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Insulin Glargine Treatment Does Not Improve Glycaemic Control Compared To Neutral Protamine Hagedorn In Patients With Diabetes

Insulin glargine is the first long-acting insulin analogue to be produced by recombinant DNA technology using E. coli plasmid DNA. It is administered as a once-daily treatment for adult and paediatric patients with type 1 diabetes and adults with type 2 diabetes.

The structure of insulin glargine differs from that of native human insulin by 3 amino acids. This alteration leads to a delay in absorption, prolonging the duration of effect and providing a fairly constant basal insulin supply.

To assess the current place in therapy for insulin glargine treatment, Fei Wang, MSc, PharmD, BCPS, with the University of Connecticut School of Pharmacy, United States, and colleagues have reviewed all available efficacy and tolerability data published since its introduction onto the market in 2000.

The review included 14 multi-centre, open-label, randomised trials (more than 100 patients for each) performed in Europe or the United States. These phase II and III studies evaluated insulin glargine treatment compared with neutral protamine Hagedorn (NPH) insulin (the most widely used insulin for basal insulin replacement) given once or twice daily in more than 5000 patients with type 1 or type 2 diabetes, or in combination with oral antidiabetic agents in insulin-naïve patients with type 2 diabetes.

The studies ranged in duration from 4 to 52 weeks. In studies longer than 4 weeks, the primary efficacy variable was improved glycaemic control, assessed as mean change in glycosylated haemoglobin (HbA1c) from baseline to end point. Secondary efficacy variables were fasting plasma glucose (FPG) and/or self-monitored fasting blood glucose (FBG) levels and the incidence of hypoglycaemia. Insulin doses were individually titrated to achieve a target fasting blood glucose level of less than 120 mg/dL.

According to the reviewers, the individual studies were typically statistically underpowered, and only 3 trials included a power analysis and had 90% statistical power to detect a mean 0.5% difference in HbA1c between the treatment groups. Given this statistical weakness, they suggest that insulin glargine does not achieve overall significant improvements in HbA1c values compared with baseline and NPH insulin, although significant reductions were detected in FPG or FBG.

One 52 week trial conducted in Europe revealed an additional 0.4% reduction in HbA1c with once-daily bedtime insulin glargine compared with NPH insulin 4 times daily in patients with type 1 diabetes, but "larger studies with adequate statistical power are required to test this finding."

Additional effects associated with insulin glargine treatment included reduction in nocturnal hypoglycaemia and greater treatment satisfaction reported from the patients. Disadvantages such as increased cost of treatment, increased pain at the injection site, and the inability to mix it with other insulin products were also reported.

The reviewers conclude that, "until insulin glargine is clearly shown to have improved clinical efficacy compared with NPH insulin, its use should be limited to patients with type 1 or type 2 diabetes taking multiple daily injections of basal/bolus regimens who have not achieved optimal glycaemic control with NPH insulin or who have episodes of symptomatic hypoglycaemia."

For insulin-naïve patients with type 2 diabetes taking oral antidiabetic agents, they recommend that this treatment "should be reserved for those who continue to have elevated morning blood glucose levels and episodes of nocturnal hypoglycaemia while taking a combination of oral agents or a combination of bedtime NPH insulin with oral antidiabetic agents."
Clin Ther 2003 Jun;25:6:1541-77, discussion 1539-40. "Insulin glargine: A systematic review of a long-acting insulin analogue"

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