Accord or Discord? Advance or Retreat?21 Jan 2009

An article from our November newsletter

Does lowering blood sugar in Type 2 Diabetes reduce complications?

Of course, it does; everyone knows that.  Well they don't actually.  Not as far as macrovascular complications is concerned.

It's an important question that is no nearer to an answer now than it ever was.

Way back in the dawn of history – in the mid-1980's, it is fair to say that everyone thought that improving glycæmic control helped to prevent complications but that no-one had really offered concrete proof.

Then the question seemed to have been answered by the Diabetes Control and Complications Trial (DCCT) which showed large drops in complications in the more tightly controlled patients.

Ah, but there were two snags.  Firstly the trial had only looked at microvascular complications (retinopathy, nephropathy and neuropathy) and secondly, the Trial was on people with Type 1 diabetes.  The concept of insulin resistance was still in its infancy and many said that the same conclusions must apply to Type 2 diabetes.  Gradually it dawned on experts that Type 2 was not the same as Type 1 diabetes.  It was a totally different disease process that was involved and it was not logical to extrapolate the conclusions.

Let's wait for the United Kingdom Prospective Diabetes Study on complications in Type 2 diabetes.  That will tell us and to a certain extent it did.  The tighter controlled group did have fewer complications than the other group.  In fact the main messages from the trial were that metformin was comparatively good at preventing complications and that controlling blood pressure was very good at preventing heart attacks and strokes.

So the researchers had another try and in the ACCORD and ADVANCE trials concentrated solely on lowering blood sugar levels.

Rarely have two such major trials gone off like two damp squibs.  If you want to hear a groan, just mention the two words ACCORD and ADVANCE at a large conference.

There was sensation when it was learned that the ACCORD Trial had been stopped early when the tight-control group suffered a higher rate of cardiovascular events.  The ADVANCE Trial ran its course.

There has been a lot of hot air generated about why the increase in CVD occurred and why the increase was found in one Trial but not the other.  Opinion seems to be that both Trials were looking for the "quick fix" and that although both trials were large, neither ran for long enough to give a meaningful result.  In particular, there was too much hurry in reducing high blood sugar levels.  Hypoglycæmia itself is dangerous.

But the hot air turned out to be fog which obscured the main issue.  Irrespective of what happened or did not happen with the terminating of trials, the plain fact is that neither trial demonstrated that lowering glycæmia levels in Type 2 Diabetes reduces the risk of developing macrovascular disease.

Macrovascular disease does seem to be different from microvascular disease.  It has been shown time and again that reducing blood sugar levels does reduce microvascular complications.  That alone is sufficient reason for striving for good glycæmic control in our patients.  But it may well be that, as far as reducing macrovascular disease, control of blood pressure and lipids is more important.

Fascinating world we live in isn't it?

• The Diabetes Control and Complications Group, Effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes Mellitus.  N Engl J Med, 1993; 329: 977-986. (DCCT)
• United Kingdom Prospective Diabetes Study Group, Intensive blood glucose control compared with conventional treatment and the risk of complications in patients with type 2 diabetes.  Lancet, 1998; 352: 837-853, 854-865. (UKPDS)
• The ADVANCE Collaborative Group, 2008 Intensive Blood Glucose Control and Vacular Outcomes in Patients with Type 2 Diabetes, NEJM 358 2560-2572
• The ACCORD Study Group 2008 Effects of Intensive Glucose Lowering in Type 2 Diabetes NEJM 358 2545-2559