rHDL attenuates platelet hyperreactivity in type 2 diabetics

Reconstituted high-density lipoprotein (rHDL) reduces the hyperreactivity of platelets of patients with type 2 diabetes, partly by lowering the cholesterol content of platelet membranes, according to a study from the Baker IDI Heart and Diabetes Institute, Australia. These findings suggest possible future therapeutic application in reducing atherothrombotic complications in diabetic patients with acute coronary syndromes. 

 The study was reviewed by HDL Forum Editor Professor Kerry-Anne Rye, Heart Research Institute, Sydney, Australia.

 Calkin AC, Drew BG, Ono A et al. Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. Circulation 2009;120:2095-104.

 Individuals with type 2 diabetes are at increased risk of cardiovascular events, not only as a result of increased atherosclerotic burden but also enhanced platelet reactivity, in turn increasing the risk of thrombotic complications (see Figure 1).

 

As a result, commonly used antiplatelet agents such as aspirin and clopidogrel are less effective than in non-diabetic individuals (1). While more potent antiplatelet therapies address the risk of thrombotic complications (2), they have only limited impact on the underlying stability of vulnerable plaque.

 Previous studies have shown that infusion of rHDL modulates various pathways implicated in atherosclerosis, and has short-term beneficial effects on atherosclerotic plaque and glucose metabolism (3-5). The current study investigated whether rHDL infusion can reduce platelet reactivity in type 2 diabetic patients.

 In this study, 17 individuals with type 2 diabetes received IV infusion of placebo (n=10) or rHDL (n=7; CSL-111 20 mg/kg/h, supplied by CSL Behring AG, Bern Switzerland) for 4 hours. The group treated with r HDL has ~1.4-fold increase in plasma HDL cholesterol levels, together with >50% reduction in ex vivo platelet aggregation and marked attenuation of platelet fibrinogen binding in response to a range of agonists including ADP and collagen-related peptide. These inhibitory effects were reversible within 72 hours.

 In a further in vitro study using platelets from healthy individuals, inhibitory effects on platelet aggregation were shown to be both time and dose-dependent. Thombus formation (height and volume) was reduced by ~50% in whole blood treated with rHDL under high wall shear rate (1800/sec). This was due to reduction in primary platelet adhesion to the collagen substrate as well as reduced incorporation of platelets into the thrombi, suggesting a defect in initial thrombus growth.

 Investigation of the mechanism of this effect showed that apolipoprotein AI had minimal effects on platelet function, cholesterol efflux or lipid raft assembly. In contrast, incubation of platelets with soybean phosphocholine attenuated ADP-induced aggregation, enhanced cholesterol efflux and reduced lipid raft assembly, similarly to the effects of rHDL. These findings imply that cholesterol depletion of platelet membranes is probably the main mechanism implicated in the attenuation of platelet function by rHDL infusion.

 Current antiplatelet therapies reduce ischaemic events in patients with acute coronary syndromes. However, given that such events are largely platelet-mediated, the findings of this study, together with previously demonstrated beneficial effects on atherosclerotic lesions and glucose metabolism (3-5), suggest a possible role for rHDL infusion in reducing or preventing atherothrombotic complications in type 2 diabetes patients. Clinical studies are now needed to investigate this further (see Conclusions).

 References

1. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. BMJ 2002;324:71-86.

2. Wiviott SD, Braunwald E, Angiolillo DJ et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcome by optimizing platelet inhibition with prasugrel: Thrombolysis in Myocardial Infarction 38. Circulation 2008;118:1626-36.

3.Tardif JC, Gregoire J, L’Allier PL et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675-82.

 4. Shaw JA, Bobik A, Murphy A et al. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ Res 2008;103:1084-91.

5. Drew BG, Duffy SJ, Formosa MF et al. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes. Circulation 2009;119:2103-11.


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