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Statin Safety for Patients With Comorbid Lipid Disorders, CKD

April 16, 2019

materaJames Matera, DO, from CentraState Medical Center in New Jersey, discusses how lipid disorders impact the management of chronic kidney disease (CKD), and whether statins are safe for use in patients with comorbid lipid disorders and CKD.

James Matera:  Hi. My name is Dr. James Matera. I'm the Senior Vice President for Medical Affairs and Chief Medical Officer at CentraState Medical Center in Freehold, New Jersey and a practicing nephrologist. Today I'm going to be speaking to you about some of the issues we have regarding lipid management in chronic kidney disease patients. There's a lot of factors that go on with this.

First of all, we know that our chronic kidney disease patients all have a very high risk for cardiovascular disease. Yet we have a little bit of confusion as to how to manage their lipids and what it may mean because of some of the adverse effects and actually some of the kidney guidelines that came out several years ago, in 2013.

It actually looked at our dialysis population and did not find a benefit to adding statins to that group of patients. What it basically said was, in patients who were predialysis and then ended up on dialysis, if they were on a statin, it could be continued. It didn't show from the evidence‑based medicine a lot of added benefit by starting a statin in dialysis. That's a very controversial point.

That leads to some gaps in understanding between the primary care and the nephrologist in regard to this. I wanted to touch on three very large, randomized placebo‑controlled trials that looked at the effect of lipid‑lowering therapy like the statins on cardiovascular outcomes in both dialysis‑dependent and CKD stage five patients not quite on dialysis.

The first one was the SHARP study. That was the Study of Heart and Renal Protection. What they used there was a fixed‑dose combination of simvastatin and ezetimibe, compared it to a placebo in over 9,000 patients who had chronic kidney disease. About 30 percent of that group was actually on dialysis. The other 70 percent were predialysis.

What they found was lipid‑lowering therapy significantly reduced the primary composite cardiovascular outcome and did not result in excess risk for adverse events. These adverse events, such as myopathy or hepatitis, abnormal liver functions, did not seem to occur in excess for the chronic kidney disease population.

The reduction in risk was actually most robust in the non‑dialysis‑dependent subgroup and did not reach statistical significance in the CKD patients who were on dialysis. That in part led to that recommendation from the KDIGO Guidelines. The efficacy of statins versus placebo in reducing cardiovascular events, in hemodialysis patients in particular, was also studied in the 4D and Aurora studies.

The Aurora study used rosuvastatin in subjects on regular hemodialysis. In both those studies, although statin therapy lowered LDL lipoproteins and cholesterol in general, there was no effect on the primary composite of cardiovascular death, MI, or stroke.

The conclusions of these trials is that there seems to be enough evidence to support the use of lipid‑lowering therapy with statins for cardiovascular‑event reduction in non‑dialysis‑dependent CKD without increasing the risk for any adverse events. Existing evidence suggests that lowering cholesterol concentration with statins does not decrease the risk for events in patients who are on dialysis.

Again, that led to the goal with the guideline. I must say in my practice, patients who are on statins who end up on dialysis, we do continue the statin at that time. One of the other important things that we have to understand in this population is that there is a dysfunction in the lipid disorders and elevated cholesterol that can participate in chronic kidney disease as well.

We know that people with CKD have profound changes in their metabolism of the lipids and in their plasma lipid profile. This can be characterized by a hypertriglyceridemia, elevated triglyceride‑rich lipoproteins, increased small‑density LDL particles, decreased plasma levels and an altered composition, and impaired function of HDL.

What that then leads to is an accumulation of atherogenic and pro‑inflammatory oxidized lipoproteins giving them their risk. The abnormalities of lipid metabolism contribute to the prevailing systemic inflammation, oxidative stress, and this high incidence of cardiovascular and overall morbidity and mortality in the CKD population.

There are also other factors that occur. There's impaired delivery of lipids to the skeletal muscles and adipose tissues. This is what in part results in hypertriglyceridemia. This plays a major part in the pathogenesis of wasting syndrome, weakness, and decreased physical capacity that is very often seen in our patients with advanced CKD.

We all know those patients when they come into our office. A lot of that has to do with their lipid metabolism.

Again, when you progress along from CKD to end‑stage renal disease, there's again a significant abnormality seen in the size of the HDL, the content, and metabolism. We know that advanced CKD has lower‑serum HDL cholesterol levels and impaired maturation of HDL from the ester‑poor HDL as well.

These impact in many different ways and start to have that impact that increases the cardiovascular risk. We've already stated the fact that our patients who are suffering from chronic kidney disease have a higher incidence of cardiovascular risks.

The question always comes up in the primary office and in the nephrology office as well, is how do these lipid disorders impact management and treatment of kidney disease and, mostly, are statins safe for use in patients with chronic kidney disease?

About 65 percent of our adults who have chronic kidney disease were recommended to be on a statin based on the 2013 American College of Cardiology and the AHA Guidelines. In reality, only 36 percent of adults with CKD were noted to be taking a statin in the time period of 2011, 2014. Not a very good penetration of this area of need.

The prevalence of statin use was lower among adults with chronic kidney disease in the absence of other conditions with high cardiovascular risk, such as diabetes mellitus. We all know that our patients oftentimes have both diabetes mellitus, chronic kidney disease, and often hypertension in association with that as well.

Again, these are higher cardiovascular risks, which put our patients in that high‑risk category. When you compare them with adults with diabetes in the absence of CKD, statin use in that group was much higher. It seems that the CKD does limit the ability to use statins. It may be because of some of the adverse effects.

I think some of our studies we spoke about earlier show that they may be very safe. When you look at the actual National Kidney Foundation's "Kidney Disease Outcomes and Quality Initiatives," when they put out their practice guidelines, they do recommend using statins or combination statin therapy to reduce the risk of major atherosclerotic events in patients with CKD.

In 2013 the KDIGO, or "Kidney Disease ‑‑ Improving Global Outcomes Clinical Practice Guidelines," were published. This is what we go by even to today. This recommended statin use for adults 50 years of age with non‑dialysis‑dependent CKD or with a kidney transplant and for adults under 50 years of age with high cardiovascular‑disease risk.

However, when you look at adults with CKD, they are often managed in a primary care setting. A low proportion of those receive secondary care from a nephrologist. The nephrologist would be the one most likely to use these KDIGO Guidelines where the primary care physician may not.

It's important for the primary care docs to know that especially in our renal transplant patients because by and large they most likely need to be on a statin. Statin use in general was lower among patients and adults with chronic kidney disease in the absence of diabetes mellitus compared to those who had diabetes mellitus in the absence of CKD. We stated that just a little while ago.

This difference is very important because it highlights that we have to recognize the high cardiovascular‑disease risk in patients with chronic kidney disease and the potential benefits of increased statin utilization. I often talk to my colleagues about how statins are often the most maligned drugs in the industry because of their potential side effects, particularly the myopathy.

Yet they're the ones that are really impacting on cardiovascular‑disease risk modification. Very, very important.

When we look retrospectively at a cohort study demonstrating that the continued use of statin therapy initiated in predialysis patients and continuing onto the post end‑stage renal‑disease period, this was associated with lower all‑cause mortality and cardiovascular mortality after transition to dialysis. Again, those patients who are on statins prior to dialysis I do continue them.

The controversy comes as in whether you start statins in end‑stage renal‑disease patients.

We do know that patients with chronic kidney disease who continued therapy with statins for at least six months during the first year after the transition to dialysis did come up with a 28 percent lower risk of death and an 18 percent lower risk of fatal cardiovascular events during the subsequent 12 months compared to patients who discontinued statins.

This benefit did not different across subgroups, demographics, or other clinical characteristics. There was no significant difference in benefit between patients who achieved a one‑year average pretransition serum LDL cholesterol lower than 70 compared with those who did not achieve this degree of LDL lowering.

As expected, cardiovascular mortality data paralleled the all‑cause mortality data and showed a significant benefit and no heterogeneity between the subgroups.

A couple of the key takeaways I would like to go from at this point is that, number one, we certainly need to recognize this population as high cardiovascular risk. In fact, that's where the mortality comes from in dialysis patients.

Number two, we also recognize that the primary care physicians are the frontline in managing chronic kidney disease often into the late stages when they're referred to the nephrologist. I think the primary care doctors need to be aware of some of these statin guidelines that I went over.

Number three is the jury is still out on whether adding statins to end‑stage renal‑disease patients has any added benefit. We'll see some more studies in that in the future. Again, my tendency is to continue the statin therapy as patients transition from chronic kidney disease to dialysis.

The fourth take‑home point is that knowing that we lower our cardiovascular risks in this subgroup of patients will certainly help improve their outcomes, overall decrease costs, and improve the triple A mode of medical therapy, which we're looking for now.

I can't emphasize enough the importance of working with your nephrology colleagues in the primary care field to answer these questions and to help lower that cardiovascular risk.

I hope this was very helpful for everyone today. This is a very important topic. I think we need to pay a lot more attention to cardiovascular risk in our chronic kidney disease patients. Thank you.

This is a transcription from a podcast originally produced by Consultant360. To listen to the original podcast, click here.

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