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Glucose control in type 2 diabetes: the VADT study

The Veterans Affairs Diabetes Trial (VADT) trial examined the benefits of intensive blood glucose control in patients with type 2 diabetes. Peter Burrill looks at the results of the study and what these mean for the management of the condition in primary care

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

In contrast to observational studies and much current clinical practice, randomised, controlled trials (RCTs) attempting to show that intensive drug strategies to control blood glucose to low target levels produce a reduction in important clinical outcomes have had disappointing results. It has been suggested that intensive blood glucose control may even increase risk of death.1

Ten years ago, the UK Prospective Diabetes Study Group (UKPDS) RCT in newly diagnosed people with type 2 diabetes found that achieving an HbA1c of 7% vs 7.9% with insulin or sulphonylureas had no statistically significant beneficial effect on all-cause mortality, macrovascular events or most microvascular events.2 The Veterans Affairs Diabetes Trial (VADT) was set up to compare the effects of intensive and standard glucose control on cardiovascular events.3

Method
VADT was an open-label RCT, involving 1,791 military veterans (mean age 60.4 years, 97% males) with a suboptional response to therapy for type 2 diabetes. Selection criteria included an inadequate response to maximal doses of an oral agent or insulin therapy. Exclusion criteria included a glycated haemoglobin level of less than 7.5%, the occurrence of a cardiovascular (CV) event during the previous six months, advanced congestive heart failure, a life expectancy of less than seven years, and a body mass index (BMI) of more than 40.
Participants were randomised to receive either intensive or standard glucose control. The goal in the intensive therapy group was an absolute reduction of 1.5 percentage points in the glycated haemoglobin level, as compared with the standard therapy group.

In both study groups, patients with a BMI of 27 or more were started on two oral agents: metformin plus rosiglitazone; those with a BMI of less than 27 were started on glimepiride plus rosiglitazone. Patients in the intensive therapy group were started on maximal doses, and those in the standard therapy group were started on half the maximal doses.

Before any change in oral medications, insulin was added for patients in the intensive therapy group who did not achieve a glycated haemoglobin level of less than 6% and for those in the standard therapy group with a level of less than 9%.
Subsequent changes in medication were determined according to protocol guidelines and local assessment. The guidelines allowed for the use of any approved drug at the discretion of the investigator.

Other modifiable CV risk factors were treated identically in the two study groups. Treatment guidelines for blood pressure and lipid control, as well as for dietary, exercise and diabetes education, were provided to all patients. All patients were prescribed aspirin and a statin unless contraindicated.
The primary outcome was the time to the first occurrence of any one of a composite of CV events, adjudicated by an endpoint committee that was unaware of assignments to study groups. The CV events were documented as:

  • Myocardial infarction.
  • Stroke.
  • Death from CV causes.
  • New or worsening congestive heart failure.
  • Surgical intervention for cardiac, cerebrovascular or peripheral vascular disease.
  • Inoperable coronary artery disease.
  • Amputation for ischaemic gangrene.

Secondary CV outcomes included new or worsening angina, new transient ischaemic attacks, new intermittent claudication, new critical limb ischaemia, and death from any cause. Secondary outcomes also included microvascular complications (retinopathy, nephropathy, and neuropathy). Adverse events, including hypoglycemia, were monitored.

The study appears to have been allocation concealed and all analyses were based on the intention-to-treat principle. The planned sample size of 1,700 patients provided a power of 86% to detect a relative difference of 21% in the rate of the composite CV outcome. The study was sponsored by the Veterans Affairs Cooperative Studies Program.

Results
A total of 1,791 patients were enrolled. The mean time since diagnosis was 11.5 years. The mean BMI was 31.3 and the mean glycated haemoglobin level at baseline was 9.4%. Hypertension was present in 72% of patients, and 40% had already experienced a CV event. At baseline, 52% were receiving insulin. The median follow-up was 5.6 years.

The mean baseline blood pressure was 132/76 mmHg in the two groups. After six years, for patients who were still in follow-up, the mean blood pressure was 125/69 mmHg in the standard therapy group and 127/68 mmHg in the intensive therapy group. In both groups, mean lipid levels improved during the study, and levels of LDL-cholesterol decreased
to 2.1 mmol/L.

The use of antiplatelet drugs increased to 91% and 94% of patients in the two groups, respectively, and statin use increased to 83% and 86% of patients, respectively. Weight and BMI were significantly greater (by 9 lb (4 kg) and 1.5, respectively; P=0.01) in the intensive therapy group after treatment.

At three months, median glycated haemoglobin levels had decreased in both groups and had stabilised at six months, with a level of 8.4% in the standard therapy group and 6.9% in the intensive therapy group. This result achieved the prespecified goal of an absolute between-group difference of 1.5 percentage points.

No significant benefit in the time to the first occurrence of a CV event was observed in the intensive therapy group (hazard ratio, 0.88; 95% confidence interval (CI), 0.74 to 1.05; P=0.14). There was no evidence that the effect of treatment varied according to either insulin status at baseline or the previous occurrence of a CV event (P=0.37 and P=0.92, respectively).

There were no significant differences in individual components of the primary and secondary outcomes. There was no significant difference in death from CV causes or death from any cause. No difference was observed between the two groups for microvascular complications (ophthalmic, nephropathic
or neuropathic).

The most common adverse event was hypoglycaemia, with significantly more episodes in the intensive-therapy group than in the standard therapy group, including episodes with symptoms (1,333 vs 383 per 100 patient-years), impaired consciousness (9 vs 3) and complete loss of consciousness (3 vs 1) (all P

Discussion
A National Prescribing Centre (NPC) review states: "Once again, intensive glucose control does not benefit people with established type 2 diabetes if other cardiovascular risk factors are addressed".4 The authors of VADT comment: "Appropriate management of hypertension, dyslipidaemia, and other cardiovascular risk factors appears to be the most effective approach to preventing cardiovascular morbidity
and mortality".3

This is echoed by the NPC: "The VADT study provides still further evidence that intensive control of blood glucose does not help people with type 2 diabetes who have attended to other risk factors".4

VADT illustrates very well the law of diminishing returns and provides strong support for following the "diabetes hand". The NPC recommends that health professionals and people with type 2 diabetes should prioritise lifestyle interventions (losing weight, healthy diet, stopping smoking if relevant), blood pressure control, taking a statin, aspirin if CV disease is present, and metformin. Individual targets should be agreed for blood glucose. Interventions to control blood glucose intensively appear to add little, and attempts to achieve very tight control of blood glucose may do more harm than good.4

VADT does not address the question as to whether early intensive control of HbA1c improves clinical outcomes, but UKPDS 332 recruited newly diagnosed patients and found that intensive control conferred limited microvascular benefits and no
macrovascular benefits.

An article that reviews the evidence for control of blood glucose level in type 2 diabetes states that it is time to challenge conventional wisdom. The author advises: "Physicians should use drugs to control blood glucose level only if demonstrated through RCTs to be both safe and efficacious in reducing important clinical outcomes (eg, metformin) or if needed for symptomatic relief. I would not recommend trying to achieve HbA1c levels lower than 7% unless it can be done through nonpharmacologic means and/or metformin therapy. Prudence would dictate not using multiple oral agents at this time."5 l

References
1. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
2. UK Prospective Diabetes Study (UKPDS) 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.
3. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39.
4. National Prescribing Centre (NPC). Once again, intensive glucose control does not benefit people with established type 2 diabetes if other cardiovascular risk factors are addressed. London: NPC; 2009. Available from: www.npci.org.uk/blog/?p=258
5. Havas S. The ACCORD Trial and control of blood glucose level in type 2 diabetes mellitus: time to challenge conventional wisdom. Arch Intern Med 2009;169:150–4.