There is real concern when considering expanding their use to patients who are well. By Michael Lim

CHOLESTEROL lowering drugs, also called statins, are one of the most commonly used drugs. The commonest side effects, muscle pain and liver abnormalities have been described in greater detail in the previous article (The Business Times Weekend, Oct 5). The muscle aches are believed to be related to the statin effect of decreasing production of Coenzyme Q10, a catalyst in the cells which is responsible for speeding up the production of energy in cells. Supplementation with Coenzyme Q has been found to be able to alleviate the symptoms for those with mild muscle aches in some studies but the data has not been consistent. Of greater concern is a 2009 publication in the Canadian Medical Association Journal which reported that a significant number of the biopsies of muscle in those with statin related muscle pain had demonstrated structural damage to the muscles.

Cancer

One of the myths on statin is its relationship with cancer. The trials have dismissed this unfounded fear and there is absolutely no evidence that the incidence of cancer was any different between statin treated groups and those who were given placebos.

Diabetes Mellitus

Current evidence points to a trend of a minor increase in blood sugar and a slightly increased risk of developing diabetes with statins. A 2010 Lancet publication based on data from combined studies showed that for every 1,000 patients given statins for four years, there will be an additional four new diabetics but this is offset by the prevention of about 22 cardiovascular events (heart attacks or strokes). For non-diabetics taking statins, on the average, the fasting blood sugars are 3mg/dl higher than those not taking statins. For diabetics, statin consumption also results in a small elevation in the blood sugar.

Impact on the brain

One of the more recent concerns of statins is its impact on cognitive function. In 2012, the US Food and Drug Administration issued a consumer advisory to inform those taking statins that some statin users experienced brain cognitive impairment, such as memory loss, forgetfulness and confusion. More recently in May 2013, researchers from Arizona University reported in the Disease Models & Mechanisms Journal, that when brain cells of an insect were treated with statins, the brain cells developed swellings which were labelled as “beads-on-a-string” (BOS) effect. The researchers postulated that the effect was akin to a traffic jam, and the development of the beads was like a traffic pileup that was so bad that it disrupted the function of the brain cell. Removal of statins resulted in disappearance of the BOS effect and restoration of normal brain cell growth. Although cognitive impairment is a rare and reversible event, it is nevertheless of concern as statin users may go about their daily activity with impaired cognitive function without realising that it is related to statin intake and not due to ageing.

For statin use in recent strokes, only high dose atorvastatin was associated with a higher risk of bleeding in the brain as was demonstrated in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study.

Kidney effects

Among the statins, rosuvastatin intake is associated with leakage of protein into the urine, especially at doses of 40-80 mg daily. This may also be associated with leakage of red blood cells into the urine. This is an effect not seen in those receiving other statins. In a small percentage of those with high dose rosuvastatin, the urinary protein leakage may be persistent and may be associated with evidence of impairment of the kidney function such as elevation of the blood creatinine levels (blood marker used to measure kidney function). A few cases of kidney failure with high dose rosuvastatin have also been documented.

The impact of statins on the kidney caught media attention when a large retrospective observational study involving more than two million patient records was published in March this year in the British Medical Journals. The study noted that those who had no kidney disease, who were started on high dose statins, had a 34 per cent increase in hospital admissions for acute damage to the kidney when compared to those who were given lower dose of statins. This effect was seen during the first four months of commencing high dose statins. In this study, statin dosage was considered as high if the patient was on 10mg or more of rosuvastatin daily, 20mg or more of atorvastatin daily and 40mg or more of simvastatin daily. In absolute numbers, the researchers estimated that one admission for acute kidney injury may be seen for 1,700 patients who are started on treatment with high dose statins. This adverse tendency was not seen in those with pre-existing kidney disease. Currently, there is conflicting data on the use of statins in those on dialysis and with chronic kidney disease with some studies showing benefits and others showing increased risk of complications and no reduction in total death.

Important statin facts

Statins as a class of drugs are generally safe and there is no doubt that statins are beneficial for those with pre-existing blockage of the heart arteries. While there is data to support the use of statins in patients who are at risk of heart disease but do not have pre-existing heart artery disease, there is real concern about the safety of statins when considering expanding the use of statins to patients who are well. When commencing statins, it is imperative to be aware that beyond the usual side effects of muscle aches and elevation of liver enzymes, there is a small but real risk of diabetes, cognitive impairment and kidney damage.

There are a few golden rules to follow. Firstly, start your statin dose at a low dose. This is especially true if you are an Asian and you are taking rosuvastatin, as blood drug level is about double that of a Caucasian for the same dosage. Secondly, higher doses of statins are associated with more adverse side effects and decreased tolerability, and hence combining a statin with ezetimibe (Ezetrol), which blocks cholesterol absorption in the intestine, may be considered first for further lowering of LDL or “bad” cholesterol before considering increasing statin doses. Thirdly, if there is pre-existing kidney disease or urinary protein leakage, it is best not to use rosuvastatin. Fourthly, for those with recent strokes, atorvastatin should be avoided. Fifthly, for those who are about to commence on statins, based on the analysis of the combined data of 135 studies on statins published in June this year in Circulation Cardiovascular Quality and Outcomes, among all the statins currently available in the market, low to moderate doses of simvastatin and pravastatin have the best safety profile and are the preferred statins.

Statins and brand names: pravastatin (Pravachol), simvastatin (Zocor), atorvastatin (Lipitor), rosuvastatin (Crestor)

This is the second of two parts on cholesterol-lowering medications