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

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 0:52.3

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. 2:25

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 4:25

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 7:11.0 Fath-Ordoubadi, F and Beatt, KJ, Circulation 1997;96:1152-1156

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

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. 6:30.5

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 7:11.0

GIK ECLA GIK pilot study Estudios Cardiológicos Latinoamérica Safety and feasibility study High-dose GIK vs Low-dose GIK vs Std Rx 407 patients enrolled 24 hours of ACS 8:19.5 Díaz, R, et. al. Circulation 1998;98:2227-2234

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

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

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 9:38.5

GIK Enrollment challenge Only 4 US sites have joined on despite the simplicity of the trial and the minimal resources required to participate. 9:38.5

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/ 9:38.5

GIK Resource issues Requires: Multiple IV drips (G/I/K) Frequent glucose and potassium monitoring Increased nursing care requirements 9:38.5