk.

NICE guidelines. Published December 2, 2015. Available here.


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