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)。
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.