Response to Jovanovič for the Comments on Our Study “Insulin Glulisine Compared to Insulin Aspart and to Insulin Lispro Administered by Continuous Subcutaneous Insulin Infusion in Patients with Type 1 Diabetes: A Randomized Controlled Trial”

Dear Editor:

W e thank Jovanovič for the comments on our study entitled “Insulin glulisine compared to insulin aspart and to insulin lispro administered by continuous subcutaneous insulin infusion in patients with type 1 diabetes: a randomized controlled trial.” ¹ On the basis of the results presented in our article, we and Jovanovič seem to come to a different overall conclusion. Whereas we base the overall conclusion on the primary outcome, Jovanovič takes several secondary outcomes into account. Secondary outcomes are secondary, and as such they need careful interpretation that we hope to have provided in the manuscript.

Also, Jovanovič queries our “suggestions that a trend toward greater occurrence of unexplained hyperglycemia and perceived infusion set occlusion seen in this study with insulin glulisine compared with insulin aspart and lispro should be taken as balancing the results from the previous study by Hoogma and Schumicki ² in which the opposite trend was seen.” Although we certainly would not pretend we did a formal meta-analysis, we do note that similar studies show opposing trends.

We fully agree with Jovanovič's warning that results of post hoc analyses must be interpreted with caution. Specifically, we performed a post hoc analysis on the primary outcome across subgroups defined by quartiles of the time interval to change of infusion set in routine. This analysis was done after the multivariate analyses had shown a significant influence of time to catheter change on the primary outcome. The interaction test treatment/time to change was not significant, so we cautiously concluded from this analysis that differences between insulins were not influenced by time to catheter change. We also think that based on the observations in our trial it is not possible to give general recommendations on when to routinely change infusion catheter sets, all the more in situations where time to catheter-related skin problems is highly variable between individuals.

As to our finding that the insulin requirement with glulisine was somewhat higher than with aspart or lispro, we hypothesized that this could be an explanation for the higher rate of hypoglycemia with glulisine in our trial. Jovanovič argues that “if the glulisine dose was high enough to lead to increased hypoglycemic events, it could be expected that average glycosylated hemoglobin levels in these patients would be decreased compared with aspart and lispro.” We do not think that a difference of 8.8 or 9.1 minor hypoglycemic episodes per patient year is likely to translate into notable differences in glycosylated hemoglobin. Also, hypoglycemia is often leveled out by a hyperglycemic period after hypoglycemia because of carbohydrate intake and counterregulatory response.