Practice Update: DIABETES

MY PERSPECTIVE 23

Recognizing and confirming a direct role of LDL-C lowering with diabetes risk, as supported by this body of work, and subsequently understanding the potential mechanisms for which low LDL-C promotes diabetes may lead to new treatment or prevention approaches.

an association with diabetes was demon- strated for a genetic score composed of variants in many different genes involved in LDL-C metabolism supports a more diffused diabetogenic effect of LDL-C low- ering. 3 Further studies are needed to settle this issue. It would be interesting to see whether the prediction of ezetimibe being diabetogenic based on the NPC1L1 genetic prediction, or if more potent LDL-C lower- ing with PCSK9 inhibitors can be confirmed in clinical practice. One caveat about these Mendelian ran- domization findings is that most of the variants considered are in non-cod- ing regions and could affect expression of additional genes that do not impact LDL-C metabolism but may nonetheless affect diabetes risk. Transcriptomic stud- ies analyzing the genome-wide impact of these variants in tissues relevant to diabe- tes could help address this concern. Using genetic markers as proxies of pharmaco- logical interventions has intrinsic limitations. While genetic variants start acting at con- ception, lipid-lowering interventions are usually introduced later in life and for a

few decades at most. Whether effects of lifelong exposures to genetic variants are representative of those associated with shorter exposure to LDL-C–lowering drugs remains to be determined. While these findings mechanistically support the diabetogenic potential of lipid-lowering drugs through LDL-C low- ering, risk must always be interpreted alongside benefit. Although statins are associated with an approximate 9% increased risk of incident type 2 diabe- tes, the risk of death from any cause is reduced by 10% for each 1-mmol/L reduc- tion in LDL-C with statins over a period of 4 years, and of similar magnitude in those with or without diabetes. 4,5 The net clini- cal benefit for people at moderate or high cardiovascular risk strongly favors LDL-C lowering. Thus, providers should continue to prescribe statins and other lipid-lowering therapy according to established guide- lines to improve cardiovascular and total mortality in patients with established ather- osclerotic disease or multiple risk factors. Nevertheless, recognizing and confirm- ing a direct role of LDL-C lowering with

diabetes risk, as supported by this body of work, and subsequently understand- ings the potential mechanisms for which low LDL-C promotes diabetes may lead to new treatment or prevention approaches.

References 1. Lotta LA, Sharp SJ, Burgess S, et al.

association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA 2016;316(13):1383-1391. 2. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015;385(9965):351-361. 3. White J, Swerdlow DI, Preiss D, et al. Association of lipid fractions with risks for coronary artery disease and diabetes. JAMA Cardiol 2016;1(6):692-699. 4. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta- analysis of randomised statin trials. Lancet 2010;375(9716):735-742. 5. Cholesterol Treatment Trialists, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376(9753):1670-1681.

VOL. 1 • NO. 1 • 2017