Two large studies, one from the United States and the other from Australia, involving more than 21,000 patients with Type 2 diabetes, found no reduction in heart risk and death from intensive control of blood sugar.
The findings from the American ACCORD and the Australian ADVANCE trials, and a comprehensive editorial comparing their methods and results, are published in the 5th June issue of the New England Journal of Medicine (NEJM).
What will come as a surprise to many diabetes experts is that neither study found evidence to support the widely held belief that aggressive reduction of blood sugar, to below the 7 per cent standard, significantly reduces cardiovascular risk and death for patients with Type 2 diabetes.
The American ACCORD study, supported by the NIH’s National Heart, Lung, and Blood Institute (NHLBI), involved over 10,000 Type 2 diabetes patients and was stopped in February this year, after an average of 3.5 years, instead of the planned 5.6 years, because of safety concerns. The intensive blood sugar reduction group had 22 per cent higher risk of death (54 more deaths), compared to the standard group. The higher risk of death started to appear within 1 to 2 years after the aggressive method of lowering blood sugar started having an effect. All the remaining patients are now following a regimen with a standard blood sugar target.
The Australian ADVANCE study, designed by experts at the Australia’s George Institute for International Health, involved over 11,000 type 2 diabetes patients from 20 different countries, who were treated and followed up for five years. The study did not find any significant increase in heart risk and death, but it did find a reduction of kidney disease risk of 4.1 percent compared with 5.2 percent among patients who followed a less aggressive regimen.
Type 2 diabetes shortens lifespan, usually because it brings a higher risk of cardiovascular disease. But while the disease is characterized by the body’s failure to control blood sugar, the relationship between blood sugar and cardiovascular risk is not straightforward. The disease itself shows a strong link with cardiovascular risk, yet the risk increase for each percentage increase in blood sugar is only modest, wrote Drs Robert G Dluhy and Graham T McMahon in an editorial accompanying the two studies in the same issue of the NEJM.
An earlier UK study (the UKPDS trial) showed that reducing blood sugar (glycated hemoglobin) from 8 to 7 per cent did not reduce cardiovascular events, although a subgroup of patients taking metformim did experience a lower risk of cardiovascular events. And another study of patients with Type 1 diabetes (the DCCT/EDIC trial), showed a long term reduction in cardiovascular complications that appeared only many years after starting on the glucose lowering regimen.
These two latest studies both investigated the effect of lowering blood sugar to near-normal levels on cardiovascular risk. Although they both compared the effect of standard versus intensive treatment, they were quite different in that most patients in both studies were given a variety of drugs, with and without insulin, but the American ACCORD study did not restrict the aggressiveness of the regimen, while in the Australian ADVANCE study, all patients had to take the sulfonylurea gliclazide (modified release) at the start, according to the editorial writers.
The two trials also differed significantly in design and the types of drugs used, although they were similar in that neither trial required patients to modify lifestyle or diet. For example, in the American ACCORD trial, the patients were randomly assigned to intensive or standard therapy for lowering blood pressure, or to receive the cholesterol lowering drug fenofibrate or placebo, whereas in the Australian ADVANCE trial, patients were randomly assigned to take either perindopril and indapamide (to lower blood pressure) or to receive placebo.
Another example of where the two trials differed was that in the the Australian ADVANCE trial fewer than 20 per cent of patients took thiazolidinediones (a class of drugs used to treat Type 2 diabetes), whereas in the American ACCORD trial, 90 per cent of patients in the intensive therapy group, and 58 per cent in the standard group took the thiazolidinedione drug rosiglitazone (Avandia).
Also, in the Australian ADVANCE trial, only about half the patients were receiving aspirin and statins to control nonglycemic cardiovascular risk, whereas in the American ACCORD trial, at least three quarters of them were.
In both trials the completed follow-up was between 3.5 and 5.0 years. The participants were typical adults with Type 2 diabetes, with an average age of 62 to 66 years, having had diabetes for 8 to 10 years, and a median blood sugar (glycated hemoglobin) level of 7.2 to 8.1 per cent when they started the trial.
On average, patients in the intensive blood sugar control group in the Australian ADVANCE trial met the treatment goal of a mean blood sugar level of 6.5 per cent, but few patients met the more aggressive goal of below 6 per cent in the American ACCORD trial, which had to finish early, as already explained.
According to Dluhy McMahon, writing in the editorial, the most compelling message from both studies is that:
“Near-normal glycemic control for a median of 3.5 to 5 years does not reduce cardiovascular events within that time frame.”
And a particularly “troubling” result from the American ACCORD trial was that:
“Near-normal glucose control (achieved with the use of combination therapy incorporating heavy use of thiazolidinediones, sulfonylureas, metformin, and insulin) is associated with significantly increased risks of death from any cause and death from cardiovascular causes, the very outcomes the trial was designed to prevent.”
However, the Australian ADVANCE trial did confirm predicted reductions in kidney disease outcomes (new-onset microalbuminuria and nephropathy), wrote Dluhy McMahon.
According to the New York Times, diabetes researchers are saying that the message from these trials is that patients should try to get at least moderate control of blood sugar to protect against eye, kidney and nerve disease, but not for protecting against heart disease, for which other measures, like drugs to control cholesterol, reduce blood pressure and reduce risk blood clotting, as well as changes to diet and exercise, are probably more effective and safer.
This is probably at odds with what the Australian investigators claimed about their study, which according to a press release, said that in addition to the reduction in kidney disease risk, they found that the study:
- Showed a 30 per cent reduction in the development of proteinuria, a well established marker of increased cardiovascular risk.
- Achieved a positive trend towards reduction in the risk of cardiovascular death (12 per cent), although not statistically significant.
A doctor told the New York Times that given the age of the patients in the trial, and the fact they had had diabetes for years, the two trials showed how difficult it was to effect changes in people in whom a lot of damage may already have been done. Perhaps a trial on younger patients, newly diagnosed with Type 2 diabetes, would have given a different result.
“Effects of Intensive Glucose Lowering in Type 2 Diabetes.”
The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD)
N Engl J Med 2008 0: NEJMoa0802743
“Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes.”
The ADVANCE Collaborative Group
N Engl J Med 2008 0: NEJMoa0802987
“Intensive Glycemic Control in the ACCORD and ADVANCE Trials.
Dluhy, Robert G., McMahon, Graham T.
N Engl J Med 2008 0: NEJMe0804182
Source:NEJM abstracts and editorial, New York Times, press statements from ACCORD, ADVANCE.
Written by: Catharine Paddock, PhD