Hyperglycemia and Acute Coronary Syndromes: Association with Outcomes and Management

Definition of Hyperglycemia During Acute Coronary Syndrome

There is presently no uniform definition of what constitutes hyperglycemia in the setting of ACS. Prior studies used various blood glucose cut points ranging from 110 mg/dL or higher to 200 mg/dL or higher. This uncertainty is compounded by variation in timing of glucose level assessments in this context. Most prior studies defined hyperglycemia based on the first available (admission or “on-arrival”) glucose value, whereas others used fasting glucose as well as glucose values averaged over a period of time, such as the first 24 hours, the first 48 hours, or the entire duration of hospitalization. The American Heart Association (AHA) scientific statement on hyperglycemia and acute coronary syndrome suggests use of a random glucose level of above 140 mg/dL observed at any point over the course of hospitalization for ACS as the definition of hyperglycemia. This recommendation is based in part on epidemiologic studies demonstrating that admission, mean 24-hour, 48-hour, and hospitalization glucose levels above approximately 120-140 mg/dL are associated with increased mortality risk, ^{, , ,} and that decline in glucose levels below approximately 140 mg/dL during ACS hospitalization is associated with better survival, although no cause-and-effect conclusions can be drawn from these data because of their observational nature.

It is important to note that the nature of the relationship between higher glucose levels and greater risk of mortality differs in patients with and without diabetes, with a paradoxically greater magnitude of association in those without versus those with prevalent diabetes. *

* References 7, 9, 10, 12, 21, 23.

The risk of mortality gradually rises when glucose levels exceed approximately 110-120 mg/dL in patients without diabetes, whereas in patients with established diabetes this risk does not increase significantly until glucose levels exceed approximately 200 mg/dL. ^, Thus, different thresholds may be appropriate to define hyperglycemia depending on the presence or absence of known diabetes.

Prevalence of Elevated Glucose Levels in Acute Coronary Syndrome

Numerous studies have documented that elevated glucose levels occur commonly in patients hospitalized with ACS. Although the definition of hyperglycemia varies across studies, the largest investigations show that the overall prevalence of elevated glucose levels (> 140 mg/dL) at the time of hospital admission varies from 51% to 58%. ^, It is important to note that more than 50% of patients with ACS who have hyperglycemia on hospital arrival do not have known diabetes.

Although glucose levels normalize in some ACS patients after admission (either spontaneously or as a result of targeted pharmacologic interventions), persistent hyperglycemia remains present in more than 40% of patients throughout the course of hospitalization, and the prevalence of severe, sustained hyperglycemia (average hospitalization glucose > 200 mg/dL) is approximately 14%. ^, Although persistent hyperglycemia occurs more commonly in patients with versus without established diabetes (78% versus 26%, respectively), more than 40% of patients with persistent hyperglycemia do not have previously diagnosed diabetes.

The Relationship Between Glucose Levels and Mortality in Acute Coronary Syndrome

Multiple studies have now proven a powerful, independent relationship between elevated glucose and increased risk of mortality and other adverse clinical outcomes in patients hospitalized with ACS. Plausible pathophysiologic underpinnings potentially contributing to these observed associations derive from a plethora of ex vivo, animal, and human studies that show that hyperglycemia may mediate adverse effects on inflammation, cell injury, apoptosis, ischemic myocardial metabolism, endothelial function, the coagulation cascade, and platelet aggregation in the setting of acute ischemia. ^, The association between higher glucose and greater mortality risk has been established across various glucose metrics ^, and across the spectrum of ACS and applies to both short- and longer-term outcomes. ^,

The relationship between hyperglycemia and adverse outcomes among patients with ACS has been quantitatively summarized based on data from a large series of relatively small human studies collected over a period of three decades by Capes and colleagues. This systematic overview demonstrated that among ACS patients without known diabetes, the relative risk of in-hospital mortality was 3.9 times higher in those with initial glucose 110 mg/dL or higher compared with normoglycemic patients (95% confidence interval [CI] 2.9-5.4). Among ACS patients with established diabetes, those with initial glucose of 180 mg/dL or higher had a 70% increase in the relative risk of in-hospital mortality, as compared with normoglycemic patients. More recent studies confirmed these findings and extended them across the broader range of ACS to include STEMI, NSTEMI, and unstable angina, demonstrating a significant increase in the risk of short- and long-term mortality, as well as incident heart failure in hyperglycemic ACS patients both with and without diabetes. ^{, ,} The largest observational study to date to address this issue used the data from Cooperative Cardiovascular Project and showed a near-linear relationship between higher admission glucose and greater risk of mortality at 30 days and at 1 year in more than 140,000 patients hospitalized with AMI. A similar relationship between elevated glucose and increased risk of death was also shown with other glucose metrics, such as postadmission fasting glucose, ^, and with outcomes other than mortality, including such intermediates associated with adverse clinical outcomes as the “no-reflow phenomenon” following percutaneous coronary intervention (PCI) ; greater infarct size ^, ; worse left ventricular systolic function ; and contrast-mediated acute kidney injury. ^,

The association between hyperglycemia and increased risk of death is not limited to the initial stages of ACS hospitalization. To the contrary, in a study of almost 17,000 patients hospitalized with acute myocardial infarction (AMI) in 40 U.S. hospitals, persistently elevated glucose during hospitalization was a better discriminator of adverse events than hyperglycemia on admission (C statistic 0.70 versus 0.62, P < 0.0001). There was a significant, gradual increase in the risk of in-hospital mortality with rising mean hospitalization glucose levels ( Fig. 20-1 ). Observational analyses from randomized clinical trials of glucose-insulin-potassium (GIK) therapy and of targeted glucose control in ACS also confirm the relationship between persistent hyperglycemia and increased mortality risk. ^,

Another important observation is that the nature of the relationship between higher glucose levels and increased mortality is different in patients with and without established diabetes. ^, Regardless of the glucose metrics used, the mortality risk starts rising at considerably lower glucose levels, and increases at a much steeper slope, in patients without previously diagnosed diabetes than in those with established diabetes (see Fig. 20-1 ). This phenomenon has been recently confirmed in other critically ill patient populations and is not well understood. Several possible explanations have been proposed. Many patients with hyperglycemia in the absence of known diabetes actually have diabetes that simply was not recognized or treated before hospitalization, representing a higher-risk cohort because other undiagnosed and untreated cardiovascular risk factors may be more prevalent in this group. Moreover, whereas the effect of targeted glucose control and insulin therapy in this clinical setting remains uncertain, nondiabetic ACS patients with hyperglycemia are less likely to be treated with insulin than those with established diabetes, even when glucose levels are markedly elevated. ^, Further contributing to this consistent observation is the fact that patients with established diabetes tend to have clustering of numerous risk factors that contribute to clinical risk, which may attenuate the magnitude of risk independently associated with any single factor, such as hyperglycemia. Finally, it is possible that higher degrees of stress and illness severity are required to produce similar degrees of hyperglycemia in patients without known diabetes compared with those with established diabetes.