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Issue No 38 March 2009        

Don’t miss out on news you want to hear

Insignificant benefits for intensive glucose control in type 2 diabetes

Dual antihypertensive therapy in patients at high risk of CV disease

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Insignificant benefits for intensive glucose control in type 2 diabetes

In keeping with other studies in people with type 2 diabetes, VADT¹ suggests that intensive control of blood glucose does not reduce the risk of CV events or death.

Action
Management of overall cardiovascular (CV) risk appears to be most effective for preventing CV events in people with type 2 diabetes. NICE guidance should be followed and priority given to lifestyle interventions (i.e. smoking cessation, weight loss, diet modification and increased exercise, as appropriate) and drug treatments to reduce CV risk (i.e. controlling blood pressure, taking a statin, taking metformin and taking aspirin if CV disease is already present).² While NICE guidance generally advocates setting an HbA1c target of 6.5% for people with type 2 diabetes, it cautions against the use of highly intensive management strategies to maintain levels of less than 6.5%. Moreover, NICE recognises the importance of involving the patient in the setting of their own target level, which may be above 6.5%.

What was the VADT study?
VADT was a randomised controlled trial (RCT) of 1,791 US military veterans (mean age 60 years) who had inadequate response to therapy for type 2 diabetes (HbA1c >7.5%, baseline median 9.4%). Treatment was open-label with blinded assessment of outcomes. Over a median of 5.6 years, intensive treatment (median HbA1c 6.9%) with oral hypoglycaemic drugs (rosiglitazone with either metformin or glimepiride) plus insulin, if necessary, was not associated with a statistically significant reduction in major CV events (a composite of myocardial infarction [MI], stroke, death from CV causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, or amputation for ischaemic gangrene) compared with less intensive, standard treatment (median HbA1c 8.4%) — HR 0.88, 95% confidence interval (CI) 0.74 to 1.05, P=0.14. There were no statistically significant differences between treatments for any of the component endpoints, for death from any cause, or for any microvascular outcomes (ophthalmic, nephropathic or neuropathic). Patients in the intensive-treatment arm were more likely to suffer hypoglycaemic episodes, including 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).

So what?
Several aspects of the study limit the applicability of the findings to routine clinical practice (see MeReC Rapid Review Blog No. 258 for more details). However, VADT generally supports the results of other RCTs, such as UKPDS,³ ADVANCE⁴ and ACCORD,⁵ which suggest that there is little to gain with regard to macrovascular outcomes from intensive glucose control in people with type 2 diabetes if other CV risk factors are addressed, and intensive control may put the patient at increased risk of harm.

References

1. Duckworth W, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–39
2. NICE. Type 2 diabetes: the management of type 2 diabetes (update). CG66. May 2008
3. 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
4. Patel A, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370;829–40
5. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2007;358:2545–59

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Dual antihypertensive therapy in patients at high risk of CV disease

The ACCOMPLISH study¹ suggests that, in patients at high risk of CV disease who require dual antihypertensive therapy to control blood pressure, benazepril (an ACE inhibitor not on the UK market) plus amlodipine may be slightly more effective than benazepril plus hydrochlorothiazide at reducing the risk of CV events.

Action
Prescribers should continue to follow the NICE clinical guideline for the management of hypertension.² The choice between a calcium channel blocker and a thiazide diuretic, either as a first-line treatment or in addition to an ACE inhibitor, should be based on their likely side-effect profiles, suitability for the individual patient and cost. Patients whose hypertension is complicated by existing CV disease, renal disease, or diabetes (type 1 or 2) should continue to be treated for their hypertension according to NICE guidelines (see www.nice.org.uk) that are specific to these conditions.

What was the ACCOMPLISH study?
The ACCOMPLISH study was a double-blind RCT of 11,506 patients (mean age 68 years) with hypertension who were at high risk of CV events. The study examined the relative benefits of using benazepril with either amlodipine or hydrochlorothiazide.¹ After a mean follow-up of 36 months there were fewer primary-outcome events (any of: death from CV causes, non-fatal MI, non-fatal stroke, hospitalisation for angina, resuscitation after sudden cardiac arrest, or coronary revascularisation) in the benazepril plus amlodipine group compared with the benazepril plus hydrochlorothiazide group (9.6% vs. 11.8%; hazard ratio [HR] 0.80, 95% CI 0.72 to 0.90, P<0.001). This suggests that 46 people would need to be treated with benazepril plus amlodipine instead of benazepril plus hydrochlorothiazide for about 30 months for one of them to have a CV event prevented. No significant differences were identified between groups with regard to CV death or death from any cause.¹

So what?
There are several aspects of the study that limit the relevance of its findings to UK clinical practice. Benazepril is not marketed in the UK, and hydrochlorothiazide is only available as a combination product. The patients in the study were not typical of the broad population of patients with hypertension. Many had existing CV disease and 60% had diabetes. Doubts have been raised over whether the diuretic regimen chosen provided adequate blood pressure control over a 24-hour period;³ the mean difference of about 1mmHg in both systolic and diastolic blood pressures between groups may have accounted for some of the differences in CV outcomes.

Choice of treatment often depends on compelling indications, contraindications, coexisting conditions and other patient factors. The results of this study do not diminish the value of treatment with the combination of an ACE inhibitor and a diuretic. Treatment recommendations should be based on the total available evidence rather than the results of any one trial.³

Further details and of the study can be found in MeReC Rapid Review Blog No. 250.

References

1. Jamerson K, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417–28
2. NICE. Hypertension: management of hypertension in adults in primary care. CG34. June 2006
3. Chobanian AV. Editorial. Does it matter how hypertension is controlled. N Engl J Med 2008;359:2485–8

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