Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Diabetes Care 31:173-175, 2008
DOI: 10.2337/dc08-9016
© 2008 by the American Diabetes Association
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nathan, D. M.
Right arrow Articles by Zinman, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nathan, D. M.
Right arrow Articles by Zinman, B.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Reviews/Commentaries/ADA Statements
Consensus Statement

Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy

Update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes

David M. Nathan, MD1,2, John B. Buse, MD, PHD3, Mayer B. Davidson, MD4, Ele Ferrannini, MD5, Rury R. Holman, FRCP6, Robert Sherwin, MD7 and Bernard Zinman, MD8

1 Diabetes Center, Massachusetts General Hospital, Boston, Massachusetts
2 Harvard Medical School, Boston, Massachusetts
3 University of North Carolina School of Medicine, Chapel Hill, North Carolina
4 Charles R. Drew University, Los Angeles, California
5 Department of Internal Medicine, University of Pisa, Pisa, Italy
6 Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Oxford, U.K
7 Yale University School of Medicine, New Haven, Connecticut
8 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

Address correspondence and reprint requests to David M. Nathan, Diabetes Center, Massachusetts General Hospital, Boston, MA 02114. E-mail: dnathan{at}partners.org

Abbreviations: CHF, congestive heart failure

The consensus algorithm for the management of type 2 diabetes was developed on behalf of the American Diabetes Association and the European Association for the Study of Diabetes approximately 1 year ago (1,2). This evidence-based algorithm was developed to help guide health care providers to choose the most appropriate treatment regimens from an ever-expanding list of approved medications. The authors continue to endorse the major features of the algorithm, including the need to achieve and maintain glycemia within or as close to the nondiabetic range as is safely possible, the initiation of lifestyle interventions and treatment with metformin at the time of diagnosis, the rapid addition of medications and transition to new regimens when target glycemia is not achieved, and the early addition of insulin therapy in patients who do not meet target A1C levels.

The availability of newly approved medications and the accrual of new clinical trial and other data should inform the algorithm. In this update, we primarily address one important issue that has received much recent attention: our current understanding of the advantages and disadvantages of the thiazolidinediones. In addition, we have revised the original Table 1 to include the dipeptidylpeptidase-4 inhibitor sitagliptin, which was not approved by the U.S. Food and Drug Administration at the time of our original publication (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1— Summary of glucose-lowering interventions as monotherapy

 
We are mindful of the importance of not changing this consensus guideline in the absence of definitive or compelling new data. 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.

The original consensus algorithm included the thiazolidinediones as one of three possible choices (insulin and sulfonylurea were the other two) that should be added to metformin and lifestyle intervention if target A1C levels (<7%) were not being achieved (Fig. 1). Several recent meta-analyses (3,4), together with one performed by the manufacturer (5) and one by regulatory authorities (6), have called into question the safety of rosiglitazone with regard to the risk of myocardial infarction. The putative 30–40% relative increase in risk of myocardial infarctions is based on data that are widely viewed as less than definitive; still, these data have led to the recommendation that clinicians exercise increased caution in prescribing rosiglitazone (7–10). Another recent meta-analysis of essentially the same dataset found no significantly increased risk of cardiovascular mortality owing to either rosiglitazone or pioglitazone (11). An interim analysis of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, designed specifically to examine cardiovascular outcomes of rosiglitazone therapy, revealed no statistically significant effects on myocardial infarction (hazard ratio 1.17 [95% CI 0.75–1.82]) but confirmed the risk for congestive heart failure (CHF) with rosiglitazone (2.15 [1.30–3.57]) (12). Furthermore, a meta-analysis of the clinical trial data regarding cardiovascular disease risk and pioglitazone has suggested that the drug exerts a protective effect (13).


Figure 1
View larger version (27K):
[in this window]
[in a new window]

  		Figure 1— Algorithm for the metabolic management of type 2 diabetes. Reinforce lifestyle intervention at every visit. aCheck A1C every 3 months until <7% and then at least every 6 months. bAssociated with increased risk of fluid retention, CHF, and fractures. Rosiglitazone, but probably not pioglitazone, may be associated with an increased risk of myocardial infarction. cAlthough three oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and lower expense.

 
In addition to the concern raised regarding the potential risk of myocardial infarction with rosiglitazone, the previously recognized risk of fluid retention and resultant CHF, which applies to both pioglitazone and rosiglitazone, has now been quantified as an approximate twofold increase (11,14). These findings have led to a "black box" warning in the prescribing information for rosiglitazone regarding the risk for myocardial infarction and for both thiazolidinediones regarding the risk for CHF (15).

Both thiazolidinediones have been associated with an increased risk for fractures, particularly in women (16,17). Of note, the majority of these fractures were in the distal upper (forearm, hand, or wrist) or lower (foot, ankle, fibula, or tibia) limb, as opposed to the classic sites of osteoporotic fractures.

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. 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 hypoglycemia 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 versus insulin or sulfonylureas as the second step in the algorithm (Fig. 1). As with other drug classes, there may well be clinically important differences between the two drugs in this class. The current decision not to remove either or both of the thiazolidinediones from the algorithm represents a balance between the preservation of options to treat a challenging and progressive serious disease and the recent unfavorable evidence.

In conclusion, 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. We therefore recommend greater caution in using the thiazolidinediones, especially in patients at risk of, or with, CHF.


   Footnotes
 
*Simultaneous publication: This article is being simultaneously published in 2008 in Diabetes Care and Diabetologia by the American Diabetes Association and the European Association for the Study of Diabetes.

D.M.N. has received research grants from sanofi-aventis and support for educational programs from GlaxoSmithKline and Pfizer. J.B.B. conducts research and/or serves on advisory boards under contract between the University of North Carolina and Amylin, Bristol-Myers Squibb, GlaxoSmithKline, Hoffman-LaRoche, Eli Lilly, Novo Nordisk, Merck, Novartis, Pfizer, and sanofi-aventis. M.B.D. has received research support from Eli Lilly, Merck, and Pfizer; serves on advisory boards to Amylin, GlaxoSmithKline, Merck, and sanofi-aventis; and is on speakers bureaus for Amylin, Eli Lilly, GlaxoSmithKline, and Pfizer. E.F. has received research support from AstraZeneca, Merck Sharp & Dohme, and Novartis and serves on scientific advisory boards for Amylin, AstraZeneca, GlaxoSmithKline, Roche, Merck Sharp & Dohme, Novartis, Servier, sanofi-aventis, Boehringer Ingelheim, and Takeda. R.R.H. has received grant support from Novartis, Bristol-Myers Squibb, Novo Nordisk, Pfizer, GlaxoSmithKline, and Merck and serves on scientific advisory boards for Amylin, Novartis, Eli Lilly, Merck, and sanofi-aventis. R.S. serves on advisory boards for Amylin, Bristol-Myers Squibb, Eli Lilly, Merck, and Takeda. B.Z. has received research support from Eli Lilly, GlaxoSmithKline, Novartis, and Novo Nordisk and is a member of scientific advisory boards and/or has received honoraria for speaking from Amylin, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Pfizer, sanofi-aventis, and Smiths Medical.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.


   References
TOP
 References
 

  1. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B: Management of hyperglycemia 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. Diabetes Care 29:1963–1972, 2006[Free Full Text]
  2. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B; Professional Practice Committee, American Diabetes Association; European Association for the Study of Diabetes: 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 49:1711–1721, 2006[Medline]
  3. Nissen SE, Wolski K: Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471, 2007[Abstract/Free Full Text]
  4. Singh S, Loke YK, Furberg CD: Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 298:1189–1195, 2007[Abstract/Free Full Text]
  5. GalaxoSmithKline Advisory Committee Briefing Document: Cardiovascular Safety of Rosiglitazone, 2007. Philadelphia, GalaxoSmithKline, p. 40–45. Available from http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-01-sponsor-backgrounder.pdf Accessed 25 October 2007
  6. U.S. Food and Drug Administration FDA Briefing Document, 2007. Rockville, MD, Food and Drug Administration, p. 13–bp105. Available from http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-02-fda-backgrounder.pdf. Accessed 25 October 2007
  7. Psaty BM, Furberg CD: Rosiglitazone and cardiovascular risk. N Engl J Med 356:2522–2524, 2007[Free Full Text]
  8. Drazen JM, Morrissey S, Curfman GD: Rosiglitazone—continued uncertainty about safety. N Engl J Med 357:63–64, 2007[Free Full Text]
  9. Nathan DM: Rosiglitazone and cardiotoxicity—weighing the evidence. N Engl J Med 357:64–66, 2007[Free Full Text]
  10. Psaty BM, Furberg CD: The record on rosiglitazone and the risk of myocardial infarction. N Engl J Med 357:67–69, 2007[Free Full Text]
  11. Lago RM, Singh PP, Nesto RW: Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomized clinical trials. Lancet 370:1129–1136, 2007[Medline]
  12. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ; RECORD Study Group: Rosiglitazone evaluated for cardiovascular outcomes: an interim analysis. N Engl J Med 357:28–38, 2007[Abstract/Free Full Text]
  13. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE: Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298:1180–1188, 2007[Abstract/Free Full Text]
  14. Singh S, Loke YK, Furberg CD: Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care 30:2248–2253, 2007
  15. U.S. Food and Drug Administration: Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl) information, 2007. Available from http://www.fda.gov/cder/drug/infopage/rosiglitazone/default.htm. Accessed 17 November 2007
  16. Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, Strotmeyer ES, Resnick HE, Carbone L, Beamer BA, Park SW, Lane NE, Harris TB, Cummings SR.: Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 91:3349–3354, 2006[Abstract/Free Full Text]
  17. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G; ADOPT Study Group: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443, 2006[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 The Diabetes EducatorHome page
M. K. Rhee, D. C. Ziemer, J. Caudle, P. Kolm, and L. S. Phillips
Use of a Uniform Treatment Algorithm Abolishes Racial Disparities in Glycemic Control
The Diabetes Educator, July 1, 2008; 34(4): 655 - 663.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nathan, D. M.
Right arrow Articles by Zinman, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nathan, D. M.
Right arrow Articles by Zinman, B.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum