1st June 2009
A meta-analysis of prospective randomised controlled trials suggests a small benefit of intensive glucose control in people with type 2 diabetes in reducing coronary heart disease (but not stroke or death). However, the benefit is not as great as that achieved by blood pressure control or lipid lowering. It remains uncertain whether intensive glucose control (e.g. the addition of hypoglycaemic drugs to reduce HbA1c to levels significantly below that often acheived in clinical practice) offers any significant benefit in addition to that achievable by successful implementation of other interventions to reduce cardiovascular risk (i.e. smoking cessation, exercise, losing weight, controlling blood pressure, lowering cholesterol, taking metformin).
Level of evidence
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria.
This analysis should not change practice with regard to the treatment of type 2 diabetes. Priority should still be given to lifestyle interventions (stopping smoking, losing weight, and taking more exercise as appropriate), controlling blood pressure, taking a statin, and taking metformin). In some patients, additional hypoglycaemic drugs may be considered to control blood glucose, for example, those with troublesome symptoms of hyperglycaemia. However, NICE guidance (CG66 and the recently updated version, CG87) should be followed and individual targets for HbA1c should be agreed with each patient. These could be above that of 6.5% set for people with type 2 diabetes in general and should take into account patient preferences and the balance of likely benefits and harms (such as hypoglycaemia) as well as the medicines management issues.
What is the background to this?
There has been considerable debate over recent years with regard to the importance of intensive glycaemic control relative to other measures for reducing cardiovascular (CV) risk in people with type 2 diabetes. Recognising the inconsistency of the evidence supporting the use of intensive glycaemic control with regard to CV outcomes, the authors of this paper set out to clarify the situation by conducting a meta-analysis (MA) of randomised controlled trials (RCTs) that compared the effects of intensive glucose-lowering therapy with standard therapy, and which included CV events as a primary outcome.
What does this study claim?
The authors found that intensive glycaemic control (see intervention section of study details below for how this was defined in the MA) reduced coronary events, but not the risk of death, compared with standard treatment. This was based on the results of a series of MAs of data extracted from five prospective RCTs that included a total of 33,040 patients. The mean reduction in HbA1c was 0.9% lower for those patients on intensive treatment than those given standard treatment. There were statistically significant reductions in non-fatal myocardial infarction (MI) (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) and coronary heart disease (CHD) (OR 0.85, 95%CI 0.77 to 0.93) for patients on intensive therapy compared with standard treatment. The number needed to treat (NNT) over five years was estimated as 87 and 69, respectively.
However, there were no significant differences between treatment groups with regard to stroke (OR 0.93, 95%CI 0.81 to 1.06) or all-cause mortality (OR 1.02, 95%CI 0.87 to 1.19). Intensive glucose control was associated with an increased incidence of hypoglycaemic episodes (38.1% vs. 28.6%) and of severe hypoglycaemic events (2.3% vs. 1.2%). Subgroup analysis of the studies suggested that glitazone use was associated with an excess risk of heart failure.
How does this study relate to other studies?
A recent blog points out the conflicting nature of evidence from RCTs with regard to the benefits and risks of intensive glucose control. RCTs, such as ACCORD, ADVANCE and VADT, all of which were included in the present MA, have not identified consistently a significant benefit of intensive glycaemic control in the treatment of type 2 diabetes (see blogs 258, 147 and 64 for more details) with regard to CV outcomes and mortality. Indeed, the ACCORD study was stopped early because of an increased risk of death in the intensive treatment arm.
We have consistently pointed out in other blogs and NPC materials on type 2 diabetes the need to consider glycaemic control in the context of other important interventions (both lifestyle and drug interventions) to reduce CV risk. Potential benefits on macrovascular and microvascular outcomes, and the risks from treatment, need to be considered. This MA suggests that intensive glycaemic control therapy may have a small beneficial effect in reducing the risk of coronary heart disease, although it would appear to have no significant effect on reducing strokes or all cause mortality.
However, there are several aspects of this study which limit the generalisation of these findings to clinical practice. A meta-analysis of RCTs is often considered to be one of the highest forms of evidence. However, in this instance, the trials combined are very different, i.e. there was considerable heterogeneity among the studies. There were marked differences in the patient baseline characteristics (e.g. presence of CV disease, duration of diabetes), the treatment protocols (e.g. drugs and doses used, HbA1c targets) and duration of follow-up. In particular, three of the studies included (ADVANCE, ACCORD and VADT) had a roughly similar design in that they examined outcomes after reducing HbA1c to below 7% for several years in typical cohorts of type 2 patients aged around 65+. The other two, UKPDS and PROactive are very different. Indeed UKPDS was actually two studies of different interventions with very different results, although this was combined to give one overall result and included in the MA as such. The methodology used here is, therefore, questionable
The forest plots suggest reasonable uniformity between the selected studies for the effects on cardiovascular outcomes. However, this was not the case for all-cause mortality, where there was significant heterogeneity between studies. The authors point out that the studies with an increased risk of death (VADT and ACCORD) included patients with the longest duration since diabetes was diagnosed (>10 years), the highest HbA1c at baseline, and a greater risk of hypoglycaemia.
The benefits of glycaemic control on coronary outcomes appear modest in comparison with the benefits that might be obtained by blood pressure control and lipid modification. The authors point out that the benefits to be obtained by intensive glycaemic control are less than those achieved from a 4mmHg reduction in blood pressure or a 1mmol/L reduction in LDL-cholesterol. This emphasises the need to consider a general approach to reduce CV risk in people with type 2 diabetes, and not to focus solely on reducing blood glucose levels.
We would agree with Richard Lehman’s assessment that:
“…. this “meta-analysis” seems designed to obscure the clear message of three trials (ADVANCE, ACCORD and VADT) that can actually inform real-life practice in long-standing diabetes, which is that lowering HbA1c below 7 in this large group has no clear benefit and increases hypoglycaemia. The other two studies lumped in with them address different questions entirely. People with diabetes need evidence which helps them to choose the treatment which will benefit them most as individuals, whereas conflating disparate data leads in the opposite direction.”
So, intensive glycaemic control can be considered, where necessary, in addition to other interventions for reducing CV risk, but any potential benefits need to be considered against the increased risk of hypoglycaemia and drug-specific adverse effects. For example, glitazones increase the risk of heart failure, double the risk of bone fracture in women and there is some evidence to suggest that rosiglitazone, in particular, may be associated with an increased risk of myocardial infarction.
Ray KK, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009;373:1765–72
Design: Meta-analysis of prospective RCTs. Patients: 33,040 patients with type 2 diabetes; mean age 62 years; mean time since diagnosis of diabetes 8 years; 62% men; BMI 30 kg/m2; mean HbA1c 7.8%.
Intervention: Intensive lowering of blood glucose regimens (varied). Trials were chosen in which patients were randomly assigned to a treatment regimen that aimed to produce a significantly lower level of HbA1c compared with the standard regimen. They included trials such as ADVANCE, ACCORD which added additional drugs to achieve a target HbA1c of <6% or <6.5%, UKPDS where a target blood glucose level was aimed for, VADT where a reduction in HbA1c of 1.5% was the aim, as well as PROactive, where additional drugs or doses of drugs were used without any specific target.
Comparison: Standard regimen (placebo, standard care, or glycaemic control of reduced intensity).
Outcomes: Non-fatal MI, coronary heart disease, stroke, all-cause mortality.
Results: Average follow-up 4.75 years; mean reduction in HbA1c 0.9% (95%CI 0.88% to 0.92%) lower with intensive treatment vs. standard treatment (7.5% vs. 6.6%). There were statistically significant reductions in non-fatal myocardial infarction (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) and coronary heart disease (CHD) (OR 0.85, 95%CI 0.77 to 0.93) for patients on intensive therapy vs. standard treatment (NNT over five years 87 and 69, respectively). There were no significant differences between treatment groups with regard to stroke (OR 0.93, 95%CI 0.81 to 1.06) or all-cause mortality (OR 1.02, 95%CI 0.87 to 1.19). Intensive glucose control was associated with an increased incidence of hypoglycaemic episodes (38.1% vs. 28.6%) and of severe hypoglycaemic events (2.3% vs. 1.2%). Although intensive treatment did not significantly affect heart failure (OR 1.08, 95%CI 0.90–1.31) there was considerable heterogeneity between studies, and subgroup analysis of the studies suggested that glitazone use was associated with an excess risk of heart failure. Intensive glycaemic control was associated with an increase in weight of 2.5kg.
Sponsorship: This was a publicly funded study. Authors are from: Department of Public Health and Primary Care, University of Cambridge, UK; Department of Cardiology, Addenbrookes Hospital, Cambridge, UK; Department of Medicine, University of Glasgow, UK.
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