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Electronic letters published:
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DPP-4 Inhibitors and Cancer
Skeletal toxicity of thiazolidinediones
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Mark R. Goldstein, MD, FACP Fountain Medical Court, Bonita Springs, FL
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markrgoldstein{at}comcast.net Mark R. Goldstein
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Regarding the informative review of Dr. Bolen, et al [1], on the effectiveness and safety of oral medications for type 2 diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors were not discussed. This is unfortunate, since the recently approved DPP-4 inhibitor, sitagliptin, is highly promoted and increasingly used, despite no long-term safety data [2]. The approval of drugs based on surrogate endpoints, in this case, glycated hemoglobin levels, is problematic and compromises public safety [3]. Dipeptidyl peptidase-4 has diverse actions and is involved in processes related to cancer metastasis [4]. In vitro studies confirm that DPP-4 inhibition increases the metastatic potential of colon [5] and prostate cancer [6]. This is of great concern given the high prevalence of these tumors in the general population [7]. Indeed, pre-market studies on sitagliptin submitted to the Food and Drug Administration (FDA) revealed an increase in malignant neoplasms in the pooled population of the phase 3 study subjects [8]. The reported data included 1538 subjects randomized to sitagliptin and 778 subjects randomized to placebo over an average duration of 0.4 years. Annualized, malignant cancer incidence was 9 and 19/1000/year in the placebo and sitagliptin groups respectively. They included a variety of tumors including colon and prostate cancers. Surprisingly, investigators considered none of the cancers drug related. The public health ramification of the widespread use of DPP-4 inhibitors is profound. The drugs will be used long-term in various segments of the population, such as the elderly, whom potentially harbor more occult cancers. Clinicians must be aware of this and use restraint if prescribing these drugs to patients with a history of malignancy. Furthermore, vigilant post-market surveillance of DPP-4 inhibitors is mandatory. References [1] Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007;147:386-399. [2] Nathan DM. Finding new treatments for diabetes - how many, how fast...how good? N Engl J Med. 2007;356:437-440. [3] Manns B, Owen Jr WF, Winkelmayer WC, Devereaux PJ, Tonelli M. Surrogate markers in clinical studies: problems solved or created. Am J Kidney Dis. 2006; 48: 159-166. [4] Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care. 2007;30:1315-1343. [5] Masur K, Schwartz F, Entschladen B, Niggemann, Zaenker KS. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Reg Pep. 2006; 137: 147-155. [6] Wesley UV, McGroarty M, Homoyouni A. Dipeptidyl peptidase inhibits maligant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Res. 2005;65:1325-1334. [7] Jenal A, Siegel R, Ward E, Murray T, Xu J, Thun M. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43-66. [8] US Food and Drug Administration. Center for Drug Evaluation and Research. Januvia (Sitagliptin Phosphate) Tablets. Company: Merck & Co., Inc. Application No.: 021995. Approval Date: 10/16/2006. Accessed at www.fda.gov/cder/foi/nda/2006/021995s000_MedR.pdf on 21 Sept 2007. Conflict of Interest:None declared |
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Andrew B Grey, MD University of Auckland
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a.grey{at}auckland.ac.nz Andrew B Grey
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Patients with type 2 diabetes mellitus are at increased risk of fracture compared to their euglycemic peers (1). In their review of the comparative safety of oral therapies for type 2 diabetes mellitus, Bolen et al refer to evidence from the ADOPT study that fracture incidence was increased, by about 2-fold, in women with type 2 diabetes mellitus taking rosiglitazone, compared to those taking either glyburide or metformin (2). An increased fracture risk in women has also been reported from a preliminary analysis of an ongoing rosiglitazone trial (3), and from a pooled analysis of randomized trials comparing pioglitazone with either placebo or active comparators (4). The likely mechanism of thiazolidinedione-induced skeletal fragility is inhibition of bone formation by PPARã-mediated diversion of mesenchymal progenitor cells into the adipocyte lineage at the expense of osteoblastogenesis (1, 5). Clinicians should be mindful of this additional adverse effect of thiazolidinedione therapy when prescribing oral hypoglycemic therapy, particularly to older women. Skeletal endpoints should also be evaluated in prospective, comparative studies of oral therapies in type 2 diabetes mellitus. References 1. Grey A. Skeletal consequences of thiazolidinedione therapy. Osteoporosis International. 2007:(in press). 2. Bolen S, Feldman L, Vassy J, et al. Systematic review: Comparative effectiveness and safety of oral medications for Type 2 diabetes mellitus. Ann Intern Med. 2007;147(6):386-399. 3. US Food and Drug Administration. Accessed at http://www.fda.gov/medwatch/safety/2007/Avandia_GSK_Ltr.pdf on 3 March 2007. 4. US Food and Drug Administration. Accessed at http://www.fda.gov/medwatch/safety/2007/Actosmar0807.pdf on 13 March 2007. 5. Grey A, Bolland M, Gamble G, et al. The peroxisome proliferator- activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab. 2007;92(4):1305-1310. Conflict of Interest:I have received consulting fees from Glaxo Smith Kline |
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