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Position statement of the Australian Diabetes Society: individualisation of glycated haemoglobin targets for adults with diabetes mellitus

N Wah Cheung, Jennifer J Conn, Michael C d’Emden, Jenny E Gunton, Alicia J Jenkins, Glynis P Ross, Ashim K Sinha, Sofianos Andrikopoulos, Stephen Colagiuri and Stephen M Twigg
Med J Aust 2009; 191 (6): 339-344. || doi: 10.5694/j.1326-5377.2009.tb02819.x
Published online: 21 September 2009

Type 1 and type 2 diabetes are associated with increased microvascular and macrovascular disease, disability and premature mortality. There is strong evidence from randomised controlled trials that better glycaemic control can reduce some of these diabetic complications. Improving glycaemic control is a principal goal of diabetes management. Most authorities have recommended a glycated haemoglobin (HbA1c) target level of ≤ 7.0%, largely based on the results of the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), which demonstrated that intensive glucose control substantially reduced onset and delayed progression of microvascular disease in type 1 and type 2 diabetes, respectively.1,2

In the DCCT, tight glycaemic control, achieving a mean HbA1c level of 7.0% (v 9.2% in the conventional-therapy arm), reduced retinopathy by 47%–76%, nephropathy by 39%–54%, and clinical neuropathy by 60% in participants with type 1 diabetes.1 In the UKPDS, intensively treated people with newly diagnosed type 2 diabetes (mean age, 53 years) had a median HbA1c level of 7.0% over 10 years (v 7.9% with standard treatment) and a 12% reduction in diabetes-related end points, mainly in microvascular events.2 Additionally, in an obese subgroup of the intensive-therapy group, metformin used as first-line therapy reduced the incidence of myocardial infarction and mortality.3 The effect was not statistically significant in participants primarily assigned to treatment with sulfonylureas or insulin.2

In 2008 and 2009, results of several large studies designed to examine the effect of even tighter glycaemic control on cardiovascular outcomes were published, as well as results of the long-term follow-up of UKPDS. The conflicting results of these studies have raised questions about the appropriateness of existing HbA1c targets, and created confusion among clinicians. This has prompted the Australian Diabetes Society (ADS) to develop recommendations for HbA1c levels, with a focus on the individualisation of targets. These will complement the soon-to-be-released National Health and Medical Research Council (NHMRC)-approved Evidence based guideline for blood glucose control in type 2 diabetes, which recommends a general HbA1c target level of ≤ 7.0%.4 The ADS recommendations are shown in Box 1 and Box 2.

A more detailed version of this position statement is available on the ADS website (http://www.diabetessociety.com.au/downloads/positionstatements/HbA1ctargets.pdf). The process used to develop the document is outlined in Box 3. Our recommendations serve as a guide to assist patient management, and it is not our intention for them to be applied dogmatically.

Type 2 diabetes
Key recent studies of tight glycaemic control
ACCORD study

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, 10 251 adults with type 2 diabetes (mean age, 62 years; disease duration, 10 years) were randomly allocated to intensive therapy (target HbA1c level, < 6.0% using any antidiabetic agent) or conventional therapy (target HbA1c level, 7.0%–7.9%).5 All participants had an established or increased risk for cardiovascular disease (CVD). At 1 year, the intensive-therapy group achieved a median HbA1c level of 6.4%, and the conventionally treated group, 7.5%.

After 3.5 years of follow-up, the intensive regimen was discontinued because of an unexpected increase in all-cause mortality (a secondary end point) in this arm (5.0% v 4.0%; hazard ratio [HR], 1.22; 95% CI, 1.01–1.46; P = 0.04). At this point, the pre-specified primary outcome, which was the first occurrence of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death, was showing a non-significant trend favouring intensive control (6.9% v 7.2%; HR, 0.90; 95% CI, 0.78–1.04; P = 0.16). No cause for the increased mortality in the intensive-therapy group was identified, though the incidence of hypoglycaemia requiring assistance was higher (10.5% v 3.5%; P < 0.001). On post-hoc subanalysis, increased mortality was observed in the intensive-therapy group among participants with known CVD or HbA1c levels > 8.5% at baseline. Weight gain > 10 kg was also more common in the intensive-therapy group.

The increased mortality in the intensive-therapy group has raised questions about the appropriateness of an HbA1c target level near the normal range in patients with, or at high risk of, CVD.

Management implications

The main concern arising from the ACCORD study is that tight glycaemic control in individuals with or at high risk of CVD increases the risk of death. When the results of ACCORD are considered together with those of the other trials mentioned above, there remains a clear benefit of maintaining an HbA1c level ≤ 7.0% for most patients. However, the risk–benefit balance is complex, and the following conclusions can also be drawn:

In light of these conclusions, practitioners need to individualise the HbA1c target level, taking into consideration the presence of CVD, diabetes duration, diabetes medication regimen, comorbidities and problems with severe hypoglycaemia (Box 1). It is important to remember that the prevention of hypoglycaemia does not rely purely on adjustment of medication, but also on patient education, including instruction in blood glucose monitoring.

Type 1 diabetes
Recent data regarding tight glycaemic control
DCCT/EDIC

Upon the completion of the DCCT, follow-up of 1394 participants (96% of DCCT survivors) continued in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Among the primary aims of EDIC were to examine the long-term effects of the earlier differences in glycaemic control on both microvascular disease and CVD. All EDIC participants were advised about intensive insulin therapy, and returned to their usual medical practitioner for diabetes care.

Subsequently, the HbA1c levels converged, with the level in the original intensive-therapy group rising to 8.0% ± 1.2% and the conventional group’s level decreasing to 8.2% ± 1.2%. The rate of progression of retinopathy,13 nephropathy14 and neuropathy15 remained lower in the prior intensive-therapy group, though there was some attenuation of the effect on retinopathy after 4 to 10 years.16 Over 17 years of follow-up in DCCT and EDIC, participants in the DCCT intensive-treatment group had a 42% lower risk of CVD events (P = 0.02), and non-fatal myocardial infarction, stroke or cardiovascular death fell by 57% (P = 0.02).16

These long-term results of DCCT/EDIC on both microvascular and macrovascular outcomes support the target HbA1c level of ≤ 7.0% for people with type 1 diabetes. Situations where it is suggested that the HbA1c target level should be less strict are outlined in Box 2. In particular, it is advisable that HbA1c be maintained at higher levels (eg, 7.0%–8.0%) for patients who suffer severe hypoglycaemic episodes or have hypoglycaemia unawareness.

Pregnancy

Pregestational diabetes is associated with serious adverse pregnancy outcomes, such as miscarriage, congenital malformation, pre-eclampsia and perinatal death. There is a continuous relationship between elevated HbA1c levels at conception and these outcomes, with increased risk at even slight elevations above the non-pregnant normal range.

A meta-analysis that included 1977 pregnant participants (the vast majority with type 1 diabetes) from seven prospective cohort studies found that for every 1 SD increase in the level of HbA1c (equivalent to 0.5% where the normal range is 4.0%–6.0%), the risk of congenital malformation increased by 20%.17 Even when the HbA1c level was only 2 SD above the mean (that is, 6.0%), there was about a 50% increase in risk (absolute risk, 3%) compared with participants with HbA1c levels at the population mean (5.0%). There are no detailed data defining the relationship between HbA1c level and fetal outcome in type 2 diabetes, beyond the recognition that high HbA1c levels in early pregnancy are associated with serious adverse fetal outcomes.18

The only randomised controlled trial data come from the DCCT, which included 270 pregnant participants with type 1 diabetes.19 Women in the intensive-therapy arm had lower HbA1c levels at conception than those in the control arm (7.4% ± 1.3% v 8.1% ± 1.7%). Despite intensification of management during pregnancy resulting in a convergence in HbA1c levels between the two groups, eight congenital malformations occurred in the conventional-therapy group, compared with one in the intensive-therapy group (P = 0.06).

We recommend that the HbA1c level at conception and during pregnancy should be ≤ 6.0%. This is achievable for many women with type 2 diabetes. Although this HbA1c target is also desirable in women with type 1 diabetes, there is a heightened risk of severe hypoglycaemia with such tight glycaemic control. Therefore, unless a lower HbA1c level can be achieved safely, a conservative target of ≤ 7.0% is recommended for women. Prepregnancy planning is essential. Other aspects of pregnancy care for women with pregestational diabetes have previously been outlined in the Journal.20

Coexistent cardiovascular risk factors

Weight control, antihypertensive therapy, lipid control and antiplatelet therapy are critical in diabetes management. The Steno-2 Study addressed multiple risk factors through control of HbA1c, blood pressure and lipids, and a regimen of aspirin and angiotensin-converting enzyme (ACE) inhibitor therapy, healthy diet, physical activity and smoking cessation.21 This long-term target-driven intervention among people with type 2 diabetes and microalbuminuria more than halved the risk of CVD, nephropathy, retinopathy and autonomic neuropathy. The UKPDS and ADVANCE also demonstrated improved outcomes with better blood pressure control.22,23 The blood pressure target is < 130/80 mmHg, and for those with ≥ 1g/day of proteinuria, < 125/75 mmHg. Statin therapy markedly reduces macrovascular events in type 2 diabetes.24,25 The main lipid target is a low-density lipoprotein cholesterol level < 2.5 mmol/L for primary prevention and < 1.8 mmol/L in secondary prevention. For most people with type 2 diabetes, the high absolute risk for macrovascular disease justifies statin treatment and an ACE inhibitor (or angiotensin-II receptor blockade), even if lipids and blood pressure are in the target range. Antiplatelet therapy (especially aspirin) is indicated for secondary and, in many cases, primary prevention in those with high absolute cardiovascular risk.26

1 Recommended glycated haemoglobin (HbA1c) target ranges for adults with type 2 diabetes

HbA1c target

Rationale for recommendation

Level of evidence for target


General target

≤ 7.0%*

UKPDS demonstrated improved outcomes with median HbA1c ≤ 7.0%; result supported by NHMRC systematic review.

I

Specific clinical situations

Diabetes of short duration and no clinical cardiovascular disease

≤ 6.0%*

UKPDS showed early treatment of diabetes to be beneficial. In epidemiological studies, the threshold level of HbA1c, beyond which increased mortality and cardiovascular events occur, lies between 5.0% and 6.0%. Risk of hypoglycaemia is negligible with lifestyle modification or metformin.

Consensus

≤ 6.5%*

UKPDS showed early treatment of diabetes to be beneficial. Risk of hypoglycaemia increases with use of most antidiabetic agents other than metformin, hence we do not recommend a target HbA1c ≤ 6.0% for this group. ADVANCE demonstrated reduced microvascular disease with target HbA1c ≤ 6.5%.

II

≤ 7.0%*

UKPDS demonstrated improved outcomes with median HbA1c of 7.0% in people with newly diagnosed diabetes, including among those treated with insulin.

II

Pregnancy or planning pregnancy

≤ 6.0%*

Observational data (albeit mainly in type 1 diabetes) demonstrate a relationship between HbA1c and adverse pregnancy outcomes when HbA1c levels exceed a threshold between 5.0% and 6.0%.

Consensus

Diabetes of longer duration or clinical cardiovascular disease (any therapy)

≤ 7.0%*

UKPDS demonstrated improved outcomes with median HbA1c of 7.0%. ACCORD indicated that attempts for even tighter control in people with relatively long duration of diabetes and cardiovascular disease were associated with increased mortality. We therefore do not routinely recommend tighter control in this group.

II

Recurrent severe hypoglycaemia or hypoglycaemia unawareness (any therapy)

≤ 8.0%

Severe hypoglycaemia is associated with significant morbidity and mortality. Risks of tight glycaemic control outweigh the benefits for such patients.

Consensus

Patients with major comorbidities likely to limit life expectancy (any therapy)

Symptomatic therapy of hyper-glycaemia§

Tight glycaemic control will be of no benefit, as diabetic complications take many years to develop.

Consensus


ACCORD = Action to Control Cardiovascular Risk in Diabetes study. ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial. NHMRC = National Health and Medical Research Council. UKPDS = United Kingdom Prospective Diabetes Study. * Achievement of HbA1c targets must be balanced against risk of severe hypoglycaemia, especially among older people.  In an older adult, long duration might be considered to be > 10–20 years, but for a person who develops type 2 diabetes at a young age, it may be considerably longer.  Examples of major comorbidities include chronic medical conditions, such as chronic kidney disease stages 4 or 5; heart failure stages III or IV (New York Heart Association grading); incurable malignancy; and moderate to severe dementia. § Where practical, suggest blood glucose target level < 15 mmol/L to help minimise risk of infection.

2 Recommended glycated haemoglobin (HbA1c) target ranges for adults with type 1 diabetes

HbA1c target

Rationale for recommendation

Level of evidence for target


General target

≤ 7.0% *

DCCT/EDIC showed that achieving a mean HbA1c of 7.0% is associated with improved outcomes.

II

Specific clinical situations

Pregnancy or planning pregnancy

≤ 7.0% *

Better pregnancy outcomes (borderline significance) were achieved for intensive-therapy group of DCCT (mean HbA1c of 7.4%). Observational data demonstrate a relationship between HbA1c and adverse pregnancy outcomes when HbA1c levels exceed a threshold between 5.0% and 6.0%, but there is a heightened risk of hypoglycaemia at such low levels. Therefore, for most women, we recommend a target HbA1c ≤ 7.0%.

II

Recurrent severe hypoglycaemia or hypoglycaemia unawareness

≤ 8.0%

Severe hypoglycaemia is associated with significant morbidity and mortality. Risks of tight glycaemic control outweigh the benefits for such patients.

Consensus

Patients with major comorbidities likely to limit life expectancy

Symptomatic therapy of hyperglycaemia and avoidance of ketosis

Tight glycaemic control will be of no benefit, as diabetic complications take many years to develop.

Consensus


DCCT = Diabetes Control and Complications Trial. EDIC = Epidemiology of Diabetes Interventions and Complications study. * Achievement of HbA1c targets must be balanced against risk of severe hypoglycaemia.  An HbA1c level ≤ 6.0% is desirable if it can be achieved safely.  Where practical, suggest blood glucose target level < 15 mmol/L to help minimise risk of infection.

  • N Wah Cheung1,2
  • Jennifer J Conn3
  • Michael C d’Emden4
  • Jenny E Gunton1,2,5
  • Alicia J Jenkins6
  • Glynis P Ross7,8
  • Ashim K Sinha9
  • Sofianos Andrikopoulos10
  • Stephen Colagiuri11
  • Stephen M Twigg2,7

  • 1 Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW.
  • 2 Department of Medicine, University of Sydney, Sydney, NSW.
  • 3 Royal Melbourne Hospital, Melbourne, VIC.
  • 4 Royal Brisbane and Women’s Hospital, Brisbane, QLD.
  • 5 St Vincent’s Clinical School, University of New South Wales, Sydney, NSW.
  • 6 Department of Medicine, University of Melbourne, St Vincent’s Hospital, Melbourne, VIC.
  • 7 Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW.
  • 8 Bankstown–Lidcombe Hospital, Sydney, NSW.
  • 9 Cairns Base Hospital, Cairns, QLD.
  • 10 Department of Medicine, University of Melbourne, Heidelberg Repatriation Hospital, Melbourne, VIC.
  • 11 Boden Institute of Obesity, Nutrition and Exercise, University of Sydney, Sydney, NSW.


Correspondence: wah@westgate.wh.usyd.edu.au

Acknowledgements: 

We thank Professor Don Chisholm, Professor Peter Colman and Associate Professor Jeff Flack for reviewing this position statement and providing valuable comments.

Competing interests:

Wah Cheung received a travel grant from GlaxoSmithKline and another from Eli Lilly to attend conferences. Jennifer Conn received travel grants from Novo Nordisk. Michael d’Emden received speaker fees, honoraria for attending advisory board meetings and support to attend meetings of the Australian Diabetes Association and European Association for the Study of Diabetes from Eli Lilly, Novo Nordisk, Novartis, Sanofi-Aventis, Bayer and Merck Sharpe & Dohme. Jenny Gunton received speaker fees from Eli Lilly. Alicia Jenkins is a member of the Merck Diabetes Advisory Board. She is a chief investigator of an investigator-initiated study, funded by Medtronic, about use of glucose sensor-augmented pumps in type 1 diabetes; she has not received a salary for this work. Glynis Ross received travel grants from Novo Nordisk to attend meetings, and speaker fees from Medtronic. Ashim Sinha has received travel grants and speaker fees from Eli Lilly, Novo Nordisk, GlaxoSmithKline and Sanofi-Aventis. He is also on an advisory board for Sanofi-Aventis. Stephen Twigg is a paid consultant for the advisory boards of Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi-Aventis. He receives speaker fees from Merck Sharp & Dohme, and meeting organiser fees from the Eli Lilly Meeting Faculty. He receives travel assistance to attend meetings from Sanofi-Aventis, GlaxoSmithKline and Novo Nordisk.

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