The SA Journal Diabetes & Vascular Disease Vol 12 No 2 (December 2015)

7 / 48

SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW
VOLUME 12 NUMBER 2 • NOVEMBER 2015 49
pleiotropic effects and may be unrelated to the cholesterol-lowering
properties of the drug. They include improvement in endothelial
dysfunction, normalised vasomotion, increased bioavailability of
nitric oxide, anti-oxidant effects, anti-inflammatory effects, plaque
stabilization, and inhibition of myocardial hypertrophy.23
Treatment with statins has been shown to improve endothelial
dysfunction and even improve coronary perfusion in previously
ischaemic segments due to improved vaso reactivity.24 Another
small study showed that endothelial function was improved in
healthy normocholesterolaemic young males within 24 hours of
treatment with atorvastatin.25 These results show that there is a
beneficial effect on endothelial dysfunction, both in the short and
long term.
Endothelial dysfunction was also improved by increasing the
bioavailability of nitric oxide via prevention of down-regulation of
endothelial nitric oxide synthase (eNOS, the enzyme that catalyses
the conversion of L-arginine to nitric oxide),26 and also directly
enhancing eNOS activity.
The anti-oxidant effect is another positive side effect of the
statins as they have the ability to scavenge free radicals. By reducing
the ability of macrophages to oxidise lipoproteins, it is thought that
oxidised low-density lipoprotein (LDL) particles become negatively
charged and contribute to cytotoxicity and inflammation.
Sanchez-Quesada and co-workers showed this positive effect in
patients with familial hypercholesterolaemia who were treated with
simvastatin. A reduction of 60% in electronegative LDL cholesterol
levels was achieved after six months of treatment.27 Vaughan
and Gotto showed that by reversing the inhibitory effect of LDL
cholesterol on eNOS, it caused direct anti-oxidant effects on LDL
cholesterol levels.23
The anti-inflammatory effects of statins are also well established.
The Cholesterol And Recurrent Events (CARE) trial28 as well as the
Pravastatin inflammation/CRP evaluation (PRINCE) trial29 showed a
reduction in levels of high-sensitivity C-reactive protein (hsCRP) in
post-myocardial infarct patients. It is this side effect that is one of the
reasons for the early beneficial effect in acute coronary syndromes.
Statins have also been shown to have a beneficial effect on the
heart musculature as demonstrated in rat models where myocyte
hypertrophy was reduced by simvastatin.30 Another beneficial
effect includes the stimulation of endothelial progenitor cell
recruitment, whereby endothelial progenitor cells play a role in
the repair of ischaemic tissue. Statins have thus been compared
to vascular endothelial growth factor (a cytokine that regulates
neovascularisation).
Immunomodulation is another area where statins can be of use.
It is hypothesised that they inhibit the promoter IV of the major
histocompatibility complex-II transactivating factor, which leads to
suppression of T-lymphocyte activation.23
Conclusion
There is a generous amount of data that has been accrued over more
than 25 years to suggest that statins are of great benefit to those
with cardiovascular disease. There were initial concerns regarding
the adverse effects of statins with regard to myopathy and liver
toxicity, but this has been shown not to be clinically relevant. By
contrast, there are several promising positive effects of statins on
the cardiovascular system that support their greater use. Although
statins have displayed a good safety profile, there is still a need for
close vigilance and improved reporting of adverse events.
Acknowledgement
Dr Faz Mahomed, Edendale Hospital, Pietermaritzburg, KwaZulu-
Natal, assisted with the writing of this article.
References
1. Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia.
New Engl J Med 1988; 319: 24–33.
2. Bays H. Statin safety: An overview and assessment of the data – 2005. Am J
Cardiol 2006; 97(suppl): 6C–26C.
3. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis.
New Engl J Med 2002; 346: 539–540.
4. Pasternak RC, Smith SC, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory
on the use and safety of statins. J Am Coll Cardiol 2002; 40: 567–572.
5. Newman CB, Palmer G, Silbershatz H, et al. Safety of atorvastatin derived from
analysis of 44 completed trials in 9416 patients. Am J Cardiol 2003; 92: 670–
676.
6. Thompson PD, Clarkson P, Karas RH. Statin associated myopathy. J Am Med
Assoc 2003; 289: 1681–1690.
7. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events
with atorvastatin in hypertensive patients with average or lower than average
cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial –
Lipid lowering Arm (ASCOT-LLA), a multicenter randomized control trial. Lancet
2003; 361: 1149–1158.
8. Waters D. Statins and safety: Applying the results of randomized trials to clinical
practice. Am J Cardiol 2003; 92: 692–695.
9. Heart Protection Study collaborative group. MRC/BHF. Heart protection study
of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a
randomized placebo-controlled trial. Lancet 2002; 360: 7–22.
10. Bitzur R, Kamari Y, Cohen H, et al. Intolerance to statins: mechanisms and
management. Diabetes Care 2013; 36: 5325–5330.
11. Schalke BB, Schmidt B, Toyka K, et al. Pravastatin associated inflammatory
myopathy. New Engl J Med 1992; 327: 649–650.
12. Mancini GB, Basker S, Bergeron J. Diagnosis, prevention and management of
statin adverse effects and intolerance: proceedings of a Canadian working group
consensus conference. Can J Cardiol 2011; 27: 635–662.
13. Parra JL, Reddy KR. Hepatotoxicity of hypolipidemic drugs. Clinics Liver Dis 2003;
7: 415–433.
14. Pelli N, Setti M. Atorvastatin as a trigger of autoimmune hepatitis. J Hepatol
2004; 40: 716.
15. Tolman KG. The liver and lovastatin. Am J Cardiol 2002; 89: 1374–1380.
16. Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study group.
Prevention of cardiovascular events and death with pravastatin in patients with
coronary heart disease and a broad range of initial cholesterol levels. New Engl J
Med 1996; 339: 1349–1357.
17. Sheppard J, Cobbe SM, Forde I, et al. Prevention of coronary heart disease with
pravastatin in men with hypercholesterolemia. New Engl J Med1995; 333: 1301–
1307.
18. Bottorf MB. Statin safety and drug interactions: clinical implications. Am J Cardiol
2006; 97(Suppl): 27C–31C.
19. Charles EC, Olson KL, Sandhoff BG, et al. Evaluation of cases with severe statin
related transaminitis within a large health maintainence organization. Am J Med
2005; 118: 618–624.
20. Eckernas SA, Roos BE, Kvidal P, et al. The effect of simvastatin and pravastatin
on objective and subjective measures of nocturnal sleep: A comparison of 2
structurally different HMG CoA reductase inhibitors in patients with moderate
hypercholesterolemia. Br J Clin Pharmacol 1993; 35: 284–289.
21. Harrison RW, Ashton CH. Do cholesterol lowering agents affect brain activity?
A comparison of simvastatin, pravastatin and placebo in healthy volunteers. Br J
Clin Pharmacol 1994; 37: 231–236.
22. Gengo P, Cwudzinski D, Kinkel P, et al. Effects of treatment with lovastatin and
pravastatin on daytime cognitive performance. Clin Cardiol 1995; 18: 209–214.
23. Vaughan CJ, Gotto AM. Update on statins: 2003. Circulation 2004; 110: 886–
892.
24. Eichstadt HW, Eskotter H, Hoffman I, et al. Improvement of myocardial perfusion
by short-term fluvastatin therapy in coronary artery disease. Am J Cardiol 1995;
76: 122A–125A.
25. Lauls U, Wassmann S, Hilgers S, et al. Rapid effects on vascular function after
initiation and withdrawal of atorvastatin in healthy noncholesterolemic men. Am
J Cardiol 2001; 88: 1306–1307.
26. Martinez-Gonzalez J, Raposo B, Rodriguez C, et al. 3-Hydroxy-3methylglutaryl
coenzyme A reductase inhibition prevent endothelial NO synthase downregulation