In the Journals

LDL cholesterol-lowering genetic variants increase risk for type 2 diabetes

Adults with naturally occurring genetic variants known to reduce LDL cholesterol are also more likely to develop type 2 diabetes vs. those who do not have the genetic variants, according to study findings published in JAMA.

“Taking statins is known to modestly increase the risk of type 2 diabetes, but it is not known if other nonstatin drugs, which reduce cholesterol levels by acting on different biological pathways, will also affect the risk of diabetes.” Luca A. Lotta, MD, PhD, of the MRC epidemiology unit at the University of Cambridge, United Kingdom, told Endocrine Today. “In this study, we investigated the association between type 2 diabetes and genetic variants that reduce cholesterol levels by influencing different cholesterol-related biological pathways. These included genetic variants in or near the genes that encode the targets of current cholesterol-lowering treatments, such as statins (HMGCR gene), ezetimibe (NPC1L1 gene; Zetia, Merck) and PCSK9 inhibitors (PCSK9 gene).”

Luca Lotta
Luca A. Lotta

In a meta-analysis of genetic association studies, Lotta and colleagues analyzed data from 50,775 adults with type 2 diabetes and 270,269 adults without diabetes (controls) participating in three large studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study, the UK Biobank study and the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) study, as well as 60,081 adults with coronary artery disease (CAD) and 123,504 controls from the CARDIoGRAM meta-analysis and CARDIoGRAMplusC4D consortium meta-analysis. Primary outcomes were ORs for type 2 diabetes and CAD.

Researchers found that genetic variants at NPC1L1 were inversely associated with CAD, with an OR for a genetically predicted 1-mmol/L reduction in LDL cholesterol of 0.61 (95% CI, 0.42-0.88), and directly associated with type 2 diabetes, with the OR for a genetically predicted 1-mmol/L reduction in LDL cholesterol of 2.42 (95% CI, 1.7-3.43).

A variant of the PCSK9 gene was associated with higher risk for type 2 diabetes, with an OR of 1.19 per 1 mmol/L of genetically predicted LDL cholesterol reduction (95% CI, 1.02-1.38).

Researchers found a similar reduction in CAD across genes when analyzing the association with disease risk of a given genetically predicted reduction in LDL cholesterol (P = .93). For the same reduction in LDL cholesterol, however, the risk for type 2 diabetes differed by gene.

“In this study, we found that the reduction in risk [for myocardial infarction] was proportional to the reduction in blood cholesterol for all the different pathways we investigated,” Lotta said. “However, the association with type 2 diabetes was different for different pathways.”

Lotta said the findings do not have immediate clinical implications for patients assigned lipid-lowering drugs.

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

According to Lotta, it will be important to assess whether the use of LDL-lowering drugs other than statins is associated with diabetes risk.

“From an etiologic viewpoint, future research should clarify what are the molecular mechanisms linking lower blood cholesterol and higher diabetes risk,” he said. – by Regina Schaffer

Disclosure: Lotta reports no relevant financial disclosures. Please see the full study for the other author’s relevant financial disclosures.

Adults with naturally occurring genetic variants known to reduce LDL cholesterol are also more likely to develop type 2 diabetes vs. those who do not have the genetic variants, according to study findings published in JAMA.

“Taking statins is known to modestly increase the risk of type 2 diabetes, but it is not known if other nonstatin drugs, which reduce cholesterol levels by acting on different biological pathways, will also affect the risk of diabetes.” Luca A. Lotta, MD, PhD, of the MRC epidemiology unit at the University of Cambridge, United Kingdom, told Endocrine Today. “In this study, we investigated the association between type 2 diabetes and genetic variants that reduce cholesterol levels by influencing different cholesterol-related biological pathways. These included genetic variants in or near the genes that encode the targets of current cholesterol-lowering treatments, such as statins (HMGCR gene), ezetimibe (NPC1L1 gene; Zetia, Merck) and PCSK9 inhibitors (PCSK9 gene).”

Luca Lotta
Luca A. Lotta

In a meta-analysis of genetic association studies, Lotta and colleagues analyzed data from 50,775 adults with type 2 diabetes and 270,269 adults without diabetes (controls) participating in three large studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study, the UK Biobank study and the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) study, as well as 60,081 adults with coronary artery disease (CAD) and 123,504 controls from the CARDIoGRAM meta-analysis and CARDIoGRAMplusC4D consortium meta-analysis. Primary outcomes were ORs for type 2 diabetes and CAD.

Researchers found that genetic variants at NPC1L1 were inversely associated with CAD, with an OR for a genetically predicted 1-mmol/L reduction in LDL cholesterol of 0.61 (95% CI, 0.42-0.88), and directly associated with type 2 diabetes, with the OR for a genetically predicted 1-mmol/L reduction in LDL cholesterol of 2.42 (95% CI, 1.7-3.43).

A variant of the PCSK9 gene was associated with higher risk for type 2 diabetes, with an OR of 1.19 per 1 mmol/L of genetically predicted LDL cholesterol reduction (95% CI, 1.02-1.38).

Researchers found a similar reduction in CAD across genes when analyzing the association with disease risk of a given genetically predicted reduction in LDL cholesterol (P = .93). For the same reduction in LDL cholesterol, however, the risk for type 2 diabetes differed by gene.

“In this study, we found that the reduction in risk [for myocardial infarction] was proportional to the reduction in blood cholesterol for all the different pathways we investigated,” Lotta said. “However, the association with type 2 diabetes was different for different pathways.”

Lotta said the findings do not have immediate clinical implications for patients assigned lipid-lowering drugs.

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

According to Lotta, it will be important to assess whether the use of LDL-lowering drugs other than statins is associated with diabetes risk.

“From an etiologic viewpoint, future research should clarify what are the molecular mechanisms linking lower blood cholesterol and higher diabetes risk,” he said. – by Regina Schaffer

Disclosure: Lotta reports no relevant financial disclosures. Please see the full study for the other author’s relevant financial disclosures.