NPC Archive Item: Better HbA1c control with biphasic or prandial insulin than basal insulin in type 2 diabetes, but more weight gain and hypoglycaemia

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Holman R et al. Addition of biphasic, prandial or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007; 357. Published on line on September 21st 2007. (the 4T study)

What is this about?
The New England Journal of Medicine has published the 1 year results of a 3 year study into the comparative effects of 3 different insulin regimens in people with type 2 diabetes – the 4T study. We should first remember that type 1 and type 2 diabetes are very different diseases – if patients with type 1 do not receive insulin quickly, they suffer serious consequences. However, in type 2 diabetes while we know that tight control of blood glucose is important in controlling symptoms, evidence suggests that the benefits obtained by patients in doing this may not necessarily result in reductions in patient-oriented outcomes such as heart attacks or strokes, nor indeed important diabetes-related endpoints such as blindness or renal failure. This study, therefore, in some ways asks the wrong question. Nevertheless, for those with type 2 diabetes who require insulin to control their symptoms or who choose to try and control their blood glucose more tightly using insulin, this study is worth looking at.

What does this study claim?
In people with type 2 diabetes with suboptimal glycaemic control, treatment with biphasic insulin aspart or prandial insulin aspart were more effective in reducing glycated haemoglobin (HbA1c) to target when added to oral therapy than was basal detemir added to oral therapy. However, biphasic or prandial aspart caused more hypoglycaemia and weight gain (for more on the types of insulin used, see below)

How does this relate to other studies?
Although control of blood glucose is important for control of symptoms, the UKPDS study showed that in type 2 diabetes tight control of blood glucose with insulin or sulphonylureas does not reduce the risk of macrovascular complications (heart attacks, strokes, etc) or most serious microvascular complications (such as kidney failure, blindness, etc). This is explored more fully on the Type 2 Diabetes section of NPC. Rapid acting insulin analogues have been promoted as offering improved metabolic control and a reduced incidence of hypoglycaemic episodes compared to soluble insulins. However, most data come from patients with type 1 diabetes – as we said earlier, a very different disease. Even so, a recent Cochrane systematic review concluded that, compared with conventional short-acting insulin they only have minor benefits in the majority of people with type 1 diabetes. This is explored more on the Type 1 Diabetes section of NPC.

So what?
This study is helpful as far as it goes but perhaps asks the wrong question: biphasic or prandial inulin analogues achieved better glycaemic control than basal long-acting insulin analogues, although the clinical significance of this is not clear. However, this was at the expense of greater weight gain and more, severe hypoglycaemic episodes. Importantly, what it does not tell us if any of the regimens was better at reducing major macrovascular or microvascular events. Nor does it compare these newer, more expensive insulin analogues with conventional insulins

A more important question to answer would be ‘does using insulin in people whose HbA1c is not controlled make them live longer or better than those in whom we try and minimise their cardiovascular risk, but who remain on metformin alone as an antihypoglycaemic agent?

Continue to manage patients with type 2 diabetes according to the ‘diabetes hand’ . As the accompanying editorial acknowledges, we should ensure that people with type 2 diabetes don’t smoke, have their blood pressure controlled, take an evidence-based dose of cost-effective statin (usually simvastatin 40 mg) and take aspirin once their blood pressure is within reasonable bounds. These measures will have more effect on macrovascular and microvascular events than controlling glycaemia alone (see the Type 2 Diabetes section of NPC).

Rather than being regarded as ‘inevitable’, use of insulin should be for those who are aware of the risks and benefits of tight blood glucose control or who continue to have symptoms of hyperglycaemia regardless of using metformin (or other oral hypoglycamics). Choice of insulin regimen should be led by patient choice and convenience.

What were the details of the study?
This is a report from the first year of a three-year open, randomised, controlled trial of three insulin regimens.

708 patients (mean age 61.7 years) with type 2 diabetes (mean duration 9 years) had HbA1c of 7.0 to 10% (mean 8.5%), despite maximum tolerated doses of sulfonylurea.

Intervention and comparison:
Subjects were randomised to the three insulin regimens mentioned above: biphasic insulin aspart twice a day, prandial insulin aspart three times a day before meals, or insulin detemir once or twice a day.

The primary outcome was glycated haemoglobin (HbA1c ) at 52 weeks. Secondary outcomes included the proportion of patients with a HbA1c of 6.5% or less as well as rates of hypoglycaemia and weight gain.

Results – benefits:
• The reduction in HbA1c from baseline was 1.3% in the biphasic group, 1.4% in the prandial group and 0.8% in the basal group.
• The difference in mean HbA1c levels in the biphasic and prandial groups (7.3% and 7.2%) were not significantly different from each other, but both were significantly lower than the basal group 7.6%, P<0.0001).
• The proportion of patients achieving HbA1c of 6.5% or less were not significantly different in the biphasic and prandial groups (17.0% and 23.9%) but much more than the basal group (8.1%, P=0.001)
• However, if patients baseline HbA1c was 8.5% or less, there was no significant difference in the likelihood of them achieving values of 6.5% or less.
Results – harms:
• Patients using basal insulin gained less weight than those in the biphasic or prandial insulin groups (1.9 kg vs 4.7 kg and 5.7 kg, P<0.001).
• The weight gain was significantly higher in the prandial group than the biphasic group (P=0.005).
• Patients in the basal group were significantly less likely to experience more severe hypoglycaemia than those in the biphasic or prandial groups (median: 0, 3.9 and 8.0 events per patient per year).

The study was sponsored by NovoNordisk, who manufacture all the insulins used

Background on insulin types:
Insulin aspart is a rapid-acting analogue( like insulin lispro), which can be injected immediately before or straight after a meal (prandial administration). This is because they act much faster than conventional soluble insulin, and their effects don’t last as long as the conventional soluble short-acting insulins. They can also be combined with intermediate-acting insulin (this combination is known as a biphasic insulin) for administration twice a day. Long acting insulin analogues such as detemir and glargine act for 20 – 24 hours. These insulin analogues are more expensive than conventional insulins and advantages over them are limited – see the Type 1 Diabetes section of NPC for more information: for example, the Data Focused Commentary, which also looks at prescribing data from England and Wales