Reading our blueprints – nature’s lessons in pathophysiology found within our DNA Written by Allison B Goldfine MD and Alessandro Doria MD, PhD, MPH 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
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I n a study recently published in JAMA , Lotta and colleagues addressed this question by exploiting nature’s own experiments through a Mendelian randomisation study. 1 Specifically, LDL-lowering alleles in or near the HMGCR, NPC1L1, and PCSK9 gene encoding targets of LDL-lowering drugs (statins, ezetimibe, and PCSK9 inhibitors, respectively) and other LDL-C-related variants near the ABCG5/G8 and LDLR genes were used as proxies to assess whether associations between pharmacological LDL-C lowering and risk of diabetes is causal. In a meta-analysis of United States and European cohorts within large genetic association studies, each LDL-lowering variant was associated with a lower odds ratio for coronary artery disease, with similar effect sizes per 1 mmol/L (39 mg/ dL) reduction in LDL-C. However, consistent with the working hypothesis, variants in NPC1L1, and to a lesser extent HMGCR and PCSK9, were also significantly associated with an increased risk of diabetes. A nonsignificant trend toward a similar effect was also observed for ABCG5/G8 and LDLR. These findings agree with those by Swerdlow et al, who also found an association between HMGCR and increased risk of type 2 diabetes, and those by White et al, who described a similar diabetes-predisposing effect with a genetic risk score based on 130 LDL-C-associated SNPs. 2,3 Taken together, these studies provide strong support for LDL-C lowering contributing to development of diabetes. However, whether the culprit is LDL-C lowering, per se, or how this goal is achieved, remains unclear. Because not all the genes hosting variants associated with lower LDL-C showed statistically robust associations with diabetes in the study by Lotta et al, it is possible the molecule or metabolic function targeted by the LDL-C-lowering drug matters most for development of diabetes. 1 On the other hand, the
reductase inhibitors – statins – have profound beneficial effects on cardiovascular event rates but are also associated with a higher risk of incident type 2 diabetes. Whether this is attributable to low-density lipoprotein cholesterol (LDL-C) lowering, per se, or to direct or indirect off-target effects of statins remains poorly understood.
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fact that an association with diabetes was demonstrated for a genetic score composed of variants inmany different genes involved in LDL-Cmetabolism supports amore diffused diabetogenic effect of LDL-C lowering. 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 lowering with PCSK9 inhibitors can be confirmed in clinical practice. One caveat about theseMendelian randomisation findings is that most of the variants considered are in non-coding regions and could affect expression of additional genes that do not impact LDL-C metabolism but may nonetheless affect diabetes risk. Transcriptomic studies analysing the genome-wide impact of these variants in tissues relevant to diabetes could help address this concern. Using genetic markers as proxies of pharmacological interventions has intrinsic limitations. While genetic variants start acting at conception, 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 thesefindingsmechanistically
support the diabetogenic potential of lipid-lowering drugs through LDL-C lowering, risk must always be interpreted alongside benefit. Although statins are associated with an approximate 9% increased risk of incident type 2 diabetes, the risk of death from any cause is reduced by 10% for each 1-mmol/L reduction 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 clinical benefit for people at moderate or high cardiovascular risk strongly favours LDL-C lowering. Thus, providers should continue to prescribe statins and other lipid-lowering therapy according to established guidelines to improve cardiovascular and total mortality in patients with established atherosclerotic disease or multiple risk factors. Nevertheless, recognising 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. References 1. Lotta LA, Sharp SJ, Burgess S, et al. JAMA 2016;316:1383-1391. 2. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. Lancet 2015;385:351-361. 3. White J, Swerdlow DI, Preiss D, et al. JAMA Cardiol 2016;1:692-699. 4. Sattar N, Preiss D, Murray HM, et al. Lancet 2010;375:735-742. 5. Cholesterol Treatment Trialists, Baigent C, Blackwell L, et al. Lancet 2010;376:1670-1681. Dr Goldfine is Associate Professor, Harvard Medical School, Co-Head, Section of Clinical Research, Joslin Diabetes Center in Boston, Massachusett. Dr Doria is Associate Professor in the Department of Epidemiology, Department of Epidemiology, Joslin Diabetes Center and Harvard Medical School in Boston.
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