Systematic review: comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes

Abstract

Background: Evidence comparing premixed insulin analogues (a mixture of rapid-acting and intermediate-acting insulin analogues) with other antidiabetic agents is urgently required to guide appropriate therapy.

Purpose: To summarize the English-language literature on the effectiveness and safety of premixed insulin analogues compared with other antidiabetic agents in adults with type 2 diabetes.

Data sources: The authors searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to February 2008 and sought unpublished data from the U.S. Food and Drug Administration, European Medicines Agency, and industry.

Study selection: Studies with control groups that compared premixed insulin analogues with another antidiabetic medication in adults with type 2 diabetes.

Data extraction: 2 reviewers using standardized protocols performed serial abstraction.

Data synthesis: Evidence from clinical trials was inconclusive for clinical outcomes, such as mortality. Therefore, the review focused on intermediate outcomes. Premixed insulin analogues were similar to premixed human insulin in decreasing fasting glucose levels, hemoglobin A(1c) levels, and the incidence of hypoglycemia but were more effective in decreasing postprandial glucose levels (mean difference, -1.1 mmol/L; 95% CI, -1.4 to -0.7 mmol/L [-19.2 mg/dL; 95% CI, -25.9 to -12.5 mg/dL]). Compared with long-acting insulin analogues, premixed insulin analogues were superior in decreasing postprandial glucose levels (mean difference, -1.5 mmol/L; CI, -1.9 to -1.2 mmol/L [-27.9 mg/dL; CI, -34.3 to -21.5 mg/dL]) and hemoglobin A(1c) levels (mean difference, -0.39% [CI, -0.50% to -0.28%]) but were inferior in decreasing fasting glucose levels (mean difference, 0.7 mmol/L; CI, 0.3 to 1.0 mmol/L [12.0 mg/dL; CI, 6.0 to 18.1 mg/dL]) and were associated with a higher incidence of hypoglycemia. Compared with noninsulin antidiabetic agents, premixed insulin analogues were more effective in decreasing fasting glucose levels (mean difference, -1.1 mmol/L; CI, -1.7 to -0.6 mmol/L [-20.5 mg/dL; CI, -29.9 to -11.2 mg/dL]), postprandial glucose levels (mean difference, -2.1 mmol/L; CI, -3.4 to -0.8 mmol/L [-37.4 mg/dL; CI, -61.0 to -13.7 mg/dL]), and hemoglobin A(1c) levels (mean difference, -0.49% [CI, -0.86% to -0.12%]) but were associated with a higher incidence of hypoglycemia.

Limitations: The literature search was restricted to studies published in English. Data on clinical outcomes were limited. The small number of studies for each comparison limited assessment of between-study heterogeneity.

Conclusion: Premixed insulin analogues provide glycemic control similar to that of premixed human insulin and may provide tighter glycemic control than long-acting insulin analogues and noninsulin antidiabetic agents.

Figure 1. Weighted mean difference of change in fasting glucose comparing premixed insulin analogues with other antidiabetic medications

Footnote: error bars represent 95% confidence intervals. * pooled results include a study by Jacober et al (43) that administered insulin lispro 50/50 in the morning and afternoon and insulin lispro 75/25 in the evening. † Nauck et al (21) excluded.

Figure 2. Weighted mean difference of change in postprandial glucose comparing premixed insulin analogues with other antidiabetic medications

Footnote: Error bars represent 95% confidence intervals. * pooled results include a study by Jacober et al (43) that administered insulin lispro 50/50 in the morning and afternoon and insulin lispro 75/25 in the evening. † Nauck et al (21) excluded. ‡ pooled results include a study by Roach et al (55) that administered insulin lispro 50/50 in the morning and insulin lispro 75/25 in the evening.

Figure 3. Weighted mean difference of change in hemoglobin A1c comparing premixed insulin analogues with other antidiabetic medications

Footnote: Error bars represent 95% confidence intervals. * pooled results include a study by Jacober et al (43) that administered insulin lispro 50/50 in the morning and afternoon and insulin lispro 75/25 in the evening. † Nauck et al (21) excluded. ‡ pooled results include a study by Roach et al (55) that administered insulin lispro 50/50 in the morning and insulin lispro 75/25 in the evening.

Figure 4. Incidence of unclassified hypoglycemia, serious hypoglycemia, mild hypoglycemia, and symptom-only hypoglycemia with premixed insulin analogues as compared to other antidiabetic medications

Footnote: Error bars represent 95% confidence intervals.

Figure 5. Incidence of clinical outcomes with premixed insulin analogues as compared to other antidiabetic medications

Footnote: Error bars represent 95% confidence intervals. * Combined outcome include all-cause mortality, and cardiovascular morbidity