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

描述（由申请人提供）：前列腺癌（PCa）是美国（US）男性中最常见的癌症，影响六分之一的男性。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患者，二甲双胍被美国糖尿病协会推荐为2型糖尿病（T2 DM）患者的一线降糖药物;而他汀类药物被美国医师学会推荐用于所有T2 DM患者，因为该人群中血脂异常合并症的患病率较高。由于11.2%（约1300万）的美国男性患有T2 DM，这是美国持续上升的流行病，因此研究二甲双胍和他汀类药物对该人群中PCa的影响很重要，因为这些药物的普遍使用。特别是在前列腺癌患者中，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T2 DM男性患者PCa的联合作用可能具有重大的公共卫生影响。知识差距。(G1)二甲双胍的降糖作用可能是评估（i）二甲双胍激活AMPK通路的可能性，因此（ii）二甲双胍对PCa风险降低作用的变化的潜在替代。他汀类药物的降脂作用可能是评估（i）他汀类药物阻断甲羟戊酸途径的可能性，因此（ii）他汀类药物对PCa风险降低作用的变化的潜在替代品。目前尚无临床研究评估二甲双胍和他汀类药物对PCa的作用是否因相应的降糖和降脂作用而异。(G2)高血糖和血脂异常均与PCa风险增加相关，且两者相关。二甲双胍和他汀类药物对PCa可能存在协同作用，可能通过其降糖降脂作用介导。目前，没有临床研究来评估这种联合作用。具体目标。开展一项原理验证研究，通过开发因果关系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医疗保健系统的T2 DM男性患者9年历史队列中PCa发病率的联合影响，以解决知识差距（G1）和（G2）。(Aim 1）评估二甲双胍的降糖作用和他汀类药物的降脂作用随时间的变化。(Aim 2）评估二甲双胍和他汀类药物对由降糖和降脂作用介导/调节的PCa发生率的独立作用。(Aim 3）评估二甲双胍和他汀类药物对PCa发病率的联合作用。(Aim 4）评估二甲双胍和他汀类药物对高级别PCa与低级别PCa的差异作用。 公共卫生相关性：二甲双胍和他汀类药物是2型糖尿病患者的常用药物，2型糖尿病患者是高级别前列腺癌风险增加的人群。如果可以证明这两种药物单独或联合显著降低2型糖尿病男性的前列腺癌发病率，那么这项拟议的研究有可能导致具有巨大公共卫生效益的干预措施，因为前列腺癌的常见发生和2型糖尿病的患病率增加。

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. PUBLIC HEALTH RELEVANCE: Metformin and Statins are commonly used medications in men with type 2 diabetes, a population at increased risk for high-grade prostate cancer. If it can be demonstrated that both medications independently or jointly reduce prostate cancer incidence significantly in men with type 2 diabetes, then this proposed research has the potential to lead to interventions with great public health benefit because of the common occurrence of prostate cancer and increasing prevalence of type 2 diabetes.