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In his Editorial (1) Home argues the possible merits and risks of
intensive blood glucose control regimens in patients with type 2 diabetes.
The quest for significant benefits on macrovascular outcomes in
intervention trials of these intensive regimens is an attempt to impute
causation from observational data on glycaemia and cardiovascular risk in
both diabetic (2) and non-diabetic subjects (3).
Yet there are problems with a glucocentric approach to managing
patients with type 2 diabetes, as can be seen using data from the UK
Prospective Diabetes Study (UKPDS) (4). In the 10 years of follow-up of
newly-diagnosed patients with a mean age of 53yrs, macrovascular events
(myocardial infarction and stroke) were 5 times more frequent than serious
microvascular events (blindness in one eye and renal failure) but, unlike
the latter, were not significantly reduced by intensive glucose lowering.
Moreover the observational data from the Study (2) showed a substantially
less steep relationship of mean glycated haemoglobin levels over 10 years
with macrovascular risk than with microvascular risk. These data imply
that if glycaemia per se plays a role in the aetiology of macroangiopathy,
the maximal potential benefit from a 1% reduction in glycated haemoglobin
is 14% for myocardial infarction and 12% for stroke. In general,
intervention studies with statins and antihypertensives have shown
benefits of around twice these amounts (5,6). Besides this, there is also
a qualitative difference for the patient between regimens based on tablets
and those based on injections (perhaps multiple) and blood glucose
monitoring, as well as the additional risk of hypoglycaemia.
The other value of UKPDS data is the possibility of calculating
Numbers Needed to Treat. In that study, the 10 year risk of macrovascular
disease was 22%, which is around 4 times that of the control group in the
ACCORD Study (1). Thus if this figure is combined with the epidemiological
data (2), the maximal potential benefit of lowering glycated haemoglobin
by 1% in a 53 year old patient with type 2 diabetes would be a reduction
of 2.4% over 10 years (ie 14% of 22%). This implies that for every 42
people treated for 10 years with an intensive glucose lowering regimen, at
least 41 would have exactly the same outcome whether or not they were
using the regimen. While absolute cardiovascular risk, and so potential
benefit, increases with age, the same is true for the potential risks of
adverse consequences of hypoglycaemia.
One hopes that the ACCORD Study will inject a note of caution before
conflating blood glucose with cholesterol and blood pressure as
cardiovascular risk factors worthy of aggressive intervention. Even if
ADVANCE and other intensive glucose lowering trials prove positive,
informed choice should require that patients be provided with full
explanations of the likely level of benefit expressed as absolute, and not
relative, risk reduction.
John S Yudkin
Emeritus Professor of Medicine, University College London
London N7 0AG
j.yudkin@ucl.ac.uk
1. Home P. Safety of very tight blood glucose control in type 2
diabetes. BMJ 2008; 336: 458-9.
2. Stratton IM, Adler AI. Neil HAW, Matthews DR, Manley SE, Cull CA,
Hadden D, Turner RC and Holman RR. Association of glycaemia with
macrovascular and microvascular complications of type 2 diabetes (UKPDS
35): prospective observational study. BMJ 2000; 321: 405-12.
3. Gerstein HC and Yusuf S. Dysglycaemia and risk of cardiovascular
disease. Lancet 1996; 347: 949-50.
4. UK Prospective Diabetes Study Group. 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 1998; 352: 837-53.
5. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM,
Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J and Baigent
C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes
in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371: 117
-25.
6. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J,
Woodward M and MacMahon S. Effects of different blood pressure-lowering
regimens on major cardiovascular events in individuals with and without
diabetes mellitus: results of prospectively designed overviews of
randomized trials. Arch Intern Med 2005; 165: 1410-9.
Very tight blood glucose control in type 2 diabetes may be a high risk, low benefit strategy
Editor
In his Editorial (1) Home argues the possible merits and risks of intensive blood glucose control regimens in patients with type 2 diabetes. The quest for significant benefits on macrovascular outcomes in intervention trials of these intensive regimens is an attempt to impute causation from observational data on glycaemia and cardiovascular risk in both diabetic (2) and non-diabetic subjects (3).
Yet there are problems with a glucocentric approach to managing patients with type 2 diabetes, as can be seen using data from the UK Prospective Diabetes Study (UKPDS) (4). In the 10 years of follow-up of newly-diagnosed patients with a mean age of 53yrs, macrovascular events (myocardial infarction and stroke) were 5 times more frequent than serious microvascular events (blindness in one eye and renal failure) but, unlike the latter, were not significantly reduced by intensive glucose lowering. Moreover the observational data from the Study (2) showed a substantially less steep relationship of mean glycated haemoglobin levels over 10 years with macrovascular risk than with microvascular risk. These data imply that if glycaemia per se plays a role in the aetiology of macroangiopathy, the maximal potential benefit from a 1% reduction in glycated haemoglobin is 14% for myocardial infarction and 12% for stroke. In general, intervention studies with statins and antihypertensives have shown benefits of around twice these amounts (5,6). Besides this, there is also a qualitative difference for the patient between regimens based on tablets and those based on injections (perhaps multiple) and blood glucose monitoring, as well as the additional risk of hypoglycaemia.
The other value of UKPDS data is the possibility of calculating Numbers Needed to Treat. In that study, the 10 year risk of macrovascular disease was 22%, which is around 4 times that of the control group in the ACCORD Study (1). Thus if this figure is combined with the epidemiological data (2), the maximal potential benefit of lowering glycated haemoglobin by 1% in a 53 year old patient with type 2 diabetes would be a reduction of 2.4% over 10 years (ie 14% of 22%). This implies that for every 42 people treated for 10 years with an intensive glucose lowering regimen, at least 41 would have exactly the same outcome whether or not they were using the regimen. While absolute cardiovascular risk, and so potential benefit, increases with age, the same is true for the potential risks of adverse consequences of hypoglycaemia.
One hopes that the ACCORD Study will inject a note of caution before conflating blood glucose with cholesterol and blood pressure as cardiovascular risk factors worthy of aggressive intervention. Even if ADVANCE and other intensive glucose lowering trials prove positive, informed choice should require that patients be provided with full explanations of the likely level of benefit expressed as absolute, and not relative, risk reduction.
John S Yudkin
Emeritus Professor of Medicine, University College London
London N7 0AG
j.yudkin@ucl.ac.uk
1. Home P. Safety of very tight blood glucose control in type 2 diabetes. BMJ 2008; 336: 458-9.
2. Stratton IM, Adler AI. Neil HAW, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC and Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405-12.
3. Gerstein HC and Yusuf S. Dysglycaemia and risk of cardiovascular disease. Lancet 1996; 347: 949-50.
4. UK Prospective Diabetes Study Group. 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 1998; 352: 837-53.
5. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J and Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371: 117 -25.
6. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, Woodward M and MacMahon S. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005; 165: 1410-9.
Competing interests: None declared
Competing interests: No competing interests