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BEYOND DIGAMI: GLYCEMIC MANAGEMENT IN ACUTE MYOCARDIAL INFARCTION
JULIA CREIDER, PGY5
ENDOCRINE & METABOLISM
OBJECTIVESUnderstand myocardial energy metabolism
Examine the effects of hyperglycemia in 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
METABOLISM BASICS
Two major forms of cellular energy production
• Glycolysis = anaerobic process• By-products are pyruvate and lactic acid
• Oxidative phyosphorylation = aerobic process• Occurs in the mitochondria• Involves the Krebs cycle and electron transport chain• By-producs are ATP, CO2 and H2O
METABOLISM BASICS
CARDIAC METABOLISM
Primarily oxidative physophorylation
Estimate of daily cardiac metabolic energy requirement:
• 300g heart – utilizes 5000g of ATP per day• Requires +++ rapid turnover of ATP pool
Myocardium uses two major substrates for energy production:
• Free fatty acids (50-80%)• Glucose (10-25%)• Other – lactate (10-25%), ketones
CARDIAC METABOLISM
FATTY ACID METABOLISM GLUCOSE METABOLISM
ENERGY METABOLISM DURING ISCHEMIA
Switches from aerobic metabolism to glycolysis
• Anaerobic process• Substrate is glucose from blood or glycogen stores• By-products include pyruvate and lactic acid• Requires less O2 than oxidation of FFAs• Reduced intracellular pH
ENERGY METABOLISM DURING ISCHEMIA
GLYCOLYSIS IS PROTECTIVE
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
ENERGY METABOLISM DURING ISCHEMIA
Increased plasma free fatty acids (FFAs)
• Due to increased lipolytic action of catecholamines +/- therapeutically administered heparin
• Causes increased myocyte FFA uptake• Decreased contractility• Increased oxygen demands• Accumulation of toxic FFA derivatives
ISCHEMIC EFFECTS ON POTASSIUM
Onset of ischemia associated with very rapid loss of intracellular potassium
Shift believed to be mediated by ATP-sensitive potassium channels
ISCHEMIC EFFECTS ON MYOCARDIUM
Ischemia is initially reversible
If persistent can become irreversible cell death
Prior to cell death, period of time where cell is viable, but is vulnerable to further injury if blood flow is restored
• Ischemia-reperfusion injury• Myocardial, vascular or electrophysiological dysfunction
induced by restoration of blood flow to previously ischemic tissue
ISCHEMIC EFFECTS ON MYOCARDIUM
Ischemia-Reperfusion Injury Mechanisms:
• Cell/organelle membrane damage• Myocyte hypercontracture• Free radical toxicity• Aggregation of leukocytes/inflammatory mediators• Platelet and complement activation• Pro-apoptotic signaling• Endothelial damage
ISCHEMIC EFFECTS ON MYOCARDIUM
Ischemia-Reperfusion Injury Clinical Manifestations:
• Reperfusion arrhythmias• Endothelial cell damage microvascular dysfunction• Myocardial stunning• Myocyte death and infarction
GLUCOSE EFFECTS ON THE HEART
Hyperglycemia:
• Causes an osmotic diuresis reduces intravascular volume
• Promotes inflammation activates transcription factors that promote expression of pro-inflammatory cytokines
• Promotes coagulation prolongs fibrinogen half-life, increased pro-thrombin fragments, factor VII
• Independent predictor of abnormal coronary vasodilation
• Promotes oxidative stress
• Shifted to polyol pathway which generates superoxide radicals
• Radicals inactivate ATP production & promote more radical production
HYPERGLYCEMIA AND ACS
US registry of 141, 680 patients ≥ 65 years presenting with ACS
<6.1 6.1-7.8
7.9-9.5
9.6-13.3
>13.30.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%Blood Glucose at Admission (m-mol/L)
**74% previously diagnosed with DM, but DM diagnosed in minority of cases in other groups
Kosiborod et al. Circulation 2005; 111:3078-86
HYPERGLYCEMIA AND ACS
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
In non-diabetics admission BG also associated with increased morbidity
• Reinfarction• Hospitalization with heart failure• Adverse ventricular remodelling
Stranders et al. Arch Int Med 2004; 164:982-8
HYPERGLYCEMIA AND ACS
1720 subjects post AMI, 72% received PCI
Ishihara et al. Am Heart J., 2005; 150:814-20
Death MACE0%
5%
10%
15%
20%
25%
Acute HyperglycemiaNormoglycemia
IS IT JUST OCCULT DIABETES?
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%
EFFECT OF DM ON MORTALITY AND CARDIOVASCULAR EVENTS
Ishihara et al. Am Heart J., 2005; 150:814-20
1720 subjects post AMI, 72% received PCI
Death MACE0%
2%
4%
6%
8%
10%
12%
14%
16%
DiabeticNon-diabetic
P = NS
P = NS
IS IT A STRESS RESPONSE?
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
SINGLE ADMISSION VS PERSISTENT HYPERGLYCEMIA
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
“GLUCOSE HYPOTHESIS”
Glucose-Insulin-Potassium (GIK) Therapy
• First postulated in 1960s• Concept that insulin may be beneficial during ACS• Rationale for GIK:
• GLUCOSE – substrate for glycolysis• INSULIN – shifts primary metabolic substrate from FFA to
glucose• POTASSIUM – prevents insulin-mediated hypokalemia
while optimizing intracellular [K+]
“GLUCOSE HYPOTHESIS”
Proposed Beneficial Mechanisms:
• Reduces myocardial O2 demand• Reduces glycolytic generation of radicals• Increases efficiency of ATP production
• Protect cell membrane• Drives transport of Ca2+
• Improves Na+ homeostasis
• Promotes cell survival• Anti-apoptotic effects• Limits effects of reperfusion injury
• Anti-inflammatory effects• CRP increase post MI blunted ~50% by insulin
• Inhibits platelet aggregation • Promote vasodilation improves myocardial perfusion
“GLUCOSE HYPOTHESIS”
Potential Drawbacks:
• Increased glycolysis could be harmful• Increased acidosis from lactate accumulation• Requires residual blood flow for lactate washout
• Risk of hyperglycemia or hypoglycemia• Volume overload
INTERVENTION TRIALS
PRE-REPERFUSION ERA
Meta-analysis – Fath-Ordoubadi F & Beatt KJ 1997 Circulation 96:1152-1156
• 9 RCTs 1965-1987, 1932 patients• Large variability in design and GIK solution
• Oral glucose, subcutaneous insulin• IV GIK (high dose vs other)
• 1 trial gave thrombolytics• Most studies excluded patients with DM• Evaluated in-hospital mortality
STUDY YEAR DELAY BETWEEN
ONSET OF MI AND RX
EXCLUSION CRITERIA
GIK REGIMEN
DURATION OF
TREATMENT
Mittra 1965 < 48 h IDDM, RF Oral GK, sc insulin
14 days
Pilcher 1967 (not available) DM Oral GK, sc insulin
14 days
Pentecost 1968 < 48 h IDDM, severe LVF
IV 48 hours
MRC 1968 < 48 h DM, RF Oral GK, sc insulin
14 days
Hjermann 1971 < 48 h Age >75, IDDM, RF
Oral GK, sc insulin
10 days
Heng 1977 < 12 h cardiogenic shock, RF
High-dose IV 6-12 hours
Stanley 1978 < 12 h (not available) High-dose IV 48 hours
Rogers 1979 <12 h Age>75, IDDM, RF
High-dose IV 48 hours
Satler 1987 < 24 h Age>75, IDDM High-dose IV 48 hours
High dose IV – 30% glucose, 50 U insulin, 80 mmol K at >1.5 ml/kg/hr
COMPARISON OF MORTALITY OUTCOME IN PATIENTS TREATED WITH GIK THERAPY COMPARED WITH PLACEBO
PRE-REPERFUSION ERA
Meta-analysis – 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.”
POST-REPERFUSION ERA
Insulin Focused Trials
• Objective to correct relative insulin deficiency• Provide fixed dosed GIK infusions• Glucose acting to prevent hypoglycemia and acting as an
alternative energy substrate• Achieving a target BG not a priority• Goal to improve myocardial metabolism
Euglycemia Focused Trials
• Insulin administered to reduce elevated BG levels to normal• Goal to reverse any direct adverse effects of hyperglycemia
INSULIN FOCUSED TRIALS• Many trials 1998-2007
• Variable design, variable outcomes measured
• Clinical (in-hospital events, CHF, re-infarct)• Biochemical (cardiac enzymes, markers of oxidative stress)• Electrocardiographic (STE resolution)• Surrogate markers (variability index, LVEF, TIMI flow)
• Variable results
Kloner RA & Nesto RWCirculation 2008; 117:2523-2533
DIGAMI – DIABETES INSULIN-GLUCOSE IN ACUTE MYOCARDIAL INFARCTION
Malmberg K et al. 1995 J Am Coll Cardiol 26:57-65
• First study of GIK in reperfusion era with euglycemia focus
• Examined effect of insulin-glucose infusion followed by multidose insulin injections on mortality in diabetic patients with acute MI
• Multicentre, randomized, blinded
• Inclusion:
• Suspected acute MI in past 24h• Known hx DM and BG >11 or BG >11 (even without known hx
DM)• Exclusion:
• Inability/refusal to participate • Outside catchment area• In other studies (or already in DIGAMI)
DIAGAMI
Stratified into 1 of 4 groups:
• No insulin, low risk• No insulin, high risk• Insulin, low risk• Insulin, high risk
High risk = 2 or more of:
• Age > 70• Previous Hx MI• Previous Hx CHF• Current Rx with digitalis
Randomized to insulin-glucose (≥ 24h) or control
Goal BG on infusion 7-10
Malmberg K et al. 1995 J Am Coll Cardiol 26:57-65
Malmberg K et al. 1995 J Am Coll Cardiol 26:57-65
DIGAMI
At Hospital Discharge
• 87% insulin-glucose group on insulin• 43% control group• P<0.0001• This difference maintained at 3 months and 1 year
Three Month HbA1c
• 7.0 +/- 1.6% insulin-glucose group• 7.5 +/- 1.8% control group• P<0.01• HbA1c decreased in both groups over 1 year, but
significantly more in insulin-glucose group
DIGAMI
No difference between insulin-glucose and control groups in:
• In-hospital or follow-up treatment
• Except anti-diabetic meds/insulin
• In-hospital morbidity
26%
19%
Malmberg K et al. 1995 J Am Coll Cardiol 26:57-65
P=0.0273
Malmberg K et al. 1995 J Am Coll Cardiol 26:57-65
DIGAMI CONCLUSIONS
Long-term mortality in diabetic patients with acute MI could be reduced with insulin-glucose infusion followed by MDI insulin
Low risk, no prior insulin group benefited most
Follow-up – mortality benefit persisted at 3 years
DIGAMI-2
Malmberg K et al. 2005 Eur Heart J 26:650-661
• Compared 3 treatment strategies in DM2 with acute MI:
• 24hr insulin-glucose infusion (goal BG 7-10) then SC MDI insulin (FBG 5-7, random <10)
• 24hr insulin-glucose infusion then standard glucose control
• Routine metabolic management as per local practice
DIGAMI-2
Multicentre, randomized, open trial with blinded evaluation
Inclusion:
• Patients with type 2 DM or admission BG > 11• Suspected acute MI
Exclusion:
• Inability to cope with insulin or to receive info on study• Outside catchment area• In other studies• Already in DIGAMI 2
Primary objective– compare total mortality between groups 1 & 2
Secondary objective – compare total mortality between groups 2 & 3
Tertiary objective – compare morbidity between all groups
1253 Subjects
Group 1 (474-38%)
24h insulin-glucose infusion then long term MDI insulin
Group 2 (473-38%)
24h insulin-glucose infusion then routine metabolic management
Group 3 (306-24%)
Routine metabolic management
Malmberg K et al. Eur Heart J 2005;26:650-661
Malmberg K et al. Eur Heart J 2005;26:650-661
RESULTS - GLYCEMIA
Malmberg K et al. Eur Heart J 2005;26:650-661
RESULTS - MORTALITY23.4% grp 121.2% grp 2
17.9% grp 3
Malmberg K et al. Eur Heart J 2005;26:650-661
DIGAMI-2 - SUMMARY
No difference in mortality or morbidity found
Limitations:
• Inadequate recruitment under powered• Glycemic control similar in all 3 groups (did not achieve
target in group 1)• During follow-up, <50% group 1 used SC MDI insulin vs
15% group 2, 20% group 3• Overall event rate lower than expected in all groups
HI-5 – HYPERGLYCEMIA: INTENSIVE INSULIN INFUSION IN INFARCTION
Chung NW et al. Diabetes Care 2006. 29:765-770
Examined effect of tight glycemic control using insulin/dextrose infusion in diabetic patients with acute MI
Multicenter, randomized, open-label
Inclusion:
• Known DM or no prior hx DM with BG >7.8• Evidence of acute MI
Exclusion:
• Pregnancy• DKA• Admission BG > 20
HI-5
Stratified into 2 groups
• Known DM or admission BG > 11.1 without prior hx DM• Admission BG 7.8-11 without prior hx DM
Randomized to insulin infusion or conventional Rx
Insulin infusion group = target BG 4-10 for at least 24hr, then managed as per usual care
Primary outcome = mortality during hospital admission and at 3 and 6 months
Cheung NW et al. Diabetes Care 2006. 29:765-770
RESULTS
No difference in mortality between groups
• Inpatient, 3 or 6 months
No difference in blood glucose at 24hr
• Mean duration prior to commencement of infusion 13hr, after reperfusion therapy
Subset analysis – BG ≤ 8 in first 24hr associated with lower mortality at 3, 6 months
IMPORTANT TRIALS OF INSULIN THERAPY IN ACS PATIENTS
Treat with insulin to a BG target
GIK Infusion
SYSTEMATIC REVIEW
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
STUDY LIMITATIONS
Paucity of non-diabetics in the euglycemia focus studies
• DIGAMI, DIGAMI2• HI-5 50% non-DM
Early, substantial decreases in BG compared to control not achieved in some studies
• CREATE-ECLA treatment arm BG actually rose, higher at 24hr compared to treatment
• CARDINAL study showed hyperglycemia in first 24hr after AMI predicts higher mortality in non-DM
All euglycemia focus trials treatment started > 12hr from time of symptom onset
STUDY LIMITATIONS
Adverse effects of hypoglycemia may be overshadowing possible benefits
• More patients in the insulin therapy or GIK infusion arms affected by low BGs
Both DIGAMI2 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
Selker H. et al. JAMA 2012. 301:1925-33
Selker H. et al. Am J Cardiol 2014. 113:1599-1605
Immediate administration of GIK at the first signs of a heart attack (pre-hospital) by EMS vs placebo
Double-blinded, randomized, placebo controlled
All-cause mortality at 30 days and 1 year
Inclusion: all patients aged >30 for whom had chest pain or other possible ACS symptoms (prediction tool)
Exclusion: CHF, on dialysis or unable to give consent
Selker H. et al. Am J Cardiol 2014. 113:1599-1605
Study Population
• Average age was 63• 71% men, 86% presented with chest pain• Demographics similar between groups• 47% of participants received PCI• Median time from symptom onset to study drug was 90min• DM
• GIK 29.4%• Placebo 26.3%
Selker H. et al. Am J Cardiol 2014. 113:1599-1605
Total Population – Results 30 days
x
Selker H. et al. JAMA 2012. 301:1925-33
Total Population – Results 1year
Selker H. et al. Am J Cardiol 2014. 113:1599-1605
Subgroup Analysis – STEMI patients
Selker H. et al. Am J Cardiol 2014. 113:1599-1605
Summary
• 30 day results• No reduction in primary end point of progression to AMI• Significant reductions in the composite end point of cardiac
arrest or mortality
• 1 year follow up• Serous end points were generally lower with GIK than
placebo but no statistically significant• In STEMI subgroup, had significant reduction in the
composites endpoints:• cardiac arrest or 1 year mortality• cardiac arrest, mortality or CHF hospitalization within
1 year
CURRENT PRACTICE
2011 Clinical Practice Guidelines
• All patients with AMI should have their BG checked regardless of history of DM
• When BG >11 mmol/L on admission, should receive glycemic control in the range of 7-10
• Patients should be maintained on strategies to achieve recommended glucose targets long term
SUMMARY
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
SUMMARY
Interventions either have insulin or euglycemia 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 may suggest possible benefit