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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.
Updated ADA and EASD Algorithm for Treating Type 2 Diabetes
Tony O’Sullivan |
Click here to download PowerPoint slides of this commentary. |
Background
So many options have become available for the treatment of Type 2 diabetes that the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) have had to update their treatment advice at short intervals. The first ADA/EASD consensus statement appeared in 2006 (Nathan et al, 2006). An update in January 2008 (Nathan et al, 2008) urged caution in the use of thiazolidinediones because of new evidence of cardiac risks (myocardial infarction and congestive heart failure). The current statement considers greater evidence and experience with newer drug classes such as glinides and incretin-based therapies.
Methods and Key Results
The ADA/EASD update was based on (1) the authors’ evidence-based review of clinical trials of anti-diabetic interventions, used alone or in combination; and (2) the collective clinical experience and judgement of the authors. For each intervention considered, the authors established the effectiveness of glucose reduction as well as salient advantages and disadvantages: extra-glycaemic effects that could reduce long-term diabetic complications, safety and tolerability, ease of use, and cost.
Based on the strength of evidence, the authors created tiers of treatments, with tier 1 containing well validated and preferred treatments and tier 2 containing less well validated, less preferred options, as follows:
Tier 1 Interventions
- Lifestyle changes to decrease weight and increase exercise
- Metformin
- Sulfonylureas (other than glibenclamide [glyburide] and chlorpropamide)
- Insulin
Tier 2 Interventions
- Thiazolidinediones (pioglitazone)
- Glucagon-like peptide-1 (GLP-1) agonists (exenatide)
Use of rosiglitazone was specifically not recommended. Other drug classes were left untiered—and thus were excluded from the formal algorithm—because they reduced glucose no better than tiered agents, had insufficient evidence of safety, or were relatively expensive. These untiered drugs were α-glucosidase inhibitors, glinides, amylin agonists (pramlintide), and dipeptidyl peptidase-4 (DPP-4) inhibitors. These drugs were deemed appropriate choices for selected individuals, but no specific guidelines for their use were offered.
Treatment algorithm
The ADA/EASD management algorithm calls for lifestyle therapy and metformin starting at diagnosis of Type 2 diabetes and continuing throughout therapy. The goal of therapy is to achieve an HbA1c <7 %; anything higher demands adjustments.
The preferred initial adjustment is to add basal insulin or a sulfonylurea. However, the algorithm now offers the less validated option of adding pioglitazone or exenatide before a sulfonylurea or insulin. According to the authors, this route may be particularly appropriate when hypoglycaemia is a special concern (pioglitazone and exenatide have safer profiles than sulfonylurea) or when weight loss is a chief goal (exenatide is associated with losses of about 2 to 3 kg over 6 months).
The final adjustment in the ADA/EASD algorithm is initiation of intensive insulin therapy. Given the lack of head-to-head trials, it is impossible to say whether one management pathway truly slows progression to this point better than another or even how the strategies compare in their ability to achieve currently recommended glucose levels. The authors only stress the importance of synergy in selecting drug combinations (i.e., combining drugs with different mechanisms of action). Although regimens using 3 oral agents (e.g., metformin, pioglitazone, and sulfonylurea) can be considered, the authors point out that insulin therapy is less costly and equally effective.
Clinical Implications
The updated ADA/EASD statement and algorithm can be applauded for simplicity, flexibility, and encouragement of the use of clinical judgement in choosing strategies for Type 2 diabetes treatment. Caution is evident throughout as well. In addition to rejecting rosiglitazone for safety concerns, the authors are not comfortable or impressed enough with α-glucosidase inhibitors, glinides, pramlintide, or DPP-4 inhibitors to build them into even second-tier pathways of the algorithm. Glinides, for example, are considered less effective than sulfonylureas at glucose reduction and are associated with weight gain and higher cost. DPP-4 inhibitors are cited for expense and unconfirmed long-term safety. α-Glucosidase inhibitors have the drawback of excessive gastrointestinal side effects.
Indeed, all options in the ADA/EASD algorithm are imperfect for the task of controlling the inexorable progression of Type 2 diabetes. So far, only the most intensive strategies have been able to achieve glucose reductions associated with reduced microvascular complications. No strategy has made a clear difference in the rate of cardiovascular complications. Nonetheless, we can be grateful for the ever expanding choices available for new strategies and for guidelines that encourage us to use these choices flexibly but judiciously.
This Website Feature is funded by an educational grant from Bristol-Myers Squibb/AstraZeneca.
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