Swerdlow Daniel I, Preiss David
aDepartment of Medicine, Imperial College London bInstitute of Cardiovascular Science, University College London cNuffield Department of Population Health, University of Oxford, Oxford, UK.
Curr Opin Lipidol. 2016 Apr;27(2):125-30. doi: 10.1097/MOL.0000000000000272.
Meta-analyses of major statin trials have suggested that statin therapy modestly increases the risk of developing diabetes. However, the quality of the data on which these findings are based is not without weaknesses and it has also been unclear whether this effect, if true, is an on-target or off-target effect of statins.
In a major Mendelian randomization study of variants in the HMGCR gene, which encodes the protein through which statins exert their effect, two polymorphisms associated with lower LDL-cholesterol were also associated with higher weight, higher waist circumference, higher glucose and higher diabetes risk. These findings correspond with findings from the statin trials. In addition, new observational studies using a genetic risk score for LDL-cholesterol suggest that other pathways linked to LDL-cholesterol metabolism may also affect diabetes risk.
Genetic studies indicate that the observed effect of statins on diabetes risk in trials is highly likely to be a true on-target effect. Although other recent studies have suggested that genetically determined lower LDL-cholesterol may be linked to diabetes risk, further data from both genetic studies and clinical trials of other LDL-cholesterol lowering agents are needed to confirm or refute this.
对主要他汀类药物试验的荟萃分析表明，他汀类药物治疗会适度增加患糖尿病的风险。然而，这些研究结果所依据的数据质量并非毫无瑕疵，而且即便这种效应存在，它是他汀类药物的靶向效应还是非靶向效应也一直不明确。
在一项针对编码他汀类药物发挥作用的蛋白质的HMGCR基因变异的大型孟德尔随机化研究中，与较低低密度脂蛋白胆固醇相关的两种多态性也与体重增加、腰围增大、血糖升高及糖尿病风险增加有关。这些发现与他汀类药物试验的结果一致。此外，利用低密度脂蛋白胆固醇遗传风险评分进行的新观察性研究表明，与低密度脂蛋白胆固醇代谢相关的其他途径也可能影响糖尿病风险。
遗传学研究表明，试验中观察到的他汀类药物对糖尿病风险的影响极有可能是真正的靶向效应。尽管最近的其他研究表明，基因决定的较低低密度脂蛋白胆固醇可能与糖尿病风险有关，但仍需要来自遗传学研究和其他降低低密度脂蛋白胆固醇药物的临床试验的进一步数据来证实或反驳这一点。
