data were obtained from the international drug monitoring program of the world health organization ( who ) . the who global individual case safety report ( icsr ) database , vigibase , is maintained by the uppsala monitoring centre and contains summaries of suspected spontaneous case reports originally summated by health care professionals and patients to national pharmacovigilance centers in 98 countries worldwide . as of may 2010 , this database contained > 5 million case reports of suspected adrs regarding specific , but anonymous , patients . the reports contain administrative data , patient data , adr data , medication data , and additional information . the information in these reports is not homogenous , at least with regard to origin , completeness of documentation , or the likelihood that the suspected drug caused the adverse events ( 18 ) . adrs are coded according to the adverse reaction terminology ( who - art ) and medical dictionary for regulatory activities ( meddra ; www.who-umc.org ) . this study was designed as a nested case - control study . the base cohort consisted of all adrs associated with the use of any antidiabetic drug ( anatomical therapeutic chemical [ atc ] code a10 ) , including oral antidiabetic drugs and insulins , in the period 1999 through 2009 . infections were defined by means of meddra adverse reaction terms , including all relevant high - level group terms and lower - level terms . all infections from the system organ class ( soc )  infections and infestations  and infections reported in other socs identified through a manual search were defined as cases . we grouped the infections on the first sublevel ( high - level group terms ) of meddra and looked at urti ( e.g. , sinusitis and nasopharyngitis ) , lower respiratory tract infections ( lrti , e.g. , bronchitis and pneumonia ) , and urinary tract infections ( uti ; e.g. , cystitis and pyelonephritis ) . antidiabetic drugs were subclassified based on the anatomical therapeutic chemical ( atc ) classification system of the who ( www.whocc.no ) : biguanides ( atc code a10ba ) , sulfonylurea derivatives ( a10bb ) , thiazolidinediones ( a10bg ) , dpp-4 inhibitors ( a10bh ) , insulins , and analogs ( a10a ) . when multiple antidiabetic drugs were reported for a certain adr , this was classified as combination therapy , irrespective of whether a drug reported was classified as potential confounding factors retrieved from the case reports included age and gender of the patient , reporting year , reporting region ( europe , north america , rest of the world ) , and reporter type , including physician , pharmacist , other caregiver , pharmaceutical company ( indirectly obtained from a health care professional ) , and patient / consumer . concomitant use of medication affecting the immune system , defined as reporting one of these drugs as a concomitant drug for an adr , was taken into account when recorded , including antibiotics ( atc code j01 ) , corticosteroids for systemic use ( h02 ) , and immunosuppressants ( l04 ) . unconditional logistic regression analysis was used to estimate the strength of the association between use of antidiabetic drugs and reporting of infections and expressed as reporting odds ratios ( rors ) with corresponding 95% cis . owing to low numbers , combination therapy was analyzed on an aggregated level , not on an individual drug - drug combination level . we focused on infections in general and more specifically on the high - level group terms urti , lrti , and uti . more adrs were usually reported for one case report , and therefore it was possible that one case report contained more than one adr of an infection . to test the effect of multiple adrs reported in one case report , we analyzed the data on the level of case reports ( one case report generally represented one patient ) . in the u.s . , dpp-4 inhibitors are indicated for monotherapy for the treatment of diabetes mellitus , whereas in the eu , these medicines are only indicated for combination therapies . to check whether this affected the results of this study , we performed a sensitivity analysis by analyzing the data for the u.s . and the rest of the world separately . in addition , to study the effect of the type of reporter ( health care professional or consumer ) on the outcome , we performed a sensitivity analysis in which the reports were assessed according to the type of reporter . data were obtained from the international drug monitoring program of the world health organization ( who ) . the who global individual case safety report ( icsr ) database , vigibase , is maintained by the uppsala monitoring centre and contains summaries of suspected spontaneous case reports originally summated by health care professionals and patients to national pharmacovigilance centers in 98 countries worldwide . as of may 2010 , this database contained > 5 million case reports of suspected adrs regarding specific , but anonymous , patients . the reports contain administrative data , patient data , adr data , medication data , and additional information . the information in these reports is not homogenous , at least with regard to origin , completeness of documentation , or the likelihood that the suspected drug caused the adverse events ( 18 ) . adrs are coded according to the adverse reaction terminology ( who - art ) and medical dictionary for regulatory activities ( meddra ; www.who-umc.org ) . this study was designed as a nested case - control study . the base cohort consisted of all adrs associated with the use of any antidiabetic drug ( anatomical therapeutic chemical [ atc ] code a10 ) , including oral antidiabetic drugs and insulins , in the period 1999 through 2009 . infections were defined by means of meddra adverse reaction terms , including all relevant high - level group terms and lower - level terms . all infections from the system organ class ( soc )  infections and infestations  and infections reported in other socs identified through a manual search were defined as cases . we grouped the infections on the first sublevel ( high - level group terms ) of meddra and looked at urti ( e.g. , sinusitis and nasopharyngitis ) , lower respiratory tract infections ( lrti , e.g. , bronchitis and pneumonia ) , and urinary tract infections ( uti ; e.g. , cystitis and pyelonephritis ) . antidiabetic drugs were subclassified based on the anatomical therapeutic chemical ( atc ) classification system of the who ( www.whocc.no ) : biguanides ( atc code a10ba ) , sulfonylurea derivatives ( a10bb ) , thiazolidinediones ( a10bg ) , dpp-4 inhibitors ( a10bh ) , insulins , and analogs ( a10a ) . when multiple antidiabetic drugs were reported for a certain adr , this was classified as combination therapy , irrespective of whether a drug reported was classified as potential confounding factors retrieved from the case reports included age and gender of the patient , reporting year , reporting region ( europe , north america , rest of the world ) , and reporter type , including physician , pharmacist , other caregiver , pharmaceutical company ( indirectly obtained from a health care professional ) , and patient / consumer . concomitant use of medication affecting the immune system , defined as reporting one of these drugs as a concomitant drug for an adr , was taken into account when recorded , including antibiotics ( atc code j01 ) , corticosteroids for systemic use ( h02 ) , and immunosuppressants ( l04 ) . unconditional logistic regression analysis was used to estimate the strength of the association between use of antidiabetic drugs and reporting of infections and expressed as reporting odds ratios ( rors ) with corresponding 95% cis . owing to low numbers , combination therapy was analyzed on an aggregated level , not on an individual drug - drug combination level . we focused on infections in general and more specifically on the high - level group terms urti , lrti , and uti . more adrs were usually reported for one case report , and therefore it was possible that one case report contained more than one adr of an infection . to test the effect of multiple adrs reported in one case report , we analyzed the data on the level of case reports ( one case report generally represented one patient ) . in the u.s . , dpp-4 inhibitors are indicated for monotherapy for the treatment of diabetes mellitus , whereas in the eu , these medicines are only indicated for combination therapies . to check whether this affected the results of this study , we performed a sensitivity analysis by analyzing the data for the u.s . and the rest of the world separately . in addition , to study the effect of the type of reporter ( health care professional or consumer ) on the outcome , we performed a sensitivity analysis in which the reports were assessed according to the type of reporter . from the who vigibase we identified 305,415 suspected adrs related to the use of antidiabetic drugs in 106,469 case reports in the study period 1999 through 2009 . patients were a mean age of 59.7 years ( sd , 14.3 ) and 59.6% were women . a total of 288,434 reports ( 94.4% ) reports involved one antidiabetic drug , 14,057 ( 4.6% ) reported a combination of two antidiabetic drugs , and 2,924 ( 1.0% ) reported three or more antidiabetic drugs ( table 1 ) . overall , the most commonly reported infections on the level of meddra lower - level terms were pneumonia ( 11.8% ) , nasopharyngitis ( 10.1% ) , utis ( 6.2% ) , infection not otherwise specified ( 5.5% ) , sinusitis ( 5.1% ) , and bronchitis ( 4.8% ) . all other types of infection were reported in < 4.5% of the reports related to infections . baseline characteristics of all spontaneous reports for antidiabetic drugs in the who vigibase ( 19992009 ) all data except patient age are shown as number ( % ) . a total of 242 infections were reported as a meddra term in 212 case reports for dpp-4 inhibitors , of which 188 ( 88.7% ) reported one infection . of the 24 case reports ( 11.3% ) with multiple infections , 12 ( 50% ) reported a nonspecific infection term , such as  infection  or urti ,  combined with a more specific infection term , such as  nasopharyngitis  or  cystitis  ( see the supplementary data for a summary of the infections according to the meddra lower - level term ) . table 2 reports the rors of infections ( overall ) per antidiabetic drug compared with biguanides . the use of dpp-4 inhibitors as monotherapy ( ror 2.3 [ 95% ci 1.92.7 ] ) , insulins as monotherapy ( ror 1.6 [ 95% ci 1.41.8 ] ) , and the combination of any oral antidiabetic drug and insulin therapy ( ror 1.8 [ 95% ci 1.32.4 ] ) were all statistically significant associated with adr reports of infections compared with biguanides . a slightly increased reporting of infections for patients using thiazolidinediones was found ( ror 1.2 [ 95% ci 1.11.4 ] ) , but no increased reporting of infections was found for sulfonylurea derivatives ( ror 1.2 [ 95% ci 1.01.4 ] ) , combination therapy of two oral antidiabetic drugs ( ror 1.0 [ 95%ci 0.81.2 ] ) , or for concomitant use of three or more antidiabetic drugs ( ror 1.0 [ 95% ci 0.71.4 ] ) . adjustment for the potential confounding factors did not affect the results . crude and adjusted rors for any infection ads , antidiabetic drugs ; dpp-4 i , dipeptidyl peptidase inhibitors ; oad , oral antidiabetic drug ; su , sulfonylurea ; tzd , thiazolidinediones . * adjusted for age , sex , reporting year , reporting region , reporter type , and comedication affecting the immune system : antibiotics ( j01 ) , corticosteroids for systemic use ( h02 ) , and immunosuppressants ( l04 ) . assessment of different types of infections ( table 3 ) showed an increased reporting of urti ( ror 12.3 [ 95% ci 8.617.5 ] ) for the dpp-4 inhibitors , whereas the reporting for lrti , uti , and other infections was not increased . in addition , an increased reporting of urti was found for users of thiazolidinediones ( ror 2.3 [ 95% ci 1.73.3 ] ) , and for concomitant use of three or more antidiabetic drugs ( ror 2.5 [ 95% ci 1.34.7 ] ) . slightly increased rors were found for the use of insulin monotherapy and the reporting of urti ( ror 1.5 [ 95% ci 1.12.2 ] ) and uti ( ror 1.7 [ 95% ci 1.12.5 ] ) . the reporting of lrti ( ror 1.8 [ 95% ci 1.42.3 ] ) and other infections ( ror 1.7 [ 95% ci 1.42.0 ] ) was also increased for insulin monotherapy . for the combination of an oral antidiabetic drug and insulin , increased reporting of uti ( ror 3.5 [ 95% ci 1.77.2 ] ) and other infections ( ror 1.7 [ 95% ci 1.12.6 ] ) was noted . crude rors for specific infections ads , antidiabetic drugs ; dpp-4 i , dipeptidyl peptidase inhibitors ; oad , oral antidiabetic drug ; su , sulfonylurea ; tzds , thiazolidinediones . the crude ror was lower for dpp-4 inhibitors but was still significantly increased ( ror 1.6 [ 95% ci 1.31.9 ] ) in the analysis of the data on the level of case reports . the sensitivity analyses showed that the country from which the case reports originates and the type of reporter did not have a major effect on the results ( data not shown ) . the point estimates changed only slightly , but because of the decreased numbers the confidence intervals became wider this study showed that infections were approximately two times more frequently reported for dpp-4 inhibitors compared with biguanides in the who vigibase . in particular , urtis , including nasopharyngitis and sinusitis , were reported more frequently for dpp-4 inhibitors , although the reporting of urti was also increased for users of thiazolidinediones , insulin monotherapy , and concomitant use of three or more antidiabetic drugs , but to a much lesser extent than for the dpp-4 inhibitors . a hypothesis resulting from the current study is that the effect of dpp-4 inhibitors results in a slight imbalance of the immune system that causes an increased risk of common , less severe infections such as ( viral ) upper respiratory infections . this is supported by the results of the pivotal randomized clinical trials that also reported increased numbers of common infections rather than serious infections ( 13 ) . as far as we are aware , no studies reporting serious infections in association with the use of dpp-4 inhibitors , the magnitude of the effects of dpp-4 inhibitors on the immune system may not be compared with the magnitude of the effects as seen , for example , with biologic agents , resulting in rather serious infections such as tuberculosis or histoplasmosis due to tumor necrosis factor- antagonists ( 19,20 ) . with the current data , however , it was not possible to further differentiate between infections of different nature and viral , bacterial , or fungal causes . the strength of this study is that the who vigibase allows studying the association between use of antidiabetic drugs and infections outside the highly controlled environment of clinical trials . nevertheless , some limitations of this study need to be addressed : first , besides the known issue of underreporting in spontaneous reporting systems ( 21 ) , the reporting pattern of adrs may differ between new and old drugs , with the most vigorous monitoring at the time of marketing and shortly thereafter , as described by weber ( 21 ) . the dpp-4 inhibitors and thiazolidinediones were introduced in the study period ( 1999 through 2009 ) , which might explain the relatively large number of reports for those drugs . however , it is unknown whether the type of adrs that are reported changes over time and how this affects the results of this study . nonetheless , second , the results of this study may be subject to reporting bias , because infections are listed in both the eu and u.s . this may have led to differential monitoring and reporting of infections for the dpp-4 inhibitors compared with other antidiabetic drugs . increased reporting ( physicians report adrs that are likely to occur ) or decreased reporting ( physicians do not report adrs that are already mentioned in summaries of product characteristics ) might have occurred . in absolute terms , the number of reported infections is low : only 3% of the cases for dpp-4 inhibitors reports involved an infection ( 242 reports of infection of 8,083 case reports ) . furthermore , differences in classification strategies or misclassification may have occurred by the translation from clinical terminology to the classification systems used by the who vigibase ( who - art or meddra terms ) . we do not expect , however , that this misclassification is different for different antidiabetic medicines , and the effect of this nondifferential misclassification on the results of this study will therefore be limited . in several case reports , more than one infection term was recorded , mainly consisting of a specific infection term ( e.g. , nasopharyngitis ) and an a - specific term ( e.g. , urti ) , which might influence the results . however , our analysis at the case - report level showed that the overall results did not change . unfortunately , we were not able to analyze the risk of infections for combination therapy on an individual drug - drug combination level owing to the low number of cases reporting each possible combination therapy . finally , we reasoned that the different indications for the dpp-4 inhibitors in the u.s . versus the rest of the world , and a possible effect of the type of reporter ( health care professional , consumer , or industry ) on the case reports , might have influenced the results of this study . however , excluding reports from the u.s . and excluding reporting from consumers and industry did not affect the results . another explanation for our results can be that diabetes itself , and its progression , are often associated with an increased risk of infections . although the literature is not yet conclusive on this , we could not exclude this possible association ; therefore , the current study was limited to case reports of antidiabetic medicines only , thereby eliminating the effect of the disease itself . some studies , however , suggest that more severe diabetes itself is also associated with higher risk of infections ( 14,22 ) , although this is not supported by strong evidence . because disease severity is therefore possibly associated with both exposure and outcome , this can be a confounding factor . dpp-4 inhibitors are indicated as a second- or third - line therapy in combination with other oral antidiabetic drugs according to treatment guidelines in different parts of the world ( 23,24 ) . therefore , patients who are treated with dpp-4 inhibitors may in general be more severely ill compared with patients being treated with , for example , biguanides or sulfonylurea derivatives . in the current study , however , most of the case reports indicated a dpp-4 inhibitor was the only antidiabetic drug , which indicates monotherapy with dpp-4 inhibitors . a question prompted by this study is whether the patients treated with dpp-4 inhibitors monotherapy were indeed the more severely ill patients , because one antidiabetic drug was sufficient for these patients . in addition , for users of a combination of an oral antidiabetic and insulin or combination therapy of two antidiabetics ( i.e. , usually the more severely ill patients ) , we did not found an increased risk of infections . this is in line with the studies that did not find an association between diabetes mellitus and infection . besides infections in general , the association between diabetes and uti has also been described ( 12,14,15,22 ) , although we did not find significantly increased reporting of adrs for utis and use of any of the antidiabetic drugs . only for combination therapy of an oral antidiabetic and insulin did we find a slightly increased reporting for uti . channeling of this combination therapy toward the more severely ill diabetes patients , for which the use of insulin combined with an oral antidiabetic drug is a marker ( 25 ) , may possibly explain this finding . this is in line with studies suggesting that the severity of the disease may play a role in the occurrence of uti ( 14,22 ) . unfortunately , the subset of the vigibase used in this study did not contain information on the severity of the underlying disease , so the effect of this phenomenon in the current study remains unclear . postmarketing evaluation of safety concerns raised during the preregistration phase of medicines is import for the assessment of the benefit - risk balance of drugs . this study adds to the knowledge of this specific safety issue for the dpp-4 inhibitors . the results of the study , using data reported to national pharmacovigilance centres , are in line with the findings from the clinical trial program that included a much more selected patient population . however , more research is needed to further evaluate the clinical and regulatory consequences of this finding , such as severity of the infections . as a result of the observed increased risk in rcts , the risk management plans for dpp-4 inhibitors also address a possible increased risk of infections . the definition of the outcome (  infection  ) in the postauthorization safety studies that are being conducted as part of the risk management plans is , therefore , of particular importance . because our study points out that several types of infections ( urtis such as sinusitis and nasopharyngitis ) are more frequently reported than others , the outcome should not be limited to infections in general but should also take specific types of infections into account . in addition , the nonserious infections seem to be neglected in the postauthorization safety studies because all studies aim to investigate the risk of serious infections ( 13 ) . although from a regulatory viewport the focus on serious infections is understandable , the effect of ( recurrent ) nonserious infections on the quality of life can also be considerable . in conclusion , the results of this study show that there is an increased reporting of infections for users of dpp-4 inhibitors compared with users of other antidiabetic drugs . although the limitations of spontaneous reporting systems ( e.g. , underreporting , the weber -effect , reporting bias ) should be taken into account , physicians and patients nevertheless should remain vigilant on the occurrence of infections and continue to report infections as possible adrs . infections may be related to diabetes , but a direct effect of the medication on the occurrence of infections should be considered .