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The VADT study found that tight control of blood glucose did not reduce the risk of major cardiovascular events, microvascular complications, or death in people with type 2 diabetes who did not smoke, whose blood pressure was well controlled, and who were taking statins.
Action
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 cardiovascular disease is present, and metformin. They should follow NICE guidance and agree individual targets 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.
What is the background to this?
In contrast to observational studies and much current clinical practice, randomised controlled trials attempting to show that intensive drug strategies to control blood glucose to low target levels produces a reduction in important clinical outcomes have produced universally disappointing results. Intensive control can even increase the risk of death (see below).
We have repeatedly stressed the importance of not being so concerned about achieving glucose targets by aggressive use of hypoglycaemic drugs at the expense of failing to provide evidence-based interventions to reduce cardiovascular (CV) events. Randomized controlled trials of blood pressure lowering and use of statins have demonstrated large benefits on important clinical outcomes (see the type 2 diabetes section of NPC).
What does this study claim?
This open-label RCT of 1,791 people with type 2 diabetes found that, over a median of 5.6 years, treatment with oral hypoglycaemic drugs (plus insulin if necessary) to achieve a median HbA1c of 6.9% compared to a median of 8.4% did not statistically significantly reduce the risk of a composite of major vascular events (myocardial infarction [MI], stroke, death from CV causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, or amputation for ischaemic gangrene): hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.74 to 1.05, P=0.14. There were no statistically significant differences in any of the component endpoints. There was no significant difference in the rate of death (HR 1.07, 95% CI 0.81 to 1.42, P=0.62) or in any microvascular outcomes (ophthalmic, nephropathic or neuropathic). Patients in the intensive-treatment arm were more likely to experience hypoglycaemic episodes, including episodes with impaired consciousness (9 vs. 3 per 100 patient years P<0.001)) or complete loss of consciousness (3 vs. 1 per 100 patient years, P<0.001).
How dose this study fit with the rest of the evidence base and NICE guidance?
There is good observational data to show that high blood glucose levels are associated with increased macro- and microvascular risk, and indeed the observational extension to the UKPDS study found an association between intensive blood glucose control and a lower risk of macrovascular risk or death, and marginal benefits on microvascular endpoints.
However, observational studies should usually be interpreted as hypotheis generating, not hypothesis testing, and results of an observational study do not negate those of well-conducted RCTs. Ten years ago, the UKPDS RCT in newly-diagnosed people with diabetes found that attaining an HbA1c of 7% versus 7.9% with insulin or sulphonylureas had no statistically significant beneficial effect on all-cause mortality, macrovascular events or most microvascular events.
More recently, the ACCORD and ADVANCE studies were set up to assess whether more intensive glucose control strategies offered any advantage over standard therapies with regard to major CV events. These were both discussed in NPCi blogs [ACCORD blog; ADVANCE blog]. In both these studies, greater reductions in HbA1c levels were not associated with any improvement in important patient-oriented outcomes (with the exception of reduced nephropathy in ADVANCE). Indeed, in ACCORD, intensive therapy was associated with an increased risk of death.
The NICE clinical guideline on diabetes provides advice on setting a target for HbA1c. Although generally advocating the setting of a 6.5% target, it cautions against the use of highly intensive management strategies to achieve levels of less than 6.5%, and recognises the importance of involving the patient in the setting of their own target level, which may be above that of the 6.5%. The guidance also includes recommendations for structured education programmes, dietary and lifestyle advice, and, where necessary, interventions to reduce blood pressure, manage blood lipids, reduce the risk of thrombosis (aspirin) and kidney disease (ACE inhibitors). Note the subsequent POPADAD trial casts doubt on the value of aspirin for primary prevention of CV events in people with type 2 diabetes.
So what?
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. In VADT, although 72% of people were being treated for hypertension (defined as a blood pressure of 140/90 mmHg or more), mean blood pressure in both groups at the end of 6 years of follow-up was around 126/68 mmHg. Around 85% of people were taking statins, and smoking prevalence fell from around 17% at study entry to 3% at the end of the study period.
A limitation of this study is that the patients recruited had established type 2 diabetes mellitus with an HbA1c of 9.5% at study entry despite 52% receiving insulin and the remainder were receiving a maximal dose of an oral agent. VADT does not address the question as to whether early intensive control of HbA1c improves clinical outcomes, but UKPDS recruited newly-diagnosed patients and found that intensive control with sulphonylureas and insulin conferred limited microvascular benefits and no macrovascular benefits.
A complicating factor in assessing the results of VADT is that rosiglitazone, which appears to increase the risk of cardiovascular events, was used. Data are not provided to show the comparative numbers of patients taking this drug.
Study details
Patients: 1,791 military veterans (mean age 60.4 years, 97% males) with a suboptimal response to therapy for type 2 diabetes. The mean time since diagnosis was 11.5 years and 40% had already had a cardiovascular event.
Intervention and comparison: 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 an HbA1c 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. The goal for glycated hemoglobin levels was an absolute reduction of 1.5 percentage points in the intensive-therapy group, as compared with the standard-therapy group. Other modifiable cardiovascular risk factors were treated identically in the two study groups, according to American Diabetes Association guidelines.
Outcomes: Over a median of 5.6 years, treatment with oral hypoglycaemic drugs (plus insulin if necessary) to achieve a median HbA1c of 6.9% compared to a median of 8.4% did not statistically significantly reduce the risk of a composite of major vascular events (myocardial infarction [MI], stroke, death from CV causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, or amputation for ischaemic gangrene): hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.74 to 1.05, P=0.14. There were no statistically significant differences in any of the component endpoints. There was no significant difference in the rate of death (HR 1.07, 95% CI 0.81 to 1.42, P=0.62) or in any microvascular outcomes (ophthalmic, nephropathic or neuropathic). Patients in the intensive-treatment arm were more likely to experience hypoglycaemic episodes, including episodes with impaired consciousness (9 vs. 3 per 100 patient years P<0.001)) or complete loss of consciousness (3 vs. 1 per 100 patient years, P<0.001).
Sponsorship: Supported by the Veterans Affairs Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development; the American Diabetes Association; and the National Eye Institute. Pharmaceutical and other supplies and financial assistance were provided by GlaxoSmithKline, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, Amylin, and Kos Pharmaceuticals.
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