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Donna Mojdami, PGY5 Understand myocardial energy metabolism Examine the effects of hyperglycemia in the post-MI state Understand the “glucose hypothesis” and the role for insulin Assess some of the major trials in glycemic management during ACS and their results Examine the DIGAMI trials Two major forms of cellular energy production Glycolysis – anaerobic process Byproducts are pyruvate and lactic acid Oxidative phosphorylation – aerobic process Occurs in the mitochondria Involves the Krebs cycle and electron transport chain Byproducts are CO2 and H2O Primarily oxidative phosphorylation Aerobic process Takes place in the mitochondria Utilizes the Krebs cycle and electron transport chain Generates ATP, H2O and CO2 Myocardium uses two major substrates for energy production: 1) Glucose 2) Free fatty acids FFAs are the main source of acetyl-CoA under normal conditions FFAs support 60% of total energy demand Ketone bodies support 27% of total energy demand Lactate supports 12% of total energy demand Glucose contributes <1% Under conditions of limited O2 and perfusion (e.g. ischemia) myocardium switches from aerobic metabolism to glycolysis Anaerobic process Substrate is glucose from blood stream or from glycogen stores Byproducts include pyruvate and lactic acid Requires less O2 than oxidation of FFAs Onset of ischemia associated with very rapid loss of intracellular K+ Shift believed to be mediated by ATP-sensitive potassium channels Studies in myocytes have shown glycolysis to prevent opening of potassium channels Maintains mitochondrial function during ischemia and reperfusion Prevents myocardial contracture Improved membrane phospholipid synthesis Hyperglycemia causes an osmotic diuresis that reduces intravascular volume Glucose promotes inflammation, an important factor in the pathogenesis of ACS Activates transcription factors that promote expression of pro-inflammatory cytokines Hyperglycemia promotes coagulation Prolongs fibrinogen half-life, increases pro-thrombin fragments, factor VII Glucose iNOS - Induces myocardial depression eNOS - Prevents: - microvascular permeability - capillary leakage - leuk adhesion & activation - intravascular coagulation & thrombosis Hyperglycemia is an independent predictor of abnormal coronary vasodilation Hyperglycemia promotes oxidative stress Excess glucose shifted to polyol pathway which generates superoxide radicals Radicals inactivate ATP production & promote more radical production U.S. registry of 141,680 patients ≥65 years presenting with ACS 30.00% 25.00% 20.00% * Blood Glucose at Admission (mmol/L) 15.00% 10.00% 5.00% 0.00% Kosiborod et al. Circulation 2005; 111:3078-86 * 74% previously diagnosed with DM, but DM diagnosed in minority of cases in other groups Hyperglycemia associated with increased in-hospital mortality Relationship stronger in non-diabetics than diabetics Non-diabetics BG 6.1-8mmol/L 3.9 fold higher risk of mortality An increase in BG by 1mmol/L associated with 4% increase in mortality over 50 months after MI Stranders et al. Arch Int Med 2004; 164:982-8 In non-diabetics admission BG also associated with increased morbidity Reinfarction Hospitalizaton with heart failure Adverse ventricular remodelling Not necessarily! Admission BG is not an independent predictor of an abnormal OGTT In those with BG >11.1mmol/L, DM only diagnosed in 50% and IGT in only 69% Post MI catecholamine response occurs during first 5 days after event Catecholamine response proportional to size of infarct Faster heart rate Poorer Killip class Lower EF on discharge Hyperglycemia may be an epiphenomenon Associated with larger infarction Associated with HF on admission In STEMI, admission hyperglycemia independently associated with Incomplete resolution of ST segment elevation Persistent occlusion of artery Reduced microvascular myocardial perfusion Not affected by HbA1c and previous diagnosis of DM 25% 20% 15% Acute Hyperglycemia Normoglycemia 10% 5% 0% Death - 1720 subjects post AMI, 72% received PCI Ishihara et al. Am Heart J., 2005; 150:814-20 MACE 16% P = NS 14% 12% P = NS 10% 8% Diabetic 6% Non-diabetic 4% 2% 0% Death - 1720 subjects post AMI, 72% received PCI Ishihara et al. Am Heart J., 2005; 150:814-20 MACE Persistent hyperglycemia more accurate predictor of death Mean glucose concentration the most practical tool Relationship between mean BG and mortality demonstrated by “J-shaped” curve Kosiborod et al. Circulation; 2008: 1018-27 Concept that insulin may be beneficial during AMI developed 45 years ago Rationale involves using glucose-insulinpotassium (GIK) infusion to shift myocardial FFA use to glucose Reduces myocardial O2 demand Reduces glycolytic generation of radicals that can further damage myocardium Focus of early uses of GIK on correcting relative insulin deficiency and NOT establishing euglycemia Reduces production and uptake of FFAs by myocardium FFAs increases myocardial O2 requirements FFAs depress myocardial mechanical function Promotes glucose as primary energy substrate Increases efficiency of ATP production Glycolytic ATP protects cell membrane, drives transport of Ca, improves Na homeostasis Promotes cell survival Anti-apoptotic effects by upregulating eNOS Limits effects of reperfusion injury Anti-inflammatory effects CRP increase post MI blunted ~ 50% by insulin Marfella et al. Diabetes Care 2003; 26:3129-35 Inhibits platelet aggregation Promotes vasodilatation Improves myocardial perfusion and coronary flow in dose dependent manner Objective to correct relative insulin deficiency Providing GIK infusion Glucose acting to prevent hypoglycemia and acting as an alternative energy substrate Achieving a target BG not a priority Goal is to improve myocardial metabolism Insulin administered to reduce elevated BG levels to normal levels Goal to reverse any direct adverse effects of hyperglycemia Meta-analysis of 9 RCTs 1965-1987 Total of 1932 patients All studies provided GIK infusion Most studies excluded patients with DM Evaluated in-hospital mortality Fath-Ordoubadi F & Beatt KJ 1997 Circulation 96:1152-1156 in-hospital mortality: 21% placebo group vs. 16.5% GIK group (P=0.004, OR 0.72, 95% CI 0.57-0.90) “…GIK therapy may have an important role in reducing in-hospital mortality after acute MI” First studies of GIK infusion in reperfusion era DIGAMI Study Published in 1995 Included only patients with DM and acute MI DIGAMI-2 Study Published in 2005 Studied 3 different management strategies in subjects with T2DM or admission BG>11.1 with acute MI In patients with T2DM and acute MI does treatment with glucose-insulin infusion followed by MDI insulin reduce mortality at 1-year compared to standard care? 620 Subjects Control Infusion Conventional CCU care +/- insulin if needed Glucose-insulin infusion target BG 7-10mmol/L ≥ 24h until BG stable Patient switched to MDI insulin T2DM = known history T2DM or admission BG >11.1 mmol/L Primary Outcome Mortality at 3 months At 3 mo P value NS At 1 year P value = 0.0273 Low cardiac risk and not previously on insulin Patients with T2DM who are immediately post MI have improved long-term mortality when given insulin-gluc0se infusion to a target BG followed by MDI insulin Are we simply seeing the benefits of better glycemic control? In patients with T2DM and acute MI does an insulin-glucose regimen followed by insulin based therapy reduce mortality more so than a glucoseinsulin infusion followed by standard care or standard care alone? 1253 subjects with T2DM or BG >11.1mmol/L suspected of acute MI (Q waves, ST segment changes) 1253 Subjects Group 1 Group 2 Group 3 24h insulin-glucose infusion then longterm MDI insulin 24h insulin-glucose infusion then routine metabolic management Routine metabolic management Glucose-insulin infusion: 80U insulin in 500mL D5W BG targets - decrease BG as fast as possible to 7-10mmol/L - While on MDI, FBG 5-7 mmol/L and post prandial <10mmol/L (Group 1) Primary outcome Mortality between Group 1 and Group 2 Secondary Outcomes Mortality between Group 2 and Group 3 Morbidity (nonfatal reinfarction, CHF etc) between all 3 groups Study failed to recruit target number of subjects Originally planned to recruit 3000 patients Recruitment stopped early because of slow rate Inability to attain major difference in BG between treatment groups Initial decrease in BG less substantial than in DIGAMI For similar glycemic control, insulin therapy is not superior to other glycemic control options GIK Infusion Treat with insulin to a BG target In their systematic review Anantharaman et al. point out that Anantharaman, R. et al. Heart 2009; 95:697-703 Trials with an insulin focus do not show any significant benefit Trials with a glycemic focus are inconclusive In general these trials also have higher admission BGs Paucity of non-diabetics in the euglycemia focus studies DIGAMI, DIGAMI-2 HI-5 50% non-DM Early, substantial decreases in BG compared to control not achieved in some studies In CREATE-ECLA treatment arm BG actually rose, higher at 24h compared to treatment CARDINAL study showed hyperglycemia in first 24h after AMI predicts higher mortality in non-DM In all euglycemia focus trials treatment started >12h from time of symptom onset Adverse effects of hypoglycemia may be overshadowing possible benefits More patients in the insulin therapy or GIK infusion arms affected by low BGs Both DIGAMI-2 and HI-5 both failed to recruit sufficient number of patients In the era of reperfusion and use of ASA, statins and beta blockers, any benefit achieved may be overshadowed Meta-analysis of RCTs comparing GIK or insulinglucose therapy vs. standard therapy in AMI in the reperfusion era Zhao, Y et al. Heart 2010; 96:1622-1626 • 11 studies identified • 8 with insulin focus, 3 with euglycemia focus Large degree of heterogeneity between trials Authors conclude: In the reperfusion era treatment with an insulinfocused strategy does not reduce mortality It may be possible that treatment with insulin infusion with glycemia focus may improve mortality in AMI Immediate administration of GIK at the first signs of a heart attack (pre-hospital) by EMS vs. placebo All-cause mortality at 30 days 15,450 participants planned to be recruited Recruitment ended July 2011 Non-diabetics and type 2 diabetics not requiring insulin admitted for AMI Study Arms Treatment: IV glulisine for ≥ 24h and duration of CCU admission then glargine insulin, target BG 56.6mmol/L Control: Usual care for AMI Primary Outcome 24h difference in mean BG between two study groups Data collection now complete All patients with AMI should have their BG checked regardless of history DM When BG >12mmol/L, insulin-glucose infusion should be used to maintain BG 7-10mmol/L for at least 24h Patients should be maintained on MDI insulin for at least 3 mo “ … reduction of glycemia per se, and not necessarily the use of insulin, is associated with improved outcomes. It remains unclear, however, whether hyperglycemia is a marker of underlying health status or is a mediator of complications after AMI. Noniatrogenic hypoglycemia has also been associated with adverse outcomes and is a predictor of higher mortality.” Treatment of Hyperglycemia in non-critically ill Patients Pre-meal targets <7.8mmol/L Random BG <10mmol/L Reassess insulin regimen if BG <5.6mmol/L “… our recommendations are based on clinical experience and judgment.” Recommend treatment of hyperglycemia when BG > 180mg/dL (> 10mmol/L) while avoiding hypoglycemia Recommend treatment of hyperglycemia when BG > 180mg/dL (> 10mmol/L) while avoiding hypoglycemia Cardiac metabolism is primarily oxidative phosphorylation with FFAs as primary energy substrates In ischemia, glycolysis becomes primary mode of energy metabolism Conserves oxygen use May have cardiac protective effects Admission hyperglycemia following AMI associated with higher mortality and major cardiac events More pronounced in non-diabetic patients Persistent hyperglycemia better predictor of death Interventions either have euglycemia focus or insulin focus In the pre-reperfusion era GIK infusion may have had mortality benefit In the reperfusion era Insulin focus trials do not show mortality benefit Euglycemia focus trials suggest possible benefit Primarily driven by DIGAMI results Without any RCTs, most clinical guidelines suggest treatment admission hyperglycemia in AMI when BG > 10-12mmol/L Emphasis on less stringent glycemic targets and avoidance of hypoglycemia There is a clear need for a well-designed, definitive randomized trial of target-driven glucose control in UA/NSTEMI patients with meaningful clinical endpoints so that glucose treatment thresholds and glucose targets can be determined. -- 2011 ACCF/AHA Guidelines for the Management of UA/NSTEMI Anantharaman, R. et al. Heart 2009; 95:697-703 Goyal, A. et al. Diabetes and Vascular Disease Research; 2008: 276 Devos, P. et al. Curr Opin Clin Nutr Metab Care 2006; 9:131-139
