New ADA/EASD Guidance on Diabetes: Assess CV Status First

Miriam E. Tucker

June 29, 2018

ORLANDO — The treatment approach to type 2 diabetes should begin with an assessment of cardiovascular disease (CVD) status, other comorbidities, and patient preferences, according to a draft of the upcoming 2018 joint consensus statement from the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD).

The final version of the 2018 update to the current 2015 ADA/EASD Management of Hyperglycemia in Type 2 Diabetes statement (Diabetes Care. 2015;38:140-149) will be presented on October 5, 2018 at the EASD annual meeting in Berlin and will be published in Diabetes Care and Diabetologia.

A preview of the draft document was presented in a 2-hour symposium on June 26 here at the American Diabetes Association (ADA) 2018 Scientific Sessions. A live webcast of the session is now available and comments can be submitted to until midnight on July 2.

The statement will aim to help clinicians navigate the increasingly complex options for management of hyperglycemia in type 2 diabetes, with particular emphasis on data published since 2014, including those suggesting cardiovascular benefit for the sodium-glucose cotransport-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

"The focus of this consensus report is not on what an individual's glycemic target should be or on how to select individualized goals, but rather how to achieve the individual patients' glycemic target taking into account patient factors and the ever-increasing choice of therapies available for glycemic control," said co-author Judith Fradkin, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, Maryland.

The draft document still recommends metformin as first-line therapy, but now favors the injectable GLP-1 agonists or SGLT2 inhibitors as second-line therapy over insulin, depending on underlying patient characteristics and other issues such as affordability/accessibility of the drugs.

Observers generally reacted well to the draft document.

In an interview, Silvio E. Inzucchi, MD, of Yale University School of Medicine, New Haven, Connecticut, who co-chaired the 2015 and 2012 ADA/EASD statement writing panels but wasn't involved in the 2018 version, said that at the time of the prior statements "there was a paucity of good clinical trial evidence on which to base decision-making, particularly regarding CVD...So it was a little unsatisfying because all it said was start with metformin and then do something else."

But now, "over the last 2 to 3 years, we have a growing dataset upon which we can actually further strategize our patient-centered approaches to care," he explained.

Others were pleased that the document also clearly states the limitations of the evidence, and that there will be some good practical advice for primary care physicians, who are increasingly having to manage type 2 diabetes. This will include a graphic clearly indicating which type 2 diabetes agents should be stopped, or have their doses reduced, when therapy is intensified. And the cost of drugs is addressed, with the acknowledgement that it may be necessary to use a generic type 2 diabetes agent or older insulin if that is all a patient can afford.  

There was some debate, however, with regards to the fact that many members of the writing panel had significant conflicts of interests with pharmaceutical companies.

First Step: Assess Cardiovascular Status

In general, the ADA/EASD document will advise assessment of cardiovascular status as the first step in determining treatment approach. Separate algorithms will address patients with atherosclerotic cardiovascular disease (ASCVD) and those with heart failure.

Lifestyle modification and metformin are still considered the cornerstones of treatment, although the panel did debate the ongoing role of metformin as the first-line pharmacologic therapy. Ultimately they opted to stick with the recommendation for now because of low cost and proven safety and efficacy.

Then, for patients in whom ASCVD predominates, a GLP-1 receptor agonist with proven CVD benefit or SGLT2 inhibitor with proven CVD benefit (provided the patient has adequate kidney function) are recommended, in that order.

The order is reversed in patients for whom heart failure predominates: listed first is an SGLT2 inhibitor with evidence of reducing heart failure in a cardiovascular outcomes trial (if the patient has adequate kidney function), with a GLP-1 receptor agonist with proven CVD benefit as an alternative option.

"What's new since 2015 is we recommend that these comorbidities be considered first and foremost, because they do influence the choice of a particular glucose-lowering medication...The presence of CVD is a compelling indication for the selection of certain glucose-lowering drugs," said another of the co-authors, Deborah J. Wexler, MD, of Massachusetts General Hospital, Boston.

The draft algorithm doesn't actually specify that an SGLT2 inhibitor or GLP-1 agonist should only be added if the patient doesn't achieve HbA1c targets with metformin and lifestyle: the language is likely to be permissive on that point, panel co-chair John B. Buse, MD, PhD, of the University of North Carolina, Chapel Hill, told Medscape Medical News.

Within the classes, preference is given to liraglutide among GLP-1 receptor agonists based on the LEADER trial, and empagliflozin among SGLT2 inhibitors based on EMPA-REG OUTCOME.

For Patients Without CVD, Focus on Other Individual Factors

For patients without ASCVD or heart failure, the next priority is to focus on the individual patient's needs and preferences for avoiding weight gain and hypoglycemia. The document provides guidance for specific agents.

Other sections will incorporate new information about chronic kidney disease, medical nutrition therapy, metabolic surgery, initiation of injectables — with a new preference of GLP-1 receptor agonists over insulin — and advice about down-titrating patients from oral medications once injectables are started. The latter is done using red, yellow, and green traffic light graphics.

Cost of medications will also be addressed, with the acknowledgement that it may still be necessary to prescribe sulfonylureas, thiazolidinediones, or older insulins if that's all the patient can afford.

Positive Feedback So Far: Good Information for Primary Care Physicians  

"The committee did a spectacular job in synthesizing the information, and also pointing out where evidence was lacking. I think the approach of determining whether someone has CVD as an initial decision node makes sense," Inzucchi told Medscape Medical News.

Asked for her opinion about the draft, M. Sue Kirkman, MD, of the University of North Carolina School of Medicine, who was involved in ADA guidelines in her former position at the association, told Medscape Medical News, "Overall the update to the consensus statement seems thoughtful. The authors have considered significant increases to the evidence base since the last version...They also fleshed out considerations of policy issues, such as drug costs."

And, Kirkman added, "They were careful to discuss the limitations of the evidence." Her "personal favorites" were the caveat that "beyond dual therapy is an evidence-free zone," and the emphasis that the cardiovascular benefits of SGLT2 inhibitors and GLP-1 receptor agonists have only been proven in patients with established CVD. 

She also particularly liked the "stop light" graphics indicating which medications should be stopped or reduced once other drugs are added, noting, "This is a common question I get from primary care providers about therapy intensification."

Conflicts of Interest: Unavoidable?

But Kirkman did fault the panel in that both co-chairs, Buse and Melanie J. Davies, MD, University of Leicester, UK, have long lists of disclosures with pharmaceutical companies that market type 2 diabetes drugs, as do some others — but not all — of the 10-member writing panel.

Audience member John Yudkin, MD, Emeritus Professor at University College London, UK, also raised the issue during the session discussion, noting that the US Institute of Medicine (IMO) (now the Academy of Medicine) guidelines call for at least one panel chair to be without disclosures.

"There seemed to have been an effort to have panel members without conflicts of interest, but the IOM Standards suggest that the chair of a panel, or at least one co-chair, be conflict-free," Kirkman told Medscape Medical News.

"Both chairs are fine people and I didn't sense particular bias towards particular drugs or classes, but optics are everything, and this could make it easy for people outside the ADA and EASD orbits to discount the statement."

Asked to comment on this issue, Inzucchi said: "I don't know if I have any solutions to this. A lot of us who are in academics and interested in this specific area end up getting involved in clinical trials. And when you're involving in clinical trials by definition there's a duality of interest...I think it's something to keep an eye on, but I certainly don't think it invalidates the committee's recommendations because some of the leading experts in the world who you really want the opinions of are working on clinical trials."

Inzucchi also noted that financial ties to pharmaceutical companies aren't the only source of bias: sometimes researchers have staked their careers on a particular concept or mechanism that they may try to defend even in the face of conflicting evidence.

"There could be some more difficult-to-define professional conflicts. So, I think the best way is to have a large committee, a good debate, and hopefully the best recommendations come out."

Inzucchi reports being a consultant to Alere, Janssen, and VTV Therapeutics, and additional relationships with AstraZeneca, Boehringer Ingelheim, Intarcia Therapeutics, Lexicon Pharmaceuticals, Novo Nordisk, and Sanofi. Buse reports receiving research support from, owns stock in, and/or is an advisor for Adocia, ADA, AstraZeneca, Dexcom, Elcelyx, Eli Lilly, Fractyl, Intarcia, Lexicon, Metavention, NIDDK, 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. Kirkman's institution receives research support from Novo Nordisk and Theracos for studies of type 2 diabetes medications, and she receives funding from the National Institutes of Health. Davies reports relationships with AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, Sanofi-Aventis, Servier, Intarcia Therapeutics, and Mitsubishi Tanabe Pharma Corporation. Fradkin and Wexler have reported no relevant financial relationships.

American Diabetes Association 2018 Scientific Sessions. June 26, 2018; Orlando, Florida.

For more diabetes and endocrinology news, follow us on Twitter and on Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.