Intensive strategies to achieve tighter blood glucose control do not improve cardiovascular outcomes in type 2 diabetes and can be harmful.
Managing cardiovascular (CV) risk factors are the priority for patients with type 2 diabetes. Although interventions (e.g. metformin and diet/lifestyle) will often be required to control the symptoms associated with having high blood glucose levels, clinicians should not become over-focussed on intensive strategies to achieve HbA1c targets. These are often unnecessary and can put patients at risk of adverse drug-related events. Clinicians should give priority to reducing the risk of macrovascular events with evidence-based interventions (e.g. smoking cessation, blood pressure control and the use of metformin/aspirin/simvastatin).
What is the background to this?
It has never been proven that the use of intensive drug strategies to control blood glucose to low target levels provides any meaningful benefits to patients in outcomes that really matter to them (i.e. living longer or better). We have repeatedly stressed the importance of not becoming so concerned about achieving glucose targets by aggressive use of anti-diabetic drugs (once symptoms have been controlled) that not enough attention is paid to providing evidence-based interventions to reduce CV events (see the diabetes floor of NPC).
As we have previously blogged, the ACCORD and ADVANCE studies were large randomised controlled studies set up to assess whether intensive glucose control strategies offered any advantage over standard therapies with regard to major CV events. These studies were recently published in the New England Journal of Medicine, together with two editorials [Editorial 1; Editorial 2]. They were also considered in a Perspective article in the same issue. This article considered the implication of ACCORD and ADVANCE alongside some other major clinical studies that evaluated the benefits of reducing risk factors, such as blood lipids, blood pressure and blood glucose levels on preventing CV disease.
In the ACCORD study, some 10,000 patients (mean age 62) with type 2 diabetes and elevated cardiovascular risk were randomised to intensive glucose lowering (target HbA1c <6.0%) or standard therapy (target HbA1c 7.0–7.9%). Intensive treatment was stopped early, after 3.5 years, because recipients showed significantly higher all-cause mortality than those on standard therapy (5.0% vs. 4.0%). The primary endpoint – a composite of myocardial infarction, stroke, and CV death – did not differ between the groups.
In the ADVANCE study, intensive gliclazide-based glucose control (target HbA1c ≤6.5%) was compared with standard therapy in about 11,000 older patients. After 5 years, intensive therapy showed no effect on macrovascular events or all-cause mortality, although it did reduce nephropathy.
What does this article claim?
The Perspective article points out that the risk:benefit ratio of interventions designed to modify risk factors can vary depending on the type and number of medications and other approaches that are concurrently incorporated. With regard to intensive glucose strategies that were examined in ACCORD and ADVANCE, it points out that the 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.
Guidelines and performance measures should reflect the evidence and highlight the particular strategies that have been shown to be of benefit to patients. This means that for treating type 2 diabetes, recommended strategies should have evidence that they not only reduce blood glucose levels, but they also offer a net benefit with regard to CV events averted or lives improved.
How does this relate to other studies and NICE guidance?
Metformin is the only oral antidiabetic drug that has been proven to reduce macrovascular complications, and is the drug of choice for first-line use in patients with type-2 diabetes (see MeReC Briefing: Type 2 diabetes (part 2): the management of cardiovascular risk factors)
Again as we have blogged, the recent 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).
MeReC Rapid Reviews have previously been published on the ACCORD and ADVANCE studies [ACCORD blog; ADVANCE blog]. For full details of the ACCORD and ADVANCE studies, please refer to the published articles cited below: