Table Of ContentTHERAPEUTIC STRATEGIES IN DIABETESAND CARDIOVASCULAR DISEASE
CONTENTS
Foreword ix
Michael H. Crawford
Preface xi
Prakash C. Deedwania
TheRoleofIntensiveGlycemicControlintheManagementofPatientswho
have Acute Myocardial Infarction 109
Stuart W. Zarich
This article discusses the role of intensive glycemic control in the management of pa-
tients who haveacute myocardialinfarction.
Role of Insulin Secretagogues and Insulin Sensitizing Agents in the
Prevention of Cardiovascular Disease in Patients who have Diabetes 119
Ali A. Jawa and Vivian A. Fonseca
This article examines the evidence in favor or against choosing treatment with insulin
secretagogues or sensitizers as the preferred way to prevent cardiovascular events. It
shouldbeemphasizedthatmostpatientseventuallywillbetreatedwithacombination
oftherapies;therefore,muchofthediscussionmaynotberelevant.Conversely,combi-
nationoftwosensitizersmayhaveaddedeffects.Also,retrospectivedatasuggestthata
combinationofsulfonylureaandmetforminmaybeassociatedwithincreasedcardiovas-
cularevents.Nevertheless,itisimportanttorecognizetherelativevalueofthesediffer-
ent agentsas we choose complex therapeutic regimens.
Diabetes and Hypertension, the Deadly Duet: Importance, Therapeutic
Strategy, and Selection of Drug Therapy 139
Prakash C. Deedwania
Thecoexistenceofhypertensionanddiabetesdramaticallyandsynergisticallyincreases
the risk of microvascular and macrovascular complications. Overwhelming evidence
supportsaggressivetreatmentofhypertensionindiabeticpatients.Tightbloodpressure
controliscost-effectiveandismorerewardingthanglycemiccontrol.Theoptimalgoalof
bloodpressurecontrolindiabeticsshouldbe130/80mmHg.Insubjectswhohavedia-
betesandrenalinsufficiency,thebloodpressureshouldbeloweredto125/75mmHgto
delaytheprogressionofrenalfailure.Thechoiceofanantihypertensiveagentshouldbe
basedonproveneffectsonmorbidityandmortalityratherthanonsurrogateparameters,
such as lipid or glucose. Limited data suggest that an angiotensin-converting enzyme
(ACE)inhibitoristheagentofchoice,especiallyinthosewhohaveproteinuriaorrenal
insufficiency.b-Blockerscanbethefirst-lineagentindiabeticswhohavecoronaryheart
Æ Æ
VOLUME23 NUMBER2 MAY2005 v
disease.Thiazidediureticsandcalcium-channelblockersarethesecond-linedrugs.An-
giotensinII-receptorblockersmayprovetobeaseffectiveasACEinhibitorsindiabetics
whohavehypertension.a-Adrenergicantagonistsshouldbeavoided.Mosthypertensive
patients require more than one agent to control their blood pressure. There is no evi-
dence to support one combination regimen over others; however, the combination of
ACE-I with a thiazide diuretic ora b-blocker maybethe mostcost effective regimen.
The Role of Lipid Management in Diabetes 153
Om P. Ganda
This article discusses the role oflipid managementin diabetes.
The Renin Angiotensin System as a Therapeutic Target to Prevent Diabetes
and its Complications 165
Kris Vijayaraghavan and Prakash C. Deedwania
Thisreviewaddressestheevidenceofpreventionofdiabetesthroughlifestylemodifica-
tion, itschallenges,andadditionalmeansthroughpharmacologicinterventions specifi-
cally targeting the renin angiotensin aldosterone system that may reduce the overall
public and economic health burden.
Percutaneous Coronary Intervention Versus Coronary Artery Bypass
Grafting in Diabetic Patients 185
Debabrata Mukherjee
Clinical outcomes in diabetic patients following coronary revascularization procedures
with bypass surgery (CABG) or percutaneous coronary intervention (PCI) are worse
than in nondiabetics. Current evidence suggests that CABG is preferable to PCI for re-
vascularizationinpatientswhohavediabetesandmulti-vesselcoronaryarterydisease.
Most trialshave notusedcontemporary adjunctivetherapies, such asGP IIb/IIIainhi-
bitorsandprolongeddualantiplatelettherapy.Itisconceivablethatimplementationof
these evidence-based therapies may improve clinical outcomes significantly in diabetic
patients who undergo PCI. In the future, emerging technologies, such as drug-eluting
stents and soluble receptor for advanced glycation end products, may further improve
outcomes after PCIand make itthepreferred revascularizationmodality in diabetics.
Comprehensive Risk Reduction of Cardiovascular Risk Factors in the
Diabetic Patient: An Integrated Approach 193
Sundararajan Srikanth and Prakash Deedwania
Thisarticlediscussesthebenefitsofanintegrated,comprehensiveapproachtoreduction
of cardiovascular risk factorsin diabetic patients.
Prevention of Cardiovascular Outcomes in Type 2 Diabetes Mellitus: Trials
on the Horizon 211
John B. Buse and Julio Rosenstock
Thisarticlefocusesonthecontinuingclinicaltrialsinpatientswhohavediabetesmelli-
tus and pre–diabetes mellitus in which cardiovascular disease outcomes—specifically,
myocardial infarction, stroke, and cardiovascular death—are examined as primary
outcomes.
Index 221
vi CONTENTS
FORTHCOMING ISSUES
August 2005
Cardio-RenalDisease
Ragavendra R.Baliga,MD, FACC, FRCP(Edin),
Rajiv Saran,MD,MPH, and
SanjayRajagopalan, MD,Guest Editors
November2005
ChestPain Units
EzraA.Amsterdam,MD,and
J.Douglas Kirk, MD,FACEP,Guest Editors
February 2006
EmergencyCardiac Care:FromEDtoCCU
AmalMattu, MD,and MarkKelemen, MD,MSc
GuestEditors
RECENT ISSUES
November2004
Diabetes andCardiovascular Disease
PrakashC.Deedwania,MD,FACC,FACP,FCCP,FAHA
GuestEditor
August 2004
Pulmonary Vascular Disease
OriBen-Yehuda,MD, GuestEditor
May2004
ContrastEchocardiography
ManiA.Vannan, MBBS,and
Anthony N.Demaria, MD,Guest Editors
VISIT OUR WEB SITE
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Accessyoursubscription atwww.theclinics.com
CardiolClin23(2005)ix
Foreword
Therapeutic Strategies in Diabetes and
Cardiovascular Disease
MichaelH.Crawford,MD
ConsultingEditor
Diabetes is now considered the equivalent of with management strategies for preventing and
having 2 or 3 major risk factors for coronary treating the cardiovascular complications of di-
atherosclerosis. Also, the presence of diabetes abetes. I am indebted to Dr. Deedwania and the
increases the risk of any procedure and is associ- group of experts he has assembled for these two
ated with a poorer prognosis compared with importantissues.Editingoneissueisabigjob,let
individuals without diabetes. Also, diabetes dic- alone two. However, Dr. Deedwania has had a
tates certain clinical approaches to disease. Thus long-standing academic and clinical interest in
today’sclinicianneedsafullunderstandingofthis diabetes andmetabolic syndrome in cardiovascu-
diseaseanditseffect onmanagement decisions. lar disease. His dedication to improving care for
I was delighted that Dr. Prakash Deedwania, these individuals is evident in these two issues of
who has had a long and productive interest in the Cardiology Clinics.
diabetesandcardiovasculardisease,waswillingto
organize and contribute to articles on this topic.
Michael H. Crawford, MD
This broad topic has been divided between two
Division of Cardiology
issues of the Cardiology Clinics. The first issue
University ofCalifornia
(November 2004) dealt with pathophysiology,
505ParnassusAve., Box0124
clinical epidemiology, and the relationship be-
SanFrancisco,CA94143-0124,USA
tween diabetes and other diseases such as heart
failure and hypertension. The second issue deals E-mail address:[email protected]
0733-8651/05/$-seefrontmatter(cid:1)2005ElsevierInc.Allrightsreserved.
doi:10.1016/j.ccl.2005.01.001 cardiology.theclinics.com
CardiolClin23(2005)xi–xii
Preface
Therapeutic Strategies in Diabetes and Cardiovascular
Disease
PrakashC.Deedwania,MD,FACC,FACP,FCCP,FAHA
GuestEditor
Cardiovascular (CV) complications are the realizethatbecauseoftheoverallincreasedabso-
leading cause of death and disability in patients lute risk of CV events, diabetic patients tend to
withtypeIIdiabetesmellitus.Asdescribedinthe benefitmorewithmostoftheeffectiveriskfactor
November2004issueoftheCariologyClinics,itis interventions.Basedontheresultsofthesestudies,
importanttorecognizethatvascularabnormalities various guideline committees have set aggressive
and dysfunction begin in the prediabetic phase, goals for therapy in diabetic patients. However,
whichoftenprecedesdevelopmentofclinicalsigns despite the available evidence and guideline rec-
and symptoms of diabetes by an average of 5 to ommendations, most diabetic patients are not at
6years. goal blood pressure, target lipid levels, or good
Althoughdueemphasishasbeenplacedontight long-termglycemiccontrol.Seriousmedicalatten-
controlofbloodglucoseindiabeticpatientsduring tion and concerted clinical efforts are needed to
the past two decades, the management of other achieve adequate control of all risk factors in
frequentlyassociatedcoronaryriskfactorshasnot diabetic patients to provide maximum CV pro-
received as much attention. A large number of tection. It is also important to realize that such
randomized clinical trials have now shown that interventionsarenotonlygoodforthesepatients,
aggressive management of most associated risk theyarecost-effectiveaswell.
factors—in particular hypertension and hyperlip- It was with the above points in mind and the
idemia in diabetic patients—is associated with obvious need to examine the benefits of various
significant reduction of the risk of future CV treatment options in diabetic patients that this
events. As a matter of fact, beginning with the issue of the Cardiology Clinics was conceived. Its
findings from the United Kingdom Prospective primary goal is to present state-of-the-art articles
Diabetes studies, many of the trials have demon- that examine and summarize the most relevant
stratedthattightcontrolofbloodpressureismore literature dealing with treatment of various com-
beneficialinreducingtherateofCVcomplications ponentsthatareassociatedwithincreasedriskof
indiabeticpatients.Similarresultsarebeginningto CVcomplicationsindiabetes.Theauthorsrepre-
emergefromthetrialswithstatinsinpatientswith sent an outstanding group of internationally
diabetes. Although more work is needed, there is recognized authorities in their field.
emerging evidence that for maximum CV pro- The first article examines the role of intensive
tection comprehensive risk reduction approach is glycemic control during the acute phase of acute
necessary and feasible. It is also important to myocardial infarction in diabetic patients. Thisis
0733-8651/05/$-seefrontmatter(cid:1)2005ElsevierInc.Allrightsreserved.
doi:10.1016/j.ccl.2004.12.001 cardiology.theclinics.com
xii PREFACE
followed by an article describing and comparing riskreductionapproachthatincorporatesaggres-
the role of traditional oral hypoglycemic drugs sive risk factor modification is necessary. The
such as insulin secretagogues and the newer articlebySrikantandDeedwaniaprovidesacrit-
insulin-sensitizing agents in preventing CV com- ical appraisal and clinically meaningful ideas to
plications of diabetes. The next article deals with incorporate an integrated approach for compre-
thecommonproblemofthedeadlyduetofdiabetes hensive CV risk reduction in diabetes. The last
and hypertension and describes the totality of article in the issue provides the rationale and
evidence demonstrating the benefits of aggressive summary of various clinical trials examining a
blood pressure reduction in reducing the rate of variety of therapeutic approaches for the pre-
coronaryevents,congestiveheartfailure,strokes, vention of CVcomplicationsin diabetes.
andrenalcomplicationsinpatientswithdiabetes. It is my hope that the compendium of articles
It is now well recognized that many diabetic in this issue spanning from established therapies
patientshaveatherogenicdyslipidemia.Anumber to emerging treatments and therapeutic ap-
of recent clinical trials have also documented the proaches in the future will help clinicians achieve
benefits of lipid-lowering therapies in diabetic thegoalofprovidingmaximumCVprotectionto
patients. The article by Ganda provides a critical patients withdiabetes.
appraisal regarding various issues dealing with IwouldliketothankMichaelCrawford,MD,
lipid abnormalities and management considera- the Consulting Editor of the Cardiology Clinics,
tionsindiabetes.Thebestapproachforprevention for inviting me to compile this second issue
of CV complications in diabetes would be pre- dealing with diabetes and CV disease. I would
ventionofdiabetesitself,anditiswiththispointin especiallyliketoexpressmygratitudetoallofthe
mindthatthenextarticleintheissuedescribesthe contributorsandcollaboratorsforprovidingtheir
preventivestrategieswithspecialemphasisonthe input and articles in a timely manner. Finally,
emergingevidencesuggestingpotentialbenefitsof I would like to thank my family and friends,
renal-angiotensin system blockade in the preven- who are always so supportive of my academic
tionofdiabetesandtherelatedCVcomplications. endeavors.
Eversincetheresultsofthebypassangioplasty
revascularizationinvestigationtrialbecameavail-
Prakash C.Deedwania, MD,
able there has been considerable controversy
FACC, FACP, FCCP, FAHA
regarding the most appropriate revasculariza-
Veterans Administration
tion strategy in diabetic patients. The article by
CentralCalifornia
Mukherjee provides a comprehensive review
Health CareSystem
regarding the role of percutaneous coronary in-
University ofCalifornia–San Franciscoat Fresno
tervention versus coronary artery bypass graft
2615E. Clinton Avenue
surgeryindiabetes.Finally,asstatedearlier,there
Fresno, CA93703,USA
isemergingevidencethattoachievethemaximum
benefits of therapeutic strategy, a comprehensive E-mailaddress: [email protected]
CardiolClin23(2005)109–117
The Role of Intensive Glycemic Control
in the Management of Patients who have
Acute Myocardial Infarction
Stuart W. Zarich, MD, FACC
DivisionofCardiovascularMedicine,DepartmentofMedicine,BridgeportHospital,
267GrantStreet,Bridgeport,CT06610,USA
YaleUniversitySchoolofMedicine,333CedarStreet,NewHaven,CT06510,USA
Individuals who have diabetes mellitus (DM) correlatenecessarilywiththeextentofmyocardial
have a twofold to fourfold increased risk of damage as measured by myocardial enzyme re-
cardiovascular disease and nearly twice the early lease [9,13]. A large, randomized, controlled trial
mortalityfromacutemyocardialinfarction(AMI) in diabetics who had AMI showed that reduced
compared with nondiabetic subjects [1–5]. Fur- short- and long-term mortality in low- and high-
thermore, the mortality difference between dia- risksubjectswasassociatedwithloweringplasma
betics and nondiabetics continues to increase glucose with insulin [14–16]. This suggests that
throughout the first year [4]. For more than 70 hyperglycemia is not just a passive by-product
years it has been recognized that glucosuria is of the stress response in the most critically
present frequently in nondiabetic patients who ill patients. Low-risk diabetic individuals and
have AMI [6]. Acute hyperglycemia is docu- those who had previous insulin use benefited
mented in up to half of all patients who have the most from aggressive management of
AMI, whereas previously diagnosed DM is pres- hyperglycemia.
entin only20%to 25%of thesepatients [7,8]. Analternativeexplanationfortherelationship
Elevated plasma glucose and glycated hemo- between glucose levels that are measured upon
globin levels at admission are recognized as in- hospital admission and prognosis is the link
dependent prognosticators of in-hospital and between insulin resistance, the metabolic syn-
long-term cardiovascular events in diabetics and drome, and cardiovascular (CV) disease. Meta-
nondiabeticswhohaveAMI[8–12].Acutehyper- bolic syndrome is characterized by insulin
glycemia is associated with an approximate four- resistance and the association with traditional
fold risk of death with AMI in nondiabetics (the ‘‘deadly quartet’’ of obesity, hypertension,
compared with a nearly twofold increased risk glucose intolerance, atherogenic dyslipidemia)
ofdeathin diabetic individuals [10]. andnovel(endothelialdysfunction,proinflamma-
It is not clear whether ‘‘stress hyperglycemia’’ torystate,hypercoagulability)riskfactorsforthe
predisposesonetoaworseprognosisorissimply development of CV disease and DM [17,18]. The
a marker for more extensive myocardial damage. metabolic syndrome is present in approximately
Acute hyperglycemia in AMI probably is not 30% of middle-aged men [17] and is associated
related simply to stress-mediated release of coun- with a threefold to fourfold increase in CV
terregulatory hormones (catecholamines, gluca- mortality as compared with controls, even when
gon, and cortisol) because glucose levels that are patients who had known CV disease and DM
measured upon hospital admission do not were excluded from analysis [18]. Patients who
have insulin resistance and frank DM also may
have a host of associated conditions (Box 1) that
E-mailaddress:[email protected] maycontribute toa poor CVprognosis.
0733-8651/05/$-seefrontmatter(cid:1)2005ElsevierInc.Allrightsreserved.
doi:10.1016/j.ccl.2004.06.004 cardiology.theclinics.com
110 ZARICH
Box1. Associated conditionswhichmay help toexplainthe pooroutcome
in DMandInsulin resistance
Maladaptive left ventricularremodelingof thenoninfarct zone
Influenced by:
Increasedprevalenceof silentmyocardial infarction
Automatic neuropathy
Increasedcollagen depositioninthe myocardium
Increasedendothelial dysfunction that leads tomyocardial ischemia
Diabetic cardiomyopathy
Increased severity andextentofcoronary artery disease
Associated conditions
Older ageand associatedcomorbidity
Endothelial dysfunction
Autonomic dysfunction (sympathovagalimbalance)
Abnormalities ofcoagulation, fibrinolysis,platelet function
Other established vasculardisease
Associated features
Hypertension
Dyslipidemia (increased very lowdensitylipoprotein, triglycerides, andsmall dense low
density lipoprotein,low highdensitylipoprotein)
Obesity
Insulin resistance
Renal disease:microalbuminuria, proteinuria, andnephropathy
Reduced developmentofcoronary collateral vessels
RecentdatashownthattheprevalenceofDM Acutehyperglycemiaisassociatedwithamyr-
or impaired glucose tolerance (IGT) may be as iadofadversemetabolicandCVeffectsthatmay
highas70%inpatientswhohaveAMI[19].In181 contribute to a poor outcome in AMI (Box 2).
consecutive nondiabetics who had AMI, more Exaggeratedmetabolicresponsestoischemiamay
than two thirds of patients were diagnosed with play a crucial role in myocardial oxygen use in
DM or IGT by oral glucose tolerance testing. AMI. Hyperglycemia is a reflection of relative
Previously undiagnosed DM accounted for one insulinopenia, which is associated with increased
halfofallpatientswhohadAMIandanabnormal lipolysis and free fatty acid (FFA) generation,
glucosemetabolism.Onlyonethirdofsubjectsmet diminished myocardial glucose uptake, and a de-
criteria for DM based on fasting blood glucose crease in glycolytic substrate for myocardial
criteria. Althougha randomblood glucoseat the energy needs in AMI [22–24]. Although glucose
timeofadmissionforAMImaynotbereliablein metabolism is a major myocardial energy source,
making the diagnosis of DM, concern that the oxidationofFFAsistheprimarysourceofenergy
diagnosisofIGTorDMiserroneousintheacute in the resting aerobic state. During myocardial
setting because of ‘‘stress hyperglycemia’’ may be ischemia, FFA oxidation rates decrease but re-
unwarranted; the results of glucose tolerance main an important source of energy. During
testing that was performed at the time of AMI reperfusion,fattyacidoxidationagaindominates
were similar to those performed 3 months later. as a source ofenergy.
Two recent studies in patients who presented for Myocardial ischemia results in an increased
coronary angiography similarly showed that pre- rate of glycogen breakdown and glucose uptake
viouslyundiagnosedDMorIGTwaspresentinup by way of translocation of glucose transport
to two thirds of patients who had angiographi- receptors (GLUT-4) to the sarcolemma [25,26].
cally-provencoronaryarterydisease[20–21]. This adaptive mechanism is important because
INTENSIVEGLYCEMICCONTROLINMANAGEMENTOFAMI 111
Box2. Acute effectsofhyperglycemia inacutemyocardial infarction
Endothelial dysfunction
Platelet hyperreactivity
Increased cytokineactivation
Increased lipolysisandFFAlevels
Reduced glycolysis andglucoseoxidation
Osmotic diuresis(potentially reducedcardiac output)
Increased oxidative stress(? increasedmyocardial apoptosis)
Impairedmicrocirculatory function (no reflowphenomenon)
Impairedischemic preconditioning
Impairedinsulin secretion andinsulin-stimulated glucose uptake
glucose oxidation requires less oxygen than FFA thrombolysis)forpatientswhohadAMIreduced
oxidation to maintain ATP production. Thus, in-hospitalmortalityby66%.Therewasaremark-
myocardial energy use is more efficient during able reduction in absolute mortality of 10%
the increased dependence on glucose oxidation (15.2% to 5.2%) in GIK-treated reperfused pa-
with ischemia (approximately 11% more ATP is tients versuscontrols.
generated from glucose oxidation as compared Despite nearly a half century of study and its
with FFA oxidation). In the setting of relative low cost and minimal side-effect profile, accep-
insulinopenia (insulin resistance or frank DM) tance of the GIK metabolic cocktail in AMI has
that is exacerbated by the stress of AMI, the not been forthcoming. The lack of enthusiasm
ischemicmyocardiumisforcedtouseFFAsmore over the use of GIK in AMI seems to stem from
than glucose for an energy source because myo- the lack of large randomized trials, controversy
cardial glucose uptake is impaired acutely. Thus, overlow-versushigh-dosetherapy,andacumber-
despite acute hyperglycemia, a metabolic crisis some mode of delivery that requires a large
may ensue as the hypoxic myocardium becomes volume load. Collectively, clinical studies suggest
lessenergyefficientinthesettingoffrankDMor that the dose of insulin must be optimized to
insulin resistance. confer benefit; little effect is seen with low-dose
InsulinaugmentsthetranslocationofGLUT-1 GIK protocols [30–31]. In addition, GIK studies
and GLUT-4 receptors to the sarcolemma and have contained only a small number of high-risk
can diminish FFA release from myocytes and patients who had congestive heart failure or
adipocytes [27]. Thus, the extent to which the cardiogenic shock.
myocardium expresses an intact response to in- Recently,VanderHorstetal[32]reportedthe
sulin, therapeutic augmentation of oxidative glu- results of the largest study to date of GIK in
cose metabolism by way of exogenous insulin, or combination with acutereperfusion withprimary
improvedinsulinsensitivitymayplayausefulrole angioplasty. Overall, in this 940-patient Dutch
for improving outcomes in patients who have study, there was no difference in mortality be-
hyperglycemia and relative insulinopenia as the tween those who received GIK and those who
resultofaninsulin-resistantstate.Theconceptof receivedplacebo(4.8%versus5.8%;P=0.5).In
ametaboliccocktailtopromoteglucoseoxidation 856 patients who did not have heart failure,
and reduce FFA levels to protect the ischemic mortality was reduced 72% with GIK as com-
myocardiumdatesbacktoSodi-Pallaresetal[28]. paredwithplacebo(1.2%versus4.2%;P<0.005).
Early studies yielded promising results; a subse- There was a nonsignificant trend toward benefit
quent meta-analysis of 1932 patients who had in the diabetic subgroup. The prevalence of the
AMIsuggestedthattherapywithglucose-insulin- highest quartile of infarct size also was reduced
potassium (GIK) reduced mortality by 28% [29]. among subjects who received GIK (22% versus
Mortality was reduced by 48% in a subgroup of 29%; P < 0.005), with a trend toward a lower
patientswhoreceived high-dose GIK to suppress prevalence of ejection fractions less than 30%
FFAlevelsmaximally.AprominentLatinAmer- (13% versus 17%; P=0.2) in subjects who
icanStudy[30]furthersuggestedthatGIKinthe received GIK compared with subjects who did
setting of acute reperfusion (predominantly not.
112 ZARICH
GIK was not beneficial, however, in patients was significantly lower than the estimated mor-
who had congestive heart failure in the Dutch tality for the group at 2 years, and the mean
study,ascomparedwithatrendtowardbenefitin hemoglobin A1c at the time of enrollment in all
the Latin American trial. The sample size of three groups was relatively low at 7.3%. The
patients who had heart failure was small in both glucose goal was not reached in the intensive
studies and the infusion rate was twice as fast in therapy group; 41% of patients in the control
theDutchstudy;thisresultedinmorethan2Lof group with routine care received extra insulin in
fluid being delivered in the first 8 hours. Addi- the hospital, and 14% received insulin infusions.
tionally, successful reperfusion was accomplished Multidose insulin for glucose lowering was given
in only a modest number of patients who had to only 42% of patients chronically in the inten-
heart failure in both studies. Outcomes were sivelymanagedgroup(comparedwith13%–15%
remarkably similar in GIK-treated patients who in the two remaining groups). Glucose control
did not have heart failure in the aforementioned over the duration of the study was similar in the
studies, despite a wide range in the duration of three groups (mean hemoglobin A1c: 6.8%). The
symptoms before GIK therapy (2.5 to 11 hours). mortality ranged between 19.3% and 23.4%
To help to address the issues that surround GIK between the three groups, which was not statisti-
therapy,alarge,randomizedtrialofGIKtherapy cally significant.
in AMI is currently in progress (GIK II: http:// There was appropriate use of cardioprotective
www.ecla.org.ar). drugs during AMI in the DIGAMI-2 trial. At
In the Diabetes Mellitus Insulin Glucose In- hospital discharge, beta-blockers were given to
fusioninAcuteMyocardialInfarction(DIGAMI) over 80% of the patients, aspirin was given to
trial[14–16],acutetreatmentforatleast24hours nearly 90% of the patients, and angiotensin-
with intravenous GIK until blood sugar was converting enzyme (ACE) inhibitors and statin
controlled, coupled with aggressive subacute therapy were given to approximately 65% of the
treatment with subcutaneous insulin, resulted in patients. The overall 2-year mortality of approx-
a 29% relative reduction in 1-year mortality in imately 20%, although significantly lower than
a cohort of patients thatpredominantly hadtype the30%notedintheDIGAMI-1trial,isevidence
2DM.Ascomparedwith43%ofcontrolpatients, that there is still much work to do. Overall these
87% of GIK-treated patients were discharged on results suggest that the mode of glucose therapy
insulin.Patientswhohadpreviousinsulinuseand may not matter as much as aggressive glucose
a low CV risk profile had the most promising control.Becauseallthreegroupsreachedasimilar
results (58% reduction in in-hospital mortality meanA1cofbelow7%,thehypothesisofthetrial
and 52% reduction in 1-year mortality). Hypo- was not fully tested. Additionally, there was
glycemia occurred in 15% of patients who re- significant crossover with the use of both acute
ceived insulin infusion; however, only 10% of intravenous insulin therapy and chronic insulin
patients required discontinuation of their insulin therapy in the three groups, complicating the
infusion. analysis of insulin-based therapy compared with
Recently, the results of the DIGAMI-2 trial the routine use of oral hypoglycemic agents after
further highlighted the importance of glucose myocardial infarction.
lowering in AMI. However, this pivotal trial, Acutely GIK therapy decreases lipolysis and
whichwasreleasedatthe 2004EuropeanAssoci- improves glucose oxidation; aggressive metabolic
ationfortheStudyofDiabetes,failedtoshowan therapyalsoisassociatedwithamyriadofeffects
improvement in total mortality in diabetic pa- in ischemic/reperfused myocardium and in non-
tients with AMI undergoing intensive insulin infarctedmyocardiumthatisexposedtoincreased
therapy.Thetrialwasinitiallydesignedtoinclude afterload stress (Box 3). FFA levels rapidly in-
3000 subjects but was stopped at 1253 subjects crease in AMI as a result of the lipolysis that is
due to poor enrollment. DIGAMI-2 compared secondary to catecholamine excess (and the pre-
acute insulin–glucose infusion followed by an sence of heparin). FFAs are directly toxic to the
insulin-based long-term glucose control with in- myocardium,promotearrhythmogenesis,and,are
sulin–glucose infusion followed by standard glu- inefficient as a metabolic substrate. GIK shifts
cosecontrolorroutinemetabolicmanagementin oxidative metabolism from FFA to glucose, low-
thethirdgroupaccordingtophysiciandiscretion. ers circulating FFA levels, and seems to protect
The results of the DIGAMI-2 trial were con- myocytes from increasing intracellular calcium
founded by several factors. The actual mortality levels that are associated with ischemia [33].
