Glucose-Insulin- Potassium (GIK) in AMI

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: Proposed mechanisms of benefit

GIK: Summary of early trials in AMI Odds ratio (99% CI) GIK betterPlacebo better P = Fath-Ordoubadi F, Beatt KJ. Circulation. 1997;96: ( ) Mortality rate (%) StudyNGIKControl Heng Stanley Rogers Satler Mittra Pilcher Pentecost MRC Hjermann All patients

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 Malmberg K et al. Eur Heart J CREATE-ECLA Trial Group Investigators. JAMA

DIGAMI 1: CVD mortality after AMI Malmberg K et al. BMJ. 1997;314: Malmberg K et al. Eur Heart J. 1996;17: Years in study ControlInsulin-glucose infusion CHF accounted for 66% of all deaths Mortality Total cohort P = RRR = 28% 26% 19% No insulin—low risk P = RRR = 51% n = 314 n = 306 n = 133 n = 139

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 Van den Berghe G. Eur Heart J CREATE-ECLA Trial Group Investigators. JAMA CREATE-ECLADIGAMI 2

CREATE-ECLA: Effect of GIK on mortality, glucose CREATE-ECLA Trial Group Investigators. JAMA. 2005;293: Mean glucose (mg/dL) Mortality, cumulative events (%) *Usual care only † 6 hours after randomization Days GIK infusion Control* Baseline (both groups) GIK group Control* 148 † †

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

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 CREATE-ECLA Trial Group Investigators. JAMA Fath-Ordoubadi F, Beatt KJ. Circulation