Memorandum

ADA and EASD publish new position statement, “Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach” – April 20, 2012

Executive Highlights

  • The ADA and EASD have jointly released a position statement on how clinicians and patients should choose the most effective set of antihyperglycemic treatments in type 2 diabetes patients.
  • The authors suggest the paper is meant as a less prescriptive alternative to previous guidelines for the development of patient treatments for hyperglycemia. The paper specifically departs from the 2009 ADA/EASD consensus statement, which took a more algorithmic approach.

Yesterday morning, the ADA and EASD jointly released a position statement on the medical management of hyperglycemia. The authors strongly advocate tailoring all treatments and glycemic targets to the needs of the individual patients and generally avoid endorsing any particular agent over another (besides metformin). Their breakdown of the pros and cons of the different agents is meant more as a set of guidelines than as a prescriptive algorithm, which the authors consider an acknowledgment of the lack of comparative-effectiveness data on the many available drugs (and the even vaster array of possible combinations). Notably, incretins are now highlighted equally with other classes. Specifically, the paper’s main figure displays metformin along with several drug classes for possible dual- and triple-therapy regimens – SFUs, TZDs, DPP-4 inhibitors, GLP-1 receptor agonists, and basal insulin – all against a background of diet/lifestyle intervention, with MDI suggested last. Alongside the graphic, each agent is succinctly described in terms of: A1c-lowering efficacy, risk of hypoglycemia, major side effects, and financial costs. As we understand it, the intent is for clinicians to navigate this figure based on their own determinations of what is important for a particular patient. So if weight loss and avoiding hypoglycemia are concerns, the clinician might choose a GLP-1 receptor agonist as the second agent; if cost is a major issue, then the clinician might choose an SFU. Overall, we think the graphic does thorough job of conveying pros and cons of specific agents, although it may seem overwhelming for PCPs and endocrinologists less focused on diabetes. We were also glad to see good guidance on combinations, e.g., long-acting insulin and GLP-1.

Nonetheless, some will find this position statement easier to use, particularly if they had a difficult time deciding whether to use the “well-validated” approach of metformin+SFU and the “less-well-validated” approaches of metformin+GLP-1 receptor agonist or metformin+TZD. Compared to the AACE/ACE algorithm, which provides a fairly prescriptive set of recommendations based on starting A1c and other aspects of disease, the new ADA/EASD statement is in some ways ‘fuzzier’ – but potentially user- friendlier in that it more readily accommodates a wider set of priorities among patients and clinicians. Worst-case scenarios would be if providers are confused by the flexibility or they use “individualized targets” as an excuse for laissez-faire treatment; in the best-case scenario, (which we hope is more likely), there is a greater recognition that every patient is different and that serving each individual best means thinking deliberately about which therapies to use. While we believe that the “front-line” PCPs may need more guidance and may not individualize treatment optimally due to time and knowledge constraints, individualization is certainly an excellent theoretical goal and this statement should make that easier. Indeed, all position statements will have pros and cons and we thank the organizations for their focus and work on this one.

  • The new ADA/EASD position statement argues that patient needs and lifestyle choices generally trump the efficacy of any particular drug. The authors argue that, in the absence of compelling evidence for the universal effectiveness of any of the myriad of currently available treatment options, clinicians are best served in developing a treatment plan that is ideally suited for the particular patient. The insulin treatment program should be guided not simply by which specific agents provoke the most favorable response from the patient, but also which provide the best fit for the patient’s diet, exercise, and diabetes education. The statement points out that any given treatment program can be enhanced or undermined by a patient’s willingness to participate, and the authors suggest that no algorithm can really hope to compensate for this at the present time. This is certainly true and very well put, although we do worry that the average doctor in the US in particular doesn’t have time to individualize therapy and we hope that ADA continues to take the time to advocate for doctors to have more time with, and to be reimbursed for greater time spent with patients.
  • Metformin is the only antihyperglycemic agent that receives an unequivocal endorsement. The authors confirm previous research indicating that metformin is, all other things being equal, the optimal first-line drug in any hyperglycemia treatment. While the statement lists several potential disadvantages – including gastrointestinal problems, acidosis, hypoxia, etc. – it points to metformin’s extensively proven ability to lower hepatic glucose production without risk of weight gain or hypoglycemia. Metformin’s low cost is also a differentiator from most of the other agents considered in the statement. Metformin’s potential cancer-protective nature could also benefit many patients, although this is far from definitive. Dr. Eric Topol, noted cardiologist at Scripps, has pointed out before that genetically, 22% of patients with European ancestry who go on metformin will not respond to metformin, and we hope this statement also pushes doctors to, when patients are unresponsive to therapy, to move faster to the next therapy. On a positive note, the next point does address the potential pitfalls of monotherapy.
  • We have some early thoughts about the commercial implications of this position statement: (i) overall, it’s a positive for incretins, which are now on the same “tier” as all the other drugs – in the consensus statement of 2009, GLP-1 receptor agonists were effectively “second-tier” in the previous guidelines, and DPP-4 inhibitors were not included in the algorithm at all; (ii) it’s a positive for DPP-4 inhibitors, which have a very positive “highly tolerable” label – that’s code for “magic” in our view with many doctors; (iii) it’s a positive for GLP-1, which are characterized by weight loss and no hypoglycemia; (iv) it’s a negative for mealtime insulin, which is recommended after the combination of basal insulin and GLP-1, a combination that has received significant attention; (v) it’s hard to tell what it will be for Actos – Actos is now on the same “tier” as everything else, although the long list of side effects associated with it may be too daunting, especially the recently added “bladder cancer” – to boot, although TZDs go generic soon, this is only footnoted, and may not be noticed. Although the “less-well-validated” label has been removed from TZDs as well as GLP-1 receptor agonists, we think the new guidance is likely a net negative for TZDs overall. We’ll be thinking further on this front and refining these thoughts over time.
  • Most treatment programs will require two- or three-drug combinations to achieve desired results. While metformin is endorsed as a near-universal player in hyperglycemia treatment, the authors acknowledge it is unlikely to achieve significant results on its own, at least not over a long period of time, given the progressive nature of diabetes. The authors do, however,strongly urge clinicians to place patient welfare and health ahead of any arbitrary waiting period, arguing that patients may justifiably require combination therapies or insulin almost immediately after beginning treatment. Possible treatment partners with metformin include, listed in order of ascending efficacy: DPP-4 inhibitor (intermediate), sulfonylurea (high), thiazoldinedione (high), GLP-1 receptor agonist (high), and basal insulin (highest). All of these but sulfonylureas (and to some extent NPH insulin) carry relatively high monetary costs, all but DPP-4 inhibitors have clear side effects, and some lack long-term data on potential safety concerns. (We understand that during the review process, which included several dozen expert clinicians besides the authors, one of the biggest points of contention was whether to widely endorse relatively new agents like GLP-1 receptor agonists and DPP-4 inhibitors.) The ‘apples-and-oranges’ set of tradeoffs is a major reason why the authors argue against an algorithmic approach, preferring instead the patient- oriented approach. This approach is more similar in some ways to the “AACE roadmap” published in 2010 although it leaves more of the ultimate decision-making up to the healthcare provider. For the best and most responsive doctors, this is a positive, although this may be considered by some as asking a great deal of PCPs who are not as educated as endocrinologists on all the new studies of various agents.
  • The authors argue against setting a single glycemic target for all patients. They argue that a more stringent approach to glycemic reduction should be taken only in certain instances, such as when patients are self-motivated, newly diagnosed, have a relatively long life expectancy and access to all necessary resources, and do not have any significant complications. In less- favorable conditions (e.g., old age, high risks associated with hypoglycemia, severe complications), the authors recommend tailoring the A1c target to a level more manageable for the patient in question. We also believe this provides another “out” for doctors who are less able to manage patients optimally. In the “real world,” it’s probably not possible to forecast life expectancy, for example, certainly not by a harried PCP. From a patient perspective, we believe that the average person with diabetes may not be happy to find out that their healthcare professional has a higher A1c target for them than has been broadly indicated, just because they are worried about the life expectancy, safety, etc. While there are, of course, very good reasons to individualize goals for patients who have experienced significant severe hypoglycemia, as an example, we would rather advocate for those patients to have access to CGM than to have a higher A1c target, despite the higher cost. To boot, we would rather the patients learn how all the therapies work and are better educated on the risks themselves; this new position statement may well be another reason for less-informed doctors not to worry if their patients are not reaching targets. We are not concerned about the best doctors not urging patients to do their best for patients and to prescribe therapy with knowledge of all the risks, as they are already overcoming many challenges in these regards. But we are concerned that already, 44% of US patients aren’t reaching the A1c target of 7% (Diabetes Care, 2010). While we agree with the authors that one- size-fits-all goals can be counterproductive (see below), in an ideal world we think the percentage of patients below 7.0% would be higher, even accounting for all the patients with more modest targets due to short lifespan, risks associated with hypoglycemia, etc. – to boot, DCCT and UKPDS both showed no lower threshold for benefits associated with reductions in A1c.
  • Broadly speaking, we wonder about the design and graphical presentation and the order of therapies presented in the document’s main table. A large body of evidence from behavioral economics demonstrates that the order in which options are presented can dramatically affect choices. While insulin is presented last in the table and metformin is presented first, there seems to be no obvious rationale for the ordering of the remaining therapies. We wonder how this fact might affect treatment choices. We do commend the authors for a thorough presentation of each therapy’s pros and cons; while the main table contains a lot of informationand makes it challenging to compare one therapy against another, the doctors who are the most engaged will certainly benefit. We hope future guidelines consider incorporating studies of human behavior and decision-making into future graphs and charts – use of color, ordering with an obvious rationale, and comparative presentation may be useful.
  • What’s the difference between the AACE/ACE algorithm and the new ADA/EASD guidelines? According to Dr. Helena Rodbard, the AACE/ACE algorithm: 1) provides more specific guidance, which is particularly important for the non endocrinologists in her view; 2) downgrades the priorities for SFUs and TZDs considerably more than the current ADA/EASD report; 3) emphasizes the beneficial effects of DPP-4 inhibitors and GLP-1 receptor agonists; 4) definitively recommends the insulin analogs (both rapid and long acting) in preference to regular insulin and NPH; 5) focuses on the total cost of care for the patient with diabetes, and not on the single element of the cost of the medications. Sulfonylureas are inexpensive, she points out, but they are associated with a very high risk of hypoglycemia, and the hypoglycemia leads to emergency room visits that immediately eliminate any savings that were attributed to the use of the cheaper agent. Metformin, DPP-4 inhibitors, and GLP-1 receptor agonists, and TZDs have markedly lower risk of hypoglycemia, she points out.
  • Ultimately, we are glad to see that this statement 1) emphasizes the importance that all targets should be based on explicit agreement between clinician and patient and 2) that a clinic’s quality should be measured in terms of how well it helps patients reach clinic-specific or patient-specific goals rather than adherence to a standard benchmark. We are very appreciative that a PCP was on the panel that produced the piece. We do believe management of diabetes is complex, and that non-endos may need more specific guidance regarding the intricacies of the current landscape of available medications. While it is terrific that ADA and EASD worked together on this, we would hope next time to see partnership with a larger group of associations, including AACE, the Endocrine Society, IDF, and the American College of Physicians. That said, it was certainly great to see a primary care physician involved in development of this paper. We hope that patients play as large a role going forward as well. We would push for greater education so that patients understand that there are goals that are appropriate goals, all to the end that no HCPs use the position statement as an “out” for why their specific patients aren’t closer to reaching their glycemic targets. Specifically, if a target is deemed too “dangerous” for patients at high risk of severe hypoglycemia, we hope they will be educated about and receive access to CGM, rather than be saddled with a higher than average A1c target that they didn’t ask for and may not deserve. It was very disappointing not to see reference to Dr. Vigersky’s work presented at ADA last year; we hope that this changes going forward. And, if an HCP does say that a patient should have a higher than average A1c goal, we hope doctors will tell the patients why and given them a choice, so that they have a clear reason for their doctors’ treatment decisions.

--by Alasdair Wilkins, Joseph Shivers, and Kelly Close