, Volume 51, Issue 1, pp 8–11

Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy

Update regarding the thiazolidinediones
  • D. M. Nathan
  • J. B. Buse
  • M. B. Davidson
  • E. Ferrannini
  • R. R. Holman
  • R. Sherwin
  • B. Zinman
Consensus statement update

DOI: 10.1007/s00125-007-0873-z

Cite this article as:
Nathan, D.M., Buse, J.B., Davidson, M.B. et al. Diabetologia (2008) 51: 8. doi:10.1007/s00125-007-0873-z



congestive heart failure

The consensus algorithm for the management of type 2 diabetes mellitus 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 healthcare 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 glycaemia within or as close to the non-diabetic 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 glycaemia is not achieved; and the early addition of insulin therapy in patients who do not meet target HbA1c 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 US Food and Drug Administration at the time of our original publication (Table 1).
Table 1

Summary of glucose-lowering interventions as monotherapy


Expected decrease in HbA1c (%)



Step 1: initial

Lifestyle to decrease weight and increase activity


Low cost, many benefits

Fails for most in first year



Weight neutral, inexpensive

GI side effects, rare lactic acidosis

Step 2: additional therapy



No dose limit, inexpensive, improved lipid profile

Injections, monitoring, hypoglycaemia, weight gain




Weight gain, hypoglycaemiaa

 Thiazolidinediones (glitazones)


Improved lipid profileb

Fluid retention, twofold increased risk of CHF, potential increase MIc, potential decrease MIb, atherogenic lipid profilec, weight gain, expensive

 Other drugs


  α-Glucosidase inhibitors


Weight neutral

Frequent GI side effects, three times/day dosing, expensive



Weight loss

Injections, frequent GI side effects, expensive, little experience



Short duration

Three times/day dosing, expensive, hypoglycaemia



Weight loss

Injections, three times/day dosing, frequent GI side effects, expensive, little experience



Weight neutral

Little experience, expensive

aSevere hypoglycaemia is relatively infrequent with sulfonylurea therapy. The longer-acting agents [e.g. chlorpropamide and glibenclamide (glyburide)] are more likely to cause hypoglycaemia than glipizide, extended-release glipizide, glimepiride or gliclazide



dRepaglinide is more effective at lowering HbA1c than nateglinide

GI, gastrointestinal

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 HbA1c 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, 8, 9, 10]. Another recent meta-analysis of essentially the same data set 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 Glycaemia 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 (hazard ratio 2.15, 95% CI 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].
Fig. 1

Algorithm for the metabolic management of type 2 diabetes. Reinforce lifestyle intervention at every visit. aCheck HbA1c every 3 months until HbA1c is <7%, and then at least every 6 months. bAssociated with increased risk of fluid retention, congestive heart failure 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 recognised risk of fluid retention and resultant CHF, which applies to both pioglitazone and rosiglitazone, has now been quantified as an approximately twofold increase [11, 14]. These findings have led to a stronger (black box) warning in the prescribing information for the thiazolidinediones [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 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 (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 unfavourable 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.

Duality of interest

The following potential conflicts of interest were reported: D. M. Nathan reports receiving research grants from Sanofi-Aventis, and support for educational programmes from GlaxoSmithKline and Pfizer. J. B. Buse 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, NovoNordisk, Merck, Novartis, Pfizer and Sanofi-Aventis. M. B. Davidson reports receiving research support from Eli Lilly, Merck and Pfizer, serves on advisory boards to Amylin, GlaxoSmithKline, Merck, Sanofi-Aventis; and is on speakers bureaus for Amylin, Eli Lilly, GlaxoSmithKline and Pfizer. E. Ferrannini reports receiving 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. Holman reports receiving grant support from Novartis, Bristol-Myers Squibb, NovoNordisk, Pfizer, GlaxoSmithKline and Merck, and serves on scientific advisory boards for Amylin, Novartis, Eli Lilly, Merck and Sanofi-Aventis. R. Sherwin reports serving on advisory boards for Amylin, Bristol-Myers Squibb, Eli Lilly, Merck and Takeda. B. Zinman receives research support from Eli Lilly, GlaxoSmithKline, Novartis and NovoNordisk, 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.

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • D. M. Nathan
    • 1
  • J. B. Buse
    • 2
  • M. B. Davidson
    • 3
  • E. Ferrannini
    • 4
  • R. R. Holman
    • 5
  • R. Sherwin
    • 6
  • B. Zinman
    • 7
  1. 1.Diabetes CenterMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  2. 2.University of North Carolina School of MedicineChapel HillUSA
  3. 3.Charles R. Drew UniversityLos AngelesUSA
  4. 4.Department of Internal MedicineUniversity of PisaPisaItaly
  5. 5.Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and MetabolismOxford UniversityOxfordUK
  6. 6.Yale University School of MedicineNew HavenUSA
  7. 7.Samuel Lunenfeld Research InstituteMount Sinai Hospital, University of TorontoTorontoCanada