This site is intended for healthcare professionals only
DiabetesontheNet Logo
Sign In / Register

Issue:

Share this article

HbA 1c and survival in type 2 diabetes

Brian Frier

When treating diabetes, it is now assumed that the lower the HbA1c, the better the outcome for the individual – to minimise the risk of long-term vascular complications. Robust evidence for the beneficial effects of strict glycaemic control was provided by the DCCT (Diabetes Control and Complications Trial; DCCT Research Group, 1993), and the UKPDS (UK Prospective Diabetes Study; UKPDS Group, 1998). In the UK, to encourage GPs to strive for stricter glycaemic control of people with diabetes, the threshold for the lowest HbA1c indicator for QOF has been lowered from 7.5% to 7.0% (58 to 53 mmol/mol).

These therapeutic aspirations are unlikely to harm people with type 2 diabetes who are managed with diet or oral antidiabetes drugs (OADs) that seldom cause hypoglycaemia. However, treatment with insulin or sulphonylureas is a different matter. The merit of pursuing a policy of ever-lower HbA1c concentrations for everyone with type 2 diabetes has been challenged by the outcome of large clinical studies (ACCORD [Action to Control Cardiovascular Risk in Diabetes] Study Group et al, 2009; Duckworth et al, 2009), which have demonstrated that the use of intensive therapy to attain very strict glycaemic control is potentially hazardous. An increased risk of serious cardiovascular (CV) events and excess mortality was observed in people with type 2 diabetes with established CV disease or who had several vascular risk factors.

Severe hypoglycaemia can cause potentially serious morbidity and sudden death (Wright and Frier, 2008), and although it was not possible to prove that hypoglycaemia had caused cardiac arrhythmias or myocardial ischaemia in the ACCORD study, it is clear that strict glycaemic control is not appropriate for every person with type 2 diabetes.

A more recent study using the large UK General Practice Research Database revealed an unfavourable risk profile of sulphonylureas compared with metformin, which could suggest a greater risk of hypoglycaemia associated with these drugs (Tzoulaki et al, 2009).

Another study using the same research database has now added to the controversy surrounding HbA1c targets. Currie et al (2010) examined the relationship between HbA1c and survival using data collected for more than 20 years from 48 000 people with type 2 diabetes. One cohort (n=27 965) had been changed from OAD monotherapy to a combination of OAD medications, while the other cohort (n=20 005) had commenced regimens that included insulin – consistent with the escalation in therapy that is associated with the progressive severity of type 2 diabetes. The primary outcome measure of all-cause mortality was examined for each decile of HbA1c in both cohorts.

The 10% of people who had the lowest HbA1c levels (<6.7%; <50 mmol/mol) had a higher mortality than all other deciles with higher HbA1c levels, with the exception of the 10% with the highest HbA1c levels of ≥9.9% (≥85 mmol/mol). The adjusted hazard ratios for all-cause mortality by HbA1c deciles showed a U-shaped curve, irrespective of how or when HbA1c was measured. The greatest risk of death and of cardiac events was associated with the lowest and highest HbA1c values – although the causes of death were not known, nor could the frequency of hypoglycaemia be determined in this retrospective analysis. Interestingly, the lowest risk was associated with HbA1c levels in the decile of 7.4–7.7% (57–61 mmol/mol). Thus it would appear that the choice of the original QOF target for the lowest HbA1c level of 7.5% (58 mmol/mol), which was made without this new information, was indeed the optimal threshold.

So what should be the lowest HbA1c target in people with type 2 diabetes? This must be tailored to the age of the individual and should address their existing comorbidities and the treatment to be used. Indiscriminate application of intensive glucose-lowering therapy that could provoke dangerous hypoglycaemia in frail older people with type 2 diabetes, or in those with overt CV disease, should be avoided. In the light of this emerging evidence, a blanket approach that aims for progressively lower HbA1c levels (as currently stipulated by QOF) could raise ethical concerns, and a risk assessment of the individual is essential before aiming to lower HbA1c below 7%.

When treating diabetes, it is now assumed that the lower the HbA1c, the better the outcome for the individual – to minimise the risk of long-term vascular complications. Robust evidence for the beneficial effects of strict glycaemic control was provided by the DCCT (Diabetes Control and Complications Trial; DCCT Research Group, 1993), and the UKPDS (UK Prospective Diabetes Study; UKPDS Group, 1998). In the UK, to encourage GPs to strive for stricter glycaemic control of people with diabetes, the threshold for the lowest HbA1c indicator for QOF has been lowered from 7.5% to 7.0% (58 to 53 mmol/mol).

These therapeutic aspirations are unlikely to harm people with type 2 diabetes who are managed with diet or oral antidiabetes drugs (OADs) that seldom cause hypoglycaemia. However, treatment with insulin or sulphonylureas is a different matter. The merit of pursuing a policy of ever-lower HbA1c concentrations for everyone with type 2 diabetes has been challenged by the outcome of large clinical studies (ACCORD [Action to Control Cardiovascular Risk in Diabetes] Study Group et al, 2009; Duckworth et al, 2009), which have demonstrated that the use of intensive therapy to attain very strict glycaemic control is potentially hazardous. An increased risk of serious cardiovascular (CV) events and excess mortality was observed in people with type 2 diabetes with established CV disease or who had several vascular risk factors.

Severe hypoglycaemia can cause potentially serious morbidity and sudden death (Wright and Frier, 2008), and although it was not possible to prove that hypoglycaemia had caused cardiac arrhythmias or myocardial ischaemia in the ACCORD study, it is clear that strict glycaemic control is not appropriate for every person with type 2 diabetes.

A more recent study using the large UK General Practice Research Database revealed an unfavourable risk profile of sulphonylureas compared with metformin, which could suggest a greater risk of hypoglycaemia associated with these drugs (Tzoulaki et al, 2009).

Another study using the same research database has now added to the controversy surrounding HbA1c targets. Currie et al (2010) examined the relationship between HbA1c and survival using data collected for more than 20 years from 48 000 people with type 2 diabetes. One cohort (n=27 965) had been changed from OAD monotherapy to a combination of OAD medications, while the other cohort (n=20 005) had commenced regimens that included insulin – consistent with the escalation in therapy that is associated with the progressive severity of type 2 diabetes. The primary outcome measure of all-cause mortality was examined for each decile of HbA1c in both cohorts.

The 10% of people who had the lowest HbA1c levels (<6.7%; <50 mmol/mol) had a higher mortality than all other deciles with higher HbA1c levels, with the exception of the 10% with the highest HbA1c levels of ≥9.9% (≥85 mmol/mol). The adjusted hazard ratios for all-cause mortality by HbA1c deciles showed a U-shaped curve, irrespective of how or when HbA1c was measured. The greatest risk of death and of cardiac events was associated with the lowest and highest HbA1c values – although the causes of death were not known, nor could the frequency of hypoglycaemia be determined in this retrospective analysis. Interestingly, the lowest risk was associated with HbA1c levels in the decile of 7.4–7.7% (57–61 mmol/mol). Thus it would appear that the choice of the original QOF target for the lowest HbA1c level of 7.5% (58 mmol/mol), which was made without this new information, was indeed the optimal threshold.

So what should be the lowest HbA1c target in people with type 2 diabetes? This must be tailored to the age of the individual and should address their existing comorbidities and the treatment to be used. Indiscriminate application of intensive glucose-lowering therapy that could provoke dangerous hypoglycaemia in frail older people with type 2 diabetes, or in those with overt CV disease, should be avoided. In the light of this emerging evidence, a blanket approach that aims for progressively lower HbA1c levels (as currently stipulated by QOF) could raise ethical concerns, and a risk assessment of the individual is essential before aiming to lower HbA1c below 7%.

REFERENCES:

Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358: 2545–59
Currie CJ, Peters JR, Tynan A et al (2010) Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 375: 481–9
Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977–86
Duckworth W, Abraira C, Moritz T et al (2009) Glucose control and vascular complications in veterans with type 2 diabetes.N Engl J Med 360: 129–39
Tzoulaki I, Molokhia M, Curcin V et al (2009) Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 339: b4731
UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–53
Wright RJ, Frier BM (2008) Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 24: 353–63

Related content
;
Free for all UK & Ireland healthcare professionals

Sign up to all DiabetesontheNet journals

 

By clicking ‘Subscribe’, you are agreeing that DiabetesontheNet.com are able to email you periodic newsletters. You may unsubscribe from these at any time. Your info is safe with us and we will never sell or trade your details. For information please review our Privacy Policy.

DiabetesontheNet Logo

Are you a healthcare professional? This website is for healthcare professionals only. To continue, please confirm that you are a healthcare professional below.

We use cookies responsibly to ensure that we give you the best experience on our website. If you continue without changing your browser settings, we’ll assume that you are happy to receive all cookies on this website. Read about how we use cookies.