Effects of lipid-lowering treatment on platelet function and hemostatic mechanisms in diabetic patients : influence of chronic kidney disease and inflammatory parameters

Diabetes mellitus (DM) and chronic kidney disease (CKD) are both associated with increased cardiovascular morbidity and mortality, and the risk is even higher when they are concurrent. Both diseases are considered to be prothrombotic states with increased inflammatory activity and major disturbances in the hemostasis. Lipid-lowering treatment (LLT) may have beneficial effects on inflammation, platelet activation and atherothrombotic mechanisms. We evaluated the prognostic implications of impaired renal function, measured as estimated creatinine clearance (eCrCl), in 808 patients with stable angina pectoris in a post hoc analysis of the Angina Prognosis Study In Stockholm (APSIS), which compared metoprolol and verapamil treatment in stable angina with a median follow-up of 40 months. A multivariate Cox analysis showed an independent prognostic importance of eCrCl for cardiovascular (CV) death and for CV death or myocardial infarction (MI). Patients with eCrCl 75 ml/min/1.73m (DM-only) in a randomized, double blind, crossover study. Parameters reflecting platelet activity, microparticles (MP) formation and inflammatory parameters were measured. At baseline, after a placebo run-in period, we found signs of increased inflammatory activity, increased platelet activation and hypercoagulability in DM-CKD compared to DM-only patients with increased formation of platelet-leukocyte aggregates (PLA), elevated levels of proinflammatory cytokines and soluble CD40L (sCD40L) in plasma, as well as elevated levels of MPs derived from platelets (PMPs), monocytes (MMPs) and endothelial cells. Simvastatin treatment alone reduced the expression of P-selectin, tissue factor (TF) and CD40L on PMPs, and TF on MMPs in both patient groups. Simvastatin also reduced levels of total procoagulant MPs, PMPs and MMPs as well as IFNγ and MCP-1 in DM-CKD but not in DM-only patients. Furthermore, the combination of simvastatin+ezetimbe reduced PLA formation and sCD40L levels in DM patients with CKD compared to DM-only patients. Most differences between DM-CKD and DM-only patients were reduced or disappeared with LLT despite similar lipid levels in the two groups both before and during LLT. In conclusion, impaired renal function carries independent prognostic information in patients with stable angina pectoris, in agreement with findings in other patient categories. Patients with CKD should be identified early, as there is need for improved CV risk reduction therapy in these high-risk patients. DM patients with CKD stages 3-4 (eGFR 15-59 mL/min/1.73m) have signs of increased inflammatory activity and platelet activation, and hypercoagulability compared to DM-patients with normal eGFR. LLT counteracted the differences between DM-CKD and DM-only patients, with reduced inflammatory activation and a less procoagulant milieu especially in the presence of CKD. This may contribute to the beneficial effects of LLT on atherothrombotic complications in DM patients with concurrent CKD. LIST OF SCIENTIFIC PAPERS I. Almquist T, Forslund L, Rehnqvist N, Hjemdahl P Prognostic implications of renal dysfunction in patients with stable angina pectoris. J Intern Med. 2006 Dec; 260(6):537-44. II. Almquist T, Jacobson SH, Lins PE, Farndale RW, Hjemdahl P Effects of lipid-lowering treatment on platelet reactivity and plateletleukocyte aggregation in diabetic patients without and with chronic kidney disease. Nephrol Dial Transplant 2012 Sep; 27(9):3540-6. III. Almquist T, Jacobson SH, Mobarrez F, Nasman P, Hjemdahl P Lipid-lowering treatment and inflammatory mediators in diabetes and chronic kidney disease. Eur J Clin Invest 2014 Mar; 44(3):276-84. IV. Almquist T, Mobarrez F, Jacobson SH, Wallen H, Hjemdahl P Effects of lipid-lowering treatment on circulating microparticles in patients with diabetes and chronic kidney disease. Manuscript. CONTENTS