Cholesterol-lowering gene variants linked to greater type 2 diabetes risk


Certain genetic variants related to reduced low-density lipoprotein cholesterol – many of which are mediated by statins and other cholesterol-lowering drugs – may raise the risk of type 2 diabetes, suggests a new study published in JAMA.

From a meta-analysis of more than half a million adults, researchers found that variants near NPC1L1 and other genes associated with the reduction of low-density lipoproteincholesterol (LDL-C) were linked to greater type 2 diabetes risk, but a lower risk of coronary heart disease.

LDL-C is often referred to as “bad” cholesterol; too much LDL-C can lead to a buildup of plaque in the arteries, increasing the risk of strokeheart attack, and heart disease.

While lifestyle changes – such as adopting a healthy diet and increasing physical activity – are the first port of call when it comes to lowering LDL-C, some patients may also require treatment with cholesterol-lowering drugs, such as statins or bile acid sequestrants.

A wealth of research has demonstrated the benefits of cholesterol-lowering medications for heart health, but some studies have suggested the drugs may lead to weight gain andgreater risk of type 2 diabetes.

The new study – conducted by senior author Dr. Luca A. Lotta, of the University of Cambridge in the United Kingdom, and colleagues – provides further evidence of this association, after identifying a number of genetic pathways mediated by cholesterol-lowering drugs that may increase type 2 diabetes risk.

Shedding light on link between cholesterol-lowering drugs and diabetes

From a meta-analysis of genetic association studies conducted in Europe and the United States between 1991-2016, Dr. Lotta and team identified 50,775 individuals with type 2 diabetes and 270,269 controls, alongside 60,801 people with coronary heart disease and 123,504 controls.

Fast facts about cholesterol

  • Around5 million adultsin the United States have high LDL cholesterol
  • Of these, fewer than 1 in 3 have the condition under control
  • Individuals with high LDL cholesterol are twice as likely to develop heart disease than those with normal levels.

The analysis revealed that individuals who possessed certain LDL-C-lowering genetic variants near the genes NPC1L1, HMGCR, and PCSK9 – which arise as a result of many cholesterol-lowering drugs – were at greater risk of type 2 diabetes.

“The results of this study show that multiple LDL-C-lowering mechanisms, including those mediated by the molecular targets of available LDL-C-lowering drugs (i.e., statins, ezetimibe, and PCSK9-inhibitors), are associated with adverse metabolic consequences and increased type 2 diabetes risk,” the authors write.

Interestingly, these LDL-C-lowering genetic variants were also linked to a reduced risk of coronary artery disease.

“On one hand, the results can be considered surprising, given that diabetes and heart disease share several risk factors that tend to affect the risk of these two diseases in a consistent direction (e.g. smoking, higher body mass index [BMI], physical inactivity),” Dr. Lotta told Medical News Today.

“On the other, previous research has shown a modest increase in type 2 diabetes risk associated with statin treatment. Also, individuals with familial hypercholesterolemia, who are at high risk of heart disease, appear to have a lower prevalence of type 2 diabetes,” he continued.

“Our research adds to these studies and furthers our understanding of associations between cholesterol-lowering pathways and a higher risk of diabetes.”

What do these findings mean for patients?

Dr. Lotta told MNT that their results do not have immediate clinical implications for patients taking cholesterol-lowering drugs.

“The therapeutic recommendations to take statins or other drugs should not change,” he said. “Our study means that we should keep monitoring the metabolic consequences of taking these drugs.”

MNT asked Dr. Lotta what their research means for the future development of cholesterol-lowering medications; could their findings be used to develop drugs that lower cholesterol without raising diabetes risk?

“A great challenge of developing new treatments is predicting early on if a drug will work safely. An emerging concept, which is at the basis of our study, is that genetic variants that occur naturally in the population can be used to make this type of prediction,” he replied.

“Using genetic information, we hope in the future to be able to identify ways to reduce cholesterol and heart disease risk without affecting diabetes risk.”

Written by Honor Whiteman


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