In recent years the principle ‘the lower the better’ has achieved prominence in terms of reduction of cardiovascular deaths and events in the management of patients with diabetes and in those at high cardiovascular risk. This principle applies to the reduction of blood pressure, cholesterol, and blood sugar in people with diabetes. Reaching consensus on the optimum targets that should be attained is extremely difficult, as clinical trials have tended to compare treatments of differing intensity, rather than treatment to defined different but specified levels.
Although the HOT (Hypertension Optimal Treatment) study did not provide an optimum systolic blood pressure to aim for, it demonstrated that there is clear benefit in terms of a reduction in major cardiovascular events in patients with diabetes whose blood pressure was lowered closer to 80 mmHg compared with a target of ?90 mmHg.1
The benefits of statin use to lower cholesterol in type 2 diabetes are also not in doubt. A meta-analysis published at the beginning of 2008 involving 17,220 individuals with type 2 diabetes revealed a one-fifth reduction in major vascular events for each mmol/l reduction in low density lipoprotein (LDL) cholesterol, at least from an initial LDL-cholesterol level of 2.6 mmol/l.2 However, there are as yet no trials to define the ideal target LDL-cholesterol level by evaluating the relative and absolute benefits of cholesterol lowering to different cholesterol targets in relation to clinical events.
The NICE guideline on Type 2 diabetes: management of glucose uses evidence from the UKPDS (UK Prospective Diabetes Study) to justify the targets for lowering blood glucose as measured by the haemoglobin A1C (HbA1C) concentration.3 The guidance from NICE sets a target blood sugar level for patients with type 2 diabetes of HbA1C between 6.5% and 7.5%, with the lower target being preferred for those who are at significant risk of macrovascular complications.
It was noted by the NICE guideline development group that patients whose blood glucose is poorly controlled are more likely to have both microvascular (eye disease, renal failure) and macrovascular (myocardial infarction [MI], stroke) complications, and, based on data from the UKPDS, it considers that the lowest risk of complications occurs in those with an average HbA1C in the normal range of <6%. Updated guidance on type 2 diabetes is due to be published by NICE later this month.
The ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) was designed to determine whether intensively lowering blood glucose in patients with type 2 diabetes, as measured by HbA1C, reduced the risk of MI, stroke, or cardiovascular death. The trial recruited 10,251 patients aged 40–79 years with type 2 diabetes diagnosed at least 10 years previously, with pre-existing cardiovascular disease (CVD), or symptoms during the previous 2 years highly suggestive of CVD (e.g. microalbuminuria), or at least two factors that increase CVD risk (e.g. smoking, body mass index >32 kg/m2). The patients were divided into two groups, one to receive standard and the other intensive therapy for glycaemia control, with HbA1C targets of 7–7.9% and <6%, respectively. In the study, which was conducted at 77 sites in the USA and Canada, clinicians could use all of the major classes of diabetes medications available.4
The glucose-lowering arm of the trial was stopped 18 months early because of an increased risk of death in the intensive therapy group (the blood pressure and lipid arms are continuing). At the time of stopping, patients had been followed up for 2–7 years and in the intensive arm 50% of patients had achieved an HbA1C of <6.4%, with half of those in the standard treatment group having an HbA1C <7.5%. In the intensive therapy glucose-lowering group, there were 257 deaths, compared with 203 deaths in the standard treatment group. This difference of 54 deaths between the two groups equates to a mortality difference of 3/1000 participants each year, although in terms of the study population the overall average death rate was surprisingly low in relation to similar population groups.5
The reason for the difference is not clear but the study group has been quick to rule out a link with rosiglitazone or with hypoglycaemia, although it has been suggested that the highly intensive treatment regimen of combining multiple insulin injections with multiple oral medications may have been a factor.6 However, it must be emphasised that these results do not apply to patients with type I diabetes and may not apply to those with recently diagnosed diabetes or people without multiple cardiovascular risk factors.
In the light of the interim ACCORD results, the data monitoring and safety committee from the ADVANCE trial (Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation) has indicated that there were no excess deaths in the intensive group, which aimed to achieve an average HbA1C concentration of <6.5%.7
So what target level of HbA1C should GPs now be helping their patients to achieve? The delivery strategy of the National Service Framework for Diabetes encourages health professionals to aim for an ideal HbA1C level of <7% by the end of the first year after diagnosis.8 Attaining clinical indicator DM7 under the QOF should not be an issue, with HbA1C levels of 7.5 and 10 not being acceptable in the long term. Ensuring that all patients with diabetes meet the DM20 clinical indicator with a HbA1C target of ?7.5% should remain the current priority.9 As with other laboratory parameters, health professionals should aim lower in order to achieve this quality target consistently as a minimum standard of care.
Although in practice very few patients will be achieving the intensive glycaemic control aimed for within the ACCORD study, on the basis of the current evidence GPs should consider whether an HbA1C level of <7% in patients with type 2 diabetes is the ideal, or whether they should still be aiming for a level of <6.5%.
- Hansson L, Zanchetti A, Carruthers S et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351 (9118): 1755–1762.
- Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney P, Blackwell L, Collins R et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371 (9607): 117–125.
- Royal College of General Practitioners. Clinical guidelines for type 2 diabetes: management of blood glucose. London: NICE, 2002. https://www.nice.org.uk/guidance/index.jsp?action=byID&o=10912
- ACCORD (Action to Control Cardiovascular Risk in Diabetes). www.accordtrial.org
- National Heart, Lung, and Blood Institute. For safety, NHLBI changes intensive blood sugar treatment strategy in clinical trial of diabetes and cardiovascular disease. http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2551
- Home P. Safety of very tight blood glucose control in type 2 diabetes. Br Med J 2008; 336 (7642): 458–459.
- The George Institute for International Health. Major international diabetes study does not confirm increased risk of death reported by US trial. www.advance-trial.com/static/html/virtual/contents.asp?P=39
- National Service Framework for Diabetes: Delivery Strategy Department of Health. www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4901843
- British Medical Association. www.bma.org.uk/ap.nsf/Content/focusQOF0308G