Efficacy and Safety of Rapid-Acting Insulin Analogs in Special Populations with Type 1 Diabetes or Gestational Diabetes: Systematic Review and Meta-Analysis

Abstract

Introduction: To assess the efficacy and safety of three available rapid-acting insulin analogs (insulins lispro, aspart and glulisine, respectively) in pregnant women, children/adolescents and people using continuous subcutaneous insulin infusion (CSII) with type 1 diabetes.

Methods: PubMed, EMBASE and Cochrane Reviews were searched electronically, and their bibliographies examined to identify suitable studies for review and inclusion in a meta-analysis. Eligible studies were randomized controlled trials that reported data on relevant clinical outcomes. A different reviewer abstracted data for each of the three subpopulations, and one reviewer abstracted data for all three. Any differences were resolved by consensus or by consulting a fourth reviewer.

Results: In people on CSII, rapid-acting insulin analogs lowered postprandial plasma glucose post-breakfast to a greater extent than did regular human insulin (RHI) (mean difference: - 1.63 mmol/L [95% confidence interval - 1.71; - 1.54]), with a comparable risk of hypoglycemia and a trend for lower glycated hemoglobin. In the pediatric population, glycemic control was similar with rapid-acting insulin analogs and RHI, with no safety concerns. Meta-analysis indicated severe hypoglycemic events were comparable for rapid-acting insulin analogs versus RHI (risk difference: 0.00 [95% confidence interval - 0.01; 0.01]). In the pregnancy group, insulin lispro and insulin aspart were safe and effective for both mother and fetus, with glycemic control being at least as good as with RHI. There were no data on insulin glulisine during pregnancy.

Conclusion: Rapid-acting insulin analogs appear generally safe and effective in these special populations; however, additional trials would be helpful.

Funding: Novo Nordisk A/S.

Keywords: CSII; Pediatrics; Pregnancy; Rapid-acting insulin analogs; Type 1 diabetes.

Fig. 1

Flow diagram showing the number of retrieved, excluded and included records. The dagger (†) indicates that the continuous subcutaneous insulin infusion (CSII) group included two pediatric CSII studies. The asterisk (*) indicates that in the CSII meta-analyses, the number of studies included varied depending on the outcome assessed. MDI Multiple daily injections, PD pharmacodynamics, PK pharmacokinetics, RCT randomized controlled trial

Fig. 2

Meta-analyses of key outcomes. a Forest plot showing the difference in risk of severe hypoglycemic episodes with insulin analog treatment compared to regular human insulin (RHI) in a pediatric population. b Forest plot showing the difference in the mean fasting blood glucose level with insulin analog treatment compared to RHI treatment in the CSII sub-review. c Forest plot showing the difference in mean postprandial blood glucose (BG) level with insulin analog treatment compared to RHI treatment in the CSII sub-review. d Forest plot showing the difference in risk of severe hypoglycemic episodes with insulin analog treatment compared to RHI treatment in the CSII sub-review. e Forest plot showing the mean difference in the rate of any hypoglycemic episodes with insulin analog treatment compared to RHI treatment in the CSII sub-review. f Forest plot showing the difference in glycated hemogloblin (HbA1c) with insulin analog treatment (lispro or aspart) compared to RHI in the CSII sub-review. Squares and diamonds represent the difference in HbA1c after intervention with the two treatments for each study (horizontal lines are 95% CI) and for all the studies combined, respectively. The I² value refers to the statistical heterogeneity for the pooled analysis. A random-effects model using generic inverse variance showed a mean difference in HbA1c of − 0.19% (95% CI − 0.46; 0.08); − 2.1 (95% CI − 5.0; 0.9) mmol/mol with insulin analog compared to RHI at the end of the treatment period. The squares and the diamond in a, d, e represent the difference in risk for each study (horizontal lines represent 95% CI) and for all studies combined, respectively. The squares and the diamond in b, c represent the difference in the glucose levels between the two treatment arms for each study (horizontal lines are 95% CI) and for all the studies combined, respectively. The results of these meta-analyses are the mean of post-breakfast BG measurements only. In a and d ‘Events’ refers to the number of patients experiencing any such episode during the treatment period as a proportion of total number of patients in that treatment group. ‘Rate’ refers to mean (± SD) of any episodes of hypoglycemia per 30 days in all the patients in the respective treatment group. In f ‘Bode, 2002 (a)’ [31] refers to the observed difference in HbA1c between the subgroup of insulin lispro vs. RHI, and ‘Bode, 2002 (b)’ [31] refers to the subgroup on insulin aspart vs. RHI; the three remaining studies compare lispro vs. RHI. The ‘I²’ value refers to the statistical heterogeneity for this pooled analysis. CI confidence interval, IV inverse variance, SD standard deviation