children with DIABETES has received several questions about possible adverse effects of Lispro (Humalog) on the heart. We referred this question to Eli Lilly directly and received the following letter in reply:
August 12, 1996
Dear Dr. Lebinger:
I am writing in response to your letter of 24 July 1996 to Dr. Paris Roach at Eli Lilly and Company. Dr. Roach has forwarded your inquiry to me.
To first address the question from West Germany regarding pediatric deaths and possible cardiac toxicity of Humalog during the clinical registration trials, the large, multinational trials of Humalog (insulin lispro) have enrolled patients between the ages of 3 and 85.
There have been NO deaths of children or adolescents in any of the Humalog trials, nor have there been any cardio-vascular complications in children or adolescents in any of the Humalog trials.
In your letter you also cited a quote from Dr. Jose Cara of Henry Ford Hospital which was published in the August Forecast magazine as a basis for such speculation. The statement by Dr. Cara centered upon a theoretical possibility that insulin lispro may increase sudden death because of the reversal of two amino acids in the B-chain (the difference between insulin lispro and human insulin.) Dr. Edward Bastyr, a Lilly clinical research physician, prepared the following additional comments for your information.
In response to Dr. Cara’s speculation, which was first discussed at the FDA Medical Advisory Board Meeting on Humalog on 29 February 1996, I presented the data regarding sudden cardiac death from the registration trials for insulin lispro. Evaluation of the patients enrolled in the controlled trials was undertaken for the number of sudden death occurrences. We defined sudden cardiac death as observed death from Ventricular Tachycardia or Ventricular Fibrillation with sudden unobserved loss of consciousness without associated cause resulting in death in less than or equal to 24 hours. Using this definition in the controlled trials, like the FDA reviewers, of the 3034 persons using insulin lispro we identified 2 sudden cardiac deaths and in the 3056 patients using regular human insulin, we identified 0 cardiac deaths. There was no statistical difference between groups. We extended their analysis to include the long-term extension trials where we identified 6 further cases of sudden cardiac death. One of 1045 patients in the insulin lispro group and 5 of 1902 patients in the non-Humalog group had sudden cardiac death (See Table 1). We concluded from this analysis that we were unable to determine a difference between the insulin lispro group and the regular human insulin group for sudden cardiac death.
Table 1 Controlled Trials Long-Term Trials Humalog Humulin R Humalog Non-Humalog n= 3034 3056 1045 1902 SCD= 2 0 1 5
Furthermore, we examined our clinical trials for patients at risk for cardiovascular events. We identified a low cardiovascular risk group, a high cardiovascular risk group, and a higher cardiovascular risk group. This identification was based upon the reporting of a pre-existing cardiovascular event term using the baseline period. Of a total population of 3634 patients, we identified 2381 in a low risk group and 1253 in a high risk group. The high risk group represented approximately 35% of the entire study population. In addition, we identified an even higher risk group (approximately 2%) as those with a reported cardiovascular event at baseline and a prolonged QTc interval. We evaluated the three groups for reporting either a new cardiovascular event or an increase in severity of the previously reported underlying cardiovascular event at baseline. Our analysis allowed us to differentiate a low risk group with 4% incidences of a new event, while the high risk group had a 10.5% incidence in reporting a new event or an increase in severity of a pre-existing event. Finally, those at highest risk had approximately 16% total incidence of an increase in severity of a pre-existing cardiovascular event or the development of a new cardiovascular event. When Humalog and Humulin R were compared in these three groups, there was no statistical difference between groups.
Table 2 Reports of New Event or Increase in Severity n Group Humalog Humulin R p value 2381 No h/o CV Event 54 (2.3%) 38 (1.6%) ns 1253 h/o CV Event 65 (5.2%) 66 (5.3%) ns 80 h/o CV Event and h/o * QTc 6 (7.5%) 7 (8.7%) ns Total Population: 3634
In conclusion, there were no statistical differences between Humalog and Humulin R in reports of cardiovascular events or sudden cardiac death. In addition, we identified both a low risk and a high risk (approximately 35%) sub-population within the Humalog studies. Humalog and Humulin R do not appear different in either the high or low risk groups for cardiovascular events or sudden cardiac death.
We would like to thank you for the opportunity to address your inquiry.
ELI LILLY AND COMPANY
James H. Anderson, Jr., M.D.
Senior Clinical Research Physician
Diabetes Care and Endocrinology
Lilly Research Laboratories
Edward J. Bastyr, III, M.D.
Clinical Research Physician
U S Medical Operations
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