Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy
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- Nathan, D.M., Buse, J.B., Davidson, M.B. et al. Diabetologia (2008) 51: 8. doi:10.1007/s00125-007-0873-z
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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.
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
Improved lipid profileb
Fluid retention, twofold increased risk of CHF, potential increase MIc, potential decrease MIb, atherogenic lipid profilec, weight gain, expensive
Frequent GI side effects, three times/day dosing, expensive
Injections, frequent GI side effects, expensive, little experience
Three times/day dosing, expensive, hypoglycaemia
Injections, three times/day dosing, frequent GI side effects, expensive, little experience
Little experience, expensive
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.
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 .
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.