Introduction
In August 2006, the ADA and the EASD published a joint consensus algorithm for the medical management of hyperglycaemia in type 2 diabetes [
1]. Recently, an update introduced a two-tier categorisation of ‘well validated’ and ‘less well validated’ therapies [
2].
Tier 1 treatments are initial metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met. These interventions are considered to be: ‘the best established and most effective and cost-effective therapeutic strategy for achieving the target glycaemic goals’. Although the authors, Nathan et al., endorse metformin plus insulin as a particularly effective combination, in practice most physicians and patients faced with these second-line options are likely to choose metformin plus a sulfonylurea. Recommended tier 2 approaches for second-line therapy comprise metformin plus either a thiazolidinedione (pioglitazone, since the authors advise against using rosiglitazone) or a glucagon-like peptide-1 (GLP-1) receptor agonist. The tier 2 treatments are recommended for consideration in selected clinical settings only.
The description of this publication as a consensus statement of the ADA and EASD is misleading, as it has not been formally endorsed by the two organisations. Indeed, the ADA states that ‘consensus statements…are not official ADA recommendations’, that they are ‘produced under the auspices of the Association by invited experts’ and that they are ‘not subject to subsequent review or approval’ [
3]. In addition, the organisation has declared that the consensus statement represents the authors’ views and not the official opinion of the association [
2]. Nevertheless, the recommendations have been published under the auspices of the two societies and are likely to have considerable influence.
We are concerned that the authors of the consensus statement have not consistently employed an evidence-based approach; we also find many of their recommendations questionable. However, we acknowledge that some data were not available at the time of publication of the updated consensus statement. This paper critically assesses the basis of the purported consensus and the resulting tiers of treatment options.
Development process
Evidence-based guidelines have advanced medical practice and supported optimal prescribing for many diseases, and processes for their development are well established [
4‐
6]. At the evidence collation stage, a systematic review of data is performed using a search strategy designed to identify all relevant data. The evidence base typically comprises a complex mix of data of variable quality and relevance, necessitating precise and explicit grading criteria [
7]. A systematic review may be followed by a meta-analysis, i.e. a mathematical method of pooling the results of studies that meet predefined criteria. In the absence of a suitable body of evidence, expert/consensus opinion may be used. However, such opinion becomes less influential as the evidence grows. While gaps exist in the management of type 2 diabetes, the evidence base is sufficiently large to allow an evidence-based approach for many aspects. Current ADA standards of care in diabetes therefore classify expert consensus or clinical experience as the lowest forms of evidence [
8]. Once collated, a working group discusses the data based on the evidence-based tables and draws conclusions. Guidelines are then developed and graded or weighted according to the strength of the supporting evidence. The draft guidelines should be subjected to peer (and sometimes public) review before being finalised.
The recommendations of Nathan et al. [
2] do not appear to meet many of these standards. For example, the strategies used to search for data systematically are not stated and there is no formal grading of evidence. The authors cite the use of ‘clinical judgment, that is, our collective knowledge and clinical experience’ as a principal secondary source of evidence. The panel comprised only seven physicians (five North American, two European). It is therefore questionable whether some recommendations can reflect the available evidence base, as outlined below in terms of the key attributes of glucose-lowering treatments.
Glucose-lowering effects
The selection of glycaemic targets and glucose-lowering treatments should be individualised on the basis of patient-specific factors (age, stage of diabetes, cardiovascular risk factors, weight, risk associated with hypoglycaemia etc.) and of effects on multiple pathophysiological aspects of type 2 diabetes [
9].
According to Nathan et al., glucose-lowering efficacy is the principal factor by which drugs should be differentiated. Their algorithm states that ‘The over-arching principle in selecting a particular intervention will be its ability to achieve and maintain glycaemic goals’ [
2]. They tabulate the reductions in HbA
1c expected with different classes used as monotherapy, but provide few supporting references. Sulfonylureas and metformin are each said to reduce HbA
1c by 1.0% to 2.0%, although the baseline levels, time-scale, patient populations, specific agent and dose are not defined. Thiazolidinediones are said to reduce HbA
1c by 0.5% to 1.4%, suggesting lower glucose-lowering efficacy, but this is not supported by evidence from large, randomised head-to-head trials, which found no significant differences vs sulfonylureas or metformin [
10,
11] and better long-term efficacy for thiazolidinediones [
12]. A systematic evidence-based review also supports the view that these agents produce similar absolute reductions in HbA
1c [
13]. We agree with Nathan et al. on the importance of maintaining long-term glycaemic control. In this context, the relegation of thiazolidinediones appears puzzling in light of evidence from A Diabetes Outcome Progression Trial (ADOPT), where rosiglitazone was significantly better than glibenclamide or metformin at maintaining glycaemic targets over 4 years [
12].
Meta-analysis of randomised controlled trials indicates that GLP-1 receptor agonists (exenatide, liraglutide) also reduce HbA
1c by ∼1% and are non-inferior to active comparators [
14]. In a head-to-head study, liraglutide was more effective than exenatide, presumably due to its longer half-life [
15]. On meta-analysis, the dipeptidyl peptidase-4 (DPP-IV) inhibitors (sitagliptin, vildagliptin) were slightly less effective than other oral glucose-lowering agents [
14,
16], but were non-inferior to sulfonylureas over 52 weeks when added to metformin [
17,
18].
In type 2 diabetes, insulin is commonly initiated as add-on therapy either as a basal dose of a long-acting analogue (insulin glargine [A21Gly,B31Arg,B32Arg human insulin] or insulin detemir [B29Lys(e-tetradecanoyl),desB30 human insulin]) or prandially using biphasic (premixed) formulations, although the optimal approach and most efficient use of the different long-acting, intermediate-acting (e.g. NPH insulin), rapid-acting and biphasic formulations remains controversial [
19]. Nathan et al. recommend the initiation of basal insulin, followed by intensification, if required. However, a recent meta-analysis suggests that greater reductions in HbA
1c can be achieved using biphasic or rapid-acting prandial formulations rather than a basal approach [
20]. Although the recent 3-year results of the Treating To Target in Type 2 Diabetes study (4-T study) showed that basal (detemir-based) or prandial (insulin aspart [B28Asp human insulin]-based) insulin regimens provided better glycaemic control when added to oral therapy vs adding to a biphasic (aspart-based) regimen, total insulin dose was highest in the basal group (88 U), prandial insulin use was higher in the basal group (51 vs 28 U in the biphasic group) and most patients eventually received more complex insulin regimens irrespective of initial therapy [
21]. Glargine appears to offer no benefit in terms of glycaemic control over NPH insulin, while detemir might be slightly less effective than NPH [
22].
Clearly, basal insulin has the advantage of greater convenience. Moreover, detemir and glargine are associated with less overall hypoglycaemia than multiple daily injections of rapid-acting analogues and biphasic or NPH insulin [
22‐
27]. However, a systematic review suggests that biphasic insulin is not associated with more nocturnal or more severe hypoglycaemia than basal insulin analogues [
27]. In recent head-to-head studies, there was no difference in glycaemic control or hypoglycaemia with glargine vs detemir [
28,
29].
Thus, basal insulin has potential advantages over biphasic or prandial insulin regimens in terms of less hypoglycaemia and less weight gain (see below). However, accumulating evidence indicates that control of postprandial hyperglycaemia is also important in achieving HbA
1c goals [
30]. We suggest that, in some patients, the glycaemic benefits of biphasic or prandial insulin regimens outweigh the risk of hypoglycaemia and these regimens should be positioned as alternatives for initial insulin therapy according to an individualised approach.
Cardiovascular benefit–risk relationships
The effects of glucose-lowering treatments on cardiovascular outcomes are of central importance, as cardiovascular disease is the major cause of death in patients with diabetes. The consensus statement algorithm states: ‘there are insufficient data to support one class (or combination) of glucose-lowering agents over another with regard to their effects on complications’ [
2]. Certainly, few prospective studies have assessed cardiovascular outcomes during long-term treatment and the cardiovascular benefit-risk relationship of some agents and combinations remains controversial.
Other important pathophysiological and clinical effects
Nathan et al. acknowledge that drug effects on non-glycaemic cardiovascular risk factors may be important [
2]. However, little explicit consideration of the evidence supporting the relative benefit of different agents is provided, and these properties do not appear to have influenced the recommendations. We argue that effects on the pathophysiological abnormalities in type 2 diabetes and in cardiovascular disease warrant greater consideration.
Consideration of adverse effects
Conclusions—implications for treatment guidelines
The algorithm published by Nathan et al. [
2] under the auspices of the ADA and EASD has provoked debate on the optimal management of hyperglycaemia in type 2 diabetes [
9,
102]. This paper is not designed to propose a specific treatment algorithm, but rather to point out important deficiencies in the algorithm of Nathan et al. and to argue for a re-evaluation of its recommendations. We believe that inconsistencies in the application of accepted evidence-based procedures have resulted in a skewed ranking of agents. In our opinion, the recommended two-tier approach is not evidence based and does not offer the best quality of treatment on the basis of our understanding of the multifactorial pathophysiology of type 2 diabetes or the need for individualised therapy. Methodologically, the ADA–EASD algorithm seems to be based more on an outdated expert opinion model than on the evidence-based approach that represents the current standard for guideline development.
In our opinion, these recommendations do not take full account of the evidence on the appropriate priorities for treatment (in particular, the potential impact on clinically important endpoints such as macrovascular events) or on the benefits of all available classes of glucose-lowering agents. In favouring initial use of metformin monotherapy followed by sulfonylurea, an approach known to fail, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction of diabetes complications.
Duality of interest
G. Schernthaner has received lecture fees from AstraZeneca/BMS, Eli Lilly, GSK, Merck, NovoNordisk, sanofi-aventis, Servier and Takeda. A. H. Barnett has received lecture fees from AstraZeneca/BMS, Eli Lilly, MSD, Novartis, NovoNordisk, sanofi-aventis and Servier. D. J. Betteridge has received lecture fees and honoraria for advisory boards from AstraZeneca, Eli Lilly, GSK Merck, NovoNordisk, Pfizer, Boehringer Ingelheim and Takeda. B. Charbonnel has received lecture fees from AstraZeneca/BMS, Boehringer Ingelheim, GSK, Merck, NovoNordisk, Roche, sanofi-aventis and Takeda. M. Hanefeld has received lecture from BACER-AG, sanofi-aventis, GlaxoSmithKline, Novartis, Takeda and MSD. M. T. Malecki has received lecture fees from Berlin-Chemie, Bioton, Eli Lilly, NovoNordisk, Roche and Servier, and grant support from Eli Lilly. R. Nesto has received lecture fees from GSK and sanofi-aventis. A. Scheen has received lecture fees from AstraZeneca/BMS, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, NovoNordisk, sanofi-aventis and Takeda. J. Seufert has received lecture fees from AstraZeneca/BMS, Bayer, Berlin Chemie, Eli Lilly, GlaxoSmithKline, Lifescan, Merck Sharp & Dohme, Novartis, NovoNordisk, Pfizer, sanofi-aventis and Takeda. R. DeFronzo has received lecture fees from Amylin, BMS, Eli Lilly, ISIS, Merck, Novartis and Takeda. The remaining authors declare that there is no duality of interest associated with this manuscript.
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