ABSTRACT
Title
Adverse Reactions to Incretin-Based Therapies: Data From The Italian Spontaneous Reporting System
Authors
P.M. Cutroneo1, L. Sottosanti2, A. Russo1, P. Cananzi3, V. Pizzimenti1, D. Crupi1, S. Potenza2, D. Morlino2, F. Ferrazin2, A.P. Caputi1
1 Dept. of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy
2 Italian Medicines Agency, Pharmacovigilance Office, Rome, Italy
3 Dipartimento Pianificazione Strategica, Assessorato della Salute Regione Sicilia, Palermo, Italy
1 Dept. of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy
2 Italian Medicines Agency, Pharmacovigilance Office, Rome, Italy
3 Dipartimento Pianificazione Strategica, Assessorato della Salute Regione Sicilia, Palermo, Italy
Abstract
Two new classes of drugs, glucagon-like peptide-1 (GLP-1) mimetics (exenatide, liraglutide) and dipeptidyl peptidase (DPP) 4 inhibitors (sitagliptin, vildagliptin, saxagliptin) have been approved by regulatory agencies for treating type 2 diabetes mellitus (T2DM). Recent studies raise concerns about risk for pancreatitis and it has also been suggested that immuno-modulatory effects of DPP-4 inhibition might increase risks for infections and cancer (Elashoff et al, 2011; Willemen et al, 2011; Stulc, 2010).
Given the observed increased prevalence of T2DM, the potential impact of adverse effects of these classes of drugs is considerable. Because spontaneous reporting is a valuable methodology for better defining the safety profile of drugs after their approval, we examined reported adverse reactions associated with incretin mimetics and DPP-4 inhibitors in the Italian spontaneous reporting system, with the aim to identify their most important features.
We performed an analysis on the database of spontaneous reports of adverse drug reactions (ADRs) managed by the Italian Medicines Agency (AIFA), where all the individual case safety reports are stored since January 2001. We selected and then analysed in detail all the case reports of suspected adverse reactions attributed to incretin mimetics and DPP-4 inhibitors collected from 2008 to 2010. Outcomes of ADRs were evaluated with respect to four different categories: patient recovered with or without sequelae, patient not recovered at the time of the report and death. Seriousness of ADRs were defined in accordance to the ICH E2D guideline. We included in the study only ADR case reports with a probable or possible causality assessment, according to the Naranjo Algorithm. ADR were considered as expected when labelled (source: www.farmadati.it). Association between drugs and adverse reactions was assessed, calculating the Proportional Reporting Ratio (PRR) as a measure of disproportionality.
Until December 31, 2010 the AIFA database contained 827 reports of suspected ADRs related to the use of GLP-1 based therapies, of which 492 associated with incretin mimetics and 335 with DPP-4 inhibitors. The mean age of these patients was 60,6 years (SD ± 10,4), and 57,4% were women (n=475). Serious ADRs, including three fatal cases, accounted for 8,7% of the total reports attributable to these antidiabetic drugs (72 out of 827). The following drugs were involved: exenatide (470 cases) and liraglutide (22); sitagliptin (150), sitagliptin + metformin (68), vildagliptin (57), vildagliptin + metformin (55), saxagliptin (5). The most frequently reactions reported with GLP-1 mimetics were nausea, vomiting, diarrhea and abdominal pain. Fourteen cases of pancreatitis and seven cases of acute renal failure were signalled in association with exenatide. As regards DPP-4 inhibitors, gastrointestinal tract and skin were the most frequently affected sites. Eight cases of pancreatitis were reported for patients administered sitagliptin + metformin (n=4; PRR 38,3; 95%CI 14,6-100,3), sitagliptin alone (n=2; PRR 8,6; 2,2 34,3) and vildagliptin + metformin (n=2; PRR 23,4; 6,0-92,1). Furthermore several cases of respiratory infections, such as pharingitis, pneumonia, bronchitis, rhinitis were identified. Seven reports of cancer (at other sites than pancreas) were associated with DPP-4 inhibitors and four cases with exenatide.
In conclusion, these data are consistent with case reports and several studies indicating an increased risk for pancreatitis with GLP-1 based therapies. Furthermore, the findings indicate an increased reporting of respiratory infections with DPP-4 inhibitors; few cases of cancer were also reported. Taking into account the limitations of spontaneous reporting systems, further research is needed to evaluate these signals.
Elashoff et al. (2011). Gastroenterology. In press.
Willemen et al. (2011). Diabetes Care. 34:369-74.
Stulc et al. (2010). Diabetes Res Clin Pract. 88:125-31.
Given the observed increased prevalence of T2DM, the potential impact of adverse effects of these classes of drugs is considerable. Because spontaneous reporting is a valuable methodology for better defining the safety profile of drugs after their approval, we examined reported adverse reactions associated with incretin mimetics and DPP-4 inhibitors in the Italian spontaneous reporting system, with the aim to identify their most important features.
We performed an analysis on the database of spontaneous reports of adverse drug reactions (ADRs) managed by the Italian Medicines Agency (AIFA), where all the individual case safety reports are stored since January 2001. We selected and then analysed in detail all the case reports of suspected adverse reactions attributed to incretin mimetics and DPP-4 inhibitors collected from 2008 to 2010. Outcomes of ADRs were evaluated with respect to four different categories: patient recovered with or without sequelae, patient not recovered at the time of the report and death. Seriousness of ADRs were defined in accordance to the ICH E2D guideline. We included in the study only ADR case reports with a probable or possible causality assessment, according to the Naranjo Algorithm. ADR were considered as expected when labelled (source: www.farmadati.it). Association between drugs and adverse reactions was assessed, calculating the Proportional Reporting Ratio (PRR) as a measure of disproportionality.
Until December 31, 2010 the AIFA database contained 827 reports of suspected ADRs related to the use of GLP-1 based therapies, of which 492 associated with incretin mimetics and 335 with DPP-4 inhibitors. The mean age of these patients was 60,6 years (SD ± 10,4), and 57,4% were women (n=475). Serious ADRs, including three fatal cases, accounted for 8,7% of the total reports attributable to these antidiabetic drugs (72 out of 827). The following drugs were involved: exenatide (470 cases) and liraglutide (22); sitagliptin (150), sitagliptin + metformin (68), vildagliptin (57), vildagliptin + metformin (55), saxagliptin (5). The most frequently reactions reported with GLP-1 mimetics were nausea, vomiting, diarrhea and abdominal pain. Fourteen cases of pancreatitis and seven cases of acute renal failure were signalled in association with exenatide. As regards DPP-4 inhibitors, gastrointestinal tract and skin were the most frequently affected sites. Eight cases of pancreatitis were reported for patients administered sitagliptin + metformin (n=4; PRR 38,3; 95%CI 14,6-100,3), sitagliptin alone (n=2; PRR 8,6; 2,2 34,3) and vildagliptin + metformin (n=2; PRR 23,4; 6,0-92,1). Furthermore several cases of respiratory infections, such as pharingitis, pneumonia, bronchitis, rhinitis were identified. Seven reports of cancer (at other sites than pancreas) were associated with DPP-4 inhibitors and four cases with exenatide.
In conclusion, these data are consistent with case reports and several studies indicating an increased risk for pancreatitis with GLP-1 based therapies. Furthermore, the findings indicate an increased reporting of respiratory infections with DPP-4 inhibitors; few cases of cancer were also reported. Taking into account the limitations of spontaneous reporting systems, further research is needed to evaluate these signals.
Elashoff et al. (2011). Gastroenterology. In press.
Willemen et al. (2011). Diabetes Care. 34:369-74.
Stulc et al. (2010). Diabetes Res Clin Pract. 88:125-31.