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Type 2 diabetes and glucose control: are we missing the point?

When it comes to type 2 diabetes, current guidelines recommend fairly tight glucose control. But is this necessary? Peter Burrill takes another look at the results of the ADVANCE trial, and what these mean to our current treatment of type 2 diabetes

Peter Burrill
BPharm(Hons) MRPharmS DipPresSci FCPP FFPMM
Specialist Pharmaceutical Adviser for Public Health
Derbyshire County PCT

The prevalence of type 2 diabetes is increasing and most people with diabetes will die or be disabled as a consequence of vascular complications. Prospective observational studies have shown continuous associations between blood glucose and glycated haemoglobin levels and the risk of major vascular events. However, randomised controlled trials (RCTs) have failed to provide conclusive evidence that tight control of blood glucose is of benefit in terms of enabling people with type 2 diabetes to live longer or have an improved quality of life.
The UK Prospective Diabetes Study was an ambitious attempt to demonstrate the effect of blood glucose control on outcomes in type 2 diabetes, but ended up demonstrating that you do nothing for cardiovascular outcomes by reducing HbA1c from 8% to 7%, and precious little for any other hard outcome. Nevertheless, current guidelines recommend a target HbA1c of 7% or less.

The trial
The ADVANCE trial was designed to assess the effects on major vascular outcomes of lowering the glycated haemoglobin value to a target of 6.5% or less in a broad cross-section of patients with type 2 diabetes.(1)

Method
The ADVANCE trial was a factorial RCT conducted at 215 collaborating centres in 20 countries. Eligibility criteria were a diagnosis of type 2 diabetes mellitus at 30 years of age or older, an age of at least 55 years at the time of study entry, and a history of major macro-vascular or microvascular disease or at least one other risk factor for vascular disease.
Participants were randomised to undergo either a strategy of intensive blood glucose control (target glycated haemoglobin value Patients who were randomly assigned to undergo intensive glucose control were given gliclazide (modified release, 30-120 mg daily) and were required to discontinue any other sulfonylurea. Although the timing, selection and doses of all other treatments were at the discretion of the treating physician, a treatment protocol was suggested. On the basis of the glycated haemoglobin level at each visit, this protocol initially advised increasing the dose of gliclazide MR (modified release), with the sequential addition or increase in dose of metformin, thiazolidinediones, acarbose or insulin. Patients in the standard-control group who were using gliclazide MR when they entered the study were required to substitute this drug with another sulfonyl-urea if continued therapy was required.
The primary study outcomes were a composite of macrovascular events and a composite of microvascular events, considered both jointly and separately.

Macrovascular events were defined as:

  • Death from cardiovascular causes.
  • Nonfatal myocardial infarction.
  • Nonfatal stroke.

Microvascular events were defined as:

  • New or worsening nephropathy, ie, development of macroalbuminuria (defined as a urinary albumin:creatinine ratio of more than 300 µg of albumin per mg of creatinine, or doubling of the serum creatinine level to at least 200 µmol/l), the need for renal-replacement therapy, or death due to renal disease.
  • Retinopathy, ie, development of proliferative retinopathy, macular oedema or diabetes-related blindness, or the use of retinal photocoagulation therapy.


Prespecified secondary outcomes were numerous and included:

  • Death from any cause.
  • Death from cardiovascular causes.
  • Major coronary events.
  • Major cerebrovascular events.
  • Heart failure.
  • Nephropathy.
  • Retinopathy.
  • Neuropathy.
  • Development of microalbuminuria.

Hypoglycaemia was defined as a blood glucose level of less than 2.8 mmol/l or the presence of typical symptoms and signs of hypoglycemia without other apparent cause. Patients with transient dysfunction of the central nervous system who were unable to treat themselves (requiring help from another person) were considered to have severe hypoglycemia.
The trial appears to have been allocation concealed and analyses were conducted according to the intention-to-treat principle.
The mean age of participants was 66 years and 42.5% were female. The average duration of diabetes was eight years and 32% had a history of major macrovascular disease. The median duration of follow-up was five years.

Results

  • The mean baseline glycated haemoglobin was 7.5%. At the end of follow-up, the mean values were 6.5% in the intensive-control group and 7.3% in the standard-control group.
  • The mean body weight during follow-up was 0.7 kg greater in the intensive-control group than in the standard-control group (p
  • At the end of the follow-up period, the mean systolic blood pressure was lower in the intensive-control group than in the standard-control group (135.5 versus 137.9 mmHg; average difference, 1.6 mmHg; p
  • During the follow-up period, the use of most classes of oral hypoglycaemic drug and of insulin had increased to a greater degree in the intensive-control group than in the standard-control group. Insulin was prescribed for 40.5% and 24.1% of patients in the intensive-control group and the standard-control group, respectively, by the end of the follow-up period.
  • The use of blood-pressure-lowering, lipid-modifying and antiplatelet treatments was similar between the two groups during the follow-up period.
  • A total of 2,125 participants had a major macrovascular or microvascular event: 18.1% in the intensive-control group and 20.0% in the standard-control group (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.82 to 0.98; p=0.01). Thus it was estimated that such an event would be averted during a five-year period in one of every 52 participants undergoing intensive control, ie, the number needed to treat (NNT) was 52.
  • Compared with standard control, intensive control resulted in a significant reduction in the incidence of major microvascular events (HR, 0.86; 95% CI, 0.77 to 0.97; p=0.01; NNT=63) but not in the incidence of major macrovascular events. The reduction in microvascular events was primarily because of a reduction in the incidence of nephropathy (HR, 0.79; CI 0.66 to 0.93; p=0.006; NNT=91).
  • The component of new or worsening nephropathy most clearly reduced through intensive glucose control was the development of macroalbuminuria (2.9% versus 4.1% with standard control; HR, 0.70; 95% CI, 0.57 to 0.85; p
  • A total of 1,031 participants died: 8.9% in the intensive-control group and 9.6% in the standard control group (p=0.28).
  • There were no significant differences between the two groups for any of the other prespecified secondary outcomes.
  • More patients undergoing intensive control were hospitalised for any cause (44.9% versus 42.8% of those in the standard-control group; HR, 1.07; 95% CI, 1.01 to 1.13; p=0.03; number needed to harm [NNH]=48), with some of the excess of hospitalisations due to severe hypoglycemia (1.1% versus 0.7%; p=0.04).
  • Severe hypoglycaemia occurred more frequently in the intensive-control group than in the standard-control group: 150 patients (2.7%) undergoing intensive control had at least one severe hypoglycaemic episode, compared with 81 patients (1.5%) undergoing standard control (HR, 1.86; 95% CI, 1.42 to 2.40; p

Implications
The ADVANCE trial did not show a significant effect of intensive glucose control on the risk of major macro-vascular events. Intensive glucose control resulted in a reduction by one-fifth in the development of new or worsening nephropathy, mainly due to a reduction in the development of macroalbuminuria. There was no reduction in the need for renal replacement therapy or death from renal causes. There was also no reduction in new or worsening retinopathy, including retinal photocoagulation, or in neuropathy.
Intensive glucose control was associated with an increased risk of hospitalisation and severe hypoglycaemia compared with standard control. An important question to ask is whether an NNT over five years of 83 to prevent one person developing macroalbuminuria is worth an NNH of 48 for hospitalisation or an NNH of 83 for severe hypoglycaemia?
Another recent study investigating intensive glucose lowering in type 2 diabetes (ACCORD) showed no benefit for reducing major cardiovascular events and found an increase in mortality with intensive control.(2)
Metformin remains the only hypoglycaemic agent shown to improve mortality and is the key agent for lowering blood glucose in type 2 diabetes. After managing the symptoms of hyperglycaemia, is there really any benefit from chasing a specific blood glucose target? As a "perspective" article says: "We should no longer support the use of targets without reference to the strategies used to achieve them. Guidelines and performance measures should reflect the evidence about interventions that are known to be beneficial."(3) This article also states that "a quality measure for tight glucose control should require evidence that a proper strategy provides a strong net benefit for patients."

Conclusion
Clinicians caring for patients with type 2 diabetes should focus on smoking cessation, dietary and exercise counselling, blood pressure control and providing metformin, simvastatin and aspirin. They should not be overfocused on intensive strategies to achieve HbA1c targets, which are often unnecessary and can put patients at risk of adverse drug-related events.(4) We must "lend a hand" to people with type 2 diabetes.(5)

The major financial sponsor of the study was Servier, with some grants from the National Health and Medical Research Council of Australia.

References

  1. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.
  2. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
  3. Krumholz HM, Lee TH. Redefining quality -implications of recent clinical trials. N Engl J Med 2008;358:2537-9.
  4. Putting blood glucose control in type 2 diabetes into perspective. National Prescribing Centre online blog. Available from: http://www.npci.org.uk/blog/?p=147
  5. WeMeReC. Type 2 diabetes: important aspects of care. WeMeReC Bulletin October 2005. Available from: http://www.wemerec.org/Documents/Bulletins/Diabetes_bulletin.pdf