Forty-two studies, and an additional four extension studies of trials already included were included (n=19,005), of which 27 were in type 1 diabetes and 15 in type 2 diabetes. Of the type 1 diabetes studies, eleven (plus two extension studies) investigated rapid-acting analogues (n=6,412), thirteen (plus one extension study) investigated basal analogues (n=5,093) and three investigated all analogue versus all human regimens (n=679). Of the type 2 diabetes studies, four (plus one extension study) investigated premix insulin analogues (n=864), seven investigated basal analogues (n=3,916) and four investigated basal-bolus therapy (n=2,041).
Type 1 diabetes.
When investigating rapid-acting insulin analogues compared with human insulin, the reduction in HbA1c was greater with insulin aspart in most trials (HbA1c lower by 0.12 to 0.16% in favour of aspart; significant for two of the three trials, as well as two extension studies), significant in one of seven trials of insulin lispro (lower by 0.2%, 12 months), and significant for one study of insulin glulisine ( 0.13%, 12 months). The majority of studies of insulin aspart or insulin lispro reported significantly lower rates of nocturnal hypoglycaemia with the analogues compared with human insulin, and some also reported lower rates of overall hypoglycaemia for insulin lispro. In most studies, significantly lower values of PPG levels were seen with insulin analogues than with human insulin.
For basal-bolus therapy using insulin detemir or insulin glargine (where doses were titrated to achieve glycaemic targets), no differences in HbA1c values were seen between the insulin analogue and NPH insulin (13 trials). Most phase III trials of glargine or detemir found significant reductions in hypoglycaemia, particularly nocturnal hypoglycaemia, for insulin analogues compared with NPH. Some of the trials of insulin detemir reported reduced within-person variability of FBG compared with NPH. Patients consistently showed less weight gain with insulin detemir than with NPH, and also with glargine in the one study where this outcome was measured.
Comparing all analogue with all human insulin regimens (three trials), a significantly larger decrease in HbA1c was seen in two of the three trials identified with the analogue regimens. Nocturnal hypoglycaemia was significantly lower with insulin glargine/insulin lispro than with NPH/human insulin and, overall, minor and nocturnal hypoglycaemia were significantly reduced with insulin detemir/insulin aspart compared with NPH/human insulin. PPG was significantly lower with the analogue regimens. With insulin detemir/insulin aspart, both within-person variation in blood glucose and weight gain were significantly less than with NPH/human insulin.
Type 2 diabetes.
For patients with type 2 diabetes, treatment with premix insulin analogues generally showed similar results in terms of HbA1c and hypoglycaemia compared with biphasic human insulin (four trials). PPG levels were significantly lower with the premix analogues.
For basal therapy used once or twice daily (seven trials), results for HbA1c were similar when comparing insulin glargine or insulin detemir with NPH insulin, but three trials showed significantly lower rates of hypoglycaemia with the analogues, two trials showed significantly lower PPG, and two trials showed less weight gain.
Four trials comparing rapid-acting analogues with human insulin in basal-bolus regimens gave mixed results with respect to HbA1c and hypoglycaemia, but PPG was significantly lower with the rapid-acting analogues. Two trials studied basal analogues in basal-bolus therapy. One study compared insulin detemir with NPH, with both groups using insulin aspart, and found no differences in HbA1c, FBG or hypoglycaemia. The other study compared insulin detemir plus insulin aspart with NPH plus human insulin and found that nocturnal hypoglycaemia, weight gain and within-person variation of self-monitored glucose levels were significantly lower with the all-analogue regimen.