TRIALS IN DIABETES PATIENTS

Van den Berghe trial
Van den Berghe’s first study used an intensive regimen of insulin treatment (IIT) with the aim of keeping blood glucose concentrations at or below 6.1 mmol/litre (110 mg/dl).

A criticism of the study was that the patients were largely post-cardiac surgery.

Subsequent studies conducted by others have not shown a mortality benefit and some had safety issues associated with IIT.

However, the practice of IIT still continues in most ICUs and a similar approach to the intra- and postoperative management of patients has been gaining momentum.

Van den Berghe’s study in critically ill patients
The use of intensive insulin therapy to maintain blood glucose at a level that did not exceed 110 mg/dl reduced mortality in the intensive care unit, in-hospital mortality, and morbidity among critically ill patients.

IIT reduced the number of deaths from multiple-organ failure with sepsis, regardless of whether there was a history of diabetes or hyperglycemia.

According to Van den Berghe and colleagues IIT confers a mortality benefit when controlling blood glucose concentrations to normoglycaemia [below 6.1 mmol/ litre (110 mg/ dl )] but agree on the need for more trials.

SepNet trial
In the SepNet trial the use of IIT was in patients severe sepsis with in ICUs, since it had been argued that most of the mortality reported in Van den Berghe’s 2001 paper had been in such patients.

But the trial was stopped early on safety grounds as the use of IIT placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycaemia. Serious hypoglycaemia was roughly four times more common in the patients given IIT.

NICE-SUGAR Trial
In April 2009, the NICE-SUGAR study was published.

The NICE-SUGAR study recruited 6104 patients from 42 hospitals in Australia, New Zealand, and Canada.

The groups of patients were assigned target blood glucose levels of either 4.5–6.0 mmol /litre (IIT) or 8.0–10.0 mmol/ litre (conventional glucose control) and the main outcome measure was 90 day mortality.

More patients in the IIT group died than in the conventional control group (27.5% vs 24.9%).

The causes of death in the two groups were similar,although deaths from cardiovascular causes were more common in the IIT group (41.6% vs 35.8%).

Severe hypoglycaemia (defined as blood glucose of 2.2 mmol/litre ) occurred in 6.8% of the IIT patients compared with only 0.5% of the conventional control patients and there were no long-term sequelae in any patient.

ACCORD study
Another important study published in 2008 was the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.

This was a randomized trial of IIT in 10,251 patients with type 2 diabetes who had a median glycosylated haemoglobin level of 8.1%.

Patients were assigned to receive IIT (target glycosylated haemoglobin level 6.0%) or standard therapy (target 7.0–7.9%).

The primary outcome measure was a composite of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes.

The patients were followed for 3.5 years but the trial was prematurely halted due to excess mortality in the IIT group (257 deaths compared with 203 deaths in the standard therapy group).

Also, severe hypoglycaemia requiring intervention and weight gain of more than 10 kg were more common in the IIT group.

DIGAMI study
People with diabetes who suffer an acute myocardial infarction are at increased risk of future cardiovascular morbidity and mortality.

The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial evaluated the influence of intensive insulin therapy on morbidity and mortality of diabetic patients with MI.

The results indicated that intense, insulin-based glucose management via insulin-glucose infusion in the first 24 hours following MI was successful in reducing 1-year mortality by 30% and 11% by the 3.4-year follow-up.

It compared "conventional" anti-diabetic therapy to intensive insulin therapy consisting of acute insulin infusion during the early hours of MI and thrice-daily subcutaneous insulin injection for the remainder of the hospital stay and a minimum of 3 months thereafter.

Although there was an overall reduction in adverse outcomes and mortality in patients receiving the intensive insulin regimen, it is unclear which component (the IV insulin infusion or the intensive chronic therapy) was responsible.

DIGAMI 2 study
Patients with type 2 diabetes have increased risk for cardiovascular events and mortality.

This group accounts for more than 20% of individuals admitted for suspected myocardial infarction and has a higher risk of death after MI.

The current study (DIGAMI 2) is a follow-up of DIGAMI.

The study design of DIGAMI 2 was similar to that of DIGAMI in that patients (1,253) with diabetes were randomized to three groups:
1) Acute insulin-glucose infusion followed by long-term, insulin-based, glucose control;
2) Insulin-glucose infusion followed by standard non–insulin-based glucose control; or
3)Routine metabolic management according to local practice. The primary endpoint was all-cause mortality between groups 1 and 2 according to intention-to-treat analysis. Mortality and morbidity differences between groups 2 and 3 served as secondary and tertiary endpoints, respectively.

Results- 1) There were no significant differences in mortality between the groups in DIGAMI 2
2) There were no statistical differences in terms of stroke or second MI
3) All the study groups showed an overall mortality of 18.4%, lower than the expected 22.

Conclusion- Cardiovascular outcomes similar to those seen in individuals without diabetes.

Glucose levels were confirmed as a strong independent predictor of mortality following acute MI, suggesting that patients with diabetes should be treated as intensively as possible.

In 2007, one of the largest randomized trials reported the effect of IIT in adults with and without diabetes who were undergoing on-pump cardiac surgery.

The primary outcome measure was a composite of death, sternal infections, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure, within 30 days of surgery.

Patients received either continuous insulin infusion to maintain intraoperative glucose levels between 4.4 and 5.6 mmol /litre (80–100 mg /dl ) or conventional treatment, where patients were not given insulin during surgery unless glucose levels were .11.1 mmol/ litre (200 mg /dl ). Both groups were treated with an insulin infusion to maintain normoglycaemia after surgery.

Adverse events occurred in 82 of 185 patients (44%) in the IIT group and 86 of 186 patients (46%) in the conventional treatment group. There were more deaths in the IIT group (4 vs 0, P¼0.061) and strokes (8 vs 1, P¼0.02) than in the conventional treatment group.

The authors concluded that IIT during cardiac surgery did not reduce the perioperative death or morbidity rates.

The DIGAMI-2 study of 1253 type 2 diabetic patients who had a myocardial infarction failed to show that acutely introduced, followed by subsequent long-term, IIT, improved survival compared with conventional management, or that IIT decreased the number of non-fatal myocardial re-infarctions and strokes.

Cardiac function is highly dependent on the myocardial energy source which is affected by substrate availability and concentrations of metabolic hormones such as insulin. Under normal circumstances, most of the energy needs of a healthy heart come from fatty acid oxidation.

Glucose–insulin–potassium administration has been suggested to prevent hyperglycaemia and hyperlipidaemia during reperfusion after cardiac interventions and was also thought to reduce inflammatory responses.

However, in patients undergoing CABG, high-dose insulin administration with a glucose infusion to maintain blood glucose levels within a target range of 4.0–5.5 mmol litre , fatty acid concentrations decreased to very low levels.

The only proposed mechanism which has received any attention is that of glucose toxicity in the context of ischaemia–reperfusion.

Glucose is transported into cells by several transporter systems called glucose transporters or GLUT but only GLUT4 is insulin dependent.

Van den Berghe has suggested that excess glucose is toxic to cells, particularly mitochondria, and that this occurs in cells that take up glucose in proportion to the circulating glucose concentration, independently of insulin.

This may be related to GLUT4 transport in specific cells allowing glucose to be safely used as a fuel or converted to a storage medium rather than in other cells, where more potentially toxic pathways are utilized.

In effect, exogenously administered insulin is decreasing circulating glucose and thus making less available for the glucose transporters that are concentration-dependent.

It is therefore argued that it is the excess glucose that is toxic and the insulin merely acts to lower the circulating concentrations of glucose.

- by Dr Amarja