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Kendrick asks...could aggressive blood glucose lowering be harmful?

To kick off his new fortnightly clinical column, Dr Malcolm Kendrick asks whether the orthodox view in diabetes – the more aggressive the treatment the better – could be doing more harm than good

To kick off his new fortnightly clinical column, Dr Malcolm Kendrick asks whether the orthodox view in diabetes – the more aggressive the treatment the better – could be doing more harm than good

As part of an article I wrote a couple of years ago, I asked: ‘Can lowering a biochemical measurement – in this case blood sugar – actually cure a disease?'

This still seems to me to be a strange form of thinking. Surely the ‘disease' in type 2 diabetes is the underlying abnormality – whatever it is – that causes the blood sugar to be high in the first place. Cure the abnormality and the blood sugar will fall. On the other hand, forcing the blood sugar lower seems highly unlikely to cure the underlying abnormality – unless by some miraculous coincidence your treatment cures both the biochemical sign and the underlying abnormality at the same time.

To put it more simply, is a raised blood sugar actually dangerous and damaging? Or is it just a ‘marker' for an underlying biochemical abnormality?

To suggest this flies in the face of current medical orthodoxy. Almost everyone is certain that it is the raised blood sugar itself that is damaging.

It's an idea that certainly has a long history. Two thousand years ago the Romans recognised the condition we call type 1 diabetes and noted that the urine of those who died smelled sweet. I am not sure if they blamed the sugar for the death, but an association between sugar and death had formed very early on.

More recently, when Banting and Best injected insulin into their experimental dog, the blood sugar level fell and the dog recovered.

Moving on, we now know that in type 1 diabetes, the tighter the blood sugar control, the better the outcomes are. And epidemiological evidence has confirmed that a raised blood sugar is strongly associated with increased morbidity and mortality in type 2 diabetes.

Given this, nobody could possibly argue against the very powerful connection between raised blood sugar and morbidity and mortality. But is it truly a causal association?

For most people this is a non-question. Raised blood sugar is the undisputed villain.

But I would suggest there is another possibility. All of the other substances in the blood that are also ‘abnormal' in type 2 diabetes are not merely innocent bystanders. They may be the very factors that cause the damage. Which means that our obsession with lowering blood sugar levels could be completely misplaced.

For example, whenever we have insulin resistance – in type 2 diabetes or the metabolic syndrome – we also have raised blood clotting factors such as plasminogen activation inhibitor – 1, fibrinogen and Von Willebrand factor. Any of these increases the likelihood of clot formation and infarction.

In addition to this, you'll find raised free fatty acids (FFAs) and inflammatory cytokines – which have been clearly shown to damage the vascular system.

In fact, diabetes researchers believe insulin resistance, FFAs and inflammatory cytokines released from adipocytes appear more important than hyperglycaemia in causing chronic endothelial atherogenesis and thrombus formation. This may explain why insulin resistance is associated with complications, especially MI, in patients who are still normoglycaemic.1

Perhaps most importantly, in an insulin-resistant state, we have chronically raised insulin levels. Although insulin is a vital hormone, there is a strong possibility that high concentrations may be damaging. Indeed, the warning signs have been out there for a long time. Here is some data from a Scottish study looking at use of metformin and sulphonylureas:

‘Patients in the sulphonylureas-only cohort had increased risks of mortality and cardiovascular mortality, with unadjusted relative risks of 3.12 and 3.71 respectively.'2

And this is just one of a number of studies that strongly suggest drugs that force the ß-cells to produce more insulin may do more harm than good.

But metformin, which improves insulin sensitivity, and thus reduces insulin levels, may be far more beneficial.

The idea that raised insulin levels may in themselves be dangerous is supported by recent research:

‘The hyperinsulinaemia hypothesis suggests that elevated levels of insulin and free insulin growth factor 1 promote proliferation of colon cells and lead to a survival benefit of transformed cells, ultimately resulting in colorectal cancer.

In patients with type 2 diabetes, studies show an increased risk for colorectal cancer and an even higher risk if patients are treated with sulphonylureas or insulin. Moreover, tumour progression at hyperinsulinaemia is more rapid and tumour-associated mortality is increased.'3

Also: ‘Chronic insulin therapy significantly increases the risk of colorectal cancer among type 2 diabetes patients.'4

Insulin is a growth factor – and a powerful growth factor for tumour cells.

As most of the strategies for lowering blood sugar in type 2 diabetes involve increasing insulin levels in the blood to overcome resistance, this raises the possibility that intense blood sugar lowering, rather than doing good, could be associated with significant morbidity and mortality.

Which brings us to ACCORD – the Action to Control Cardiovascular Risk in Diabetes study. This was a trial that involved using a combination of agents to aggressively reduce HbA1c to levels of less than 6%.

The conclusions were: ‘Compared with standard therapy, the use of intensive therapy to target normal glycated haemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognised harm of intensive glucose lowering in high-risk patients with type 2 diabetes.'5

If you believe that raised blood sugar truly is the villain of the piece, this study does not appear to make sense. But this result fits perfectly if you favour an alternative hypothesis – that raised blood sugar may merely be a marker for an underlying disease and that other factors such as high insulin levels or inflammatory cytokines may, in fact, be the abnormalities causing the damage.

The simple fact is that ACCORD provides strong evidence that aggressively lowering blood sugar levels may cause more harm than good. So far, everyone has searched desperately to find other reasons for this finding, but it is the only explanation that makes sense.

Dr Malcolm Kendrick is a GP in south Manchester

The glucose test

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