Insulin glargine: A systematic review of a long-acting insulin analogue

Background: Insulin glargine is the first long-acting basal insulin analogue indicated for subcutaneous administration once daily at bedtime in adults with type 1 or type 2 diabetes mellitus and pediatric patients aged ≥ 6 years with type 1 diabetes. It differs in structure from native human insulin by 3 amino acids, a structural modification that provides a delayed onset of action and a constant, peakless effect that has a duration of at least 24 hours. Objective: The goal of this article was to help determine the current place in therapy of insulin glargine by reviewing all available efficacy and tolerability data published since its introduction onto the market. Methods: Relevant English-language articles were identified through searches of MEDLINE, PubMed, and EMBASE from 1966 to October 2002 and PREMEDLINE for November 2002. The search terms used were insulin, analogs, analogues, diabetes mellitus, glargine, HOE901, HOE-901, efficacy, safety, comparative study, treatment outcome, and case report. The reference lists of the identified articles were searched for additional relevant publications. Pharmacokinetic and pharmacodynamic data were reviewed and summarized. All large clinical trials (≥ 100 patients) evaluating the efficacy and tolerability of insulin glargine in patients with type 1 or type 2 diabetes were included in the review. Studies were compared in terms of their designs, primary and secondary efficacy parameters (glycosylated hemoglobin [HbA1c], fasting plasma glucose [FPG] and/or fasting blood glucose [FBG] level, incidence of hypoglycemia), and tolerability assessments. Results: Fourteen trials met the criteria for inclusion in this review, 7 of them published only in abstract form. All were multicenter, randomized, open-label, parallel-group trials conducted in Europe or the United States, and ranged in duration from 4 to 52 weeks. They compared insulin glargine with neutral protamine Hagedorn (NPH) insulin given once or twice daily in >5000 patients with type 1 or type 2 diabetes, or in insulin-naive patients with type 2 diabetes that was poorly controlled by oral antidiabetic agents. Insulin doses were individually titrated to achieve a target FBG level ≤120 mg/dL (6.7 mmol/L). The studies were typically statistically underpowered to detect a significant difference in HbA1c between treatment groups; only 3 trials were of an adequate size to have 90% statistical power to detect a mean 0.5% difference in HbA1c. Furthermore, analysis of the data from these trials was associated with a number of methodologic problems relating to inconsistencies in reporting. Given these limitations, the available data suggest that insulin glargine treatment produces statistically significant reductions in FPG or FBG levels at end point both compared with baseline and compared with NPH insulin (P < 0.001) without achieving overall significant improvements in HbA1c values. However, a recent abstract of a small 52-week trial in patients with type 1 diabetes reported a 0.4% additional decrease in HbA1c with insulin glargine treatment compared with NPH insulin. Patients have reported greater treatment satisfaction with insulin glargine compared with NPH insulin. The findings varied regarding weight gain, overall incidence of hypoglycemia, and incidence of nocturnal hypoglycemia. Currently, the cost of insulin glargine is twice that of NPH insulin on a per-unit basis. Conclusions: As a basal insulin replacement, insulin glargine administered once daily demonstrates a steady time-action profile over 24 hours without a pronounced peak. Based on the evidence from published clinical trials, insulin glargine appears to have equal clinical efficacy to NPH insulin, produces similar reductions in HbA1c, and is associated with lower FPG and FBG levels and a consistent and significant reduction in the incidence of nocturnal hypoglycemia in patients with type 2 diabetes.