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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.
The ADVANCE Study
Paul Van Crombrugge |
Click here to download PowerPoint slides of this commentary. |
Background
Morbidity and mortality in diabetes arise from both macrovascular disease (atherosclerosis) and microvascular disease (retinopathy, nephropathy, and neuropathy). The role of glycaemic control in preventing vascular disease, particularly myocardial infarction and stroke, has been difficult to establish in Type 2 diabetes despite more than a decade of inquiry. Consider these conflicting findings from major diabetes treatment trials:
- The UKPDS (United Kingdom Prospective Diabetes Study) reported that intensive blood glucose therapy aimed at a fasting plasma glucose <6.0 mmol/l (108.1 mg/dl) reduced the risk of heart attack (P=0.052) but not stroke (P=0.52) compared with conventional therapy (UKPDS, 1998).
- A meta-analysis of 6 treatment trials found an incidence rate ratio of 0.81 (95% confidence interval (CI): 0.73 to 0.91) for any macrovascular event with intervention versus standard care, due mainly to reductions in stroke and peripheral vascular events (Stettler et al, 2006).
- The ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) reported a 35% greater risk of cardiovascular deaths in individuals receiving aggressive therapy aimed at an HbA1c <6 % (lower than the current guideline of <7 %). However, individuals in the aggressive therapy group had a significantly lower risk of non-fatal myocardial infarction than individuals receiving standard care and no increase in non-fatal stroke (ACCORD, 2008).
The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) is the largest Type 2 treatment trial to date and as such may help clarify central issues in vascular disease prevention in Type 2 diabetes. In 2007, the ADVANCE team reported on an arm of the trial that assessed blood pressure treatment: major vascular events and deaths were reduced significantly with treatment over 4.3 years. Measured separately, however, macrovascular and microvascular events were not reduced significantly (Patel et al, 2007). The current ADVANCE report addresses the vascular impact of intensive versus standard blood glucose control in the same population over 5 years.
Methods and Key Results
ADVANCE enrolled 11,140 individuals from centers in Asia, Australasia, Europe, and North America between 2001 and 2003. All participants had a diagnosis of Type 2 diabetes and major macrovascular or microvascular disease or at least one other vascular risk factor. Mean age at baseline was 66 years, and mean HbA1c at inclusion was 7.5 %. In parallel with the blood pressure arm, ADVANCE participants were assigned to either intensive or standard blood glucose control. Intensive control had a target HbA1c of ≤6.5 % and was based initially on sulfonylurea therapy with gliclazide (modified release) 30 to 120 mg/day. Treating physicians were advised to make gradual dose increases or add sequential drugs as needed—metformin, thiazolidinediones, acarbose, or insulin. Individuals under standard care did not use gliclazide; otherwise, their treatments and glucose targets were determined by the treating physician. Primary end points in ADVANCE were macrovascular events (cardiovascular-related death, non-fatal myocardial infarction, or non-fatal stroke) and microvascular events (new or worsening nephropathy or retinopathy) assessed together and separately.
At the end of 5 years, mean HbA1c was 6.5 % in the intensive group and 7.3 % in the standard group (P<0.001). The combined microvascular and macrovascular end point was significantly lower in the intensive control arm: 18.1% versus 20.0% with standard control (hazard ratio 0.90; 95% CI: 0.82 to 0.98, P=0.01). Microvascular events were also reduced significantly, largely because of a 21% risk reduction in new or worsening nephropathy (P=0.006). However, there were no significant differences between treatment groups in terms of macrovascular events or cardiovascular deaths. Intensive control was associated with an increased risk of severe hypoglycaemia and a higher rate of hospitalization from any cause.
Clinical Implications
The ADVANCE report on blood glucose control offers much to be grateful for. As the authors point out, renal impairments are predictive of future major vascular events and deaths in individuals with diabetes. The 21% reduction in nephropathy seen in the trial (along with a smaller but still significant reduction in new-onset microalbuminuria) re-emphasizes the preventive potential of intensive glucose control via renal effects.
ADVANCE also contradicts the finding of increased cardiovascular mortality reported from the ACCORD trial (smaller than ADVANCE by only 889 patients). The ACCORD finding could have reflected several other explanations rather than the effects of intensive blood glucose control per se: there was a clear difference in the use of statins and aspirin (lower in the ADVANCE study), in the rate of reduction in HbA1c (very fast in the ACCORD study), in the use of thiazolidinediones and insulin (higher in the ACCORD trial), and in the patient profile (baseline HbA1c much higher in ACCORD). For the more 'everyday' diabetic individuals in ADVANCE, the target of 6.5 % was of clear benefit with acceptable risk. The chief trade-off was an excess but still low rate of hypoglycaemic events (0.7 severe incidents per 100 patients per year, substantially lower than the rate seen in the UKPDS).
Three new sets of data offer compelling insights on cardiovascular protection. At the 2008 sessions of the European Association for the Study of Diabetes, the ADVANCE investigators reported that the trial’s combination of intensive glucose therapy and blood pressure control reduced cardiovascular mortality by 24%. In addition, a 20-year follow-up of participants in UKPDS revealed that compared with conventional therapy, sulfonylurea-based intensive glucose control produced a 15% relative risk reduction (P=0.01) in myocardial infarction, and with metformin-based therapy a 33% reduction (P=0.005) (Holman et al, 2008). Results of VADT (Veterans Affairs Diabetes Trial) (still to be published) were also presented at this congress and did not show a significant change (either positive or negative) with intensive glycaemic control on the cardiovascular endpoints but was probably underpowered (1791 participants) to give a clear answer on this.
The picture regarding macrovascular prevention is still not complete, but the recent results of these old and new studies (UKPDS, ADVANCE, ACCORD, VADT, Steno-2) give us some clear clinical messages for the treatment of Type 2 diabetes: lowering lipids, treating hypertension, and using anti-thrombolytic drugs are crucial, and good glycaemic control is essential (aiming for an HbA1c of 6.5 % where this can be attained without an excess of hypoglycaemia and compromising to a realistic value in individuals with a shorter life expectancy or with already well-established severe vascular complications) (Home, 2008).
This Website Feature is funded by an educational grant from Pfizer Inc.
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