三项研究证明甘精胰岛素与癌症无关

费城(EGMN)——在美国糖尿病学会(ADA)2012科学年会上报告的3项大规模管理数据库分析研究一致表明，与其他类型的胰岛素相比，每日使用甘精胰岛素(来得时)不增加任何类型癌症的发病风险，包括乳腺癌、前列腺癌、结直肠癌、肺癌、胰腺癌或其他类型的癌症。

 

法国里昂国际预防研究院院长Peter Boyle 博士在会上称，2009年有4篇论文同时提出了甘精胰岛素与癌症相关的担忧，之后研究者、医生和患者一直都很担心这类药物对自身健康风险的影响。因此必须尽可能地就这些问题给出肯定的答案，否则会带来非常严重的后果。“我们最担心的是，到2030年全球将有超过5亿人患有糖尿病，其中许多人都需要使用胰岛素，如果不用则很可能过早死亡。如果我们不对胰岛素-癌症相关性进行更加系统的研究，在研究过程中不应用一些常识，那么我们将失去这类非常必要的药物来治疗糖尿病这一极其常见的疾病。”

 

Boyle博士是“北欧胰岛素与癌症研究(Northern European Study of Insulin and Cancer)”的主要研究者，这是迄今为止最大规模的评价甘精胰岛素和NPH胰岛素及其癌症相关性的登记库研究。这项研究加上会上报告的另外2项研究共纳入患者615,000多例，数据超过150万患者- 随访年。

 

Boyle博士在447,821例每日使用胰岛素的糖尿病患者中评估了甘精胰岛素与癌症之间的相关性。这项研究在5个国家开展：苏格兰、挪威、瑞典、丹麦和芬兰。这是3项研究中随访时间最长的一项，对使用甘精胰岛素的患者随访了3年，对使用其他类型胰岛素的患者随访了3.5年。研究比较了两组患者的癌症发生率：一开始就使用甘精胰岛素或者其他胰岛素的患者，以及从另一种胰岛素改为使用甘精胰岛素的患者。

 

研究期间，共出现了17,800例新发癌症病例。但分析结果显示，“无论是对每一种癌症单独分析，还是对所有类型癌症进行总体分析，我们都没有找到任何证据提示与其他类型的胰岛素相比，使用甘精胰岛素与癌症发病风险增加相关。即便不同国家在癌症发生率上存在一定的差异，但针对任何国家的风险分析都远远没有达到统计学显著性水平。”

 

来自各国研究中心的数据一致表明，与其他类型的胰岛素相比，使用甘精胰岛素的患者罹患结直肠癌的总体风险为0.86。

 

有关前列腺癌的结果一致性稍差。Boyle博士指出，这很可能是因为部分国家开展了许多前列腺癌筛查项目，“而某些国家事实上禁止开展PSA检查”。尽管如此，甘精胰岛素较之其他胰岛素的前列腺癌总体风险为1.11，仍然没有统计学意义。有关乳腺癌的结果也类似，甘精胰岛素较之其他类型胰岛素的总体相对风险为1.12。

 

研究者根据事先定义的探索性分析评估了肺癌和胰腺癌的发病风险。甘精胰岛素与其他类型的胰岛素相比，发生肺癌的总体相对风险为0.97，发生胰腺癌的相对风险为0.99。Boyle博士说：“所以我们没有发现任何问题。”

 

然后研究者又根据药物暴露时间的长短来分析癌症风险。乳腺癌是唯一一种提示了略微相关性的癌症类型，但结果却不统一。在大部分国家，乳腺癌的发病风险随着用药时间的延长而下降，但“来自苏格兰的数据却显示，用药时间越长，危险就越大。这两种结果实在差得太远，我们需要进一步详细分析”。

 

Boyle博士还指出，不过，上述矛盾结果也真实反映了采用大规模监测数据库预测药物-不良事件相关性所存在的问题。“这些管理数据库并不是为流行病学研究而设计的。我们只能尽量得出真实的有意义的结果。在这项研究中还有一些重要的零散信息是缺失的，比如我们不知道患者改变治疗方案的原因。”

 

美国凯撒医疗集团(Kaiser Permanente)的Laurel Habel博士也报告了类似的研究结果：暴露于甘精胰岛素不会导致癌症风险增加。这项研究是基于凯撒北加州和南加州医疗保险申报及编码数据库，共涉及115,000例糖尿病患者，其中100,000例使用NPH胰岛素，27,000例使用甘精胰岛素，12,000例两者都用。使用甘精胰岛素患者的中位随访期为2.3年，使用NPH胰岛素患者的随访期为3.6年。

 

Habel博士报告称：“没有任何证据提示甘精胰岛素使用者发生前列腺癌或结直肠癌的风险增加，无论是一开始就使用还是从其他治疗改为使用甘精胰岛素。”

 

针对乳腺癌风险的时间暴露分析显示，基线时就已经在使用甘精胰岛素的患者“24个月后其发病风险略有增加，约为1.6。”奇怪的是，从另一种胰岛素改为使用甘精胰岛素至少2年的患者其发病风险并无增加。“我们得到的结果完全不支持短期使用甘精胰岛素与癌症风险增加相关的假设。”对于前列腺癌和结直肠癌，所有分析以及时间依赖性比较均没有发现任何显著的相关性。

 

美国北卡罗来纳大学的Til Stürmer博士报告的是这3项研究中规模最小的一项，但结果与前2项研究完全一致。用于对照的52,553例患者也是来自一个大规模医疗保健数据库。甘精胰岛素和其他胰岛素组的中位随访期均为1.5年。

 

Stürmer博士评价了患者发生乳腺癌、前列腺癌、结肠癌以及所有类型癌症的相对风险。结果显示，无论是一开始就使用还是从其他治疗改为使用甘精胰岛素，均与癌症风险增加无关。与其他胰岛素相比，甘精胰岛素使用者出现乳腺癌、前列腺癌、结肠癌以及所有类型癌症的相对风险分别为1.1、1.2、0.9和1.1。

 

美国麻省总医院临床疾病管理研究中心主任James Meigs博士在谈到上述研究结果的临床意义时说，2009年6月6日，4篇关于甘精胰岛素与偶发癌症之间潜在相关性的文章同时发表。虽然作者在其结论中措词较保守，但媒体却登出了骇人听闻的大标题：“胰岛素治疗会导致癌症！”。于是公众开始相信胰岛素真的对糖尿病患者有害。为此，研究者立即开展了仔细的数据库分析以解答这一疑问，希望了解药物监测数据库在反映安全性信号方面的有效性，临床医生则希望确定甘精胰岛素的安全性。“这几项研究带给我们的最重要信息就是，甘精胰岛素是安全的，其收益明显超过其风险。”

 

但是另一个问题不那么容易回答。管理数据库只能提示这些关于患者及其使用经验的信息，混杂问题是可能危及这些分析结论的关键因素。最严重的问题是数据缺失。例如，登记库数据中通常都没有关于患者吸烟状况的数据，但是吸烟在糖尿病患者中很常见，并且吸烟也是一个极其重要的癌症危险因素。

 

此外，关于药物暴露时间的数据也不足。对于一开始就使用甘精胰岛素的患者，确定暴露时间很容易；但是对于那些从其他治疗改为使用甘精胰岛素的患者，其既往的药物暴露情况则不得而知。为了准确评估患者结局，我们需要随访足够长的时间才能观察到疾病发病。这就引出了另一个问题：癌症可以有很长的潜伏期，发病前可能患者正好暴露于某种药物，就可能造成两者相关的错觉，其实患者可能一直都有一些亚临床表现，只是没有明显发病罢了。

 

最后，两者相关并不等于两者具有因果关系。Meigs博士表示：“要准确开展这类研究确实很难，但武断地宣称药物暴露与某种风险相关是不负责任的做法，甚至会导致不良后果，特别是对于甘精胰岛素与癌症相关这一话题。”

 

上述所有登记库研究均接受了赛诺菲公司提供的研究经费。除此之外，所有发言者均声明不存在任何与其研究相关的经济利益关系。Meigs博士也声明无相关经济利益冲突。

 

爱思唯尔  版权所有

BY MICHELE G. SULLIVAN
Elsevier Global Medical News
Breaking News

 

PHILADELPHIA (EGMN) – Daily insulin glargine for patients with diabetes appears to have no effect on the occurrence of breast, prostate, colorectal, lung, pancreatic, or any other type of cancer.

 

Studies of three large administrative databases agree: Compared with other forms of insulin, glargine (Lantus) confers absolutely no increase in the risk of any of these cancers.

 

Since 2009, when four articles simultaneously raised the specter of a glargine-cancer connection, researchers, physicians, and patients have struggled with concerns that the compound could impart its own health risks. These questions must be answered as definitively as possible, Peter Boyle, Ph.D., said at the annual scientific sessions of the American Diabetes Association.

 

Not doing so could have devastating consequences.

 

“The big worry is that by 2030, we will have more than 500 million people living with diabetes. Many of them will require insulin. Without it, they will die unnecessarily prematurely. If we don’t take a more regulated approach [into researching the cancer association], and use a lot of common sense while doing so, there could be a shortage of a drug that we absolutely need to treat this very common disease.”

 

Dr. Boyle is the primary investigator of the Northern European Study of Insulin and Cancer, the largest-yet registry study of glargine and NPH insulin, and their relation to cancer. His study, combined with the two others presented at the same session, comprised more than 615,000 patients, with well over 1.5 million patient/years of follow-up data.

 

Dr. Boyle examined the glargine-cancer connection in 447,821 patients with diabetes who used daily insulin. This study had the longest follow-up of the trio – 3 years for patients using glargine and 3.5 years for those using other types of insulin.

 

It was conducted in five countries: Scotland, Norway, Sweden, Denmark, and Finland. This study also had the longest follow-up time – 3 years for patients using glargine and 3.5 years for those using other insulins. It compared cancer incidence in two groups: patients taking glargine or other insulin for the first time, and patients who switched from another insulin to glargine.

 

Over the study period, 17,800 new cases of cancer developed, said Dr. Boyle, president of the International Prevention Research Institute, Lyon, France. “In none of the individual cancers, nor in the overall analysis, did we see any evidence at all of an increased risk of cancer associated with the use of glargine, compared with other forms of insulin. Even though we saw some inconsistencies [in cancer incidence] across the different countries, none of the risk analyses came anywhere close to meeting statistical significance.”

 

The overall risk for colorectal cancer in patients taking glargine, compared with other forms of insulin, was 0.86 – a finding consistent over all the study centers.

 

Findings for prostate cancer were less consistent, but this was most likely because some of the countries in the study conduct many prostate cancer screenings, “while in other countries, PSA testing is virtually verboten,” Dr. Boyle said. Nevertheless, the overall risk for prostate cancer in glargine vs. other insulins was 1.11 – still not statistically significant.

 

Breast cancers showed a similar finding, with an overall relative risk of 1.12 for glargine, compared with other forms of insulin.

 

A predefined exploratory analysis examined risks associated with lung and pancreatic cancer. For glargine vs. other forms of insulin, the overall relative risk for lung cancer was 0.97; for pancreatic cancer, the relative risk was 0.99.

 

 “There is just nothing there at all,” Dr. Boyle said.

 

The second portion of the analysis examined cancer risk in light of exposure length. Breast cancer was the only type that showed any signal, and that was a confusing one, he said. While in most countries, the risk declined with time, “In the Scottish data, increasing use was associated with increasing hazard. This really is terribly inconsistent, and we need to look into it in greater detail.”

 

However, he said, the contradictory finding perfectly illustrates the trouble with using large surveillance databases to make any kind of prediction about drug/adverse event associations.

 

“Quite frankly, these administrative databases were not designed for epidemiologic studies. We’ve got to do our best to come up with real findings that mean something rather than just torturing the data until something shows up. Critical bits of information are missing from these pictures. We don’t know why a patient might change from one therapy to another, for instance. There are a lot of questions like that, and these are the first things that a clinician needs to know.”

 

Dr. Laurel Habel, a senior researcher at Kaiser Permanente, presented similar findings of no increased cancer risk from glargine exposure. Her study was based on Kaiser’s northern and southern California claims and coding databases. The study group comprised 115,000 patients with diabetes – 100,000 took NPH insulin, 27,000 took glargine, and 12,000 took both. The median follow-up time was 2.3 years for glargine and 3.6 years for NPH.

 

 “We found no evidence of increased prostate or colorectal cancer for glargine users, whether they were new users or whether they had switched to it,” she said.

 

In a time exposure analysis of breast cancer risk, those who had been on glargine at baseline had a “suggestion of a very modest increase in risk, of 1.6.” after 24 months. Curiously, she said, there was no risk increase for patients who had been on glargine for at least 2 years after switching from another insulin.

 

 “We can’t think of any biological reason why we would only see this in the new users, so it might be a case of confounding,” she said. “None of our results support this hypothesis that short-term use of glargine is associated with any form of cancer.”

 

For prostate and colorectal cancers, there were no significant associations in any of the analyses, or in the time-dependent comparisons.

 

Dr. Til Stürmer of the University of North Carolina at Chapel Hill presented the smallest study, but had results entirely consistent with those of his colleagues. Again, the comparison group of 52,553 patients was drawn from a large healthcare database. Median follow-up was 1.5 years for both the glargine and other insulin groups.

 

In looking at the relative risks of breast, prostate, colon. and all cancer, Dr. Stürmer found no significant associations with either new glargine users or those who switched medications. Compared with other insulins, glargine had a relative risk of 1.1 for breast cancer, 1.2 for prostate cancer, 0.9 for colon cancer, and 1.1 for all forms of cancer.

 

 “In a subgroup looking at breast cancer stratified by time [0-6 months, 6-12 months, 12-24 months and longer than 24 months] the hazard ratios jumped around the null, but we only had 14 cancers in 4,000 person/years,” he added.

 

In a presentation on the clinical implications of the findings presented by Dr. Boyle, Dr. Habel, and Dr. Stürmer, Dr. James Meigs said that on June 6, 2009, four articles about a possible link between the drug and incident cancer were simultaneously published. Although the authors were somewhat temperate in their conclusions, the lay press took this up with the screaming headline, “Insulin Treatment Causes Cancer!”

 

The public deemed insulin harmful to people with diabetes. And immediately, database scrutiny attempted to address this question, Dr. Meigs, director of the Massachusetts General Hospital’s clinical disease management research unit, in Boston, said.

 

Researchers want to know what we can learn about the usefulness of pharmacosurveillance databases for safety signals. And clinicians want to know if it’s safe to prescribe glargine.

 

If there is one take-home message from this group of studies, presented at the American Diabetes Association’s 2012 meeting – it’s “Yes. Glargine is safe and the benefits clearly outweigh the risks.”

The other question is not so easy to answer.

 

Administrative databases can only tell us so much about patients and their experiences. Confounding is a crucial factor that often jeopardizes theses analyses. Missing data are the worst problem here. For instance, smoking status is typically missing in registry data. And yet smoking is common in diabetes and a huge risk factor for cancer. But missing smoking data do not equate to nonsmoking status. You can’t control for confounders that aren’t even measured.

 

Nor do these databases tell us much about exposure. Exposure time is easy enough to see in patients new to glargine. But we know nothing about prior exposure in those who switched to glargine. To accurately assess outcomes, we need to follow exposure with enough time to allow disease to develop in accordance with its natural history – which brings up another problem. Cancer has a very long latency. Its development can precede an exposure by years, creating the illusion that there is a relationship – when it was really present subclinically all along, he said.

 

And finally – association does not imply causation. An association is just that – an association – until proven otherwise.

 

 “The punchline is this: It’s really hard to do these studies correctly. Cavalier publications of this or that exposure and risk are irresponsible and even harmful – particularly in the case of the glargine-cancer connection,” said Dr. Meigs.

 

Insulin is lifesaving. We need it to treat diabetes. And we don’t want to limit our treatment options by prematurely worrying about signals coming up in poorly constructed studies.

 

All of the registry studies received support from Sanofi. Other than this funding, none of the presenters had any financial declarations relevant to their studies. Dr. Meigs said that he had no financial disclosures.