Genetic high cholesterol 'may help protect against t...

"High cholesterol LOWERS the risk of diabetes," is the Daily Mail's rather misleading headline, going on to say that, "New study reveals why taking statins may be harmful".

But this study looked at familial hypercholesterolemia (FH) and not at the more common form of high cholesterol, which is associated with a high-fat diet.

FH is caused by an abnormal gene that affects how much cholesterol is absorbed by cells (cholesterol uptake). People with FH usually require lifelong statin treatments. Statins are drugs that help reduce cholesterol levels, which can reduce the risk of serious complications of the condition, such as a heart attack.

As greater cholesterol uptake by cells has been linked to increased type 2 diabetes risk, the researchers expected that diabetes may be less common in people with FH.

The researchers studied 60,000 relatives of people with FH who were having a DNA test to see if they also had the condition. They compared how common type 2 diabetes was in those found to have the condition and those who were unaffected.

Overall, they found diabetes was slightly less common in those diagnosed with FH (1.75%) compared with those who did not have the condition (2.93%).

These findings certainly do not suggest that high cholesterol is good for you and taking statins is bad. Statins could potentially be lifesaving – without treatment, high circulating cholesterol levels could put people at a very high risk of heart attacks or strokes.

Where did the story come from?

The study was carried out by researchers from the Academic Medical Centre in the Netherlands.

The individual researchers in this study received various research grants, including those from the Netherlands Organisation for Scientific Research, the Cardiovascular Research Initiative and the European Union.

The study was published in the peer-reviewed medical journal JAMA.

The Daily Mail's headline, which claimed that "High cholesterol LOWERS the risk of diabetes: New study reveals why taking statins may be harmful", is misleading and arguably irresponsible.

This study specifically looked at people with a genetic condition that leads to raised cholesterol levels. It found they were less likely to have type 2 diabetes than their unaffected relatives.

The findings suggest poor cellular uptake of cholesterol could confer a lower risk of type 2 diabetes. But the biological link is not confirmed at this stage and requires further study.

As statins increase the cellular uptake of cholesterol, the Mail suggested they could therefore be harmful. But this study has not actually examined the effects of statins.

The headline should have made it clear, as the researcher quoted in the article said, that statins have a "clear overall benefit" in high-risk patients.

What kind of research was this?

This was a cross sectional study aiming to look at the link between familial hypercholesterolemia and type 2 diabetes.

Familial hypercholesterolemia (FH) is a genetic condition where a person has very high cholesterol levels (both total cholesterol and LDL, or "bad" cholesterol) as the result of an abnormal gene.

People with FH have a high risk of cardiovascular disease from a young age and usually require lifelong statin treatment following diagnosis.

About 1 in 500 people in the general population have FH. If you have a parent with the condition, you have a one in two chance of having FH.

This study included people who had relatives with FH who were being screened by DNA testing to see if they also had the abnormal gene.

The researchers say the risk of type 2 diabetes has been found to be increased in statin users. This is believed to be the result of statins increasing the amount of LDL cholesterol receptors on body cells, causing an increased uptake of cholesterol.

People with FH have problems with cholesterol regulation and uptake, and in the majority of cases this is caused by an abnormality of the LDL receptor gene. As their body cells – including the insulin-producing cells of the pancreas – have decreased cholesterol uptake, the researchers therefore expected this might decrease their diabetes risk.

The researchers aimed to look at how common diabetes was in the relatives of people with FH who were screened in the Netherlands. They wanted to see whether prevalence differed between relatives who were also found to have the condition and those found to be unaffected.

What did the research involve?

The research included 63,320 first-degree relatives (parents, siblings or children) of people with FH. These people had DNA testing in the Netherlands between 1994 and 2014 to see if they also had the condition.

They also had their blood cholesterol levels measured. People were considered to have FH if they had one of the mutations known to cause the condition.

The main outcome the researchers looked at was whether a person had type 2 diabetes, as defined by self-report on a questionnaire.

They examined the difference in type 2 diabetes prevalence between those found to have FH and their unaffected relatives. They adjusted their analyses for the following potential confounders:

age
body mass index (BMI)
HDL ("good") cholesterol levels
triglycerides (another fat) levels
statin use
smoking
cardiovascular disease

What were the basic results?

Of the 63,320 relatives tested, 40% were found to have FH, and 60% were found to be unaffected and not carrying an FH mutation. Of those found to have FH, 86% had a mutation of the LDL receptor gene and others had less common mutations.

People with FH tended to be younger, have a lower BMI, higher "bad" LDL cholesterol but lower "good" HDL cholesterol, smoked less, and had greater statin use.

The overall prevalence of type 2 diabetes was 1.75% in people with FH (440 of 25,137) and 2.93% in unaffected relatives (1,119 of 38,183). This was a significant difference, calculating that people with FH had 38% reduced odds of type 2 diabetes (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.55 to 0.69).

Repeating the analysis after adjusting for confounders still found that type 2 diabetes prevalence was lower in people with FH (1.44%) compared with unaffected relatives (3.26%), which was a significant difference (OR 0.49, 95% CI 0.41 to 0.58).

How did the researchers interpret the results?

The researchers concluded that, "In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives."

They say that if this finding is confirmed in further studies, it would raise the possibility that the transport of cholesterol into cells via the LDL receptor could be directly contributing to type 2 diabetes.

Conclusion

This cross sectional study included 60,000 first-degree relatives of people with FH who were undergoing genetic testing in the Netherlands to see if they also had the condition.

It compared the prevalence of type 2 diabetes between those relatives found to have the condition and those found to be unaffected. Overall, it found that those affected had lower prevalence of type 2 diabetes than those who were unaffected.

Compared with those who were unaffected, people with FH tended to have a lower BMI, higher LDL cholesterol, be less likely to be smokers, and more likely to be using statins at the time they were diagnosed.

This suggests they could have been taking statins and making healthy lifestyle changes as they already knew they had higher cholesterol, even before this was confirmed to be genetic FH.

However, their lower prevalence of type 2 diabetes was still found to be significantly lower than those without FH, even after adjustment for statin use and these healthier lifestyle factors.

This suggests, as the researchers propose, that the genetic abnormality in cholesterol regulation and cellular uptake – including the insulin-producing cells of the pancreas – could make people with FH less likely to develop type 2 diabetes.

But these results do not suggest high cholesterol is good for you and taking statins is bad, which is a simplistic interpretation of this study.

If the link is caused by the cellular uptake of cholesterol, statins may increase this process and could therefore potentially lead to a small increase in risk of type 2 diabetes.

Other research has also linked statin use with type 2 diabetes, as we discussed in September 2014. However, any potential risk must be weighed up against the benefits of statins in terms of reducing cardiovascular risk.

For people with FH, statins can really be viewed as a potentially lifesaving treatment – without these drugs, high circulating cholesterol levels put these people at a very high risk of cardiovascular disease at a young age.

Even for people who have raised cholesterol without having the genetic condition FH, the benefits of statins in terms of reducing cardiovascular risk are likely to outweigh any small increase in diabetes risk.

Overall, this study suggests the transport of cholesterol into cells via the LDL receptor may be linked with type 2 diabetes risk. But further study is needed to determine whether this is actually the case.