The observation that elevated glucose occurs frequently in the setting of acute myocardial infarction was made decades ago. Since then numerous studies have documented that hyperglycemia is a powerful risk factor for increased mortality and in-hospital complications in patients with acute coronary syndromes. While some questions in this field have been answered in prior investigations, many critical gaps in knowledge continue to exist and remain subjects of intense debate. This review summarizes what is known about the relationship between hyperglycemia, glucose control, and outcomes in critically ill patients with acute coronary syndromes, addresses the gaps in knowledge and controversies, and offers general recommendations regarding glucose management in the coronary care unit.
DateyKNandaN. Hyperglycemia after acute myocardial infarction: its relation to diabetes mellitus. N Engl J Med.1967;276 (5): 262–65.
2.
KosiborodMRathoreSSInzucchiSEMasoudiFAWangYHavranekEPKrumholzHM. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation.2005;111 (23): 3078–86.
3.
BellodiGManicardiVMalavasiVVeneriLBerniniGBossiniPDistefanoSMagnaniniGMuratoriLRossiGHyperglycemia and prognosis of acute myocardial infarction in patients without diabetes mellitus. Am J Cardiol.1989;64 (14): 885–8.
4.
CapesSEHuntDMalmbergKGersteinHC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet.2000;355 (9206): 773–8.
5.
FooKCooperJDeanerAKnightCSulimanARanjadayalanKTimmisAD. A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes. Heart.2003;89 (5): 512–6.
6.
IwakuraKItoHIkushimaMKawanoSOkamuraAAsanoKKurodaTTanakaKMasuyamaTHoriMFujiiK. Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction. J Am Coll Cardiol.2003;41 (1): 1–7.
7.
LeorJGoldbourtUReicher-ReissHKaplinskyEBeharS. Cardiogenic shock complicating acute myocardial infarction in patients without heart failure on admission: incidence, risk factors, and outcome. SPRINT Study Group. Am J Med.1993;94 (3): 265–73.
8.
MadsenJKHaunsoeSHelquistSHommelEMaltheIPedersenNTSengelovHRonnow-JessenDTelmerSParvingHH. Prevalence of hyperglycaemia and undiagnosed diabetes mellitus in patients with acute myocardial infarction. Acta Med Scand.1986;220 (4): 329–32.
9.
MakKHMahPKTeyBHSinFLChiaG. Fasting blood sugar level: a determinant for in-hospital outcome in patients with first myocardial infarction and without glucose intolerance. Ann Acad Med Singapore.1993;22 (3): 291–5.
10.
O'SullivanJJConroyRMRobinsonKHickeyNMulcahyR. In-hospital prognosis of patients with fasting hyperglycemia after first myocardial infarction. Diabetes Care.1991;14 (8): 758–60.
11.
OswaldGACorcoranSYudkinJS. Prevalence and risks of hyperglycaemia and undiagnosed diabetes in patients with acute myocardial infarction. Lancet.1984;1 (8389): 1264–7.
12.
OswaldGASmithCCBetteridgeDJYudkinJS. Determinants and importance of stress hyperglycaemia in non-diabetic patients with myocardial infarction. Br Med J (Clin Res Ed).1986;293 (6552): 917–22.
13.
SalaJMasiaRde MolinaFJ GonzalezFernandez-RealJMGilMBoschDRicartWSentiMMarrugatJ; REGICOR Investigators. Short-term mortality of myocardial infarction patients with diabetes or hyperglycaemia during admission. J Epidemiol Community Health.56 (9): 707–12.
14.
SewdarsenMJialalIVythilingumSGovenderGRajputMC. Stress hyperglycaemia is a predictor of abnormal glucose tolerance in Indian patients with acute myocardial infarction. Diabetes Res.1987;6 (1): 47–9.
15.
WahabNNCowdenEAPearceNJGardnerMJMerryHCoxJL. Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era?. J Am Coll Cardiol.2002;40 (10): 1748–54.
16.
YudkinJSOswaldGA. Stress hyperglycemia and cause of death in non-diabetic patients with myocardial infarction. Br Med J (Clin Res Ed).1987;294 (6574): 773.
17.
BolkJvan der PloegTCornelJHArnoldAESepersJUmansVA. Impaired glucose metabolism predicts mortality after a myocardial infarction. Int J Cardiol.2001;79 (2–3): 207–14.
18.
OswaldGAYudkinJS. Hyperglycaemia following acute myocardial infarction: the contribution of undiagnosed diabetes. Diabet Med.1987;4 (1): 68–70.
19.
WongVWRossDLParkKBoyagesSCCheungNW. Hyperglycemia: still an important predictor of adverse outcomes following AMI in the reperfusion era. Diabetes Res Clin Pract.2004;64 (2): 85–91.
20.
HadjadjSCoisneDMaucoGRagotSDuenglerFSosnerPTorremochaFHerpinDMarechaudR. Prognostic value of admission plasma glucose and HbA in acute myocardial infarction. Diabet Med.2004;21 (4): 305–10.
21.
StrandersIDiamantMvan GelderRESpruijtHJTwiskJWHeineRJVisserFC. Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus. Arch Intern Med.2004;164 (9): 982–8.
22.
IshiharaMInoueIKawagoeTShimataniYKurisuSNishiokaKUmemuraTNakamuraSYoshidaM. Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction. Am J Heart.2003;146 (4): 674–8.
23.
SvenssonAMMcGuireDKAbrahamssonPDellborgM. Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J.2005;26 (13): 1255–61.
24.
KadriZDanchinNVaurLCottinYGueretPZellerMLablancheJMBlanchardDHananiaGGenèsNCambouJP; USIC 2000 Investigators. Major impact of admission glycaemia on 30-day and one-year mortality in non-diabetic patients admitted for myocardial infarction: results from the nationwide French USIC 2000 study. Heart.2006;92 (7): 910–5.
25.
SuleimanMHammermanHBoulosMKapeliovichMRSuleimanAAgmonYMarkiewiczWAronsonD. Fasting glucose is an important independent risk factor for 30-day mortality in patients with acute myocardial infarction: a prospective study. Circulation.2005;111 (6): 754–60.
26.
MeierJJDeifussSKlamannALaunhardtVSchmiegelWHNauckMA. Plasma glucose at hospital admission and previous metabolic control determine myocardial infarct size and survival in patients with and without type 2 diabetes: the Langendreer Myocardial Infarction and Blood Glucose in Diabetic Patients Assessment (LAMBDA). Diabetes Care.2005;28 (10): 2551–3.
27.
DeedwaniaPKosiborodMBarrettECerielloAIsleyWMazzoneTRaskinP; American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation.117 (12): 1610–19.
28.
KosiborodMInzucchiSEKrumholzHMXiaoLJonesPGFiskeSMasoudiFAMarsoSPSpertusJA. Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk. Circulation.2008;117 (8): 1018–27.
29.
SinnaevePRStegPGFoxKAVan de WerfFMontalescotGGrangerCBKnobelEAndersonFADabbousOHAvezumA; GRACE Investigators. Association of elevated fasting glucose with increased short-term and 6-month mortality in ST-segment elevation and non-ST-segment elevation acute coronary syndromes: the Global Registry of Acute Coronary Events. Arch Intern Med.169 (4): 402–9.
30.
AronsonDHammermanHKapeliovichMRSuleimanAAgmonYBeyarRMarkiewiczWSuleimanM. Fasting glucose in acute myocardial infarction: incremental value for long-term mortality and relationship with left ventricular systolic function. Diabetes Care.2007;30 (4): 960–6.
31.
PorterAAssaliARZahalkaAIakobishviliZBroshDLevEIMagerABattlerAKornowskiRHasdaiD. Impaired fasting glucose and outcomes of ST-elevation acute coronary syndrome treated with primary percutaneous intervention among patients without previously known diabetes mellitus. Am Heart J.2008;155 (2): 284–9.
32.
VergesBZellerMDentanGBeerJCLaurentYJanin-ManificatLMakkiHWolfJECottinY. Impact of fasting glycemia on short-term prognosis after acute myocardial infarction. J Clin Endocrinol Metab.2007;92 (6): 2136–40.
33.
DiazRGoyalAMehtaSRAfzalRXavierDPaisPChrolaviciusSZhuJKazmiKLiuLBudajAZubaidMAvezumARudaMYusufS. Glucose-insulin-potassium therapy in patients with ST-segment elevation myocardial infarction. JAMA.2007;298 (20): 2399–405.
34.
CheungNWWongVWMcLeanM. The Hyperglycemia: Intensive Insulin Infusion in Infarction (HI-5) study: a randomized controlled trial of insulin infusion therapy for myocardial infarction. Diabetes Care.2006;29 (4): 765–70.
35.
GoyalAMahaffeyKWGargJNicolauJCHochmanJSWeaverWDTherouxPOliveiraGBTodaroTGMojcikCFArmstrongPWGrangerCB. Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study. Eur Heart J.2006;27 (11): 1289–97.
36.
KosiborodMInzucchiSEKrumholzHMMasoudiFAGoyalAXiaoLJonesPGFiskeSSpertusJA. Glucose normalization and outcomes in patients with acute myocardial infarction. Arch Intern Med.2009;169 (5): 438–46.
37.
ChaudhuriAJanickeDWilsonMFTripathyDGargRBandyopadhyayACalieriJHoffmeyerDSyedTGhanimHAljadaADandonaP. Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation.2004;109 (7): 849–54.
38.
KoskenkariJKKaukorantaPKRimpiläinenJVainionpääVOhtonenPPSurcelHMJuvonenTAla-KokkoTI. Anti-inflammatory effect of high-dose insulin treatment after urgent coronary revascularization surgery. Acta Anaesthesiol Scand.2006;50 (8): 962–9.
39.
VisserLZuurbierCJHoekFJOpmeerBCde JongeEde MolBAvan WezelHB. Glucose, insulin and potassium applied as perioperative hyperinsulinaemic normoglycaemic clamp: effects on inflammatory response during coronary artery surgery. Br J Anaesth.2005;95 (4): 448–57.
40.
WongVWMcLeanMBoyagesSCCheungNW. C-reactive protein levels following acute myocardial infarction: effect of insulin infusion and tight glycemic control. Diabetes Care.2004;27 (12): 2971–3.
41.
GaoFGaoEYueTLOhlsteinEHLopezBLChristopherTAMaXL. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation.2002;105 (12): 1497–502.
42.
JonassenAKAasumERiemersmaRAMjosODLarsenTS. Glucose-insulin-potassium reduces infarct size when administered during reperfusion. Cardiovasc Drugs Ther.2000;14 (6): 615–23.
43.
JonassenAKBrarBKMjosODSackMNLatchmanDSYellonDM. Insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible anti-apoptotic mechanism. J Mol Cell Cardiol.2000;32 (5): 757–64.
44.
JonassenAKSackMNMjosODYellonDM. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res.2001;89 (12): 1191–8.
45.
LautamakiRAiraksinenKESeppanenMToikkaJHarkonenRLuotolahtiMBorraRSundellJKnuutiJNuutilaP. Insulin improves myocardial blood flow in patients with type 2 diabetes and coronary artery disease. Diabetes.2006;55 (2): 511–6.
46.
WestonCWalkerLBirkheadJ. Early impact of insulin treatment on mortality for hyperglycaemic patients without known diabetes who present with an acute coronary syndrome. Heart.2007;93 (12): 1542–6.
47.
ScognamiglioRNegutCDe KreutzenbergSVTiengoAAvogaroA. Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients. Circulation.2005;112 (2): 179–84.
48.
ScognamiglioRNegutCde KreutzenbergSVTiengoAAvogaroA. Effects of different insulin regimes on postprandial myocardial perfusion defects in type 2 diabetic patients. Diabetes Care.2006;29 (1): 95–100.
49.
MorigiMAngiolettiSImbertiBDonadelliRMichelettiGFigliuzziMRemuzziAZojaCRemuzziG. Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. J Clin Invest.1998;101 (9): 1905–15.
50.
AljadaAFriedmanJGhanimHMohantyPHofmeyerDChaudhuriADandonaP. Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Metabolism.2006;55 (9): 1177–85.
51.
AljadaAGhanimHMohantyPSyedTBandyopadhyayADandonaP. Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations. Am J Clin Nutr.2004;80 (1): 51–7.
52.
PandolfiAGiaccariACilliCAlbertaMMMorviducciLDe FilippisEABuongiornoAPellegriniGCapaniFConsoliA. Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat. Acta Diabetol.2001;38 (2): 71–6.
53.
GreselePGuglielminiGDe AngelisMCiferriSCiofettaMFalcinelliELalliCCiabattoniGDaviGBolliGB. Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus. J Am Coll Cardiol.2003;41 (6): 1013–20.
54.
CerielloAGiacomelloRStelGMotzETabogaCTonuttiLPirisiMFalletiEBartoliE. Hyperglycemia-induced thrombin formation in diabetes. The possible role of oxidative stress. Diabetes.1995;44 (8): 924–8.
55.
CerielloAGiuglianoDQuatraroADello RussoPMarchiETorellaR. Hyperglycemia may determine fibrinopeptide A plasma level increase in humans. Metabolism.1989;38 (12): 1162–3.
56.
CerielloAGiuglianoDQuatraroADello RussoPTorellaR. Blood glucose may condition factor VII levels in diabetic and normal subjects. Diabetologia.1988;31 (12): 889–91.
57.
JonesRLPetersonCM. Reduced fibrinogen survival in diabetes mellitus. A reversible phenomenon. J Clin Invest.1979;63 (3): 485–93.
58.
SakamotoTOgawaHKawanoHHiraiNMiyamotoSTakazoeKSoejimaHKugiyamaKYoshimuraMYasueH. Rapid change of platelet aggregability in acute hyperglycemia. Detection by a novel laser-light scattering method. Thromb Haemost.2000;83 (3): 475–9.
59.
KawanoHMotoyamaTHirashimaOHiraiNMiyaoYSakamotoTKugiyamaKOgawaHYasueH. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol.1999;34 (1): 146–54.
60.
GuhaMBaiWNadlerJLNatarajanR. Molecular mechanisms of tumor necrosis factor alpha gene expression in monocytic cells via hyperglycemia-induced oxidant stress-dependent and -independent pathways. J Biol Chem.2000;275 (23): 17728–39.
61.
MohantyPHamoudaWGargRAljadaAGhanimHDandonaP. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab.2000;85 (8): 2970–3.
62.
OliverMF. Metabolic causes and prevention of ventricular fibrillation during acute coronary syndromes. Am J Med.2002;112 (4): 305–11.
63.
TanseyMJOpieLH. Relation between plasma free fatty acids and arrhythmias within the first twelve hours of acute myocardial infarction. Lancet.1983;2 (8347): 419–22.
64.
MalmbergKRydénLEfendicSHerlitzJNicolPWaldenstromAWedelHWelinL. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol.1995;26 (1): 57–65.
65.
MalmbergKRydénLWedelHBirkelandKBootsmaADicksteinKEfendicSFisherMHamstenAHerlitzJHildebrandtPMacLeodKLaaksoMTorp-PedersenCWaldenstromA; DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J.26 (7): 650–61.
66.
MarfellaRDi FilippoCPortogheseMFerraraccioFRizzoMRSiniscalchiMMusacchioED'AmicoMRossiFPaolissoG. Tight glycemic control reduces heart inflammation and remodeling during acute myocardial infarction in hyperglycemic patients. J Am Coll Cardiol.2009;53 (16): 1425–36.
67.
CeremuzynskiLBudajACzepielABurzykowskiTAchremczykPSmielak-KorombelWMaciejewiczJDziubinskaJNartowiczEKawka-UrbanekTPiotrowskiWHanzlikJCieslinskiAKawecka-JaszczKGessekJWrabecK. Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial. Cardiovasc Drugs Ther.1999;13 (3): 191–200.
68.
KosiborodMInzucchiSESpertusJAWangYMasoudiFAHavranekEPKrumholzHM. Elevated admission glucose and mortality in elderly patients hospitalized with heart failure. Circulation.2009;119 (14): 1899–907.
69.
Van den BergheGWoutersPWeekersFVerwaestCBruyninckxFSchetzMVlasselaersDFerdinandePLauwersPBouillonR. Intensive insulin therapy in the critically ill patients. N Engl J Med.2001;345 (19): 1359–67.
70.
BrunkhorstFMEngelCBloosFMeier-HellmannARagallerMWeilerNMoererOGruendlingMOppertMGrondSOlthoffDJaschinskiUJohnSRossaintRWelteTSchaeferMKernPKuhntEKiehntopfMHartogCNatansonCLoefflerMReinhartK; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med.358 (2): 125–39.
71.
GandhiGYNuttallGAAbelMDMullanyCJSchaffHVO'BrienPCJohnsonMGWilliamsARCutshallSMMundyLMRizzaRAMcMahonMM. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med.2007;146 (4): 233–43.
72.
GrayCSHildrethAJSandercockPAO'ConnellJEJohnstonDECartlidgeNEBamfordJMJamesOFAlbertiKG; GIST Trialists Collaboration. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol.6 (5): 397–406.
73.
Van den BergheGWilmerAHermansGMeerssemanWWoutersPJMilantsIVan WijngaerdenEBobbaersHBouillonR. Intensive insulin therapy in the medical ICU. N Engl J Med.2006;354 (5): 449–61.
74.
NICE-SUGAR Study Investigators, FinferSChittockDRSuSYBlairDFosterDDhingraVBellomoRCookDDodekPHendersonWRHébertPCHeritierSHeylandDKMcArthurCMcDonaldEMitchellIMyburghJANortonRPotterJRobinsonBGRoncoJJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med.2009;360 (13): 1283–97.
75.
MoghissiESKorytkowskiMTDinardoMEinhornDHellmanRHirschIBInzucchiSEIsmail-BeigiFKirkmanMSUmpierrezGE; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care.32 (6): 1191–31.
76.
KosiborodMInzucchiSClarkBKrumholzHJonesPO'KeefeJSpertusJA. National patterns of glucose control among patients hospitalized with acute myocardial infarction. J Am Coll Cardiol.2007;49 (9): 1018–183: 283A.
77.
KosiborodMInzucchiSClarkBKrumholzHJonesPSpertusJ. Variability in the hospital use of insulin to control sustained hyperglycemia among acute myocardial infarction patients. J Am Coll Cardiol.2007;49 (9): 1018–186: 284A.
78.
PintoDSSkolnickAHKirtaneAJMurphySABarronHVGiuglianoRPCannonCPBraunwaldEGibsonCM; TIMI Study Group. U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol.46 (1): 178–80.
79.
KosiborodMInzucchiSEGoyalAKrumholzHMMasoudiFAXiaoLSpertusJA. Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA.2009;301 (15): 1556–64.
80.
MellbinLGMalmbergKWaldenstromAWedelHRydenL; DIGAMI 2 investigators. Prognostic implications of hypoglycaemic episodes during hospitalisation for myocardial infarction in patients with type 2 diabetes: a report from the DIGAMI 2 trial. Heart.95 (9): 721–7.
GoldbergPASiegelMDSherwinRSHalickmanJILeeMBaileyVALeeSLDziuraJDInzucchiSE. Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit. Diabetes Care.2004;27 (2): 461–7.
83.
KosiborodMInzucchiSHamburgMRiggsLKoshySKrumholzHXiaoLKhalidASpertusJA. Feasibility, effectiveness and safety of intensive glucose control in critically ill hyperglycemic patients hospitalized with acute coronary syndromes. Circulation.2007;116 (16): 3529: II-799.
84.
BarsheshetAGartyMGrossmanESandachALewisBSGottliebSShotanABeharSCaspiASchwartzRTenenbaumALeorJ. Admission blood glucose level and mortality among hospitalized nondiabetic patients with heart failure. Arch Intern Med.2006;166 (15): 1613–9.
85.
BerryCBrettMStevensonKMcMurrayJJNorrieJ. Nature and prognostic importance of abnormal glucose tolerance and diabetes in acute heart failure. Heart.2008;94 (3): 296–304.
86.
NewtonJDSquireIB. Glucose and haemoglobin in the assessment of prognosis after first hospitalisation for heart failure. Heart.2006;92 (10): 1441–6.
