Sorting Out the Relationship between Cholesterol and Neuropathy in T2D

with Felix Kurz, MD, Brian Callahan, MD, and Marie E McDonnell, MD 

Heart disease is a well-known concern for anyone with type 2 diabetes (T2D), and keeping blood cholesterol levels in check is the best way to reduce that risk. However, this may not be the best strategy for everyone if results of recent research implicating reduced cholesterol as a possible cause of diabetic polyneuropathy (DPN) holds.

A team of researchers from Heidlebergled a study in which they followed 100 individuals with T2D—both those with peripheral nerve dysfunction arising from poorly controlled diabetes, and those with no neuropathy—who underwent a method of imaging (by magnetic resonance neurography) of their right leg nerves between 2015 and 2018;1 the results were published in the journal, JAMA Network Open.

Conflicting Reports On the Role of Cholesterol in Diabetic Neuropathy

The researchers examined the nerve diameter and lipid equivalent lesion load (lipid load) since prior research demonstrated that a lower level of arterial lipids was evident in individuals with diabetic peripheral neuropathy in people with type 2 diabetes.2

Diabetic peripheral neuropathy, the most common complication arising in diabetes, affects at least 20% of individuals with type 1 diabetes (T1D) and in upwards of half of all individuals who have had type 2 diabetes after 10 years.3

Some investigators have suggested that the combination of poorly controlled blood glucose, elevated lipids, and high blood pressure may be contributory factors;4 however, DPN doesn’t seem to improve once blood glucose levels are managed in people with T2D the way it does in type 1 diabetes.5

While there have been reports that having a lower blood cholesterol leads to a  reduction in diabetic peripheral neuropathy6,7 there are also studies that show an association of increased neuropathy with lowered cholesterol levels. 8-11 The goal of this study was to see if a clearer answer to how blood cholesterol levels impact DPN.

Could Treating High Cholesterol Worsen Diabetic Peripheral Neuropathy?

In evaluating the imaging results from their study participants, Dr. Kurz and his team see a positive relationship between lipid load with the size of nerve lesion and the maximum length of lesion. The lipid load appears negatively associated with cholesterol levels, including HDL, LDL and total cholesterol, meaning that the higher the lipids, the less neuropathy is evident. Furthermore, the individuals who had DPN (n=64) also had lower cholesterol levels than their counterparts (n=36).1

“We found that total cholesterol and LDL cholesterol were lower in patients with more severe nerve damage,” says senior study author Felix Kurz, MD, a neuroradiologist at the Heidelberg University Hospital in Germany.  

“Our data suggest that lowering serum cholesterol is not beneficial for patients who suffer from diabetic neuropathy,” he tells EndocrineWeb. “One has to keep in mind, however, that our study is based on cross-sectional data, which is why we cannot prove that lowering cholesterol is the cause for peripheral nerve damage in the patients examined.”

At the outset, Dr. Kurz and his team believed that lower levels of LDL cholesterol and total blood cholesterol would be associated with less evidence of nerve damage. “We were quite surprised when our results showed the opposite,” he said.

Don’t Stop Those Statins So Fast As Findings Raise More Questions than Answers

Admittedly, this study was small,1 he says, so it should be repeated a larger number of individuals. In addition, whether taking statins help people with T2D who are at risk of polyneuropathy and differently than other cholesterol-lowering medications presents another area of important study in our effort to settle this question. Dr. Kurz thinks “there may be a threshold for total serum cholesterol below which the regenerating nerve is no longer sufficiently supplied with cholesterol.”

Since circulating blood cholesterol is required for the regeneration of nerve fibers, Dr. Kurz suggests that if the threshold is at a level that is not critical for a patient's cardiovascular situation, it should be possible to adjust lipid levels in a way that protects both heart and nerves. 

“This hypothesis of the association of nerve damage, cholesterol levels, and statin use will be investigated further in future studies. Yet, we think that physicians should pay close attention to early signs of peripheral neuropathy in diabetic patients under lipid lowering therapies,” he says.

“Anyone with diabetes who is being treated for polyneuropathy might want to discuss the possible impact that lipid lowering drugs may have on the course of their disease while the relationship is investigated in longitudinal studies.”

With T2D, Reducing Your Risk of Heart Disease Remains the Overriding Goal  

Two diabetes experts caution that much more work needs to be done before anyone is advised to stop their cholesterol-lowering treatment. When asked to review the findings for EndocrineWeb, Brian Callahan, MD, MS, associate professor of neurology at the University of Michigan called the study findings “misleading". 

Suggesting that anyone with type 2 diabetes shouldn’t be trying to reduce high cholesterol to lower the risk of heart disease is misguided, Dr. Callahan says, particularly because DPN is associated with a higher amount of nerve lesions, which wasn’t the focus of the study.1 We do not know whether treating cholesterol improves or worsens neuropathy, says Dr. Callahan, but there’s no question that reducing the risks associated with heart disease remain paramount.  

The only conclusion we can draw from this small, cross-sectional study is that patients with lower cholesterol, both good (HDL) and bad (LDL), have more MRI lesions in their nerves,1 says Dr. Callahan, “which is why better studies are needed so we can know whether there is a causal relationship [between blood cholesterol levels and diabetic neuropathy] and whether lowering cholesterol affects neuropathy outcomes.”

Reinforcing the limits of this study, Marie E. McDonnell, MD, who is director of the Brigham and Women’s Diabetes Program says that “cross-sectional studies, such as this one,1 are prone to bias. For instance, it’s impossible to control for factors that independently lead to neuropathy and low cholesterol without them being directly linked.”

“An example would be if aggressive statin therapy was more likely to be prescribed in people who have more neuropathic complaints. An even more plausible scenario is that in patients with diabetes who have lower cholesterol, they simply may have had diabetes longer, and therefore will have had more time to achieve aggressive lipid lowering success on treatment. Lastly, this could be a statin-specific effect that also has been identified in smaller studies,” she said.

That said, McDonnell is impressed with the detailed of the in vivo nerve studies carried out by the researchers and looks forward to seeing more prospective work done on this topic. “It is important that we understand this [dynamic between serum cholesterol and diabetic neuropathy].”

Several of the study authors have confirmed receipt of grants and fees from industry but there’s no known conflict with this study. Neither Dr. Callahan or McDonnell has any financial conflicts regarding their comments about this study.

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