Effects of lipid-lowering treatment on platelet reactivity and platelet-leukocyte aggregation in diabetic patients without and with chronic kidney disease: a randomized trial.
BACKGROUND
Diabetes mellitus (DM) is associated with hyperreactive platelets and increased platelet-leukocyte aggregation (PLA), but the impact of concomitant chronic kidney disease (CKD) has been much less studied. Lipid-lowering treatment (LLT) may have favorable effects on platelet activation and inflammation. The objective of this mechanistic study was to investigate the impact of CKD on platelet function and inflammatory parameters in patients with DM and the effects of LLT.


METHODS
After a placebo run-in period, the effects of simvastatin alone (S) or simvastatin + ezetimibe (S + E) were compared in a randomized, double-blind, cross-over study on platelet reactivity, PLA formation and inflammatory parameters. Eighteen DM patients with estimated glomerular filtration rate (eGFR) 15-59 mL/min × 1.73 m(2) (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR >75 mL/min (DM-only) were included.


RESULTS
PLAs were elevated at baseline in DM-CKD compared with DM-only (P = 0.04). S + E reduced PLAs among total leukocytes and neutrophils in DM-CKD patients (P = 0.01 for both) but not in the DM-only group. Platelet reactivity did not differ between patient groups or with LLT. Plasma levels of sCD40L (P < 0.001), elastase (P < 0.01) and von Willebrand factor (VWF) (P < 0.001) were elevated in DM-CKD compared with DM-only. S + E reduced sCD40L in DM-CKD patients (P = 0.01), but LLT did not influence VWF or elastase.


CONCLUSIONS
DM patients with CKD stages 3-4 had increased PLA and inflammatory activity compared with DM patients with normal GFR. Simvastatin + ezetimbe decreased PLAs and plasma sCD40L in DM patients with concomitant CKD. Clinical Trial registration http://www.clinicaltrials.gov. Identifier NCT01035320.
Department Medicine Solna, Clinical Pharmacology Unit, Karolinska Institutet, Karolinska University Hospital/Solna, Stockholm SE-171 76, Sweden.
Tora
T
Almquist
Stefan H
SH
Jacobson
Per-Eric
PE
Lins
Richard W
RW
Farndale
Paul
P
Hjemdahl
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001384:Azetidines / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D048909:Diabetes Complications / Q000188:drug therapy* / Q000209:etiology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology*; D004311:Double-Blind Method; D000069438:Ezetimibe; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000209:etiology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D011379:Prognosis; D012307:Risk Factors; D019821:Simvastatin / Q000627:therapeutic use; D055815:Young Adult
D000924:Anticholesteremic Agents; D001384:Azetidines; D008055:Lipids; D019821:Simvastatin; D000069438:Ezetimibe