Do Elevated Lipid Levels Protect Against Diabetes? Gene Study Sheds Light

Patrice Wendling

August 05, 2016

OXFORD, UK — A provocative analysis finds that higher levels of all three major lipids—LDL-C, HDL-C, and triglycerides (TGs)—are associated with a lower risk of diabetes, even as elevated LDL-C and TG predict increased risk of coronary artery disease[1].

"We know from clinical trials and genetic studies that statins increase the risk of diabetes, and what we tried to do here is ask the question, 'Is this something unique to statins or is this a general characteristic of LDL-cholesterol lowering?' And our data suggest the latter," senior author Dr Michael V Holmes (University of Oxford, UK) told heartwire from Medscape.

As such, the findings should not change practice, nor should patients stop taking statins or consider genetic testing, he added.

Dr Danish Saleheen (University of Pennsylvania, Philadelphia) and colleagues write in an accompanying editorial[2], "The findings from White et al will no doubt fuel the controversy on the causal association of major plasma lipids with [type 2 diabetes] T2D."

What's likely to give rise to the most debate is the potentially protective effect of TGs in type 2 diabetes.

CAD Findings

The analysis, published August 3, 2016 in JAMA Cardiology, used a conventional Mendelian randomization (MR) approach as well as newer genetic methods to generate genetic instruments specific for LDL-C, HDL-C, and TG based on 130 to 140 lipid-associated single nucleotide polymorphisms identified from published cardiometabolic genomewide-association studies.

A one-standard deviation (SD) genetically instrumented elevation in LDL-C levels (equivalent to 38 mg/dL) was found to be significantly associated with higher CAD risk (odds ratio [OR] 1.68; 95% CI 1.51–1.87)

"Unequivocally we show that LDL-cholesterol causes coronary heart disease," according to Holmes.

For HDL-C, there appeared to be a protective effect when conventional MR randomization was used, but this attenuated after researchers used the newer multivariate MR and MR-Egger approaches to account for pleiotropy, or the potential for the genetic traits to associate with other biomarkers. The corresponding OR for HDL-C (equivalent to a 16-mg/dL increase) was 0.95 (95% CI 0.85–1.06).

When the newer approaches were applied to triglycerides, the association was robust, with one-SD elevation in TG levels (equivalent to 89 mg/dL) associated with significantly higher CAD risk (OR 1.28; 95% CI 1.13–1.45).

"This is really encouraging because it suggests that we really should be pursuing drugs that lower triglycerides as a new way to lower the risk of coronary heart disease," Holmes said.

In this regard, all genetic evidence points to a beneficial role for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in reducing coronary heart disease, although the picture is less clear for the new cholesteryl ester transfer protein (CEPT) inhibitors, given that they are nonspecific to HDL-C, he added.

Diabetes Findings

The editorialists note that while MR studies have been successful in solving the causal relevance of major lipids in CHD (LDL-D and TG, yes, and HDL-C, no), other approaches are need to further evaluate the causal relevance of these lipid fractions in association with type 2 diabetes.

"The importance of this issue is clear: it has the potential to provide new insights into the pathogenesis of T2D and has implications for the effect of specific lipid-altering therapies on the development of T2D," Saleheen and colleagues write.

For LDL-C and HDL-C, the MR analyses were very similar, with ORs of 0.79 (95% CI, 0.71–0.88) and 0.83 (95% CI, 0.76–0.90), respectively, per one-SD elevation.

For TGs, however, the effect on diabetes was observed only with use of the MR-Egger approach (OR 0.83; 95% CI 0.72–0.95) per one-SD elevation.

Both the editorialists and Holmes note that the protective effect of TGs in the risk of diabetes is novel, yet potentially "counterintuitive."

Observational studies report that increases in TGs are associated with an increased risk of diabetes, but insulin resistance also results in disturbances in TG metabolism, suggesting that "the direction of the causal association is not clear," Holmes and colleagues write.

They caution that the data suggesting TGs may provide protection from diabetes should be interpreted with caution, especially given the inconsistency in the three MR approaches, but add that the findings are consistent with those from recent genetic studies in Europeans and African Americans.

If the evidence is true, Saleheen and colleagues write that "the implications of this are substantial, including the potential that intervention to reduce TG levels could paradoxically increase the risk for T2D. That said, there have been a number of large TG-lowering trials to date, primarily with fibrates, and in those studies, there is currently no suggestion of increased T2D risk in those participants randomized to active treatment."

They add, "Given the time it took to uncover the association between statin therapy and increased risk for T2D (approximately 20 years), it will be important to monitor outcomes for these trials carefully."

Holmes suggests that one of the biggest implications of the study may be on testing of new drugs such as PCSK9 inhibitors.

"Given that lowering of LDL cholesterol seems to increase the risk of diabetes, I suspect that clinical trials may well build in glycemic markers such as HbA1c or fasting glucose and diabetes cases as secondary outcomes, just to really carefully scrutinize whether or not their drug is associated with this glycemic effect," he said.

Homes reported no relevant financial relationships; disclosures for the coauthors are listed in the article. The editorialists report no relevant financial relationships.

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