Diabetes mellitus, especially type 2 diabetes mellitus, is characterized by a high incidence of cardiovascular disease,¹ with a 4-fold increase in the incidence of coronary artery disease compared with patients without diabetes. Macrovascular disease accounts for 80% of deaths in patients with type 2 diabetes. Approximately 25% to 30% of patients admitted to the hospital with acute coronary syndromes (ACS) have concomitant diabetes mellitus, although this has not been previously diagnosed in a substantial proportion of patients. Furthermore, many patients with ACS exhibit marked degrees of insulin resistance, particularly during acute ischemia, resulting in potential for the development of hyperglycemia.

It has been recognized for many years that diabetic patients represent a particularly high-risk subset of patients with ACS. In studies of populations both with ST-segment elevation myocardial infarction (STEMI) and unstable angina/ non–Q-wave myocardial infarction (UAP/NQMI), diabetes has typically been associated with approximately 2-fold increases in risk of mortality and nonfatal complications.² In studies with STEMI patients with associated cardiogenic shock, there are frequently a very high proportion of diabetic patients.

It has become apparent that among such patients, hyperglycemia, rather than any marker of complications of long-term diabetes, is associated with incremental mortality risk.³ This has caused some investigators to focus on the implications of hyperglycemia as a marker of ineffective myocardial glucose utilization. The Diabetes and Insulin-Glucose in Acute Myocardial Infarction (DIGAMI)-1 study provided evidence to suggest that among diabetic patients with STEMI, rapid correction of hyperglycemia via intravenous infusion of insulin, combined with subsequent tight control of blood sugar level, improved medium-term outcomes.⁴ The DIGAMI-2 trial, however, which was terminated prematurely and was markedly undersized, was inconclusive as to long-term implications of tight blood sugar control.⁵

The effects of hyperglycemia on outcomes in ACS extend beyond changes in myocardial metabolism and include abnormal reactivity of endothelium and platelets. Endothelial dysfunction is a key feature of hyperglycemic individuals. Both in vivo and in vitro studies have shown that hyperglycemia directly attenuates endothelium-dependent relaxation.⁶ Although endothelial dysfunction is typically present in diabetic patients,⁷ vascular "nitric oxide (NO) resistance" (ie, diminution of vascular responsiveness to NO) has also been reported in the brachial⁸ and coronary⁹ arteries. Platelet hyperaggregability is also likely to play a part in the increased susceptibility to ACS of type 2 diabetes patients. There is an increase in platelet adhesion and aggregation in response to adenosine diphosphate (ADP).¹⁰

Platelet NO resistance (ie, hyporesponsiveness to the anti-aggregatory effects of NO donors) may also be present in patients with type 2 diabetes and obesity.¹⁰ Our initial observation in this respect was a decrease in platelet guanylate cyclase activity and reactivity in diabetes, especially in patients with type 2 diabetes.¹¹ Recently, we also documented increased platelet aggregation in type 2 diabetes patients compared with healthy controls (P < .05).¹² In that study, sodium nitroprusside (SNP; Nitropress) and nitroglycerin inhibited ADP-induced aggregation to a significantly lesser extent in subjects with type 2 diabetes than in control subjects. Platelet abnormalities were also associated with increased oxidative stress. Importantly, platelet NO resistance was not critically related to body mass index, contrary to the findings of a previous study.¹⁰

The pro-aggregatory effects of hyperglycemia are also, in part, reversed by insulin. It has recently been shown that high glucose concentrations decrease platelet NO production.¹³ The anti-aggregatory effects of insulin in vitro are partially mediated by incremental NO release from platelets¹⁴ due to the activation of platelet NO synthase.¹⁵ Furthermore, insulin infusion (3-hour, at 1 mU/kg/ min) in humans inhibits ex vivo platelet aggregation in response to collagen, thrombin receptor-activating peptide, ADP, and epinephrine.¹⁶

We recently considered the possibility that hyperglycemia in patients with UAP/NQMI might be associated with net platelet hyperaggregability via diminution of platelet responsiveness to NO, a physiologically important inhibitor of aggregation and the primary biochemical mediator of the therapeutic effect of organic nitrates such as nitroglycerin in patients with ACS. We performed a prospective population study and randomized intervention to test this hypothesis.¹⁷ That study had 2 components: (1) an examination of the relationship between admission blood sugar levels and platelet responsiveness to NO in diabetic patients with UAP/NQMI; and (2) a randomized evaluation of the relative impact of rapid correction of hyperglycemia with intravenous insulin infusion (vs subcutaneous insulin) in a similar group of patients.

Subjects and methods

The main parameter evaluated in our study was platelet responsiveness to NO. Studies were performed using a dual-channel impedance aggregometer, with aggregation being evaluated in whole blood primarily in order to be able to evaluate the effects of interaction between platelets and other formed elements of blood, particularly leukocytes, which are the main sources of release of superoxide anion radical (O_2^–) into the circulation. A schema for the method of assessment of platelet responsiveness to NO is shown in Figure 1. Aggregation was induced with a low concentration of ADP (1 µmol/L), and the extent of inhibition of this aggregation with NO was evaluated using SNP (10 µmol/L) as a source of NO (nitroglycerin was not used primarily because subjects were being treated with intravenous nitroglycerin and we were concerned that results might be affected by any degree of nitrate tolerance). In normal subjects, SNP inhibits ADP-induced aggregation by (approximately) 65% ± 15% under these conditions.

Figure 1. Assessment of platelet responsiveness to nitric oxide (NO). Inhibition of adenosine diphosphate-induced (1 ìmol/L) platelet aggregation in whole blood by sodium nitroprusside (SNP; 10 μmol/L) as an NO donor.

The 3 other major parameters evaluated were blood sugar level, whole-blood O₂–content, and plasma asymmetric dimethylarginine (ADMA; a marker/mediator of endothelial dysfunction) level. The intervention component of the study was performed only in subjects (n = 60) in whom initial blood sugar level was ≥ 11.1 mmol/L. Randomized treatments were either intravenous insulin infusion according to the DIGAMI protocol⁴ or subcutaneous insulin injected every 8 hours according to a sliding scale. Platelet aggregation, O₂–content, and ADMA were evaluated serially for the next 12 hours and correlated with changes in blood sugar level.

Results

Seventy-six subjects with diabetes were evaluated, of whom 68% had previously received oral hypoglycaemic agents and/or insulin. Twenty-nine percent of subjects had had NQMI, although in most cases, it was not associated with marked hemodynamic impairment at admission. Initial blood sugar level values ranged from 5.1 to 31.7 mmol/L (mean, 14.3 mmol/L). There was a significant inverse relationship between admission blood sugar level and platelet responsiveness to SNP (P < .01; Figure 2). Although there was considerable scatter, mean response to SNP was approximately 45% for subjects with a blood sugar level of 5 to 10 mmol/L, compared with approximately 20% for subjects with a blood sugar level > 25 mmol/L. Furthermore, elevation of blood sugar level was associated with a marked (P < .001) elevation of the chemiluminescence measure of whole blood O_2^– content.

Figure 2. Relationship between platelet sodium nitroprusside (SNP) response and admission blood sugar level (r = –0.31; P = .007). (Adapted with permission from Worthley MI, Homes AS, Willoughby SR, et al.The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes. J Am Coll Cardiol. 2007;49[3]:304-310.)

Within the randomized intervention subgroup of patients, initial blood sugar level was approximately 16 mmol/L; decreases in blood sugar levels over 12 hours were greater with intravenous than with subcutaneous insulin, with mean blood sugar levels after 12 hours of approximately 7.9 and 10.5 mmol/L, respectively. Intravenous insulin infusion was associated with significant increases in platelet SNP response, together with decreases in O_2^– content and plasma ADMA concentration.

These results may be of particular importance regarding the clinical management of hyperglycemic diabetic patients presenting with ACS. Although the main postulated benefit for acute correction of hyperglycemia has been restoration of normal myocardial metabolism (and thus limitation of infarct size), it now seems more appropriate for correction of hyperglycemia to be regarded as a therapeutic strategy to normalize platelet physiology and thus to expedite reversal of a prothrombotic milieu.

Discussion

The main conclusion to be drawn from the results of this study is that admission blood sugar elevation is associated with reversible impairment of platelet function in patients with ACS and diabetes. Importantly, the nature of this impairment is not fully evident merely by measuring aggregation response to ADP, the "core" test in most evaluations of platelet function. Rather, the main anomaly is impairment of platelet responsiveness to NO, a major physiologic inhibitor of aggregation and the main mediator of effectiveness of nitroglycerin and other organic nitrates in patients with ACS.

We have previously shown that NO resistance, which occurs in platelets and blood vessels (and probably in other tissues), is common in patients with UAP/NQMI, even in patients without diabetics.^17-20 Nitric oxide resistance results largely from a combination of "scavenging" of NO (either endogenous or from exogenous sources) by O_2^– and of (reversible) inactivation of soluble guanylate cyclase (Figure 3); hence, the finding that O_2^– levels were elevated in association with NO resistance was not surprising. However, the strong correlation between blood sugar level and whole blood O_2^– content had not previously been described.

Figure 3. Schematic of biochemical pathways mediating physiological effects of nitric oxide (NO), either endogenous (endothelium-derived relaxing factor [EDRF]) or from exogenous sources (eg, nitroglycerin [NTG] or sodium nitroprusside [SNP]). "NO resistance" reflects both scavenging of NO by superoxide anion radical (O2–) and partial inactivation of soluble guanylate cyclase. GTP indicates guanosine triphosphate; cGMP, cyclic guanosine monophosphate.

It is likely that the phenomena of NO resistance and "endothelial dysfunction" are closely linked, partially via the role of O_2^–. However, endothelial dysfunction is also mediated, in part, by diminution of NO formation, largely due to the inhibitory effects of ADMA. Acute restoration of normal blood sugar level with intravenous insulin infusion is therefore likely to have had 2 components of beneficial effect on vascular homeostasis: reversal of platelet (and vascular) NO resistance (via reduction in O_2^– generation) and improved formation of NO by virtue of reduction in ADMA levels.

These results may have a number of clinical implications for the management of patients with ACS, including both STEMI and UAP/NQMI groups. First, they provide a basis for the beneficial effects of correction of hyperglycemia beyond previously postulated changes in myocardial metabolism. In focusing attention on platelet aggregation, it is relevant that NO resistance, whether at the platelet or vascular levels, is an important marker of adverse outcomes. For example, in patients with UAP/NQMI, platelet NO resistance was associated with marked increases in long-term risk of mortality, as well as cardiovascular morbidity.¹⁸

The finding that correction of hyperglycemia reverses platelet NO resistance adds to previous information about therapeutic options for the treatment of such high-risk patients. To date, there is evidence that the prophylactic antianginal agent perhexiline, angiotensin-converting enzyme inhibitors, and possibly statins improve platelet responsiveness to NO^19,20; these effects may contribute to overall cardioprotection by these agents.

How should these data influence the treatment of individual patients with UAP/NQMI? As NO resistance is associated with ongoing ischemia and its rapid reversal with suppression of ischemia, reversal of hyperglycemia should be an urgent priority in all cases of ACS. It is likely that this relatively simple maneuver may reduce the risk of ongoing ischemia, increase the safety of percutaneous coronary intervention procedures, and diminish the need for extensive therapy with antiaggregatory agents, such as glycoprotein IIb/IIIa inhibitors in the context of UAP/NQMI.

Acknowledgments

This work was supported in part by grants from the National Health and Medical Research Council and the National Heart Foundation of Australia.

References

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A more detailed discussion of this topic can be found in Worthley MI, Homes AS, Willoughby SR, et al. The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes. J Am Coll Cardiol. 2007;49(3):304-310.