Should we take statins? 

Should we take statins? 
Statins have suffered significant bad press of late with one Sunday Express article claiming statins have 20,000 side effects including death.

The Telegraph too resorted to alarmist headlines so every man and his dog will now blame Type 2 Diabetes on their doctor. 
Receiving no publicity outside a narrow medical fraternity was a small study looking at whether statins could help patients with ADPKD. 

But aren’t statins all about cholesterol? 
Well, yes …. And no. 

Aside from cholesterol-lowering, statins have been shown to be antiproliferative, anti-inflammatory and anti-oxidant. And all of these effects are independent of any change in cholesterol. 

What exactly IS a statin? 
3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor
(Well you did ask!)
Slightly more manageable is the label “HMG-CoA reductase inhibitors” but you can easily see why the word “statins” was adopted. 
The first statin was introduced in the 1970s following the new “lipid hypothesis” that high cholesterol led to heart disease so reducing cholesterol will reduce heart disease. The evidence supporting this hypothesis didn’t really emerge until the results of the 4S study in 1994. In this, 4444 patients with raised cholesterol levels were treated with simvastatin and, in short, there was a 35% reduction in cholesterol and a 42% reduction in deaths due to MI (heart attacks). This heralded my start in general practice and the statin bandwagon. Initially cost prohibited widespread use but now they have mostly come off patent the clinical benefit can be judged more fairly. 

The detailed science bit (feel free to skip)
Cholesterol is a biomolecule, one of over 30,000 “isoprenoids”, a group that includes haem and steroid hormones. 

The chemical process that makes isoprenoids is called the “mevalonate pathway” which begins with the conversion of HMG-CoA to mevalonate. This reaction is encouraged by the enzyme “HMG CoA Reductase”. So this is where the statins come in – they stop the reductase enzyme form working and so stop the production of mevalonate. Thus the synthesis of certain isoprenoids is interrupted. Cholesterol is just one of those isoprenoids. 
You can work out that acting so high up in the pathway, statins will have more than one effect, they don’t just reduce cholesterol, they are pleiotropic (I know, but I like the word!)
It is these other effects that are relevant to us with PKD. They include changes in signal transduction (the cells internal email) and cell proliferation (increase in numbers of cells) and cell polarity (which way up a cell sits, on its bottom or its head).  
In simplifying the explanation I have made it all sound so obvious – of course statins will help PKD if they can change the cell messaging and stop proliferation and prompt the tubule cells about where they are in the kidney and what they are supposed to be doing so they don’t get sidetracked into forming cysts. Sadly it isn’t quite that simple and the exact mechanisms for statin effects on the kidney have yet to be elucidated. 

What have studies shown about statins and PKD? 
I shall mention just 6 studies that specifically involve PKD, there are many more using patients with chronic kidney disease but not specifying PKD. 

  1. Twenty years ago, a study in rats with PKD, showed a significant reduction in cystic kidney size when they were given lovastatin (Gile et al, 1995). They had reduced density of cysts and the serum urea nitrogen level fell – a measure of kidney function (lower is better). The study was repeated by other researchers more recently and also showed a reduction in kidney weight and improved blood flow in the kidneys. 
  2. In 2001 actual PKD patients were studied in a double blind cross-over trial of simvastatin/placebo (van Dijk et al, 2001) and although small, at just 10 patients, there was a significant improvement in renal blood flow with the simvastatin. 
  3. The next study of note (Namli et al, 2007) was based on the knowledge that statins have an effect on endothelial dysfunction (endothelium lines blood vessels and when it doesn’t work properly the vessels stiffen leading to high blood pressure and other problems). They took 16 patients with ADPKD, so still a small study, and demonstrated an improvement in the flexibility of the brachial artery after 6 months of statin treatment. These patients were all in the early stages with fairly good kidney function at the time, which underlies the importance of early treatment even when the signs of the disease may not be apparent. 
  4. Three years later a Scandinavian study looked at the effects of pravastatin on kidney function as measured by protein in the urine (proteinuria). Over the 2-year period no significant benefit was seen in the treatment group. However the dose used was low, the patients all had reasonable eGFR levels and some would argue that proteinuria is not a valid marker in ADPKD since it occurs late in the disease. 
  5. The most recent study of note is reported in last month’s issue of Nephrology, Dialysis and Transplant (Zand et al, 2016). This one did not agree with the previous ones when it looked at renal blood flow in ADPKD patients treated with simvastatin. There was no significant effect of the drug when used over a 4 week period. Like the other studies, it was small, just 21 patients, and all were in the mild or moderate category (eGFR averages at 86 and 47). This seems disappointing but is important to keep in mind despite its limitations in order to balance the arguments. 
  6. There has been one very important study (Cadnapaphornchai et al, 2014) looking at pravastatin in children with ADPKD. There are generally few studies performed in children. This one began with 110 paediatric patients between 8 and 22 years, all with ADPKD and normal renal function. 91 of them completed the 3 year study in which they were randomly allocated to pravastatin or placebo. All of them were already taking lisinopril. The kidney volume (height adjusted to allow for age differences) did not increase in the group taking pravastatin as much as it did in the control group. Since there were no differences in the final cholesterol so between the two groups it is presumed the effects were not due to cholesterol lowering. The study is well designed, accurately undertaken and uses valid analyses so the conclusion is significant: that there are benefits from using statins in early ADPKD.  

But are there real problems with taking statins?
7 million British people take statins and 1 in 4 Americans over the age of 45 has been prescribed a statin. 
There have been papers on the adverse effects – an increase in breast cancer, increased insulin resistance, reduced ketone production and rhabdomyolysis (severe muscle damage) are just some of the side effects to reach mainstream media reports. But most people do not experience side effects of this magnitude. NHS Choices lists headache, nausea, nose bleeds and rhinitis but gives no indication as to how common these might be or how serious they tend to become. As a clinician the commonest side effect I heard from patients was aching muscles and of course we were quick to stop the statin because of fear of the serious rhabdomyolysis. It should be noted however that early treatment in the 1990s was at a higher dose than is currently used. Somewhat inappropriately one former head of NHS England claimed in public that he stopped taking statins due to the terrible side effects and lack of benefit – but the headlines skipped over his 7 pints of beer on Fridays and fried food 5 nights a week (apparently – note I am giving no names here) That same person went on to say that “GPs should do more to change a patient’s lifestyle” – what does he think GPs have been doing for the past 20 years? Don’t answer that!
Anyhow, media coverage of the ill-effects is followed by reduction in prescriptions and probably by more bathroom cabinets overflowing with untaken statins. But all this relates to statins in the general population, taken to lower cholesterol and protect from heart disease. How relevant is it to those of us with ADPKD who are trying to slow the progressive increase in cysts and kidney size? 

There is no bottom line
I was really hoping to reach a conclusion on this topic, to come down off the fence and decide one way or another whether I should take statins. Sadly, in the list of current clinical trials (clinicaltrials.gov) there are none dealing with statins and ADPKD. There will most likely be studies in animal models to advance knowledge of physiology and the mechanism of action of statins in PKD, but at this point in time, my original question remains unanswered: 

 Should we take statins?

References: 
Gile RD et al, Effect of lovastatin on the development of PKD in the Han:SPRD rat. Am J Kidney Dis 1995;26:501-507
Van Dijk et al, Effect of simvastatin on renal function in ADPKD.Nephrol Dial Transplant 2001;16:2152-2157
Namli et al, Improvement of endothelial dysfunction with simvastatin in patients with ADPKD. Renal Failure 2007;29:55-59
Fassett et al, Effects of pravastatin on kidney function and urinary protein excretion in ADPKD. Scand J Urol Nephrol 2010;44:56-61
Zand et al, Renal haemodynamic effects of HMG-CoA reductase inhibitors in ADPKD. Nephrol Dial Trans 2016;31:1290-1295
Cadnapaphornchai et al, Effect of pravastatin on total kidney volume, left ventricular mass index and microalbuminuria in paediatric patients with ADPKD. Clin J Am Soc Nephrol 2014;9:889-890

There is no bottom line, so we wait for more studies.

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2 responses to “Should we take statins? 

  1. Really interesting article, again! 😉 I agree that the side effects of statins are probably overemphasised. My suspicion is that statins achieve their effects via mechanisms like inflammation and endothelial function, and that cholesterol is just a cofactor. ED and inflammation are such fundamental processes, underlying so many common diseases whereas the role of blood cholesterol is very much disputed. But yes, we can only speculate at present. These mechanisms can also be influenced with diet and herbal treatment however, which may be a safer option. Green tea for example has been shown to reverse endothelial dysfunction, as have dark chocolate and nuts.

    Like

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