Friday, February 29, 2008


In diabetes, there is reduce insulin activity either from insulin deficiency or insulin resistance (example, in metabolic syndrome). This results in too much sugar in the blood stream, but no sugar in the cells that so desperately need the sugar to function, almost reminding us of the poet who said "water water everywhere, but not a drop to drink". Naturally, this understanding gave rise to the notion, that controlling blood sugar saves lives. That is by and large true, in some ways thanks to the seminal work done by Dr Best when he discovered insulin. While insulin injections are life-saving for patients with insulin deficiency they are not so good for patients with insulin resistance.

As diabetes treatment developed further, we soon began to understand that it was a very complicated disease requiring a multi-disciplinary approach. Diabetologist (specialist in diabetes treatment) evolved as a specialty. They soon began to realise that patient with diabetes usually die from cardiovascular complications. Yes, those with hyper or hypo-glemia, can die from a direct sugar problem, but not usually, especially after insulin became available and after Prof Alberti taught us how to manage diabetic coma. I dare say nowadays, diabetic coma is a rarity.

Diabetologist soon began to attend cardiology meetings as it became more and more obvious that diabetes may in fact be a cardiovascular disease, and a CAD equivalent. When we began to hold joint meetings, it became rather obvious that we were speaking slightly different languages. In Sept 1998, diabetologist in UK carried out a very important and very large landmark diabetes study called the UKPDS. At that time, it cost them 2 million pounds. It showed that when blood sugars were controlled, cardiac complications and cardiac death, reduced. This was indeed very important fact to know. Sadly, however, all later diabetic studies rely on blood sugar levels and HbA1c level as their primary endpoint. Cardiologist, on the other hand find this very inadequate, as blood sugar and blood HbA1c level is at best a surrogate endpoint. Blood sugars may be well controlled by the drugs that they study, but what is important for us is, did the better sugar level control resulted in reduction in MACCE? When we ask that, they always reply that that was shown in UKPDS. It is very strange that this very cardinal point of diabetes management rely almost entire in one large clinical study. For example, to establish the important position of "statins " cardiologist undertook no less than 6 large clinical trials, across all three large continents, before we are prepared to accept it as infallible truth.

Now comes the problem. Over the Chinese New Year period, the researchers of the ACCORD study, terminated their study prematurely because their Drug Safety and Data Monitoring Committee reported that their intensive treatment arm, had more cardiac events when compared to the standard treatment arm. The ACCORD study, was undertaken to see if intensive sugar lowering was better than standard levels of control. In technical terms, is lowering HbA1c to less than 6.5% better than lowering HbA1c to 7%. Well, the ACCORD investigators stopped the study early because they noticed that the intensive sugar lowering arm, had more cardiac problems. That was bad news and as clinicians, we became very concern, maybe partly due to the fact that one of the drug used in the study was rosiglitazone. And we all know the controversy with rosiglitazone. Well of course, the problem did not end there.

There is currently an ongoing trial called ADVANCE, undertaken in Australia, looking at the same issue, is intensive lowering of blood sugar better than standard treatment? This study was not due to end, but because of the results from ACCORD, the Drug safety and data monitoring committee decide to take a look at their data, without unblinding, and found that there was no difference in cardiac events, despite almost the same level of blood sugar and HbA1c control. Now, we are really confused. Is it the treatment regimes, the drugs and their doses, the population under study, the level of BP control or is it just chance or bad luck? I really do not know. We await the studies to be completed and the data unblinded, or perhaps other data from other studies. How I wish that someone out there will repeat a UKPDS look alike study (if possible not to use rosiglitazone), to help us be sure that lowering blood sugar does reduce cardiac events. Now we are confused, uncertain of our bearings and our yardstick.

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