A new meta-analysis of genetic association studies, published today in the Journal of the American Medical Association (JAMA), is shedding light on the mechanisms through which LDL-cholesterol lowering drugs can lead to an increased risk of diabetes – with implications for how we might develop drugs in the future.

A great challenge of developing new treatments is predicting early on if a drug will work safely. An emerging concept is that genetic variants that occur naturally in the population can be used to help in this sort of prediction.

For instance, statins are used to reduce LDL-cholesterol in the blood by blocking its production in the body. Researchers have found that DNA sequence variants resulting in reduced cholesterol production appear to “mimic” the effects of these drugs. In fact, people from the general population who inherit these genetic variants from their parents tend to have lower blood cholesterol and also a lower risk of heart attack.

Taking statins is known to modestly increase the risk of type 2 diabetes, but it is not known if other non-statin drugs, which reduce cholesterol levels by acting on different biological pathways, also affect the risk of diabetes.

In this new study, led by the MRC Epidemiology Unit at the University of Cambridge, the researchers investigated the association between type 2 diabetes and genetic variants that reduce cholesterol levels by influencing different cholesterol-related biological pathways. These included pathways that are targeted by current cholesterol-lowering drugs such as statins, ezetimibe and PCSK9-inhibitors.

They studied these genetic variants in 50,775 people with type 2 diabetes and 270,269 people without diabetes, and 60,801 individuals with coronary artery disease and 123,504 without. Data collection took place in Europe and the United States between 1991 and 2016. They found that people with these genetic variants had lower blood cholesterol, lower risk of heart attack, but higher risk of type 2 diabetes.

They also found that the reduction in the risk of a heart attack was proportional to the reduction in blood cholesterol for all the different pathways investigated. However, the association with type 2 diabetes was different for different pathways, and not proportional to the reduction in blood cholesterol.

Lead author Dr Luca Lotta from the MRC Epidemiology Unit, University of Cambridge said:

“Our study suggests that some biological processes associated with lower blood cholesterol may lead to a higher risk of type 2 diabetes. It also indicates that the risk of diabetes associated with altering different pathways is likely to be specific to each given pathway.

“Our study does not alter the strong evidence that the cardiovascular benefits of statins outweigh side effects, including any increase in type 2 diabetes risk. However, now that these associations have been found, further studies in this area may eventually lead to the development of safer strategies to reduce blood cholesterol without affecting diabetes risk.”

• Read the full paper: Association between Low-Density Lipoprotein Cholesterol Lowering Genetic Variants and Risk of Type 2 Diabetes, JAMA, 4 October 2016 doi:10.1001/jama.2016.14568