Are statins bad? Should you be considering other options

High levels of cholesterol is associated with a higher risk of heart disease and other disorders related to the impaired or reduced circulation of the blood. This is a significant source of preventable death worldwide; recent estimates indicate that up to 30% of all deaths may be attributed to cardiovascular illnesses. This is mainly due to the strong link between lipoproteins (molecules that bind to cholesterol and contribute to its accumulation) and cardiovascular disease. Not all lipoproteins are equal, or thought of as culprits in this worldwide epidemic, however. 

High-density lipoproteins (HDLs) are associated with a reduced risk of heart disease, which may be due to their efficiency in binding cholesterol and transporting it for storage and breakdown.

Low-density lipoprotein type C (LDL-C) is strongly associated with an increased risk of cardiac events, or of other cardiovascular disorders such as stroke and high blood pressure.

Poor transport of cholesterol is associated with the build-up of this substance on the interior surfaces of blood vessels (arterial plaque), which is known as atherosclerosis.

Cholesterol is a large form of lipid that is the basis for many steroid-type molecules.

Statins

The prevention and treatment of heart and cardiovascular disease is often based on the reduction of concentrations of LDL-C. A class of drugs that has been found to have both properties are statins.

The mechanism of action of statins is based on inhibition of an initial step in the conversion of dietary fats (triglycerides) to LDL. Statins block the action of an enzyme called HMG-CoA reductase (HMGCR), which start off this process. This is associated with a reduction in the amount of LDL-C, and a relative increase in its high-density analog, HDL-C2.

These drugs are increasingly linked to worrying reports of adverse effects, such as liver damage, macular degeneration and arthritis. However, there is little evidence to support these links. Conversely, there may be some evidence to support the claim that the drugs are associated with a slightly increased risk of dementia and Parkinson's disease.

Myopathy and muscle damage 

This is a progressive breakdown of muscle tissue, which may cause pain and weakness in the areas of the body affected. The research into this side-effect produces wildly different results. One such report indicated that the risk of myopathy was somewhat increased by statin intake, but that rhabdomyolysis (advanced muscle breakdown) occurred only once in 10,000 cases. However, other research indicates that this risk is influenced by interactions with other drugs taken by patients in conjunction with statins.

Chemicals that may increase statin-induced myopathy include niacin (vitamin B3) and certain molecules found in grapefruit juice.

Type 2 Diabetes 

There may be a slightly stronger association between statins and the increased risk of type II diabetes. This condition is an acquired resistance to insulin (the major controller of glucose metabolism) and is also associated with the development of cardiovascular disease. One study found a 2.25% increase in the risk of diabetes associated with prolonged use of statins. However, this probability is relatively low, and is often outweighed by the benefits of these drugs. The probability of type II diabetes onset while taking statins may also be influenced by genetic factors.

Alternatives to Statins

There are alternatives to statins for those who may be at higher risk of developing the aforementioned side-effects or are concerned about doing so. Many of the alternatives to statins target the production or accumulation of cholesterol in other ways. These alternatives include novel drugs that are currently under clinical investigation for their potential in reducing risk factors for heart disease.

Future developments

Upcoming statin alternatives may be directed at the inhibition of other biological molecules involved in the formation of cholesterol.

These include apolipoprotein-B100, microsomal triglyceride transfer protein (MTP), proprotein-convertase subtilisin/kexin type 9 (PCSK9), and cholesteryl ester transport protein (CETP). Others promote 'beneficial' lipoproteins, such as apolipoprotein A1, and their mechanisms of production, e.g. adenosine triphosphate-binding cassette transporter A1 (ABCA1).

Fibrates

Until these are available on the market, there are other options extant that reduce either cholesterol or triglyceride levels. These include fibrates, which are a statin alternative that activates peroxisome proliferator-activated receptors (PPARs). These play a role in controlling lipid and glucose metabolism. Fibrates are associated with a reduction in circulating triglycerides16. They are also associated with a modest increase in HDLs.

Ezetimibe

Ezetimibe is a drug that reduces dietary cholesterol absorption in the gut. It was found to inhibit the binding of cholesterol to apolipoprotein B, which together form an intermediate of LDL, in a recent trial18. In combination with phenofibrate, it also reduced the concentration of LDL.

Phytosterols

Phytosterols (stanols and sterols) are molecules found in many foods; most notably yogurt and margarine brands advertising cholesterol-lowering properties. These have in fact been shown to lower LDL concentrations in independent research settings. A recent study demonstrated the ability of approximately three grams of phytosterols a day to reduce LDL by up to 12%. A recent trial also reported a reduction of up to 9% in circulating triglycerides in response to two grams of phytosterols a day. Therefore, these molecules may also be a reliable alternative to statins.

Vitamins

Some B-vitamins are also associated with the potential to combat atherosclerosis. They are associated with the reduction of homocysteine, another biological molecule implicated in the formation of arterial plaque. These B-vitamins include B6, B12 and folic acid.

Vitamin B3, also known as niacin, is also associated with the reduced risk of cardiovascular disease. It has been used in combination with statins, but may increase the risk of side-effects, as mentioned above.

Niacin was shown to increase HDL-C by 17%, and reduce triglycerides by 13%, in a recent trial. Therefore, it may be a viable standalone alternative to statin therapy.

In conclusion

The negative effects of statins may not be as severe as they may be perceived to be. On the other hand, some individuals may be at higher risk of the more prevalent side-effects, such as type II diabetes, if they are taking statins for cardiovascular disease or high blood pressure. In these cases, considering alternatives to statins may be advisable. These include promising new drugs such as PCSK9 inhibitors and apolipoprotein A1 promoters. More established statin alternatives, such as niacin and ezetimibe, are also currently available. Therefore, prevention and treatment of cardiovascular disease is not dependent on statins alone.

References

1. Mendis S, Puska P, Norrving B, World Health Organization., World Heart Federation., World Stroke Organization. Global atlas on cardiovascular disease prevention and control. Geneva: World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization; 2011.
2. Wilkinson MJ, Davidson MH. Recent developments in the treatment of familial hypercholesterolemia: a review of several new drug classes. Current treatment options in cardiovascular medicine.2013;15(6):696-705.
3. Tenenbaum A, Fisman EZ. Fibrates are an essential part of modern anti-dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction. Cardiovascular diabetology.2012;11:125.
4. Zhou Z, Rahme E, Pilote L. Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. American heart journal.2006;151(2):273-281.
5. Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC medicine.2014;12:51.
6. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ (Clinical research ed.).2010;340:c2197.
7. Mendes P, Robles PG, Mathur S. Statin-induced rhabdomyolysis: a comprehensive review of case reports. Physiotherapy Canada. Physiotherapie Canada.2014;66(2):124-132.
8. Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug safety : an international journal of medical toxicology and drug experience.2010;33(3):171-187.
9. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ (Clinical research ed.).2013;346:f2610.
10. Yoon JS, Lee HW. Diabetogenic effect of statins: a double-edged sword? Diabetes & metabolism journal.2013;37(6):415-422.
11. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet.2012;380(9841):565-571.
12. Noto D, Cefalu AB, Averna MR. Beyond statins: new lipid lowering strategies to reduce cardiovascular risk. Current atherosclerosis reports.2014;16(6):414.
13. Urban D, Poss J, Bohm M, Laufs U. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. Journal of the American College of Cardiology.2013;62(16):1401-1408.
14. Tomkin GH, Owens D. Investigational therapies for the treatment of atherosclerosis. Expert opinion on investigational drugs.2014:1-11.
15. Herrick C, Litvin M, Goldberg AC. Lipid lowering in liver and chronic kidney disease. Best practice & research. Clinical endocrinology & metabolism.2014;28(3):339-352.
16. Forcadell-Peris MJ, de Diego-Cabanes C. [Rhabdomyolysis secondary to simvastatin and phenofibrate.]. Semergen / Sociedad Espanola de Medicina Rural y Generalista.2014.
17. Subedi BH, Joshi PH, Jones SR, Martin SS, Blaha MJ, Michos ED. Current guidelines for high-density lipoprotein cholesterol in therapy and future directions. Vascular health and risk management.2014;10:205-216.
18. Tribble DL, Farnier M, Macdonell G, et al. Effects of fenofibrate and ezetimibe, both as monotherapy and in coadministration, on cholesterol mass within lipoprotein subfractions and low-density lipoprotein peak particle size in patients with mixed hyperlipidemia. Metabolism: clinical and experimental.2008;57(6):796-801.
19. Ras RT, Geleijnse JM, Trautwein EA. LDL-cholesterol-lowering effect of plant sterols and stanols across different dose ranges: a meta-analysis of randomised controlled studies. The British journal of nutrition.2014:1-6.
20. Gylling H, Plat J, Turley S, et al. Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis.2014;232(2):346-360.
21. Debreceni B, Debreceni L. The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease. Cardiovascular therapeutics.2014;32(3):130-138.
22. Pang J, Chan DC, Watts GF. Critical review of non-statin treatments for dyslipoproteinemia. Expert review of cardiovascular therapy.2014;12(3):359-371.
23. Aye MM, Kilpatrick ES, Afolabi P, et al. Postprandial effects of long-term niacin/laropiprant use on glucose and lipid metabolism and on cardiovascular risk in patients with polycystic ovary syndrome. Diabetes, obesity & metabolism.2014;16(6):545-552.