ADA and ACP Docs Debate Diabetes Goals: Outcome Is Surprise

March 24, 2019

NEW ORLEANS — Two high profile physicians debated what should be the treatment goal in terms of HbA1c in type 2 diabetes "for most people" during a debate yesterday here at ENDO 2019: The Endocrine Society Annual Meeting.

This follows the issue of a highly controversial guideline for type 2 diabetes by the American College of Physicians (ACP) last year, which stated that the HbA1c goal "should be between 7% and 8% in most people."

This caused a furor at the time because it contrasted with long-standing advice from the American Diabetes Association (ADA), reiterated in its annual standards, which recommends the "HbA1c goal should be < 7% for most people."

At the beginning of the debate, moderator Marie E. McDonnell, MD, director of the diabetes program at the Brigham and Women's Hospital, Boston, Massachusetts, asked the ENDO audience to vote on whether they agreed with the statement up for debate: "A reasonable HbA1c goal for many nonpregnant adults with diabetes is < 7% (53 mmol/mol)."

Delegates voted 82% to support that assertion (the ADA stance), with the remaining 18% disagreeing and siding with ACP.

A vote was taken again at the end of the debate, and the results were somewhat surprising.

A Tactic to Avoid Unintended Consequences

First up to the podium was John B. Buse, MD, PhD, director of the Diabetes Center at the University of North Carolina School of Medicine in Chapel Hill.

Buse started out by saying, "I initially fiercely opposed this debate because I believe there is a lot more to be gained by coming to consensus, and I agree with 99% [of what's in the ACP guidance]."

And he noted, "There are many individuals for whom an HbA1c > 7% is clearly reasonable."

But, he stressed, the question up for debate is: What is the ideal target for "most" people?

He believes "the goal of an HbA1c target < 7% is fundamentally a tactic" to ensure people minimize the risks of complications while maintaining quality of life.

"There are potentially dire consequences to alternative targets, for example, a range of 7-8% [as per ACP guidance]," he said.

Buse then outlined the many clinical trials which, over the years, have led ADA to their target of < 7%.

He noted that "all was good until 2008 when the ACCORD results were published." In this trial of tight versus less intensive glucose control, the HbA1c targets were < 6% versus 7-8%, and there was excess mortality in the tight control group.

"What ACCORD told us was that the relentless pursuit of HbA1c < 6% is a bad idea," he noted.

And of course, "the focus today is on individualization, from all the guidelines, from all of the organizations," he stressed.

But to go back to the issue being debated, in the statement "a reasonable HbA1c goal for many nonpregnant adults with diabetes is < 7%," "how many is the 'many?'" he wondered.

The answer, said Buse, includes those who already have an HbA1c < 7% without adverse events and > 10 years' life expectancy, women of childbearing potential, and people with cardiovascular disease or chronic kidney disease who may benefit from some of the newer type 2 diabetes drugs, such as GLP-1 agonists or SGLT2 inhibitors.

With regard to the latter group of patients, he urged delegates to look at "the changing paradigm in caring for patients with type 2 diabetes and clinical cardiovascular disease," showing a table of numbers needed to treat (NNT) to prevent one death. Compared with an NNT of 100 for statins (taken for 5 years), the NNT is 39 for the SGLT2 inhibitor empagliflozin taken for 3 years, he stressed.

And he noted that the cardiovascular benefits of these newer agents even "emerged in trials where the drugs were added (versus placebo) in patients with cardiovascular disease and an HbA1c > 7%" as their primary aim was to demonstrated cardiovascular safety.

And although many other factors feed into the risk for complications and premature death among those with type 2 diabetes, "glycated hemoglobin [HbA1c] is still the number one risk factor," he stressed.

"What I am most afraid of, were the target HbA1c to shift to 7-8% for most patients, are 'unintended consequences,'" he said. Physicians must complete a variety of assessment forms in order for their patients to qualify for certain medications, and one of the key questions to gain coverage for newer medications pertains to HbA1c level, he stressed.

"If we lose this vote, it is going to dramatically impact our ability to use these life-saving [newer] drugs in patients," Buse concluded.

ACP Takes Stand, Discusses Newer Drugs, the "Elephant in the Room"

Next up to argue against the proposition was Timothy Wilt, MD, MPH, who is chair of the ACP Clinical Practice Guideline Committee and coauthored their 2018 guidance on type 2 diabetes.

Wilt started off agreeing with Buse that individualization is key.

But is it reasonable to target HbA1c < 7% for many nonpregnant adults? "No," he contended. "A pharmacologic treatment target HbA1c of 7-8% is preferred in most."

His major argument for the ACP stance is that "intensive versus less intensive" doesn't produce any meaningful benefits. Citing two UKPDS trials, as well as the ADVANCE, ACCORD, and VADT studies, he noted: "Achieving HbA1c < 7% did not reduce clinical microvascular or macrovascular outcomes," over 5 to 10 years in large clinical trials.

"There is no scientific evidence to get HbA1c below 7% to improve outcomes," and in fact, there were some "substantial harms," he noted. Indeed, the ACP stance is to "de-intensify" therapy in those in whom HbA1c is < 6.5%, he added.

In essence, more intensive HbA1c targets lead to greater healthcare burden and costs, with higher doses of drugs and more hypoglycemic medications, necessitating increased patient and glucose monitoring — and more adverse events.

Moving on to discuss the newer classes of drugs for type 2 diabetes and whether these should be part of the armamentarium, Wilt called this, "the big elephant in the room," referring to the fact that the ACP guidance did not consider evidence from recent cardiovascular outcomes trials with these newer agents.

ACP was much maligned for this stance at the time, but Wilt said ACP deemed that the issue of the benefits of newer agents was "an area of uncertainty and future research need."

And he argued that some of these newer agents "have serious adverse events of their own," such as diabetic ketoacidosis, amputations, and fungal infections adding, "there is no free lunch."

He also picked apart some of the trial data. With dipeptidyl peptidase-4 (DPP-4) inhibitors, for example, he said: "the data [on these agents] suggest no clinical benefit. I don't use them at all."

Paying for Convenience

Wilt went on to say that with these newer drugs "we are paying for a little bit of convenience."

Of the most expensive 25 medications in the United States, six are diabetes drugs, and we spend "$33 billion a year" on these, he observed.

This means "many patients are paying high costs, too," he emphasized. "How much are we and our patients and our healthcare systems willing to pay for convenience?"

He went on to list the annual retail prices of some drug classes for diabetes: sulfonylureas came in at $206 per year, metformin at $327, pioglitazone at $2483, a DPP-4 inhibitor such as sitagliptin at $6486, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor such as empagliflozin at $6600, and a glucagon-like peptide 1 (GLP-1) analog such as liraglutide at a hefty $12,844.

For insulin, the annual retail price of NPH insulin is $288, compared with $9600 for a glargine pen and $8100 for aspart pens.

He then showed calculations of cost per cardiovascular event prevented — which, for liraglutide at the annual retail price quoted, equates to more than $2 million, he said, and for empagliflozin, $1.2 million.

"Are these newer cost options high value?" he wondered.

He reminded delegates of the American Board of Internal Medicine's professionalism charter: "Physicians are required to provide healthcare based on the wise and cost-effective management of limited clinical resources. They should be committed to working with other physicians, hospitals, and payers to develop guidelines for cost-effective care."

Throughout his presentation, Wilt detailed one patient: a 60-year-old man with type 2 diabetes and hypertension taking metformin, glipizide, sitagliptin, and insulin glargine initially, with an HbA1c of 6.5%, who could no longer afford his medication.

Wilt said the physician got rid of the DPP-4 inhibitor, sitagliptin, and switched the man's insulin to NPH. This resulted in his healthcare costs going from thousands of dollars a year to just $800, with a resultant HbA1c of 7.3%

"Clinicians should personalize goals for glycemic control in patients with type 2 diabetes based on a discussion of benefits and harms of pharmacotherapy, patients' preferences, patient's general health and life expectancy, treatment burden, and costs of care," he concluded.

More Common Ground Than Differences?

In rebuttal, Buse said the example of the patient on sitagliptin together with glipizide was just "bad doctoring," since the only advantage for using DPP-4 inhibitors "is that they are not associated with hypoglycemia" so they "shouldn't be used with drugs that induce hypoglycemia (sulfonylureas)."

And he said that the trials cited by Wilt as evidence against the HbA1c < 7% target — ADVANCE, ACCORD, and VADT — were all in quite specific patient populations.

And Buse emphasized "multiple data" showing that the newer drugs for type 2 diabetes that have demonstrated cardiovascular benefit "are cost effective because they lower healthcare costs down the line."

Wilt responded that he is "skeptical" about who did those cost-effectiveness analyses, noting, "I haven't seen them."

Closing the debate, McDonnell, the moderator, said: "It occurs to me that when we set a target, we don't actually get to it. I'd like to talk to the two of you about 'targets' versus what is actually achievable."

Buse agreed wholeheartedly: "The HbA1c target of < 7% is a tactic to get to 7-8%," he emphasized.

"My concern is that when you say the target is 7-8%," then the average HbA1c will creep up to 7.9%, he stressed.

Wilt said: "Give clinicians some latitude. Until science suggests 8% is bad versus < 8% — there is no evidence that it leads to bad health outcomes."

It seems that the endocrinologist audience at ENDO agreed with him.

On repeating the vote at the end of the debate, the audience had changed its mind somewhat.

Just 58% now agreed with Buse that "a reasonable HbA1c goal for many nonpregnant adults with diabetes is < 7%" and 42% disagreed. A win for the ACP this time, it would seem.

Buse has reported receiving research support from, owning stock in, and/or being an advisor for Adocia, ADA, AstraZeneca, Dexcom, Elcelyx, Eli Lilly, Fractyl, Intarcia, Lexicon, Metavention, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, NovaTarg, Novo Nordisk, Sanofi, Shenzhen Hightide Biopharmaceutical, VTV Therapeutics, Boehringer Ingelheim, Johnson & Johnson, National Center for Advancing Translational Sciences, National Heart, Lung, and Blood Institute, Patient-Centered Outcomes Research Institute, and Theracos. Wilt has reported no relevant financial relationships.

ECCO 2019. Saturday March 23, 2019. Debate E03.

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