On April 19, 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) released the much-anticipated new statement on the management of type 2 diabetes mellitus (T2DM).1 The previous statement produced by the consensus panel, condensed into an “algorithmic” approach, has been a mainstay for directing diabetes care for almost a decade,2 but it has not been without its detractors.3 In a world where the incidence of diabetes is increasing exponentially and new anti-diabetic therapies are being developed at a similar exponential pace, the new document seeks to bring improved and more timely direction to diabetes care.
While not exactly delivering an “out with the old and in with the new” doctrine, there are clear therapeutic winners and losers in this position statement as well as some therapies whose position in diabetes care remains mostly unchanged. To me, the major difference between old and new is that the new statement does not claim to be a guideline or an algorithm. As the authors state, it is much less prescriptive than it is descriptive of how one might craft a properly individualized plan for diabetes management on a patient-by-patient basis.
So let’s start with my perception of the “losers” in this new document. The statement is clearly guided by the principle of primum non nocere, especially as that concept has been shaped by results of the ACCORD,4 ADVANCE,5 and VADT6 trials. This new document also drills down on the importance of beta-cell failure as a central aspect of T2DM development.7 In light of these concerns, it seems to me that sulfonylureas, (SFUs), thiazolidinediones (TZDs), pre-mixed insulins and, to some extent, nonanalog insulins all are called out on significant safety or adverse-effect issues.
Proceed with caution
Sulfonylureas, often favored for their affordability, were cited as posing a high risk for hypoglycemia, contributing to weight gain, and lacking durability related to glycemic control (“beta-cell burnout”). Concern was also expressed about poor cardiovascular outcomes in some trials. In a significant comment, the statement authors address the fact that the low cost of medication must be weighed against the potential higher costs of morbid outcomes from poorly managed diabetes. This new document, patient-centric at its heart, actually draws attention to the fact that the real cost of diabetes management is controlling the cost of complications, not just the price of the pills!
TZDs (actually, only pioglitazone is considered viable in this document) also were cited for concern about safety and adverse effects; among the latter are the risk of weight gain, fluid retention, congestive heart failure, and bone fractures in women. While pioglitazone appeared to have a modest impact on reducing cardiovascular events in one study, I was left feeling that the agent’s multiple negatives clearly outweigh the tenuously proven cardiovascular benefits. Pioglitazone also has been associated with a possible increased risk of bladder cancer, a fact the authors note but do not expand on. Still unclear is whether bladder cancer, or for that matter a variety of cancers (as noted in the position statement), are drug-related issues or disease-state complications. Until this matter is clarified, I suspect most clinicians will opt for caution, limiting their use of potentially carcinogenic agents.
Pre-mixed and non-analog insulins (regular human insulin [RHI] and neutral protamine Hagedorn [NPH]) also drew cautionary comments in the new document. The primary concern about both products focused on weight gain or hypoglycemia—both highly undesirable adverse effects as demonstrated by results from the referenced landmark diabetes treatment trials.4-6 It is difficult to titrate pre-mixed insulins to maximum effectiveness without causing hypoglycemia or weight gain,7 a fact cited in this and in all previous ADA/EASD guidelines on management of T2DM. NPH and RHI have action profiles that do not align with the patterns of physiologic need and, therefore, set the stage for inadvertent hypoglycemia.
Now, let’s turn attention to the “winners.” The updated statement conferred clear approval on the newer “incretin-based” therapies—the dipeptidyl peptidase-4 (DPP-4) inhibitor and glucagon-like peptide-1 receptor agonist (GLP-1 RA) agents. They now sit at the table as equal options with “established” therapies, some of which, as noted, are cast in a negative light. Insulin (especially, basal or basal +1 analog therapy) continues to be a favored candidate for early use.
The DPP-4s, modestly effective in A1C reduction, made the winner’s circle because of their weight neutrality, freedom from hypoglycemia, and a very favorable adverse-effect profile (primum non nocere). While still somewhat expensive, these once-daily agents are well-tolerated, convenient, and effective, especially if deployed early in treatment and used in combination therapy.
The GLP-1 RA group shows up as a next-step option after metformin, with comments that support efficacy in lowering A1C and their established value in achieving weight loss. To date, there are no other available agents that offer the combined promise of glucose control and weight loss. It is not clear whether the limited occurrence of pancreatitis seen with this class is causative or associative. It is clear, however, that pancreatitis is associated with the disease state of diabetes. While the GLP-1 RA agents have noted gastrointestinal adverse effects, these seem to decline dramatically with time. Despite issues with adverse effects and cost, it is clear that the class produces robust reduction of A1C and weight—two prized properties of any antidiabetic agent.
Lifestyle modification and metformin are still winners as foundational therapies (no change from the previous statements). Everything we do to manage T2DM should be built on a solid foundation of diet, exercise, and weight management (see last month’s commentary). If the patient with newly diagnosed T2DM is very close to goal A1C, lifestyle changes alone may be sufficient to achieve control. If target A1C is more distant and/or lifestyle modification alone seems unlikely to achieve desired results, metformin should be used concomitantly. Unless contraindicated, metformin remains the first-line pharmacologic therapy for most patients with T2DM.
The 2012 position statement continues to place value on analog basal insulin as an add-on shortly after metformin and/or an additional oral agent to establish control while minimizing risk of hypoglycemia or weight gain. While glycemia can be reduced with RHI or NPH, the job can be done more safely with analog basal (and rapid-acting at mealtime where needed) insulin.
So, what or who is the biggest winner of all in the new position statement? Clearly, the patient.
In the olden days (a few months ago) the clinician sat in the pilot’s seat, while the patient sat in row 36, seat B, accepting whatever was doled out on the journey. In this new patient-centric, shared-decision-making model, the patient has been called forward to take the co-pilot’s seat, not only free, but invited, to give input on and veto strategies deemed unacceptable or likely to fail (ie, based on a poor fit with lifestyle and resources).
We have “given the keys to the patients!” a friend noted after reviewing this new document, implying a transfer of clinical decision making power. This struck me as a challenge and provoked a lot of contemplation. On the surface, she is right. On reflection, I realized patients have always held the keys. Instead of open exchange with us, diabetic patients took our pronouncements home and accepted or rejected them privately, not after frank discussion and negotiation with the clinician. This new document prescribes discussion and shared decision making to craft the optimal treatment strategy for an individual patient. Our diabetes patients deserve to sit beside us as co-pilots and help define their journey with diabetes.
1. Inzucchi SE, Bergenstahl RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. Published online ahead of print. April 19, 2012.
2. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2006;49:1711-1721.
3. Jellinger PS, Davidson JA, Blonde L, et al. Road maps to achieve glycemic control in type 2 diabetes mellitus: ACE/AACE Diabetes Road Map Task Force. Endocr Pract. 2007;13:260-268.
4. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2559.
5. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
6. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.
7. DeFronzo RA, Abdul-Ghani MA. Clinical review: preservation of β-cell function: the key to diabetes prevention. J Clin Endocrinol Metab. 2011;96:2354-2366.