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可以降低PCa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作为2型糖尿病（T2DM）患者的一线降糖药；而他汀类药物被美国医师学会推荐用于所有的2型糖尿病患者，因为该人群中高发的血脂异常合并症。由于11.2%（约1300万）的美国男性患有2型糖尿病，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PCa的影响非常重要，因为他们普遍使用这些药物。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2型糖尿病男性前列腺癌的联合作用可能具有重大的公共卫生影响。知识缺口。（G1）二甲双胍的降糖作用可能是评估(i) AMPK通路被二甲双胍激活的可能性，以及（ii）二甲双胍对PCa风险降低作用的变化的潜在替代指标。他汀类药物的降脂作用可能是评估(i)甲羟戊酸途径被他汀类药物阻断的可能性的潜在替代品，因此（ii）他汀类药物对PCa风险降低作用的变化。目前尚无临床研究评估二甲双胍和他汀类药物对PCa的降糖和降脂作用是否不同。（G2）高血糖和血脂异常都与前列腺癌风险增加相关，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，可能通过其降血糖和降脂作用介导。目前，尚无临床研究来评估这种联合效应。具体的目标。通过建立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行政医疗保健系统的9年T2DM男性患者PCa发病率的联合影响，开展一项原理验证研究，以解决知识缺口（G1）和（G2）。（目的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。（目的2）评估二甲双胍和他汀类药物对由降血糖和降脂作用介导/调节的PCa发病率的独立影响。（目的3）评估二甲双胍和他汀类药物对PCa发病率的联合作用。（目的4）评估二甲双胍和他汀类药物对高级别PCa和低级别PCa的不同影响。

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.