Metformin, Statins, and Prostate Cancer Prevention in Type 2 Diabetes

描述(申请人提供)：前列腺癌(PCa)是美国男性中最常见的癌症，六分之一的男性会受到影响。最近的研究表明，降糖药物二甲双胍和降脂药物他汀类药物可以降低前列腺癌的风险。对于那些没有药物禁忌症的人，美国糖尿病协会推荐二甲双胍作为2型糖尿病(T2 DM)患者的一线降糖剂；而美国医师学会建议他汀类药物作为所有T2 DM患者的一线降糖药，因为这一人群中血脂异常并存的比例很高。由于11.2%(约1300万)的美国男性患有T2 DM，这是一种在美国持续上升的流行病，由于二甲双胍和他汀类药物的广泛使用，研究这些药物对这一人群中PCa的影响是很重要的。特别是，在患有前列腺癌的男性中，糖尿病与高级别前列腺癌的风险增加有关。因此，研究二甲双胍和他汀类药物对男性T2 DM患者前列腺癌的联合作用可能会对公众健康产生重大影响。知识鸿沟。(G1)二甲双胍的降糖作用可作为一种潜在的替代物用于评估(I)二甲双胍激活AMPK通路的可能性，从而(Ii)二甲双胍在前列腺癌风险降低中的作用变化。他汀类药物的降脂作用可能成为评估(I)他汀类药物阻断甲羟戊酸途径的可能性，从而(Ii)他汀类药物在降低前列腺癌风险方面的变化的潜在替代药物。目前还没有临床研究来评估二甲双胍和他汀类药物对前列腺癌的作用是否与相应的降糖和降脂作用有关。(G2)高血糖和血脂异常都与PCa风险增加相关，而且两者是相关的。二甲双胍和他汀类药物对前列腺癌可能存在协同作用，可能是通过它们的降血糖和降脂作用来实现的。目前，还没有临床研究来评估这种联合作用。明确的目标。通过开发一个因果可解释的预测模型来评估二甲双胍和他汀类药物对来自全国退伍军人管理卫生保健系统的9年历史队列中T2 DM患者的前列腺癌发病率的联合影响，进行一项原则验证研究，以解决知识差距(G1)和(G2)。(目的1)评价二甲双胍的降糖作用及他汀类药物的降脂作用。(目的2)评价二甲双胍和他汀类药物对降糖降脂作用介导/调节的前列腺癌发生的独立作用。(目的3)评价二甲双胍和他汀类药物对前列腺癌发生的联合作用。(目的4)评价二甲双胍和他汀类药物对高级别与低级别PCa的疗效差异。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most prevalent cancer among men in the United States (US), affecting one man in six. Recent studies have shown that the glucose-lowering medication metformin and the lipid-lowering medication statins could reduce PCa risk. For those without medication contraindications, metformin is recommended by the American Diabetes Association as the first-line glucose-lowering agent for individuals with type 2 diabetes (T2DM); while statins are recommended by the American College of Physicians for all individuals with T2DM because of the high prevalence of dyslipidemia comorbidity in this population. As 11.2% (~13 millions) of the US men have T2DM, a continuously rising epidemic in the US, it is important to study the effects of metformin and statins on PCa in this population due to their prevalent use of these medications. Particularly, among men with PCa, diabetes is associated with an increased risk of high-grade PCa. Thus studying the joint effects of metformin and statins on PCa in men with T2DM may have substantial public health impact. Knowledge Gaps. (G1) The glucose-lowering effect of metformin could be a potential surrogate for assessing (i) the likelihood of the AMPK pathway being activated by metformin, and hence (ii) the variation of metformin effect on PCa risk reduction. The lipid-lowering effect of statins could be a potential surrogate for assessing (i) the likelihood of the mevalonate pathway being blocked by statins, and hence (ii) the variation of statins effect on PCa risk reduction. Currently no clinical studies exist to assess whether effects of metformin and statins on PCa vary by the corresponding glucose-lowering and the lipid-lowering effects. (G2) Both hyperglycemia and dyslipidemia are associated with an increased PCa risk, and the two are correlated. There may exist a synergistic effect associated with metformin and statin on PCa, potentially mediated through their glucose- and lipid- lowering effects. Currently, no clinical studies exist to assess this joint effect. Specific Aims. To conduct a proof-of-principle study to address Knowledge Gaps (G1) and (G2) by developing a causally interpretable prediction model to assess the joint impacts of metformin and statins on PCa incidence in a nine-year historical cohort of men with T2DM from the nationwide Veteran Administrative Health Care System. (Aim 1) Assess the variation of glucose-lowering effect of metformin and the lipid- lowering effect of statins over time. (Aim 2) Assess the independent effects of metformin and statins on PCa incidence mediated/moderated by the glucose-lowering and lipid-lowering effects. (Aim 3) Assess the joint effects of metformin and statins on PCa incidence. (Aim 4) Assess the differential effects of metformin and statins on the high-grade PCa vs. low-grade of PCa.