Editorial Angiology 1-3 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319715591743 ang.sagepub.com
Rosuvastatin and Mean Platelet Volume in Diabetes N. Papanas, MD1 and E. Maltezos, MD1
Increased mean platelet volume (MPV) is a marker of platelet activation, as shown in diabetes mellitus (DM),1,2 especially in the presence of its vascular complications.3,4 Additionally, increased MPV is encountered in atherosclerosis, dyslipidemia, hypertension, and ischemic heart disease (IHD),4-6 while it is also linked with inflammation and increased vascular morbidity in diverse conditions, such as obstructive sleep apnea,7 chronic obstructive pulmonary disease,8 or Behc¸et disease.9 Interestingly, elevated MPV can serve as a predictor of acute cardiovascular events in patients with IHD or stroke, irrespective of the presence of DM.10-13 Statins, the most important class of hypolipidemic agents,14,15 may exert an antiplatelet action.16,17 Indeed, they may reduce platelet reactivity and thromboxane formation.16,17 Moreover, simvastatin therapy has very recently been shown to reduce P-selectin, platelet-derived microparticles, and expression of CD62P on resting and thrombin-activated platelets after ischemic stroke.18 In acute coronary syndrome, rosuvastatin has been shown to improve platelet–leukocyte interaction.19,20 There is also evidence that simvastatin harbors antiplatelet actions via peroxisome proliferator-activated receptor g, such as inhibition of the phosphorylation of mitogen-activated protein kinases, increase in cyclic adenosine monophosphate formation, and inhibition of protein kinase B phosphorylation and intracellular calcium.21 Finally, atorvastatin has been demonstrated to exert antiplatelet activity by inhibiting the formation of reactive oxygen species in the platelets.22 There is evidence from 2 studies that rosuvastatin administration reduces MPV.23,24 It has been shown for the 10, 20, and 40 mg/d dosages for a follow-up period of 8 to 12 weeks.23,24 Of note, there was no correlation between reduction in MPV and improvement in serum lipids following treatment.23,24 Atorvastatin can also decrease the MPV.25,26 Of note, this beneficial effect appears to be more pronounced in patients exhibiting the strongest lipid reduction.25 Conversely, pravastatin treatment did not lower the MPV.27 More recently, the study of Akyu¨z et al28 examined 178 patients with DM receiving high-dose rosuvastatin (40 mg/d) for dyslipidemia. After 6 months of treatment, there was a significant (P < .001) decrease in MPV. At the same time, significant improvements were observed in total cholesterol, triglyceride, low-density lipoprotein cholesterol, and highdensity lipoprotein cholesterol.28 However, MPV reduction was not correlated with any improvements in serum lipids.
The strengths of the study by Akyu¨z et al28 include specific examination of patients with DM in whom MPV is more frequently elevated, longer study period, use of a steady statin dosage, and the adequate number (n ¼ 178) of patients included. This study also has some limitations.28 Of foremost importance, it was not a double-blind randomized controlled trial, and, indeed, the effect of rosuvastatin on MPV was seen only in a single treatment arm and not judged against a comparator (other treatment or placebo). Second, observations were made retrospectively. Furthermore, most patients also received aspirin or clopidogrel, which may have, to some extent, affected MPV, although their dosages were unaltered during the study period.28 Moreover, MPV was the sole index of platelet function evaluated in the study. Finally, seasonal variations in MPV29 were not considered, but this is the case in the vast majority of studies on MPV. Taken together, the more recent findings28 and those from the earlier studies suggest that rosuvastatin23,24 and atorvastatin,25,26 but not pravastatin,27 exert an additional beneficial action on MPV. With rosuvastatin this action is not mediated by the improved serum lipids,28 whereas atorvastatin achieved a significant MPV reduction in patients with the strongest concomitant lipid changes.25 This emerging difference needs to be revisited. Given the importance of MPV as a marker of activated platelets4 and as a predictor of vascular events,4,6 including DM,12,13,30 this effect of rosuvastatin and atorvastatin is encouraging. In contrast, it is worth mentioning that nicotinic acid/laropiprant increases MPV.31 At present, the underlying mechanism and why this action is not shared by pravastatin, and perhaps by other statins, needs to be determined. Such knowledge will help us better appreciate the clinical relevance of this effect.32,33 In conclusion, rosuvastatin and atorvastatin reduce MPV by a hitherto unknown mechanism, which may be lipid independent. However, the evidence may be criticized for being rather
1
Second Department of Internal Medicine, Diabetes Clinic, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
Corresponding Author: Nikolaos Papanas, Second Department of Internal Medicine, Diabetes Clinic, G. Kondyli 22c, Alexandroupolis 68100, Greece. Email: [email protected]
Downloaded from ang.sagepub.com at DALHOUSIE UNIV on June 24, 2015
2
Angiology
preliminary. Although more research is needed, this effect is a good beginning, a promising ‘‘home’’ to start from.34 Authors’ Note This editorial was written independently.
Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr N Papanas has been an advisory board member of TrigoCare International; has participated in sponsored studies by Novo Nordisk and Novartis; has received honoraria as a speaker for Astra-Zeneca, Eli-Lilly, Novo Nordisk and Pfizer; and attended conferences sponsored by TrigoCare International, Novo Nordisk, Sanofi-Aventis and Pfizer. Professor E Maltezos has participated in sponsored studies by Novo Nordisk and Novartis and attended conferences sponsored by Wyeth, Pfizer and Bayer.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Papanas N, Symeonidis G, Maltezos E, et al. Mean platelet volume in patients with type 2 diabetes mellitus. Platelets. 2004; 15(8):475-478. 2. Jagroop A, Mikhailidis DP. Platelets and diabetes: a complex association. Platelets. 2015;26(3):267-268. 3. Papanas N, Mavridis G, Karavageli E, Symeonidis G, Maltezos E. Peripheral neuropathy is associated with increased mean platelet volume in type 2 diabetic patients. Platelets. 2005;16(8):498-499. 4. Gasparyan AY, Ayvazyan L, Mikhailidis DP, Kitas GD. Mean platelet volume: a link between thrombosis and inflammation? Curr Pharm Des. 2011;17(1):47-58. 5. Varol E, Aksoy F, Bas HA, Ari H, Ozaydin M. Mean platelet volume is elevated in patients with low high-density lipoprotein cholesterol. Angiology. 2014;65(8):733-736. 6. Tsiara S, Elisaf M, Jagroop IA, Mikhailidis DP. Platelets as predictors of vascular risk: is there a practical index of platelet activity? Clin Appl Thromb Hemost. 2003;9(3):177-190. 7. Nena E, Papanas N, Steiropoulos P, et al. Mean platelet volume and platelet distribution width in non-diabetic subjects with obstructive sleep apnoea syndrome: new indices of severity? Platelets. 2012;23(6):447-454. 8. Steiropoulos P, Papanas N, Nena E, et al. Mean platelet volume and platelet distribution width in patients with chronic obstructive pulmonary disease: the role of comorbidities. Angiology. 2013; 64(7):535-539. 9. Acikgoz N, Karincaoglu Y, Ermis N, et al. Increased mean platelet volume in Behc¸et’s disease with thrombotic tendency. Tohoku J Exp Med. 2010;221(2):119-123. 10. Sahin DY, Gu¨r M, Elbasan Z, et al. Mean platelet volume and extent and complexity of coronary artery disease in diabetic and nondiabetic patients with ST elevation myocardial infarction. Angiology. 2013;64(7):505-511.
11. Murat SN, Duran M, Kalay N, et al. Relation between mean platelet volume and severity of atherosclerosis in patients with acute coronary syndromes. Angiology. 2013;64(2):131-136. 12. Han JY, Choi DH, Choi SW, et al. Stroke or coronary artery disease prediction from mean platelet volume in patients with type 2 diabetes mellitus. Platelets. 2013;24(5):401-406. 13. Papanas N, Mikhailidis DP. Mean platelet volume: a predictor of mortality in diabetic and non-diabetic patients with STEMI? J Diabetes Complications. 2014;28(5):581-582. 14. Mikhailidis DP, Athyros VG. Dyslipidaemia in 2013: new statin guidelines and promising novel therapeutics. Nat Rev Cardiol. 2014;11(2):72-74. 15. Agouridis AP, Filippatos TD, Katsiki N. Current lipid-modifying agents. Expert Opin Pharmacother. 2015;16(7):1117-1118. 16. Huhle G, Abletshauser C, Mayer N, Weidinger G, Harenberg J, Heene DL. Reduction of platelet activity markers in type II hypercholesterolemic patients by a HMG-CoA-reductase inhibitor. Thromb Res. 1999;95(5):229-234. 17. Schror K. Platelet reactivity and arachidonic acid metabolism in type II hyperlipoproteinaemia and its modification by cholesterol-lowering agents. Eicosanoids. 1990;3(2):67-73. 18. Pawelczyk M, Chmielewski H, Kaczorowska B, Przybyła M, Baj Z. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke. Arch Med Sci. 2015;11(1):115-121. 19. Sexton TR, Wallace EL, Macaulay TE, et al. The effect of rosuvastatin on platelet-leukocyte interactions in the setting of acute coronary syndrome. J Am Coll Cardiol. 2015;65(3):306-307. 20. Sexton TR, Wallace EL, Macaulay TE, et al. The effect of rosuvastatin on thromboinflammation in the setting of acute coronary syndrome. J Thromb Thrombolysis. 2015;39(2):186-195. 21. Du H, Hu H, Zheng H, Hao J, Yang J, Cui W. Effects of peroxisome proliferator-activated receptor g in simvastatin antiplatelet activity: influences on cAMP and mitogen-activated protein kinases. Thromb Res. 2014;134(1):111-120. 22. Violi F, Carnevale R, Pastori D, Pignatelli P. Antioxidant and antiplatelet effects of atorvastatin by Nox2 inhibition. Trends Cardiovasc Med. 2014;24(4):142-148. 23. Coban E, Afacan B. The effect of rosuvastatin treatment on the mean platelet volume in patients with uncontrolled primary dyslipidemia with hypolipidemic diet treatment. Platelets. 2008;19(2):111-114. 24. Sivri N, Tekin G, Yalta K, Aksoy Y, Senen K, Yetkin E. Statins decrease mean platelet volume irrespective of cholesterol lowering effect. Kardiol Pol. 2013;71(10):1042-1047. 25. Kucera M, Balaz D, Kruzliak P, et al. The effects of atorvastatin treatment on the mean platelet volume and red cell distribution width in patients with dyslipoproteinemia and comparison with plasma atherogenicity indicators-A pilot study. Clin Biochem. 2015;48(9):557-561. 26. Akin F, Ayc¸a B, Ko¨se N, et al. Effect of atorvastatin on hematologic parameters in patients with hypercholesterolemia. Angiology. 2013;64(8):621-625. 27. Broijersen A, Eriksson M, Larsson PT, et al. Effects of selective LDL-apheresis and pravastatin therapy on platelet function in familial hypercholesterolaemia. Eur J Clin Invest. 1994;24(7): 488-498.
Downloaded from ang.sagepub.com at DALHOUSIE UNIV on June 24, 2015
Papanas and Maltezos
3
28. Akyu¨z A, Akkoyun DC¸, Deg˘irmenci H, Oran M. Rosuvastatin decreases mean platelet volume in patients with diabetes mellitus [published online on May 5, 2015]. Angiology. 2015. doi: 10. 1177/0003319715584725. 29. Crawford VL, McNerlan SE, Stout RW. Seasonal changes in platelets, fibrinogen and factor VII in elderly people. Age Ageing. 2003;32(6):661-665. 30. Mikhailidis DP, Barradas MA, Jeremy JY, Dandona P. Effect of alpha a-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in type 2 (non-insulindependent) diabetes mellitus. Diabetologia. 1989;32(2): 147-149.
31. Kei A, Elisaf M. Nicotinic acid/laropiprant reduces platelet count but increases mean platelet volume in patients with primary dyslipidemia. Arch Med Sci. 2014;10(3):439-444. 32. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance. J Clin Lipidol. 2012;6(1):93. 33. Kargiotis K, Katsiki N, Athyros VG, et al. Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report. Curr Vasc Pharmacol. 2014;12(3):505-511. 34. Eliot TS. Collected Poems 1909-1962. London: Faber and Faber; 1986: 203.
Downloaded from ang.sagepub.com at DALHOUSIE UNIV on June 24, 2015
Rosuvastatin and Mean Platelet Volume in Diabetes N. Papanas, MD1 and E. Maltezos, MD1
Increased mean platelet volume (MPV) is a marker of platelet activation, as shown in diabetes mellitus (DM),1,2 especially in the presence of its vascular complications.3,4 Additionally, increased MPV is encountered in atherosclerosis, dyslipidemia, hypertension, and ischemic heart disease (IHD),4-6 while it is also linked with inflammation and increased vascular morbidity in diverse conditions, such as obstructive sleep apnea,7 chronic obstructive pulmonary disease,8 or Behc¸et disease.9 Interestingly, elevated MPV can serve as a predictor of acute cardiovascular events in patients with IHD or stroke, irrespective of the presence of DM.10-13 Statins, the most important class of hypolipidemic agents,14,15 may exert an antiplatelet action.16,17 Indeed, they may reduce platelet reactivity and thromboxane formation.16,17 Moreover, simvastatin therapy has very recently been shown to reduce P-selectin, platelet-derived microparticles, and expression of CD62P on resting and thrombin-activated platelets after ischemic stroke.18 In acute coronary syndrome, rosuvastatin has been shown to improve platelet–leukocyte interaction.19,20 There is also evidence that simvastatin harbors antiplatelet actions via peroxisome proliferator-activated receptor g, such as inhibition of the phosphorylation of mitogen-activated protein kinases, increase in cyclic adenosine monophosphate formation, and inhibition of protein kinase B phosphorylation and intracellular calcium.21 Finally, atorvastatin has been demonstrated to exert antiplatelet activity by inhibiting the formation of reactive oxygen species in the platelets.22 There is evidence from 2 studies that rosuvastatin administration reduces MPV.23,24 It has been shown for the 10, 20, and 40 mg/d dosages for a follow-up period of 8 to 12 weeks.23,24 Of note, there was no correlation between reduction in MPV and improvement in serum lipids following treatment.23,24 Atorvastatin can also decrease the MPV.25,26 Of note, this beneficial effect appears to be more pronounced in patients exhibiting the strongest lipid reduction.25 Conversely, pravastatin treatment did not lower the MPV.27 More recently, the study of Akyu¨z et al28 examined 178 patients with DM receiving high-dose rosuvastatin (40 mg/d) for dyslipidemia. After 6 months of treatment, there was a significant (P < .001) decrease in MPV. At the same time, significant improvements were observed in total cholesterol, triglyceride, low-density lipoprotein cholesterol, and highdensity lipoprotein cholesterol.28 However, MPV reduction was not correlated with any improvements in serum lipids.
The strengths of the study by Akyu¨z et al28 include specific examination of patients with DM in whom MPV is more frequently elevated, longer study period, use of a steady statin dosage, and the adequate number (n ¼ 178) of patients included. This study also has some limitations.28 Of foremost importance, it was not a double-blind randomized controlled trial, and, indeed, the effect of rosuvastatin on MPV was seen only in a single treatment arm and not judged against a comparator (other treatment or placebo). Second, observations were made retrospectively. Furthermore, most patients also received aspirin or clopidogrel, which may have, to some extent, affected MPV, although their dosages were unaltered during the study period.28 Moreover, MPV was the sole index of platelet function evaluated in the study. Finally, seasonal variations in MPV29 were not considered, but this is the case in the vast majority of studies on MPV. Taken together, the more recent findings28 and those from the earlier studies suggest that rosuvastatin23,24 and atorvastatin,25,26 but not pravastatin,27 exert an additional beneficial action on MPV. With rosuvastatin this action is not mediated by the improved serum lipids,28 whereas atorvastatin achieved a significant MPV reduction in patients with the strongest concomitant lipid changes.25 This emerging difference needs to be revisited. Given the importance of MPV as a marker of activated platelets4 and as a predictor of vascular events,4,6 including DM,12,13,30 this effect of rosuvastatin and atorvastatin is encouraging. In contrast, it is worth mentioning that nicotinic acid/laropiprant increases MPV.31 At present, the underlying mechanism and why this action is not shared by pravastatin, and perhaps by other statins, needs to be determined. Such knowledge will help us better appreciate the clinical relevance of this effect.32,33 In conclusion, rosuvastatin and atorvastatin reduce MPV by a hitherto unknown mechanism, which may be lipid independent. However, the evidence may be criticized for being rather
1
Second Department of Internal Medicine, Diabetes Clinic, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
Corresponding Author: Nikolaos Papanas, Second Department of Internal Medicine, Diabetes Clinic, G. Kondyli 22c, Alexandroupolis 68100, Greece. Email: [email protected]
Downloaded from ang.sagepub.com at DALHOUSIE UNIV on June 24, 2015
2
Angiology
preliminary. Although more research is needed, this effect is a good beginning, a promising ‘‘home’’ to start from.34 Authors’ Note This editorial was written independently.
Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr N Papanas has been an advisory board member of TrigoCare International; has participated in sponsored studies by Novo Nordisk and Novartis; has received honoraria as a speaker for Astra-Zeneca, Eli-Lilly, Novo Nordisk and Pfizer; and attended conferences sponsored by TrigoCare International, Novo Nordisk, Sanofi-Aventis and Pfizer. Professor E Maltezos has participated in sponsored studies by Novo Nordisk and Novartis and attended conferences sponsored by Wyeth, Pfizer and Bayer.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Papanas N, Symeonidis G, Maltezos E, et al. Mean platelet volume in patients with type 2 diabetes mellitus. Platelets. 2004; 15(8):475-478. 2. Jagroop A, Mikhailidis DP. Platelets and diabetes: a complex association. Platelets. 2015;26(3):267-268. 3. Papanas N, Mavridis G, Karavageli E, Symeonidis G, Maltezos E. Peripheral neuropathy is associated with increased mean platelet volume in type 2 diabetic patients. Platelets. 2005;16(8):498-499. 4. Gasparyan AY, Ayvazyan L, Mikhailidis DP, Kitas GD. Mean platelet volume: a link between thrombosis and inflammation? Curr Pharm Des. 2011;17(1):47-58. 5. Varol E, Aksoy F, Bas HA, Ari H, Ozaydin M. Mean platelet volume is elevated in patients with low high-density lipoprotein cholesterol. Angiology. 2014;65(8):733-736. 6. Tsiara S, Elisaf M, Jagroop IA, Mikhailidis DP. Platelets as predictors of vascular risk: is there a practical index of platelet activity? Clin Appl Thromb Hemost. 2003;9(3):177-190. 7. Nena E, Papanas N, Steiropoulos P, et al. Mean platelet volume and platelet distribution width in non-diabetic subjects with obstructive sleep apnoea syndrome: new indices of severity? Platelets. 2012;23(6):447-454. 8. Steiropoulos P, Papanas N, Nena E, et al. Mean platelet volume and platelet distribution width in patients with chronic obstructive pulmonary disease: the role of comorbidities. Angiology. 2013; 64(7):535-539. 9. Acikgoz N, Karincaoglu Y, Ermis N, et al. Increased mean platelet volume in Behc¸et’s disease with thrombotic tendency. Tohoku J Exp Med. 2010;221(2):119-123. 10. Sahin DY, Gu¨r M, Elbasan Z, et al. Mean platelet volume and extent and complexity of coronary artery disease in diabetic and nondiabetic patients with ST elevation myocardial infarction. Angiology. 2013;64(7):505-511.
11. Murat SN, Duran M, Kalay N, et al. Relation between mean platelet volume and severity of atherosclerosis in patients with acute coronary syndromes. Angiology. 2013;64(2):131-136. 12. Han JY, Choi DH, Choi SW, et al. Stroke or coronary artery disease prediction from mean platelet volume in patients with type 2 diabetes mellitus. Platelets. 2013;24(5):401-406. 13. Papanas N, Mikhailidis DP. Mean platelet volume: a predictor of mortality in diabetic and non-diabetic patients with STEMI? J Diabetes Complications. 2014;28(5):581-582. 14. Mikhailidis DP, Athyros VG. Dyslipidaemia in 2013: new statin guidelines and promising novel therapeutics. Nat Rev Cardiol. 2014;11(2):72-74. 15. Agouridis AP, Filippatos TD, Katsiki N. Current lipid-modifying agents. Expert Opin Pharmacother. 2015;16(7):1117-1118. 16. Huhle G, Abletshauser C, Mayer N, Weidinger G, Harenberg J, Heene DL. Reduction of platelet activity markers in type II hypercholesterolemic patients by a HMG-CoA-reductase inhibitor. Thromb Res. 1999;95(5):229-234. 17. Schror K. Platelet reactivity and arachidonic acid metabolism in type II hyperlipoproteinaemia and its modification by cholesterol-lowering agents. Eicosanoids. 1990;3(2):67-73. 18. Pawelczyk M, Chmielewski H, Kaczorowska B, Przybyła M, Baj Z. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke. Arch Med Sci. 2015;11(1):115-121. 19. Sexton TR, Wallace EL, Macaulay TE, et al. The effect of rosuvastatin on platelet-leukocyte interactions in the setting of acute coronary syndrome. J Am Coll Cardiol. 2015;65(3):306-307. 20. Sexton TR, Wallace EL, Macaulay TE, et al. The effect of rosuvastatin on thromboinflammation in the setting of acute coronary syndrome. J Thromb Thrombolysis. 2015;39(2):186-195. 21. Du H, Hu H, Zheng H, Hao J, Yang J, Cui W. Effects of peroxisome proliferator-activated receptor g in simvastatin antiplatelet activity: influences on cAMP and mitogen-activated protein kinases. Thromb Res. 2014;134(1):111-120. 22. Violi F, Carnevale R, Pastori D, Pignatelli P. Antioxidant and antiplatelet effects of atorvastatin by Nox2 inhibition. Trends Cardiovasc Med. 2014;24(4):142-148. 23. Coban E, Afacan B. The effect of rosuvastatin treatment on the mean platelet volume in patients with uncontrolled primary dyslipidemia with hypolipidemic diet treatment. Platelets. 2008;19(2):111-114. 24. Sivri N, Tekin G, Yalta K, Aksoy Y, Senen K, Yetkin E. Statins decrease mean platelet volume irrespective of cholesterol lowering effect. Kardiol Pol. 2013;71(10):1042-1047. 25. Kucera M, Balaz D, Kruzliak P, et al. The effects of atorvastatin treatment on the mean platelet volume and red cell distribution width in patients with dyslipoproteinemia and comparison with plasma atherogenicity indicators-A pilot study. Clin Biochem. 2015;48(9):557-561. 26. Akin F, Ayc¸a B, Ko¨se N, et al. Effect of atorvastatin on hematologic parameters in patients with hypercholesterolemia. Angiology. 2013;64(8):621-625. 27. Broijersen A, Eriksson M, Larsson PT, et al. Effects of selective LDL-apheresis and pravastatin therapy on platelet function in familial hypercholesterolaemia. Eur J Clin Invest. 1994;24(7): 488-498.
Downloaded from ang.sagepub.com at DALHOUSIE UNIV on June 24, 2015
Papanas and Maltezos
3
28. Akyu¨z A, Akkoyun DC¸, Deg˘irmenci H, Oran M. Rosuvastatin decreases mean platelet volume in patients with diabetes mellitus [published online on May 5, 2015]. Angiology. 2015. doi: 10. 1177/0003319715584725. 29. Crawford VL, McNerlan SE, Stout RW. Seasonal changes in platelets, fibrinogen and factor VII in elderly people. Age Ageing. 2003;32(6):661-665. 30. Mikhailidis DP, Barradas MA, Jeremy JY, Dandona P. Effect of alpha a-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in type 2 (non-insulindependent) diabetes mellitus. Diabetologia. 1989;32(2): 147-149.
31. Kei A, Elisaf M. Nicotinic acid/laropiprant reduces platelet count but increases mean platelet volume in patients with primary dyslipidemia. Arch Med Sci. 2014;10(3):439-444. 32. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance. J Clin Lipidol. 2012;6(1):93. 33. Kargiotis K, Katsiki N, Athyros VG, et al. Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report. Curr Vasc Pharmacol. 2014;12(3):505-511. 34. Eliot TS. Collected Poems 1909-1962. London: Faber and Faber; 1986: 203.
Downloaded from ang.sagepub.com at DALHOUSIE UNIV on June 24, 2015
