胰島素Glargine和癌症風險之間有關但無因果關係

作者：Becky McCall  
出處：WebMD醫學新聞

　　October 2, 2009 (奧地利維也納) — 專家同意，胰島素類似物與癌症風險之間有關，但無因果關係。研究也顯示，胰島素glargine(商品名Lantus，Sanofi-Aventis藥廠製造)與其他胰島素製劑相比並無特殊風險。
　　
　　在歐洲糖尿病協會(EASD)第45屆年會「糖尿病治療與癌症」這個專題中，6位專家對於胰島素和胰島素類似物(特別是胰島素glargine)與癌症的可能關聯提出看法。EASD現任理事長、瑞典Sahlgrenska大學醫院的Ulf Smith醫師表示，他目前還不會改變他的臨床實務，因為胰島素類似物和癌症之間的關係太弱了。
　　
　　Smith醫師表示，這個關聯沒有因果關係，它顯示的是，高劑量胰島素與增加癌症風險之間的關聯。這是很新且複雜的領域，對這方面的所有問題都還沒有答案。
　　
　　他提出需要後續研究來瞭解這些關聯的機轉。Smith醫師觀察發現，問題的核心在於：這是由於體循環的胰島素量高、或者是肥胖和第2型糖尿病相關的基本問題，也就是所謂的胰島素阻抗性？細胞層級的基礎科學證據和動物研究顯示，胰島素阻抗性可能是個重要因素。無法從流行病學研究來確認。
　　
　　今年稍早，EASD的Diabetologia期刊發表一篇德國的觀察研究(2009; 52:1732-1744)，以及瑞典、蘇格蘭和英國所進行的三個研究，之後即有諸多論辯。瑞典研究顯示，胰島素glargine與乳癌之間的關聯有統計上的顯著意義(Diabetologia. 2009;52:1745-1754)，蘇格蘭的研究發現，和乳癌的關聯不顯著(Diabetologia. 2009;52:1755-1765)，英國的研究則發現，與任何癌症之間都沒有關聯(Diabetologia. 2009;52:1766-1777)。
　　
　　基於這些研究，美國食品藥物管理局宣布進行安全回顧。最近，Sanofi-Aventis藥廠也宣布，他們將在歐美開始一系列的流行病學研究，以加強實證基礎。再者，EASD的研究機構、歐洲糖尿病研究基金會宣布，它將提供300萬歐元(440萬美金)給EASD獨立研究計畫，目標在資助未來三年有關糖尿病與癌症關聯的新研究。
　　
　　英國Bristol大學臨床科學系主任、糖尿病內科Edwin Gale醫師，以及威爾斯Cardiff大學流行病學專家Craig Currie博士強調，一個新研究顯示，以胰島素治療的糖尿病患，發生大腸腫瘤的機會是服用metformin者的2倍，單用胰島素者發生胰臟癌的風險是使用胰島素加metformin者的4.5倍。
　　
　　會議中引述了美國糖尿病協會今年稍早的一篇加拿大研究(Simpson SH等人，2009年6月5-9日路易斯安那紐奧良第69界科學會議：摘要1013-P)，相較於單用metformin者，使用磺醯尿素類之病患診斷有癌症的風險增加了30%。該分析也顯示，使用胰島素病患有癌症診斷的可能性，相較於單用磺醯尿素類者，顯著增加了67%，且癌症風險與使用的胰島素量增加成正比。
　　
　　邁阿密大學小兒科暨心理學教授Jay Skyler醫師在接獲一系列有關癌症風險與各種胰島素之關聯的研究之後表示，在那篇德國研究的各方面資料中，風險比為1，因此沒有統計上的顯著意義。若要說有何研究貢獻，德國的資料庫明顯認為，glargine的癌症風險比其他胰島素低。
　　
　　回顧許多既有的胰島素類似物，包括glargine和癌症風險的資料之後，他結論表示，分析廣泛的臨床試驗資料後顯示，使用胰島素glargine的各種癌症及乳癌風險並沒有比較高。無控制組的試驗則是支持包括乳癌等各種癌症的風險，並未因使用胰島素glargine而比美國流行病監督及最終結果資料庫(Surveillance, Epidemiology and End Results，SEER)的預估比率增加 。一篇大型長期隨機控制試驗顯示，沒有癌症顧慮。
　　
　　Skyler醫師聲稱，因此其結論是，胰島素glargine不會引起癌症，報紙頭條登載之有關Diabetologia期刊文獻的論點是錯誤的。
　　
　　Smith醫師、Currie博士、Gale醫師皆宣告沒有相關財務關係。
　　
　　歐洲糖尿病協會(EASD)第45屆年會：專題S14。發表於2009年10月1日。

Association but No Causality Between Insulin Glargine and Cancer Risk

By Becky McCall
Medscape Medical News

October 2, 2009 (Vienna, Austria) — Experts agree that there is an association but no established causal link between insulin analogues and cancer risk. Studies also show that insulin glargine (Lantus, Sanofi-Aventis) has no special risk over other insulin-based products.

Presenting at a symposium entitled Diabetes Therapy and Cancer, here at the European Association for the Study of Diabetes (EASD) 45th Annual Meeting, 6 experts commented on the potential link between insulin and insulin analogues (specifically insulin glargine) and cancer. Current president of the EASD, Ulf Smith, MD, from Sahlgrenska University Hospital in Goteborg, Sweden, said that he would not alter his clinical practice at the moment because the link between insulin analogues and cancer is too weak.

"An association is not causal," Dr. Smith said. "It shows a link between high insulin dose and increased cancer risk. This is a very new and complicated area and we have yet to answer all the questions."

He drew attention to the need for further research to understand the mechanism driving the association. "At the core of the matter is this: Is this due to high circulating insulin or is it the basic defect associated with both obesity and type?2 diabetes, that is, insulin resistance? Basic science evidence at the cellular level and in animals suggests that insulin resistance may be a very important factor. This cannot be determined from epidemiological studies," Dr. Smith observed.

After controversy surrounding the publication of German observational studies published earlier this year in the journal of the EASD, Diabetologia (2009; 52:1732-1744), 3 more studies were conducted on the basis of data derived from Sweden, Scotland, and the United Kingdom. The Swedish study showed a statistically significant link between insulin glargine and breast cancer (Diabetologia. 2009;52:1745-1754), the Scottish study found a nonsignificant link with breast cancer (Diabetologia. 2009;52:1755-1765), and the British study found no link with any type of cancer (Diabetologia. 2009;52:1766-1777).

Following these studies, the US Food and Drug Administration announced the launch of a safety review. Recently, Sanofi-Aventis also announced that they will begin a series of epidemiologic studies across Europe and the United States to expand the evidence base. Furthermore, the European Foundation for the Study of Diabetes, the research arm of the EASD, announced that it would provide €3?million ($4.4?million) to the EASD stand-alone research program aimed at funding new studies on the relation between diabetes and cancer over the next 3 years.

Craig Currie, PhD, medical epidemiologist from Cardiff University, Wales, and Edwin Gale, MD, from the Department of Diabetic Medicine and head of the Department of Clinical Science at the University of Bristol in the United Kingdom, highlighted a new study, which showed that diabetic patients treated with insulin were twice as likely to develop colon carcinomas as those taking metformin, and patients taking insulin alone had 4.5 times the risk for pancreatic cancer as those taking insulin plus metformin.

A Canadian study cited at the meeting but reported earlier in the year at the American Diabetes Association (Simpson SH et al. 69th Scientific Sessions, June 5-9, 2009; New Orleans, LA: abstract 1013-P) showed that patients receiving sulfonylureas, compared with those receiving metformin alone, had a 30% greater risk of being diagnosed with cancer. The same analysis showed that patients receiving insulin had a significant 67% increase in the likelihood of a cancer diagnosis, relative to those receiving sulfonylurea alone, and cancer risk was directly proportional to the increasing number of insulin prescriptions.

Jay Skyler, MD, professor of medicine, pediatrics and psychology at the University of Miami in Florida, referred to a list of studies on the cancer risk associated with various insulins. "In every case except for the German database, the hazard ratios span 1 and are therefore not statistically significant. If anything, the German database statistically suggests a decrease of cancer risk with glargine versus other insulins."

After reviewing the large volume of available data on cancer risks and insulin analogues, including glargine, he concluded that the analysis of extensive clinical trial data indicated that the risks for all cancers and breast cancers were not higher with insulin glargine than with comparators. "Uncontrolled trials provided supporting evidence that the risk of all cancers, including breast cancers, with insulin glargine was not increased, compared with expected rates from the US Surveillance, Epidemiology and End Results (SEER) database. A large long-term [randomized controlled trial] showed there was no cause for concern," he added.

"So my conclusion is that insulin glargine does not cause cancer and that newspaper headlines that accompanied the first appearance of the Diabetologia article were incorrect," Dr. Skyler asserted.

Dr. Smith, Dr. Currie, Dr. Gale have disclosed no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 45th Annual Meeting: Symposium S14. Presented October 1, 2009.