LETTER

A critique of the 2012 ADA/EASD position statement

H. W. Rodbard & P. S. Jellinger

Received: 7 May 2012 /Accepted: 6 June 2012 /Published online: 18 July 2012# Springer-Verlag 2012

Keywords Algorithm . Clinical management .

Pharmacoeconomics . Pharmacotherapy . Type 2 diabetesmellitus

AbbreviationsAACE American Association of Clinical

EndocrinologistsACE American College of EndocrinologyDPP-4 Dipeptidyl peptidase IVGLP-1 Glucagon-like peptide 1NPH Neutral protamine Hagedorn

To the Editor: We write as the co-chairs of the task force thatdeveloped the American Association of Clinical Endocri-nologists (AACE)/American College of Endocrinology(ACE) diabetes algorithm. The 2012 position statement ofthe American Diabetes Association (ADA) and the Europe-an Association for the Study of Diabetes (EASD) for themanagement of hyperglycaemia in type 2 diabetes [1] isconsiderably improved compared with the 2009 statement[2], and brings the position of the ADA/EASD much closer

to the AACE/ACE algorithm [3]. The AACE/ACE algorithmis still current with only minor modifications: (1) rosiglitazoneis no longer available; (2) sitagliptin, exenatide and liraglutidehave been approved by the US Food and Drug Administrationfor use with insulin; (3) weekly exenatide QW is now avail-able; and (4) additional types of dipeptidyl peptidase IVinhibitors have become available.

Table 1 provides a concise statement of some of the majorsimilarities and differences between the three approaches totherapy with respect to 25 key characteristics. These are dis-cussed in more depth here.

1. The 2012 ADA/EASD statement emphasises the need toindividualise treatment goals. This is also addressed bythe AACE/ACE algorithm.

2. The ADA/EASD statement includes stratification oftreatment by HbA1c and has a three-pronged approach,involving initial monotherapy, dual therapy or insulin ther-apy for HbA1c values below 9% (75 mmol/mol), between9% and 10% (between 75 and 86 mmol/mol), or ≥10%(86 mmol/mol). The AACE/ACE algorithm recommendsthresholds of ≤7.5% (≤59 mmol/mol), 7.6–9.0%(60–75 mmol/mol) or >9.0% (>75 mmol/mol), respectively.

3. The ADA/EASD statement does not appear to distinguishbetween the insulin analogues and regular or neutralprotamine Hagedorn (NPH) insulin, except to note thecost difference, that insulin glargine and insulin detemir‘are associated with modestly less overnight hypoglycae-mia than NPH’, and that insulin analogues ‘generally donot result in clinically significantly lower HbA1c’. Thenature of treat-to-target studies implies that differentagents will achieve nearly the same goal: distinction be-tween therapies becomes apparent only by using a two-dimensional plot showing the frequency of hypoglycae-mia vs HbA1c level achieved [4, 5]. In contrast, theAACE/ACE algorithm indicated a strong preference forboth the long- and rapid-acting insulin analogues, in view

An abridged version of this letter is being published in Diabetes Careas the ADA/EASD position statement was published simultaneously inboth journals

H. W. Rodbard (*)Endocrine and Metabolic Consultants,3200 Tower Oaks Blvd,Rockville, MD 20852, USAe-mail: hrodbard@comcast.net

P. S. JellingerThe Center for Diabetes and Endocrine Care,Hollywood, FL, USA

P. S. JellingerDivision of Endocrinology, University of Miami,Miami, FL, USA

Diabetologia (2012) 55:2850–2852DOI 10.1007/s00125-012-2646-6

Table 1 Comparison of the ADA/EASD algorithm, the AACE/ACE algorithm and the ADA/EASD position statement

ADA/EASD, 2009 [2] AACE/ACE, 2009 [3] ADA/EASD, 2012 [1]

Nature of document Algorithm Algorithm Position statement

Target level for HbA1c 7.0% (53 mmol/mol) or, ‘aslow as possible withouthypoglycaemia’

6.5% (48 mmol/mol),with caveats

<7% (53 mmol/mol)a

6.0–6.5%b

7.5–8%c

Frequency of adjustment of regimenif not at goal

2–3 months 2–3 months 3–6 months

Lifestyle, diet, exercise, weight loss ✓ ✓ ✓

Insulin therapy: basal, premixed,basal-bolus, with or without otheragents

✓ ✓ ✓

Metformin as preferred agent formonotherapy

✓ ✓ ✓

Summary of risks and benefitsfor different classes of therapy

✓ ✓ ✓

Specificity of advice fortherapeutic agents

High: algorithm with specifiedorder for selection of agentsand regimens

High: algorithm with specifiedorder for selection of agentsand regimens, with rationale

Low: Fig. 2 states ‘order notmeant to specify any specificpreference’

Priority for sulfonylureas High (used in dual andtriple therapy)

Low (because of hypoglycaemia,weight gain, short duration ofeffectiveness); not recommendedfor monotherapy

No specific preferences (firstoption listed for dual andtriple therapy in Fig. 2)

Priority for thiazolidinediones High (second of fiveoptions)

Low (because of weight gain,CHF, fractures)

No specific preferences (secondoption listed for dual andtriple therapy in Fig. 2)

Priority for incretin-basedtherapies: DPP-4 inhibitorsor GLP-1 receptor agonists

DPP-4 inhibitors:‘insufficient experience’

High (high efficacy and excellentsafety, low risk of hypoglycaemia)

No specific preferences

GLP-1 receptor agonist:‘Tier 2: less well-validated’

Priority for basal insulin ‘Tier 2: less well-validated’ High High

Preference for insulin analogues(rapid- and long-acting) relativeto regular and NPH insulins

None: no discussion ofrapid- and long-actinginsulin analogues

High: regular and NPH insulinsnot recommended (Table A1)

Ambiguous, no preference stated

Colesevelam Not considered Included Mentioned briefly (in Table 1,but not in Fig. 2)

Bromocriptine Not available Intentionally excluded Included, low priority

α-Glucosidase inhibitors Not considered Included Mentioned briefly (in Table 1but not in Fig. 2)

Sensitivity to cost of medication High Low High

Sensitivity to total cost of care Not discussed High Not discussed

Number of therapeutic classesconsideredd

5 (Fig. 2) 11 (Table 1) 7 (Fig. 2)

Number of regimens consideredd 8 (Fig. 2) 22 (Fig. 1) 14 (Fig. 2)

Monotherapy regimensd 1 (metformin only; Fig. 2) 5 (metformin + 4 options; Fig. 1) 1 (metformin only; Fig. 2)

Dual therapy regimensd 3 9 5

Triple therapy regimensd 4 6 8

Initiation of therapy with dual therapy Not considered If HbA1c 7.6–9.0% (60–75 mmol/mol) If HbA1c ≥9% (≥75 mmol/mol)

Initiation of therapy with insulinor triple therapy

Not considered If HbA1c >9% (>75 mmol/mol) If HbA1c ≥10% (≥86 mmol/mol)

a HbA1c target of 7% (53 mmol/mol), in general, to reduce incidence of microvascular diseaseb For selected patients (short disease duration, long life expectancy, no significant cardiovascular disease)c For selected patients (if severe hypoglycaemia, limited life expectancy, advanced complications, extensive comorbid conditions or inability toachieve desired target)d In main treatment flowchart

CHF, congestive heart failure

Diabetologia (2012) 55:2850–2852 2851

of their reduced risk of hypoglycaemia and pharmacody-namics that more closely simulate normal physiology andprovide less variability. Regular insulin and NPH insulinwere designated as ‘not recommended’ (Table A1 of [3]).

4. The ADA/EASD statement fails to indicate preferencesfor the many alternative therapeutic combinations (Fig.2 of [1]). In contrast, the AACE/ACE algorithm indi-cates strong preferences and a sequential order (fromtop down in Fig. 1 of [3]). We believe that this moreprescriptive approach of the AACE/ACE algorithm ishighly advantageous when used as a teaching tool andas a guide for the treatment of patients by primary carephysicians.

5. Like the ADA/EASD statement [1], the AACE/ACEalgorithm assigned lower priority to colesevelam andα-glucosidase inhibitors, and the AACE/ACE omittedcycloset in view of its limited efficacy and very limitedclinical experience.

6. The AACE/ACE algorithm [3] significantly reduced thepriority for sulfonylureas and thiazolidinediones, con-siderably more so than the new ADA/EASD positionstatement [1]. This was due to the very substantial riskof hypoglycaemia associated with sulfonylureas, com-bined with weight gain, fluid retention and limited du-ration of effectiveness (also noted by the ADA/EASDstatement). Sulfonylureas were intentionally not recom-mended for monotherapy [3].

7. AACE/ACE lowered the priority for thiazolidinedionesas a result of multiple adverse events (congestive heartfailure, weight gain, fluid retention, fractures).

8. We regard it as unfortunate that the ADA/EASD state-ment [1] presents sulfonylureas and thiazolidinedionesbefore the incretin-based therapies both in Table 1 andFig. 2. Some readers of the ADA/EASD statement arelikely to misinterpret this order as a ranking in terms ofpriority, despite the repeated disclaimer. Although sul-fonylureas are less expensive than other medications(except metformin) in terms of medication cost, whenone factors in the morbidity, mortality, visits to theemergency rooms and resulting hospitalisations causedby hypoglycaemia, and the fact that glucose-loweringmedication costs are only a small fraction of the totalcost to society for management of diabetes, the totalcosts of sulfonylurea therapy are more expensive tosociety than other medications [6]. The dramaticallyhigher frequency of hypoglycaemia associated with sul-fonylureas has been clearly documented [1, 7].

In conclusion, the 2012 ADA/EASD position statement [1]is an important improvement relative to the 2009 ADA/EASDalgorithm [2], but does not include several important consid-erations and the specific prioritisation of alternative modalitiesof therapy provided by the AACE/ACE algorithm [3]. Practi-tioners would benefit from critical review of both documents[1, 3] side by side.

Duality of interest H. W. Rodbard conducts clinical research, serveson advisory panels, consults, and lectures with support of Amylin,Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Merck, Novo Nordisk,Novartis, Roche and Sanofi. P. S. Jellinger serves on advisory panels,consults, and lectures with support of Amylin, Boehringer Ingelheim, Lilly,Merck and Novo Nordisk.

Contribution statement HWR was responsible for the conception,design and drafting of the manuscript. PSJ was responsible for theconception and design of the manuscript, and revision of the manu-script for intellectual content. Both authors approved the final versionfor publication.

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