NICE Still Has It Wrong on Type 2 Diabetes Guidance, Say Docs

August 13, 2015

A group of eminent diabetes doctors is once again lamenting the position taken by the UK health watchdog, the National Institute for Clinical Excellence (NICE), in its latest draft of clinical practice guidelines for the treatment of type 2 diabetes.

The original draft NICE guidelines were first issued in January this year, and experts warned at the time that the part pertaining to pharmacotherapy in particular could adversely affect patient care or simply end up being ignored.

Among other issues, the recommendations advise a number of older drugs as second-line therapy after metformin, purely on the basis of cost, but don't take into account the overall healthcare costs associated with side effects of these agents, such as higher risks of hypoglycemia, say the doctors.

They note also that the committee advising NICE, in an attempt to avoid people with conflicts of interest, had few currently practicing diabetologists on it, with the result that the draft guidelines have ended up being devised by people who don't really treat type 2 diabetes anymore.

Now, following a period of public consultation, NICE has revised the draft, but it has not significantly altered any of the advice that drew the most criticism, say J Paul O'Hare, FRCP, from the University of Warwick Medical School, Coventry, United Kingdom, and colleagues in a letter published online August 4 in Lancet Diabetes & Endocrinology.

"Little has changed in the guideline regarding advice on drug treatment to control blood glucose despite, and contrary to, the advice of most leading specialists in the specialty," the clinicians assert.

And this will have important implications for the treatment of type 2 diabetes that will go beyond even the UK shores, Dr O'Hare told Medscape Medical News.

While secondary-care providers may feel confident enough to stray from the NICE guidance, "general practitioners and primary-care providers cannot ignore them, as they will go into formularies and the least confident will blindly follow them," he noted.

In addition, may other countries with healthcare systems similar to the United Kingdom look to NICE for guidance on treatment, he adds.

But as a separate, newly issued report shows that spending on diabetes medications has almost doubled in the past 10 years, from just over 6% of the total National Health Service drug budget for England to 10%, one US clinician says NICE may have a point when it comes to cost containment.

David Nathan, MD, director of Massachusetts General Hospital Diabetes Center and Clinical Research Center, Boston, told Medscape Medical News, "There isn't enough attention paid to the pharmacoeconomics of the diabetes drugs — cost needs to be taken into account."

"I remain perplexed by the level of affection that diabetologists seem to have for many of these new drugs, which are often less effective in lowering glycemia compared with older and less expensive medications and which have a whole variety of new side effects and risks."

And none of these newer drug classes "has been shown to reduce long-term complications, and none has the duration of experience as the older drugs," Dr Nathan asserted, adding, "I suspect that I may agree with at least some of the NICE recommendations."

No Individualization; Sulfonylureas, Repaglinide, and Pioglitazone Poor Choices

One of the major criticisms by Dr O'Hare and colleagues is the fact that the proposed NICE guidance doesn't really leave any room for individualization of therapy for type 2 diabetes, 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, updated recently in Diabetes Care.

The latter leaves doctors "to choose what they think is the right treatment for type 2 diabetes," said Dr O'Hare, whereas the NICE recommendation is purely "cost-driven."

NICE recommends first-line treatment with metformin, which no one disagrees with, but then treatment intensification only when HbA1c is 7.5% or greater, whereas in reality this decision is highly dependent on individual patient characteristics, say the doctors.

And sulfonylureas still feature prominently in the guidelines for all stages of treatment intensification, "despite the well-recognized side effects of hypoglycemia and weight gain — the very issues that NICE states clearly in its preamble should be avoided," they point out.

Dr O'Hare said there is still a place for sulfonylureas, in patients in whom HbA1c is >9%, because of their powerful glucose-lowering effects, which newer agents that lower glucose less intensively cannot match.

"You would start with a low dose of sulfonylureas and titrate up," he noted.

But otherwise, the risk of hypoglycemia, and its attendant costs to manage, is too high with this drug class, he says, noting that NICE does not explain how, in its pharmacoeconomic analysis, it judges the cost of something like hypoglycemia and its management.

Dr O'Hare and colleagues also take issue with the NICE recommendation to use repaglinide as first-line therapy in patients intolerant of metformin, a drug that is rarely used anywhere else in the world and "is effectively a short-acting sulfonylurea," said Dr O'Hare.

Furthermore, this recommendation was based on a flawed network meta-analysis, in trial populations "totally unrepresentative of patients with type 2 diabetes in the UK," the doctors stress.

They are also critical of the recommendation for pioglitazone as a second-line alternative to metformin, again citing side effects. "In our professional opinion, pioglitazone still has a place in treatment, but only when other oral drugs have failed and only with careful monitoring," they write.

Silly Guidance on GLP-1 Agonists, Insulin, and SGLT2 Inhibitors

There are other concerns. For example, the draft recommendations state that injectable glucagonlike peptide-1 (GLP-1) receptor agonists can be used only in patients with type 2 diabetes and a body mass index (BMI) of over 35 kg/m2, which is "illogical," the doctors say, particularly in light of the fact that NICE itself defines obesity as a BMI of >30.

"We believe a logical compromise is a weight cutoff of BMI of >30 kg/m2 for use of GLP-1 agonists in white European patients and >27.5 kg/m2 in black and South Asian patients," Dr O'Hare said.

NICE also totally omits a new class of oral antidiabetes drugs, the SGLT2 inhibitors, with just a footnote on them, say Dr O'Hare and colleagues.

"The idea that a new NICE guideline can effectively ignore a class of oral antidiabetes drugs that have been available in the UK for more than 2 years does not make sense (and is in stark contrast to the recent joint US and European guidelines)."

And this is an even stranger decision given that a Health Technology Appraisal is shortly due on SGLT2 inhibitors, which NICE could have waited for before drafting its guidance, says Dr O'Hare.

He acknowledged, however, that a recently identified rare new side effect with SGLT2 inhibitors, diabetic ketoacidosis, had not been reported when these guidelines were drafted and admitted that this requires further investigation.

Also under attack are the proposed rules for insulin use in type 2 diabetes, which recommend older insulins, such as insulin isophane, which have a much higher risk of hypoglycemia, the doctors argue..

This recommendation stems from the belief, from the UKPDS study, "that patients with type 2 diabetes don't have a problem with hypoglycemia," says Dr O'Hare. But in reality this is untrue, he asserts.

"Out there in the community, we see type 2 diabetes patients starting on insulin all the time with hypoglycemia, and we need to use the safest product."

"In our opinion, for a guideline to suggest that patients must wait to have their first serious hypoglycemic event before they are allowed the safer alternative insulins is against the basic principles of our profession," he and his colleagues say.

It also raises the question of why long-acting insulin analogs are recommended as a first-line option for patients with type 1 diabetes (in the current draft NICE guideline for type 1 diabetes) but denied to people with type 2 diabetes, they assert.

Many Newer Drugs Coming Off Patent: NICE Needs to "Get Real"

In response to Dr Nathan's comments about the need for cost containment, Dr O'Hare acknowledges that in some healthcare systems, where patients may have to pay for drugs themselves, it may be that they can only afford sulfonylureas or pioglitazone, both of which are available generically.

But in a system where the state pays, there is a need to look at the overall healthcare costs of any intervention, he urges.

"We would accept that [NICE] stress using the lowest acquisition cost if there's a class effect," Dr O'Hare noted.

But he points out that NICE has missed a huge opportunity by not recognizing in this draft guidance that many of the branded drugs are in fact close to the end of their patents.

For example the oral DPP-4 inhibitor sitagliptin (Januvia, Merck) and insulin glargine (Lantus, Sanofi) are almost off patent and will soon be available generically, and biosimilar insulins are also on the horizon, which will be cheaper than branded versions.

NICE could have addressed this issue — given that it expects this new advice to stay in place for 5 years — but chose not to, he explained, adding, "They just need to get real, because this is the way [more experienced] clinicians will move."

Also, there are often big differences in cost between different members of the same drug class that should be taken into account, which again should have been mentioned in this guidance but was not, he said.

For example, the GLP-1 agonist lixisenatide (Lyxumia, Sanofi), costs around £700 a year in the United Kingdom, but a similar agent, liraglutide (Victoza, Novo Nordisk), is almost double that, at a cost of £1200 per annum, he noted.

Final Guidance Expected in October

Summing up, Dr O'Hare and his colleagues say, "We strongly recommend that in further revisions to the NICE guideline, repaglinide is withdrawn as a first-line treatment, the prominence given to sulfonylureas at all stages of intensification is reduced, the BMI restrictions and stopping rules for GLP-1 receptor agonists are redrawn, and the SGLT-2 inhibitors are fully included. "

Furthermore, individualized care for insulin management should mean just that, rather than restricting choice on the basis of cost.

Dr O'Hare said his group of specialists have communicated all of their concerns to NICE and its chairperson Dr David Haslam.

A NICE spokesperson told Medscape Medical News that a public consultation period on the revised draft type 2 diabetes guidelines ran from June 26 until July 24.

"We cannot respond to individual comments while the guideline is in draft form. The committee will now meet again to consider all comments received before the guideline is finalized," she added, noting that this is likely to be October.

Dr O'Hare and his colleagues conclude: "Primary-care doctors and nurses, in particular, are struggling to look after growing numbers of patients with type 2 diabetes. These healthcare professionals need clear, sensible guidance, based on evidence (and cost), but most importantly on safety."

Dr O'Hare receives lecture fees and advisory honoraria from Sanofi and Novo Nordisk. Disclosures for the coauthors are listed in the article. Dr Nathan has no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online August 4, 2015. Abstract

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