Guidelines Revised for Management of Type 2 Diabetes Mellitus

November 30, 2007 — The American Diabetes Association and the European Association for the Study of Diabetes have issued a consensus statement on the management of hyperglycemia in type 2 diabetes mellitus. This consensus algorithm for the initiation and update regarding the thiazolidinediones was published in the November 27 Online First issue of Diabetologia.
"New information suggests additional hazards associated with the use of either thiazolidinedione, and rosiglitazone in particular may result in an increased frequency of myocardial infarctions," write David M. Nathan, MD, from the Diabetes Center, Massachusetts General Hospital, Harvard Medical School, in Boston, Massachusetts , and colleagues. "We therefore recommend greater caution in using the thiazolidinediones, especially in patients at risk of, or with, CHF [congestive heart failure]."
Approximately 1 year ago, the American Diabetes Association and the European Association for the Study of Diabetes commissioned development of an evidence-based, consensus algorithm for the management of type 2 diabetes mellitus, which was designed to help clinicians choose the most appropriate treatment regimens from the expanding armamentarium of available drugs.
The guidelines authors note that newly approved medications and new data from clinical trials and other studies should be considered in the management of type 2 diabetes, thereby warranting an update of the algorithm. The present update mainly focuses on recent understanding of the advantages and disadvantages of the thiazolidinediones.
The guidelines also now include the dipeptidylpeptidase-4 inhibitor sitagliptin as a management option in the revised algorithm, noting that this agent was not yet approved by the US Food and Drug Administration (FDA) when the original algorithm was issued. Comments concerning sitagliptin are that expected percentage decrease in hemoglobin A1c (HbA1c) levels is 0.5% to 0.8%. Advantages of sitagliptin are that it is weight neutral, but disadvantages are that there is scant clinical experience with the drug, and it is expensive.
The revised guidelines continue to support the major features of the original algorithm, including the need for tight glycemic control within, or as close to, the nondiabetic range without compromising safety; beginning lifestyle interventions and treatment with metformin at the time of diagnosis; rapidly adding medications and changing to new regimens when target glycemia is not reached; and adding insulin treatment for patients not achieving target HbA1c levels.
"We are mindful of the importance of not changing this consensus guideline in the absence of definitive or compelling new data," the guidelines authors write. "Future updates are planned to consider further revisions of the algorithm, guided by the evidence base and clinical experience with the newer classes of glucose-lowering medications."
In the original consensus algorithm, the thiazolidinediones, insulin, and sulfonylurea were 3 possible options that should be added to metformin and lifestyle intervention if target HbA1c levels (< 7%) were not achieved. However, recent meta-analyses, including 1 performed by the maker (GlaxoSmithKline) and 1 by regulatory authorities, have highlighted the potential risk for myocardial infarction associated with the use of rosiglitazone (30% - 40% relative increase in risk for myocardial infarctions). Although the underlying data are not thought to be conclusive, clinicians are still warned to use extra caution when considering use of rosiglitazone.
However, another recent meta-analysis, reviewing virtually the same data, showed that neither rosiglitazone nor pioglitazone was associated with a significantly increased risk for cardiovascular death.
The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study was designed specifically to evaluate cardiovascular outcomes associated with rosiglitazone therapy. Although an interim analysis of RECORD showed an increased risk for CHF associated with rosiglitazone (hazard ratio [HR], 2.15; 95% confidence interval [CI], 1.30 - 3.57), no statistically significant effects of rosiglitazone on myocardial infarction were observed (HR, 1.17; 95% CI, 0.75 - 1.82).
A meta-analysis of clinical trial data concerning the risk for cardiovascular disease associated with use of pioglitazone actually suggested that this drug may have a protective effect. However, both pioglitazone and rosiglitazone have been linked to an increased risk (approximately double) for fluid retention and CHF, which has resulted in a stronger black box warning in the prescribing information for the thiazolidinediones.
Especially in women, both pioglitazone and rosiglitazone have been associated with increased risk for fractures, mostly in the distal extremities (forearm, hand, wrist, foot, ankle, fibula, or tibia), where osteoporotic fractures do not typically occur.
"At this time, we do not view as definitive the clinical trial data regarding increased or decreased risk of myocardial infarctions with rosiglitazone or pioglitazone, respectively," the guidelines authors conclude. "Nor do we think that the increased risk of CHF or fractures with either of the available thiazolidinediones is of a magnitude to warrant their removal as one of the possible second-step medications in our algorithm, given that they cause hypoglycaemia less frequently than other second-step drugs. On the other hand, we do believe that the weight of the new information outlined above should prompt clinicians to consider more carefully whether to use this class of drugs vs insulin or sulfonylureas as the second step in the algorithm."
The guidelines further note that there may be clinically important differences between pioglitazone and rosiglitazone and that maintaining both thiazolidinediones in the current algorithm represents a balance between the need for multiple options to treat a challenging and progressively serious disease such as diabetes and the recent unfavorable data.
Some of the guidelines authors have disclosed various financial relationships with the University of North Carolina, Sanofi-Aventis, GlaxoSmithKline (maker of rosiglitazone), Pfizer, Amylin, Bristol-Myers Squibb, Hoffman-LaRoche, Eli Lilly, NovoNordisk, Merck (maker of sitagliptin), Novartis, AstraZeneca, Merck Sharp & Dohme, Roche, Servier, Boehringer Ingelheim, Takeda (maker of pioglitazone), Johnson & Johnson, and Smiths Medical.
Diabetologia. Published online November 27, 2007.