癌症、胰腺炎数据尚不影响降糖药使用

美国临床内分泌医师协会(AACE)和美国内分泌学会(ACE)日前联合发表了一份共识声明，强调关于降糖药物可能增加胰腺炎和某些癌症风险的现有数据尚不足以改变临床实践。这份共识声明同时发表在《内分泌实践》杂志的在线版和纸质版上(2013;19:675-93)。

声明指出，这些现有数据中并无来自大型随机对照研究的数据，而且“存在局限性和矛盾性”。医务人员“在依据现行临床实践指南使用所有FDA批准的降糖药物时应当更有信心”。

不过这份共识声明也提醒道：“临床医生在为具有特定器官相关风险的患者选择降糖药物时应当谨慎，要考虑到降糖药物与癌症的潜在关联……应当警惕这些潜在风险，并且对患者进行更严密的监测。”

今年7月，FDA和欧洲药品管理局(EMA)针对上述相关性发布了声明。AACE在8月20日举行的共识声明发布会上指出，这份共识声明与FDA和EMA的声明基本一致，后者声称降糖药物使用数据“尚不足以确定这种关联，目前不必修改有关潜在风险的正式标签”。

共识声明特别工作组共同主席、美国代谢研究所医学总监Yehuda Handelsman博士在声明中指出：“多种降糖药物与癌症的潜在关联引起了医生和患者的严重关切，但是现有证据尚不足以支持停用降糖药物，停药将会给糖尿病或肥胖患者带来不良后果。除非获得更多决定性的证据，否则降糖治疗的获益始终能压倒对潜在低级别癌症风险的任何担忧。”

这份声明引述了今年3月份FDA发布的安全通讯，后者声称FDA正在评估一项新研究，这项研究显示肠促胰岛素类似物治疗与2型糖尿病患者发生癌前细胞变化的风险增加有关。不过声明还补充道：“这项研究的质量、相关性和重要程度均不明确。”

二甲双胍已被证明对癌症发病和癌症死亡“无影响或有保护作用”，同时还有数据显示，使用该药与结直肠癌、肺癌和乳腺癌风险降低有关。噻唑烷二酮(TZD)类药物吡格列酮已被证实与膀胱癌风险增加有关，尤其是在长期使用、累计剂量较大的情况下，不过近期数据提示膀胱癌风险增加幅度不大。基于这些数据，临床医生“应当有信心继续使用TZD类药物”，不过的确应当按照FDA的建议对使用吡格列酮的患者加强监测，并避免对膀胱癌风险较高或有膀胱癌病史的患者使用该药。

一种尚未在美国获准的钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂dapagliflozin已显示出与乳腺癌和膀胱癌风险增加有关，但未达到统计学显著性。不过包括canagliflozin在内的其他SGLT2抑制剂“尚未显示出任何与癌症有关的迹象”。

体重指数(BMI)增加与多种癌症风险增加的相关性得到了流行病学数据的支持。根据这些数据，肥胖、胰岛素抵抗和糖尿病患者的癌症风险显著增加，而且基础研究“提示这些疾病似乎与癌症的发生有关”。“为了完善有关这一复杂问题的证据体系，需要包括内分泌专家和肿瘤专家在内的临床医生开展更深入的协作研究，同时也需要基础、临床和流行病学研究者的支持。”BMI与子宫内膜癌、胆囊癌、食管癌(腺癌)、肾癌、甲状腺癌、卵巢癌、乳腺癌和结直肠癌的相关性最强。这一关联“提示有必要提倡肥胖患者改善饮食、增加体力活动和早期接受癌症筛查”。

此外，FDA今年3月宣布正在评估一篇尚未发表的报告，该报告提示接受某些降糖治疗的2型糖尿病患者的胰腺炎(已被纳入肠促胰岛素类似物的警告部分)和胰管化生风险增加。7月份，EMA宣布已完成了对高血糖素样肽-1(GLP-1)激动剂相关性胰腺炎和胰管化生改变的多份报告的调查，结论是现有数据“未能证实这类药物增加胰腺不良事件风险”。由欧盟委员会资助的2项针对降糖治疗风险特征的大型研究将在2014年公布结果，在此之前，EMA将继续严密监测和评估这些药物的相关信息，“以确保其获益仍然超过风险”。

FDA发言人在接受采访时表示，EMA的结论“与我们目前对数据的理解是一致的”。“FDA认为，基于已获准GLP-1的治疗的现行标签反映了我们对当下安全信号的理解。这类药物的心血管结局试验正在进行中，FDA正在从中收集胰腺炎和胰腺癌的数据，还有一项流行病学研究也在进行中。”GLP-1受体激动剂已被证实与大鼠甲状腺C细胞癌风险增加有关，但尚无此类药物与人类甲状腺髓样癌相关的证据。

在接受基于肠促胰岛素的治疗、GLP-1受体激动剂以及二肽基肽酶-4(DPP-4)的患者中已有多例急性胰腺炎的报告，但“因果关系尚未得到证实，而且与胰腺癌的关联尚不明确”。

已在美国上市的肠促胰岛素类似物包括艾塞那肽(百泌达和Bydureon)、利拉鲁肽(诺和力)、西格列汀(Januvia、Janumet、Janumet XR和Juvisync)、沙格列汀(安立泽和Kombiglyze XR)、阿格列汀(Nesina、Kazano和Oseni)，以及利格列汀(Tradjenta和Jentadueto)。

Handelsman博士披露称接受了多家药企的研究资助、咨询费和演讲酬金。其余11名作者的利益冲突包括接受了多家药企的演讲费、咨询费、研究合同和(或)持有其股票。作为这份共识指南的基础，AACE会议的部分经费来自Amylin、百时美施贵宝、阿斯利康、礼来、默克、诺和诺德和赛诺菲安万特。

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By: ELIZABETH MECHCATIE, Oncology Practice

Available data on a possible link between antihyperglycemic drugs and an increased risk of pancreatitis and certain cancers do not justify making changes in clinical practice, according to a consensus statement on diabetes and cancer released by the American Association of Clinical Endocrinologists and American College of Endocrinology.

The available data do not include data from large, randomized controlled studies and are "limited and conflicting," the statement said. Health care professionals "should have greater confidence in prescribing all FDA-approved antihyperglycemic medications’according to current clinical practice recommendations."

The consensus cautioned that "clinicians should exercise caution when choosing medications’implicated in the etiology of cancer for patients with the specific organ-related risk ... Clinicians should be alert to the potential risk and should monitor patients more closely."

The statement was published online and in print in the July/August issue of Endocrine Practice (2013;19:675-93).

In July, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued statements on the associations. The consensus statement is "in line" with those statements, which said that the data on medications’used to manage hyperglycemia are "not substantial enough to make the connection and there is no need to change the official labeling about potential safety risks," according to the Aug. 20 press release from the American Association of Clinical Endocrinologists (AACE) announcing publication of the consensus statement.

"The implication of various medications’ role in the development of cancer has concerned physicians and patients alike, but the sum of evidence presents a very compelling case and suggests the risk of cancer is unproven," Dr. Yehuda Handelsman, cochair of the consensus statement task force, said in that statement.

"The research conducted to date is incomplete and, thus, insufficient to warrant withholding treatment that will result in adverse outcomes for those who have diabetes or are obese," added Dr. Handelsman, the medical director of the Metabolic Institute of America, Tarzana, Calif. "Until more definitive evidence becomes available, the benefits of treatment should take precedence over any concerns for potential low-grade cancer risk."

The statement includes information on the FDA safety communication in March 2013, which said the agency was evaluating a new study that treatment with incretin mimetics was associated with an increased risk for precancerous cellular changes in people with type 2 diabetes, although the statement adds, "the quality, relevance, and importance of the study are not clear."

Metformin has been associated with a "neutral to decreased" effect on the incidence of cancer and cancer mortality, and there also are data associating its use with a decreased risk of colorectal, lung, and breast cancers. Pioglitazone, a thiazolidinedione (TZD), has been associated with an increased risk of bladder cancer, particularly with longer use and larger cumulative doses, but recent data indicate the risk of bladder cancer is small. Based on these data, clinicians "should be confident and continue to use TZDs," but should monitor patients on pioglitazone and, as recommended by the FDA, avoid prescribing it to patients with a high risk or history of bladder cancer.

A sodium-glucose cotransporter 2 (SGLT2) inhibitor not approved in the United States (dapagliflozin) has been associated with an increased incidence of breast and bladder cancer, which was not statistically significant. But other drugs in this class, including canagliflozin, the SGLT2 inhibitor approved in the United States, "have not shown any cancer signal and are not presently implicated in cancer development," the statement said.

Epidemiologic data support an association between an increased body mass index and an increased risk of various cancers. Based on epidemiologic data, the risk of cancer is significantly increased with obesity, insulin-resistant states, and diabetes, and basic research has "suggested plausible mechanisms linking these conditions to the development of cancer."

"Further collaborative research between clinicians, including endocrinologists and oncologists, as well as basic, clinical, and epidemiologic researchers, is necessary to complete the evidence on these complex issues," the statement said.

The associations with body mass index were strongest for endometrial, gall bladder, esophageal (adenocarcinoma), renal, thyroid, ovarian, breast, and colorectal cancer. This relationship "supports the need to advocate for improved diet, greater physical activity, and early cancer screening in obese patients," the statement said.

Furthermore, in March 2013, the FDA announced that it was evaluating unpublished reports suggesting that the risk of pancreatitis (included in the warning section of incretin mimetics) and pancreatic duct metaplasia was increased in patients with type 2 diabetes treated with those drugs. In July, the EMA announced that its investigation into these reports of pancreatitis and changes in pancreatic duct metaplasia associated with glucagonlike peptide-1 (GLP-1) agonists was completed, and concluded that the available data "do not confirm recent concerns over an increased risk of pancreatic adverse events with these medicines." Until the results of two large studies, funded by the European Commission, on the risk profile of diabetes treatments are available in 2014, and other data are available, the EMA is continuing to closely monitor and evaluate information on these medicines "to ensure that their benefit-risk balance remains positive."

The FDA is aware of the EMA’s analyses and believes that the EMA’s conclusions "are consistent with our current understanding of the data," an FDA spokesperson said in an interview. "FDA believes that the current labeling for approved GLP-1 based therapies reflects the extent of our understanding of the safety signals at this point in time," she added, noting that the FDA’s review is ongoing as pancreatitis and pancreatic cancer data are being collected in the cardiovascular outcome trials being conducted with this class of drugs, and there is an ongoing epidemiological study.

GLP-1 receptor agonists have been associated with an increase in thyroid C-cell carcinomas in rats, but there is no evidence these drugs are associated with medullary thyroid cancer in humans, data that include an analysis of 10 studies conducted by the EMA, according to the consensus statement.

The incretin-based treatments, GLP-1 receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors have been associated with some reports of acute pancreatitis, but "causal mechanisms have not been established," and "the link to pancreatic cancer is unclear," the statement said.

The incretin mimetics available in the United States include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto).

Dr. Handelsman disclosed having received research grant support, consulting fees, and speaker’s honoraria from various pharmaceutical companies. The disclosures of the remaining 11 authors and task force members included having received speaker’s fees, consulting fees, and research contracts from, and/or holding shares in, various pharmaceutical companies. The consensus statement and the AACE conference that was the basis of the statement were supported by AACE. The conference was partly funded with grants from Amylin Pharmaceuticals, Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Merck, Novo Nordisk, and Sanofi-Aventis US.