1. Glucose-Insulin- Potassium (GIK) in AMI

2. Glucose-insulin-potassium “cocktail” Glucose (G)  Energy efficiency of the heart—becomes preferred fuel Insulin (I)  Circulating FFA level and uptake—toxic to ischemic myocardium Potassium (K)  Depleted K levels in myocytes—lowers risk of ventricular arrhythmias CREATE-ECLA Trial Group Investigators. JAMA. 2005;293:437-46. Proposed mechanisms of benefit

3. GIK: Summary of early trials in AMI 00.511.52 Odds ratio (99% CI) GIK betterPlacebo better P = 0.004 Fath-Ordoubadi F, Beatt KJ. Circulation. 1997;96:1152-6. 0.72 (0.57-0.90) Mortality rate (%) StudyNGIKControl Heng 1977 278.30 Stanley 1978 1107.316.4 Rogers 1979 1346.512.3 Satler 1987 1700 Mittra 1965 17011.828.2 Pilcher 1967 10213.929.3 Pentecost 1968 20015.016.0 MRC 1968 96821.423.6 Hjermann 1971 20410.620.0 All patients193216.121.0

4. Major trials of GIK in AMI Study (Year) NTreatment*Outcomes DIGAMI 1 (1995) 620 DMIV GIK ≥24 hr + multidose sc insulin ≥3 months Mortality  18% In-hospital (NS)  21% 90-days (NS)  29% 1-year (P < 0.05) DIGAMI 2 (2005) 1253 DMIV GIK ≥24 hr ± multidose sc insulin >3 months Mortality neutral CREATE-ECLA (2005) 20,201IV GIK 24 hrMortality, cardiac arrest, cardiogenic shock, reinfarction neutral *vs usual care Malmberg K et al. J Am Coll Cardiol. 1995. Malmberg K et al. Eur Heart J. 2005. CREATE-ECLA Trial Group Investigators. JAMA. 2005.

5. DIGAMI 1: CVD mortality after AMI Malmberg K et al. BMJ. 1997;314:1512-15. Malmberg K et al. Eur Heart J. 1996;17:1337-44. Years in study 012345 ControlInsulin-glucose infusion 012345 CHF accounted for 66% of all deaths Mortality Total cohort 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 P = 0.011 RRR = 28% 26% 19% No insulin—low risk P = 0.004 RRR = 51% 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 n = 314 n = 306 n = 133 n = 139

6. DIGAMI 2 and CREATE-ECLA outcomes show need for glucose control Treatment groups had identical glucose control Results show long-term benefit in DIGAMI 1 is explained by better glucose control and not by GIK Not a glucose control trial Patients randomized irrespective of baseline glucose Mean glucose increased from baseline in GIK group Malmberg K et al. Eur Heart J. 2005. Van den Berghe G. Eur Heart J. 2005. CREATE-ECLA Trial Group Investigators. JAMA. 2005. CREATE-ECLADIGAMI 2

7. CREATE-ECLA: Effect of GIK on mortality, glucose CREATE-ECLA Trial Group Investigators. JAMA. 2005;293:437-46. Mean glucose (mg/dL) Mortality, cumulative events (%) *Usual care only † 6 hours after randomization Days 051015202530 0 12.0 GIK infusion Control* 2.0 4.0 6.0 8.0 10.0 Baseline (both groups) GIK group Control* 148 † 162 187 † 200 150 100 50 0

8. CREATE-ECLA: Correlation of baseline glucose with mortality CREATE-ECLA Trial Group Investigators. JAMA. 2005;293:437-46. Glucose tertile Mortality at 30 days (%) Control group, n = 10,107

9. What CREATE-ECLA shows about GIK “Regardless of its scientific rationale and the positive results of small studies, this definitive trial, combined with a previous overview that showed only a modest potential benefit, answers the question beyond reasonable doubt: there is no benefit of GIK therapy.” Califf RM. JAMA. 2005. CREATE-ECLA Trial Group Investigators. JAMA. 2005. Fath-Ordoubadi F, Beatt KJ. Circulation. 1997.