睾酮治疗增加死亡、心梗和卒中风险

《美国医学会杂志》11月5日在线发表的一篇报告显示，对睾酮偏低的男性补充睾酮会增加死亡、心肌梗死(MI)和缺血性卒中的风险。

德克萨斯大学西南医学中心的Rebecca Vigen医生介绍，原本已有和没有冠状动脉疾病的男性的风险均升高，而且不受血压或预防性药物使用等心血管危险因素差异的影响。

上述研究结果增加了人们对睾酮治疗潜在安全性的担忧，研究者认为值得开展随机临床试验以澄清这一问题。“虽然临床医生应继续与患者讨论睾酮治疗在缓解症状方面的益处，但也要告知患者，睾酮治疗的长期风险仍是未知数，不排除该治疗有害的可能性。”

既往研究已经表明，睾酮治疗可提高性功能和强度，并且可以改善一些心血管危险因素，如血脂紊乱和胰岛素抵抗。这些试验并未检测到不良心血管效应，“但它们通常专注于中介终点、持续时间短，没有足够效能检验临床终点”。一项纳入大量心血管疾病男性患者的临床试验，在2010年因睾酮组心血管事件明显超过安慰剂组而被提前终止。

Vigen博士及其同事利用退伍军人管理局临床评估报告和追踪(CART)计划的数据，在一个回顾性队列中评估了睾酮治疗的潜在心血管风险。CART计划中收集了在全国76个退伍军人事务部(VA)心导管室进行的所有操作的信息。他们确定了2005~2011年在这些机构接受冠状动脉造影、医学记录显示总睾酮水平＜300 ng/dl的所有男性。

这个由8,709名男性组成的队列有较高的合并症负担：20%有MI病史，半数患有糖尿病，80%以上患有冠状动脉疾病。这些合并症的患病率在服用和不使用睾酮的男性之间大致相等。其中共有1,223名男性正在接受睾酮疗法以解决睾酮水平过低的问题。大约有1%使用睾酮凝胶，36%使用注射剂，63%使用贴剂。使用睾酮的男性倾向于更年轻和更健康。

在平均28个月的随访期间，发生了1,710次相关不良事件：748人死亡，443人发生MI，519人发生卒中。这些事件的绝对风险在睾酮使用者中明显更高：1年时高1.3%，2年时高3.1%，3年时高5.8%(JAMA 2013 [doi:10.1001/jama2013.280386])。

进一步校正后数据分析显示，睾酮的使用仍然与死亡、MI或卒中风险增加密切相关，危险比(HR)为1.29。这表明，睾酮使用者比不使用者发生这些不良结局的可能性增加29%。

在进一步校正有/无冠状动脉疾病和接受/不接受冠状动脉血管重建手术之后，上述结果没有改变。三种剂型的睾酮在不良结局风险方面没有显著差异。

研究者指出，睾酮治疗增加心血管疾病风险的潜在机制有如下几种。睾酮治疗会增加血小板聚集，导致动脉粥样斑块形成。睾酮治疗会增强内皮中的单核细胞活化，从而促进动脉粥样硬化，后者是急性冠状动脉综合征的病因。睾酮治疗会加剧睡眠障碍性呼吸，后者是另一个心血管危险因素。

这项研究获得了美国退伍军人事务部的支持。未报告相关利益冲突。

随刊述评：睾酮治疗需谨慎

宾夕法尼亚大学内分泌、糖尿病与代谢学系的Anne R. Cappola博士指出，Vigen等人的研究结果应引起临床医生和患者的警惕，尤其是在处方量巨大和“睾酮生产商积极营销”的形势下(JAMA 2013;310:1805-6)。Cappola博士同时也是JAMA的副主编。

该研究结果带来的最重要问题可能是，如何可以将其外推至使用睾酮的广大男性人群中：因“低睾酮综合征”或为了抗衰老而使用睾酮的男性，以及为了强化躯体而使用睾酮的更年轻男性。

“心肌梗死、缺血性卒中或死亡的风险增加29%的结果，是否适用于这些人群？使用睾酮的益处——不论是真实的还是感觉的——是否值得这些男性冒这些风险？目前只有零星的证据提示睾酮对这些人是安全的。”

据估计，年龄＞40岁的美国男性约有3%被开具了睾酮治疗处方，尽管有证据表明它的不良心血管效应是可以累积的。该研究结果提醒我们“应当谨慎使用睾酮和开展进一步研究”。

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By: MARY ANN MOON, Clinical Endocrinology News Digital Network

Testosterone therapy taken for "low T" raises the risk of mortality, myocardial infarction, and ischemic stroke, according to a report published online Nov. 5 in JAMA.

The risk elevation is consistent in both men who have existing coronary artery disease and men who do not, and is not affected by differences in cardiovascular risk factors such as blood pressure or by the use of preventive medications, said Dr. Rebecca Vigen of the University of Texas at Southwestern Medical Center, Dallas, and her associates.

These findings, from what the investigators describe as the first observational study to suggest a causal link between testosterone therapy and adverse cardiovascular outcomes, "raise concerns about the potential safety of testosterone therapy." Randomized clinical trials are warranted to clarify this issue, they noted.

"Although physicians should continue to discuss the symptomatic benefits of testosterone therapy with patients, it is also important to inform patients that long-term risks are unknown and there is a possibility that testosterone therapy might be harmful," Dr. Vigen and her colleagues added.

Previous studies have shown that testosterone therapy improves sexual function and strength, as well as some cardiovascular risk factors such as lipid profiles and insulin resistance.

They have not detected adverse CV effects, "but these trials were generally focused on intermediate endpoints, of short duration, and not powered for clinical endpoints," the investigators wrote.

One clinical trial that included many men with CV disorders was halted early in 2010 when the group receiving testosterone was found to have an excess of CV events, compared with the placebo group.

Dr. Vigen and her associates examined the potential CV risks of testosterone therapy in a retrospective cohort study using data from the Veterans Administration’s Clinical Assessment Reporting and Tracking (CART) program, which collects information on all procedures performed in the 76 VA cardiac catheterization laboratories across the country.

They identified all men who underwent coronary angiography at these facilities in 2005-2011 (who therefore had well-characterized cardiovascular profiles) and whose medical records also showed a total testosterone level of less than 300 ng/dL.

This cohort of 8,709 men had a high burden of comorbidities: 20% had a history of MI, half had diabetes, and more than 80% had coronary artery disease. Rates of these comorbidities were approximately equal between men taking testosterone and men not taking testosterone.

A total of 1,223 of these men were taking testosterone therapy to address their low testosterone levels. Roughly 1% of them were using testosterone gel, 36% were using injections, and 63% were using patches. Men who used testosterone tended to be younger and healthier than those who did not.

During an average of 28 months of follow-up, there were 1,710 adverse events of interest: 748 men died, 443 had MIs, and 519 had strokes. The absolute risk of these events was significantly greater in testosterone users than in nonusers: 1.3% higher at 1 year, 3.1% higher at 2 years, and 5.8% higher at 3 years, the investigators said (JAMA 2013 [doi:10.1001/jama2013.280386]).

In a further, adjusted analysis of the data, testosterone use remained strongly associated with increased risk of death, MI, or stroke, with a hazard ratio of 1.29. This indicates that testosterone users were 29% more likely than were nonusers to experience these adverse outcomes.

These findings were unchanged after the data were further adjusted to account for the presence or absence of CAD and the use or nonuse of coronary revascularization procedures.

There was no significant difference in risk of adverse outcomes among the three formulations of testosterone.

The researchers noted that there are several potential mechanisms by which testosterone therapy might increase cardiovascular risk. It increases platelet aggregation, which contributes to arterial plaque formation.

It enhances monocyte activation in the endothelium, which promotes atherosclerosis and is implicated in the pathogenesis of acute coronary syndromes. And it aggravates sleep-disordered breathing, another CV risk factor, they said.

This study was supported by the U.S. Department of Veterans Affairs. No financial conflicts of interest were reported.

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Be wary of testosterone therapy

The findings by Vigen et al. should prompt wariness among clinicians and patients alike, especially in light of the high volume of prescriptions and "aggressive marketing by testosterone manufacturers," said Dr. Anne R. Cappola.

The most important question raised by the study results may be how they can be generalized to the broader population of men taking testosterone: men of this age group who are taking testosterone for "low-T syndrome" or for antiaging purposes, and younger men taking it for physical enhancement.

"Does the 29% increased risk of myocardial infarction, ischemic stroke, or mortality apply to these groups? Are the benefits – real or perceived – for these groups of men worth any increase in risk? These populations represent a sizable group of testosterone users, and there is only anecdotal evidence that testosterone is safe for these men."

Testosterone treatment is prescribed for an estimated 3% of U.S. men over age 40 years, even as evidence indicating that it exerts adverse cardiovascular effects is accumulating. The study results warrant "both cautious testosterone prescribing and additional investigation," she said.

Dr. Anne R. Cappola is in the division of endocrinology, diabetes, and metabolism at the University of Pennsylvania, Philadelphia. She is also an associate editor of JAMA. She reported ties to Abbott Laboratories and BioSante Pharmaceuticals. These remarks were taken from her editorial accompanying Dr. Vigen’s report (JAMA 2013;310:1805-6).