Darren K McGuire, MD Senior Fellow Duke Clinical Research Institute Durham, NC

1. Got GIK? Darren K McGuire, MD Senior Fellow Duke Clinical Research Institute Durham, NC

2. GIK Where it all began • 1912-Cane sugar suggested as a therapy for cardiovascular disease • 1914-Mechanistic explanation of the benefit of glucose therapy for heart disease reported • 1933-Insulin/glucose suggested as a therapy for angina pectoris and heart disease • 1960’s-Sodi-Pallares, et al introduced GIK for the treatment of AMI

3. GIK History 1962-Demetrio Sodi-Pallares introducs “Polarizing Therapy”for acute MI • Based on Ko/Ki perturbation with MI • Insulin/Glucose used to facilitate “passive” entry of K+ into cells • Recent knowledge suggests insulin is the therapeutic agent.

4. GIK Limitations of trials • Most obvious limitation is the lack of power of each of the trials reported • Confounding this are: • inconsistency in dosing of GIK • inconsistency of initiation (12-48 hrs) • inconsistency of termination of infusion (6 hr-14 d) • most excluded age >75 • Pre-thrombolytic era with poor outcomes

5. GIK GIK trials meta-analysis Mortality Rate (%) Year Study N GIK Control 1977 Heng 27 8.3 0 1978 Stanley 110 7.3 16.4 1979 Rogers 134 6.5 12.3 1987 Satler 17 0 0 1965 Mittra 170 11.6 28.2 1967 Pilcher 102 13.9 29.3 1968 Pentecost 200 15.0 16.0 1968 MRC 968 21.4 23.6 1971 Hjermann 204 10.6 20.0 All Patients 1932 16.1 21.0 Fath-Ordoubadi, F and Beatt, KJ, Circulation 1997;96:1152-1156

6. GIK GIK trials meta-analysis 2 Odds Ratio (99% CI) GIK Better Placebo Better Year Study 1977 Heng 1978 Stanley 1979 Rogers 1987 Satler 1965 Mittra 1967 Pilcher 1968 Pentecost 1968 MRC 1971 Hjermann Total p=0.004; 95% CI 0 0.5 1 1.5 2

7. GIK Questions and hurdles Will this apparent benefit persist given today’s modern therapies? Because it is a non-proprietary therapy, it has been ignored by the pharmaceutical industry and many opinion leaders. GIK is not mentioned as a potential therapy option in the current ACC/AHA guidelines.

8. GIK Use in clinical practice “In the developing world, in non-western societies, it is a little bit more of an issue if an effective therapy like GIK can be used in addition to, or even instead of thrombolytic or other expensive therapies.” Darren K McGuire, MD Senior Fellow Duke Clinical Research Institute Durham, NC

9. GIK ECLA GIK pilot study • Estudios Cardiológicos Latinoamérica • GIK Pilot Study • Safety and feasibility study • High-dose GIK vs Low-dose GIK vs Std Rx • 407 patients enrolled 24 hours of ACS Díaz, R, et. al. Circulation 1998;98:2227-2234

10. 0.1 1 10 GIK ECLA GIK: In hospital events Death Overall Reperfused CHF(Killip>2) Overall Reperfused VentricularFibrillation Overall Reperfused Death/CHF/Vfib Overall Reperfused GIK Better Std Rx Better

11. GIK ECLA GIK: Conclusions • Trends favor GIK added to “modern” therapy • Benefit appears to be complementary to reperfusion therapies • Warrants further investigation in a full-scale clinical trial

12. GIK ECLA GIK-2 • Open-label randomized multi-center study • Comparison of GIK + Std Rx vs Std Rx alone for ST-elevation MI • 300 Centers planned: • Latin America, North America, Europe, Australia, New Zealand, South Africa, and Asia • 10,000 patients planned • 90% power to detect 20% difference at =0.05 in Primary Endpoint: 30-day Mortality

13. GIK Enrollment challenge Only 4 US sites have joined on despite the simplicity of the trial and the minimal resources required to participate.

14. GIK Joining ECLA GIK-2 Darren McGuire Duke Clinical Research Institute P.O. Box 17969 Durham NC 27715 Tel: 919-668-8583 Web: http://www.dcri.duke.edu/forsites/

15. GIK Resource issues Requires: Multiple IV drips (G/I/K) Frequent glucose and potassium monitoring Increased nursing care requirements