Yesterday the National Heart Lung and Blood Institute (NHLBI) in the USA announced that it has stopped the intensive blood-glucose-lowering arm of a large type 2 diabetes trial due to findings that intensively lowering blood glucose below current US recommended targets increased the risk of death compared with a less-intensive standard treatment strategy.
What is the background to this?
People with type 2 diabetes are at increased risk of cardiovascular disease (CVD) events compared to similar people without diabetes. The ACCORD study is a large, ongoing trial looking at the effects of intensive blood glucose, blood pressure lowering and lipid lowering in people with type 2 diabetes at high risk of CVD events. More details of the trial are provided at the end of this blog. The trial started in 2001 and was scheduled to follow up participants for four to eight years.
All 10,251 participants were randomised to a therapeutic strategy that targeted an HbA1c of < 6.0% or a strategy that targeted an HbA1c of 7.0% to 7.9% (with the expectation of achieving a median level of 7.5%). This was to be achieved through diet and lifestyle measures and drug therapy including metformin, sulphonylureas, glitazones, acarbose, meglitinides (eg repaglinide) and insulin.
What concerns have been raised?
After about 4 years of follow-up, people in the intensive treatment arm had a 27% higher relative risk of dying than those in the standard treatment arm. This is a number needed to harm (NNH) of 95 and equates to 3 extra deaths per 1,000 participants per year, over an average of 4 years of treatment. The increased risk between the two groups outweighed potential benefits of the intensive treatment strategy on non-fatal events. Accordingly, the NHLBI made the decision to stop this intensive treatment approach of the trial – comments from the investigators can be found here. Although there were fewer non-fatal CVD events in the intensive treatment group, it appeared that, if a heart attack did occur, it was more likely to be fatal. In addition, the intensive treatment group had more unexpected sudden deaths, even without a clear heart attack.
ACCORD researchers have extensively analysed the data available to date and have not identified any specific cause for the higher death rate among the intensive blood glucose lowering arm. They have established that the higher death rate was not due to episodes of hypoglycemia, or due to any single drug, including rosiglitazone, or combination of drugs.
As we have recently blogged, the currently available evidence suggests that for people with Type 2 Diabetes Mellitus, after controlling blood glucose to the extent sufficient to control symptoms (probably using diet and lifestyle measures along with metformin), managing other CVD risk factors should be the next priority. This may include encouraging smokers to stop smoking, controlling blood pressure, adding a statin (ideally simvastatin 40 mg/day) and adding aspirin once their blood pressure is controlled. The best available evidence suggests that such measures are likely to achieve far more with regard to reducing the risk of macrovascular and microvascular complications than tight blood glucose control. In our experience, some patients and practitioners become preoccupied with glycaemic control to the neglect of these other measures. You can find more information on the type 2 diabetes section of NPC.
Patients with type 2 diabetes should not adjust their treatment without discussing this with their doctor, pharmacist or specialist nurse. However, some patients and some health professionals looking after people with type 2 diabetes may need to review their priorities in managing diabetes carefully.
ACCORD is a randomised, multicentre, double 2 x 2 factorial design clinical trial in 10,251 patients with type 2 diabetes, which started in 2001. The protocol for this study can be found here. The participants have several factors that put them at higher risk of cardiovascular disease (CVD): at study entry they all had had diabetes for at least 10 years, their average age was 62, their mean HbA1c was 8.2% and they also either had known heart disease or at least two risk factors, in addition to diabetes, including high blood pressure, high cholesterol levels, obesity, and smoking. ACCORD was designed to answer three questions – in middle-aged or older people with type 2 diabetes who are at high risk for having a CVD event because of existing clinical or subclinical CVD or CVD risk factors:
does a therapeutic strategy that targets a HbA1c of < 6.0% reduce the rate of CVD events more than a strategy that targets a HbA1c of 7.0% to 7.9% (with the expectation of achieving a median level of 7.5%)?
in the context of good glycaemic control, does a therapeutic strategy that uses a fibrate to raise HDL-C/lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C?
In the context of good glycemic control, does a therapeutic strategy that targets a systolic blood pressure (SBP) of < 120 mm Hg reduce the rate of CVD events compared to a strategy that targets a SBP of < 140 mm Hg?
All 10,251 participants were included in the overarching glycaemia trial. In addition, one 2 X 2 trial is addressing the lipid question in 5,518 of the participants and the other 2 X 2 trial is addressing the blood pressure question in 4,733 of the participants.
After a mean of four years of follow up, there were 257 deaths among the 5128 participants in the intensive glucose lowering group (5.01%) and 203 deaths in the 5123 participants in the standard treatment group (3.96%). This is a relative risk of death of 1.265 (a relative risk increase of around 27%) and an absolute increase of 1.05%. This is a number needed to harm (NNH) of 95 and equates to 3 extra deaths per 1,000 participants per year, over an average of 4 years of treatment.