Intense Insulin Therapy in Diabetics after Myocardial Infarction : An underutilized therapy

1
Intense Insulin Therapy in Diabetics after
Myocardial Infarction An underutilized therapy ?

• Jeffrey Hyde M.D.
• December 7, 1999
• Resident Grand Rounds

2
CASE PRESENTATION

• 52 y/o obese white male with DM, HTN, and
  hypercholesterolemia is admitted to the CCU after
  AMI followed by PTCI to LAD. Presently patient is
  pain free and without complaints.
• Medications (prior to hospitalization)
• Glucotrol XL 5mg
• Lipitor 20mg
• Tenormin 50mg

3
CASE PRESENTATION

• Physical Exam
• Vitals T 98.4 HR 68 BP 106/82 RR 16
• Neck No JVD
• Lungs Minimal bibasilar crackles
• CV RRR nl S1,S2 No M/R/G
• Ext No edema
• Labs
• CK 486/CKMB 128 and Troponin 16
• CMP normal except for Blood Glucose of 286

4
CLINICAL QUESTIONS

• Would rapid control of blood sugar benefit our
  patient ( morbidity and/or mortality )?
• Would long term ( 1 year ) insulin therapy
  effect mortality post MI? (i.e. secondary
  prevention)

5
DIABETES and HEART DISEASE

• Framingham Study
• Diabetes Mellitus doubles risk of Cardiovascular
  disease in men and triples risk in women
• Multiple Risk Factor Intervention Trial (MRFIT)
• Cardiovascular death three times higher in
  diabetic men as compared to men without diabetes
• Cardiovascular death five times higher in
  diabetic men as compared to men without diabetes
  when optimal risk factor status is obtained

6
DIABETES MELLITUS Mortality after Myocardial
Infarction

• Multiple prospective studies approximate
  in-hospital mortality after myocardial infarction
  to be two times greater in diabetics than non
  diabetics
• FINMONICA MI Register (1988-1992) - one year
  mortality after MI
• 44.2 diabetic men vs 32.6 non diabetic men
• 36.9 diabetic women vs 20.2 non diabetic women
• Increased mortality is attributed to left
  ventricular dysfunction despite no significant
  difference in infarct size

7
DIABETES MELLITUS Extensive nature of Coronary
Artery Disease

• Coronary Artery Disease is more extensive in
  patients with diabetes mellitus proven
  angiographically and at autopsy
• Higher incidence of two and three vessel disease
• Lower incidence of one vessel disease
• Why is atherosclerosis accelerated and more
  severe in diabetics?

8
DIABETES MELLITUS Lipid Abnormalities

• Increased VLDL
• Increased atherogenicity of VLDL
• Increased apo E
• Increased Small density LDL
• Decreased HDL
• Increased oxidation and glycation of LDL
• Increased free fatty acids
• Increased oxidation of free fatty acids

9
Platelet function in diabetes

• Platelets play important role in atherosclerotic
  plaque formation and thrombus formation during
  plaque rupture
• Platelet function is ABNORMAL in DM with higher
  rates of aggregation and consumption
• Substances elevated in hyperglycemia include
• Thromboxane A2 (platelet aggregation and vascular
  spasm)
• Beta-thromboglobulin (increased platelet
  activity)
• platelet factor-4 (increased platelet activity)

10
(No Transcript)
11
Platelet function in diabetes

• Prostacyclin, which slows platelet-platelet
  interactions, found at lower levels in DM
• Platelet aggregation linked to recurrent MI
• Coincident with these findings
• time of onset of AMI parallels the circadian
  variation in platelet reactivity

12
Coagulopathy in diabetes mellitus

• Abnormalities in coagulation, hemostasis, and
  fibrinolysis
• lower AT-III levels and an acquired Protein C
  deficiency
• increased intrinsic pathway activity secondary to
  increased kallikrein, factor XII, factor VIII
• increased plasminogen activator inhibitor-1
  (PAI-1)

13
Acute Coronary Syndromes(ACS)

• PAST Slow progression of luminal obstruction
  secondary to atherosclerosis responsible for ACS
• PRESENT Coronary atherosclerosis progresses in a
  nonlinear, abrupt fashion leading to occlusion or
  near occlusion (i.e. thrombosis complicating
  atherosclerosis)

14
Acute Coronary Syndromes Vascular Lesions
15
Acute Coronary Syndrome

• Whether plaque disruption leads to coronary
  thrombosis depends on several factors
• (1) the thrombogenicity of the exposed
  components (i.e.balance of thrombotic and
  thrombolytic components)
• (2) endothelial function
• (3) presence of trigger activities (acute risk
  factors)

16
(No Transcript)
17
Acute Coronary Syndromes

• Thrombogenicity
• Intrinsic components (within plaque)
• lipid core (tissue factor) and collagen matrix
• Extrinsic components
• tissue factor vs protein C and S
• tPA vs PAI-1
• Endothelial function
• atherosclerosis associated with dysfunction
  (paradoxical vasoconstriction)
• nitric oxide

18
Acute Coronary Syndromes

• Trigger activities (acute risk factors)
• vigorous exercise
• emotional stress
• cold weather
• time of day

19
Acute Coronary Syndromes

• Complex interaction of these factors determines
  whether plaque disruption leads to coronary
  thrombosis
• Would modification of negative biochemical
  factors (prothrombotic, antifibrinolytic,
  platelet aggregation) produce stabilization of
  plaque or reduction in propagation of thrombosis?

20
The Effect of Insulin (Improved Glycemic Control)
on Biochemical Parameters in Diabetes Mellitus

• Suppresses Free Fatty Acid (FFA) levels
• Reduces FFA oxidation
• Decreases Thromboxane A2 levels
• Decreases Plasminogen Activator Inhibitor - 1
  levels
• Correction of disturbed lipoprotein pattern
• Preservation of myocardium through unclear
  mechanisms

21
Glucose-Insulin-Potassium (GIK) Infusions

• GIK infusions as treatment for AMI in nondiabetic
  patients dates to 1960 s
• Individual trials inconclusive secondary to low
  numbers, poor design, and methodological
  differences
• In 1997 a meta-analysis was performed by
  Fath-Ordoubadietal et al

22
Glucose-Insulin-Potassium Therapy for Treatment
of Acute Myocardial Infarction Meta-analysis

• Using MEDLINE, 15 randomized placebo-controlled
  studies identified between 1965-1987
• 6 studies excluded (5 for poor randomization and
  1 because diabetic patients were included)
• 9 studies included (2 double blinded and 7 open
  label)

23
GIK Infusions Meta-analysis
24
GIK Infusions Meta-analysis data
25
GIK Infusions Meta-analysis

• Study Concerns
• much heterogeneity
• delay between onset of chest pain and treatment
  varied between 12-48 hours
• duration of therapy varied between 6 hours and 14
  days
• marked differences between infusion protocols
  (concentration and rate of administration)
• lack of blinding in majority of studies

26
Effect of intravenous insulin infusion on
mortality among diabetic patients after
myocardial infarction

• British Heart Journal
• Gwilt et al

27
Gwilt et al

• Objective To determine whether IV insulin
  reduced mortality after MI in diabetics
• Location General Hospital, Birmingham England
• Population
• Control 353 diabetic patients with myocardial
  infarction through retrospective analysis treated
  with standard care
• Treatment 64 diabetic patients with myocardial
  infarction prospectively assigned to insulin
  regimen

28
Gwilt et al

• Insulin Regimen
• 1 unit per hour if FSG 0-144 mg/dl
• 2 units per hour if FSG 144-216 mg/dl
• 4 units per hour if FSG 216-432 mg/dl
• if 432 mg/dl rate adjusted to the needs of the
  patient
• Glucose Monitoring Duration of insulin drip and
  protocol for changing rate not clearly specified

29
Gwilt et al
30
Gwilt et al

• Study concerns
• (1) pre-thrombolytics
• (2) retrospective controls vs prospective
  treatment
• (3) low dose protocol
• (4) infusion rate change unclear (glucose
  targets?)
• (5) duration of infusion not clear
• (6) baseline characteristics unclear
• (7) small numbers

31
Gwilt et al

• Conclusions
• There is no difference in mortality or
  complications after MI in diabetics when
  comparing insulin infusion with standard care.

32
Effect of intravenous infusion of insulin in
diabetics with acute myocardial infarction

• British Medical Journal
• Clark et al

33
Clark et al

• Objective To determine if IV insulin reduces
  mortality in diabetic patients after MI
• Location Dundee, England
• Endpoints Mortality (in-hospital) and Cardiac
  arrhythmias requiring treatment
• Population
• Control 33 diabetics with AMI between April 1982
  and April 1983
• Treatment 29 diabetics with AMI between April
  1982 and April 1983

34
Clark et al

• Control
• Patients on diet or oral therapy continued on
  therapy unless poorly controlled then to multi
  dos insulin
• Patients on insulin were continued with
  subcutaneous insulin before meals

• Treatment
• Patients receive continuous iv insulin for four
  days with goal to maintain blood glucose between
  (72-126 mg/dl). Then patients returned to
  previous diabetes therapy.

35
Clark et al
36
Clark et al
37
Clark et al

• Study Strength
• (1) similar baseline characteristics
• (2) well defined insulin protocol
• (3) stated glucose goals
• (4) intention to treat analysis

38
Clark et al

• Study concerns
• (1) small numbers
• (2) not randomized (bias)
• (3) not blinded (bias)
• (4) performed prior to thrombolytics

39
Clark et al

• Conclusion Insulin-glucose infusion
  significantly decreased in-hospital mortality
  and arrhythmias after MI in diabetics. Previous
  study concerns make applicability questionable.

40
DIGAMI

• Diabetes Mellitus Insulin-Glucose Infusion in
  Acute Myocardial Infarction
• Malmberg et al

41
DIGAMI

• Objective Test how insulin-glucose infusion
  followed by multidose insulin treatment in
  diabetic patients with acute myocardial
  infarction affected mortality
• Location 19 Coronary Care Units in Sweden
• Population Diabetic Patients or Patients with
  elevated glucose and AMI
• Randomization 306 patients to receive treatment
  with insulin-glucose infusion followed by
  multidose subcutaneous insulin for 3 months and
  314 patients to conventional therapy

42
DIGAMI

• Inclusion criteria
• (1) Suspected MI within 24 hours (at least two of
  the following)
• (a) chest pain for at least 15 minutes
• (b) 2 CK/CK-MB values above normal after 10-16
  hours after symptoms or 2 LDH values above normal
  48-72 hours after symptoms
• (c) new q waves in at least 2 of 12 leads
• (2) Blood glucose 11 mmol/liter (198 mg/dl) with
  or without previously known diabetes

43
DIGAMI

• Exclusion criteria
• (1) inability to participate for reasons due to
  health
• (2) refusal to participate
• (3) residence outside hospital area
• (4) enrollment in other studies

44
DIGAMI
45
DIGAMI

• Risk Characterization Patients deemed high risk
  if 2 of the below are present
• (1) Age 70
• (2) Previous MI
• (3) History of CHF
• (4) Current Treatment with Digitalis

• Predefined Strata
• (1) no insulin, low risk
• (2) no insulin, high risk
• (3) insulin, low risk
• (4) insulin, high risk

46
DIGAMI Predefined Strata
47
DIGAMI Infusion protocol

• Protocol Used by the Coronary Care Unit Nurses
  for the Insulin-Glucose Infusions
• INFUSION 500 ml 5 glucose with 80 IU of soluble
  insulin (1IU / 6 ml)
• Start with 30 ml/h. Check blood glucose after 1
  h. Adjust infusion rate according to the protocol
  and aim for a blood glucose level of 7-10
  mmol/liter (126-180md/dl). Check FSG 1 h after
  change and otherwise every 2 h. If the initial
  decrease in blood glucose exceeds 30, the
  infusion rate should be left unchanged if blood
  glucose is 11 mmol/liter (198 mg/dl) and reduced
  by 6 ml/h if blood glucose is within the targeted
  range of 7-10.9 mmol/liter (126-196 mg/dl).
• If FSG stable and 10pm reduce infusion by 50

48
DIGAMI Infusion protocol

• Sliding Scale Insulin Regimen
• 15 mmol/l (270 mg/dl) Give 8 IU insulin iv and
  increase infusion rate by 6ml/h
• 11 - 14.9 mmol/l (198-268) Increase rate by 3
  ml/h
• 7 to 10.9 mmol/l (126-196) No change
• 4 to 6.9 mmol/l (72-124) Decrease rate by 6 ml/h
• Test FSG q 15 minutes until mmol/l. If
  symptomatic, give 20 ml of 30 glucose i.v. Then
  restart infusion with a rate decreased by 6 ml/h
  when FSG 7 mmol/l.

49
DIGAMI Insulin treatment

• Treatment Group Infusion continued until
  normoglycemia was obtained and always 24 hours.
  Then converted to sub q insulin as short acting
  before meals and intermediate acting at bedtime.
• Control GroupReceived insulin when it was
  deemed clinically indicated

50
DIGAMI AMI treatment

• Streptokinase (if not contraindicated)
  administered to all patients presenting within 6
  hours of symptoms and having 1 mm ST elevation
  in the limb leads or 2 mm ST elevation in the
  chest leads or new left bundle branch block.
  Streptokinase use at 50.
• Beta-blockers as i.v. and oral metoprolol
  administered to 70 of patients.
• Heparin administered to 17.
• Aspirin given to almost all ( 80 discharged
  on ASA).

51
DIGAMI

• Baseline characteristics and cardiac treatment
  similar between treatment and control groups.

52
DIGAMI Biochemical Variables
53
DIGAMI Follow-up data

• All patients were seen by the investigators at 3
  months and one year after randomization. After
  this time patients were seen at regular visits
  according to the patients need.
• At 3.4 years no (ZERO) patients were lost to
  follow-up.

54
DIGAMI Insulin Usage
55
DIGAMI Follow up glycemic control
56
DIGAMI Mortality Data
57
DIGAMI Mortality in Low Risk, No Prior Insulin
Patients (STRATUM 1)
58
DIGAMI Conclusion

• Insulin-glucose infusion followed by multidose
  subcutaneous insulin reduces mortality after
  myocardial infarction in diabetic patients.
• Patients considered low risk and not previously
  on insulin may benefit more rapidly and more
  dramatically than other patients.

59
DIGAMI Concerns and Arguments

• (1) Other medications not reported at one year
  and 3.4 years (i.e. Beta-blockers,ASA)
• (2) Sicker patients excluded
• (3) More frequent visits to physicians (thus
  better general care) in insulin group could have
  produced improved survival
• (4) Overall reduction in mortality after MI (both
  treatment and insulin group) could indicate bias

60
Intense Insulin after Myocardial Infarction in
DiabeticsConclusions

• Until recently only limited interest in intensive
  insulin therapy after MI in DM
• The pathophysiology of DM and plaque rupture
  points to potential benefit with insulin.
• DIGAMI is the first large study to show the
  benefit of insulin.
• Certain subgroups may benefit more than others
  (i.e. low risk, no prior insulin)
• DIGAMI 2 on the horizon.