Delayed gastric emptying associated with pharmacologic levels of intact GLP-1 has been associated with increased incidences of GI-related adverse experiences such as nausea and vomiting 3. Since sitagliptin increases intact GLP-1 and GIP levels by 2- to 3-fold 218, certain GI adverse experiences were pre-specified for statistical analysis (including diarrhea, nausea, vomiting and abdominal pain [including upper and lower abdominal pain and abdominal/stomach discomfort]) in the sitagliptin development program. Further, since cases of pancreatitis have been reported in association with treatment with a GLP-1 analogue 1920, this GI adverse experience was also of interest in this pooled analysis.

The DPP-4 enzyme (also referred to as the protein CD26) is expressed on activated T cells, and, although the role of DPP-4 enzyme activity in T cell function is not clear, it is unlikely related to the co-stimulatory function of CD26 2122. Animals genetically deficient in CD26 are healthy and fertile without an evident increase in infections 23, and immune function as well as lymph nodes, spleen, and bone marrow in animals treated with a selective DPP-4 inhibitor appear normal 2425. Further, in vitro proliferation of human peripheral blood monocytes is unaffected by selective DPP-4 inhibition 24. Given the possibility of immune alteration with DPP-4 inhibition, however, adverse experiences in the "Infection and Infestation" SOC were specifically reviewed in the present report.

Serious hypersensitivity reactions, including Stevens-Johnson syndrome, have been reported with the use of sitagliptin in the postmarketing environment 16. While the causal relationship between sitagliptin and such adverse experiences voluntarily reported from a population of unknown size cannot be definitively established, skin-related adverse experiences were examined in the present pooled analysis. Skin-related findings are also of interest, as preclinical administration of some DPP-4 inhibitors other than sitagliptin (e.g., vildagliptin and PHX1149) 2627 had been associated with dose-dependent necrotic skin lesions when administered to monkeys. These preclinical findings have not been observed when sitagliptin was administered to monkeys 28, and an increased incidence of skin findings consistent with the preclinical lesions has not been reported in patients in controlled clinical studies with DPP-4 inhibitors, including studies with sitagliptin, vildagliptin, alogliptin, and saxagliptin.

It has been theorized that DPP-4 inhibition could lead to increased events of angioedema, particularly in patients concomitantly treated with angiotensin-converting enzyme (ACE) inhibitors (another class of agents with peptidase activity) 29. Therefore, a potential association between ACE inhibitor use and the incidence of angioedema-related events (see Appendix I for list of events considered angioedema-related) was evaluated. For this analysis, angioedema-related events were evaluated for the periods with and without exposure to an ACE inhibitor. Exposure to an ACE inhibitor was defined as the total days of ACE inhibitor use during the double-blind treatment period. Patients contributed to patient-years of exposure to an ACE inhibitor for the actual period of time that they were reported to have been taking an ACE inhibitor and to patient-years of non-exposure for the actual period of time that they were reported not to have been taking an ACE inhibitor. Data were expressed as event rates for both incident angioedema-related events (all first events of angioedema) and total angioedema-related events (all events, including those occurring more than once for the same patient) per 100 patient-years of exposure.

Patients with type 2 diabetes are at increased risk for cardiovascular morbidity and mortality 30. Recently, there has been increased focus on treatments for diabetes and cardiovascular risk. Therefore, the between-group differences in incidence rates of cardiac (e.g., all cardiac-related adverse experiences, including ischemic and non-ischemic events) and ischemia-related adverse experiences were evaluated in this pooled analysis. This analysis presents adverse experience terms as reported by the investigator; terms for ischemia-related events reported for these studies are found in Appendix II. No formal adjudication was performed.

In this pooled analysis, there were 6139 patients overall, with 3415 in the sitagliptin 100-mg group and 2724 in the non-exposed group. At baseline, patients in the total cohort had an average age of 55 years (range: 19 to 87 years), a mean duration of diabetes of 5.5 years, and a mean A1C of 8.2%. Men comprised 55% of this cohort and the racial/ethnic breakdown was 57.4% White, 16.2% Asian, 15.2% Hispanic, 5.6% Black, and 5.6% "Other". There were no meaningful differences between treatment groups in these baseline characteristics or in the frequency or type of other medical conditions or medications used.

The mean exposure to drug and total patient-years in study were slightly greater in the sitagliptin group relative to the non-exposed group: 307.3 dosing days (range = 1 to 792) relative to 293.6 dosing days (1 to 801), respectively. In the sitagliptin group, 1343 patients were treated for at least 1 year, with 356 of these patients treated for 2 years. The corresponding numbers of patients in the non-exposed group were 981 and 290. The total duration of observation in study was 2994 patient-years for the sitagliptin group relative to 2270 patient-years for the non-exposed group. In these studies up to 2 years in duration, the proportions of patients discontinuing treatment overall were 34.9% in the sitagliptin group and 39.5% in the non-exposed group, with the reasons for discontinuations generally similar between groups (Table 2).

The following sections report the results from the primary safety analysis. The findings from the primary safety analysis (excluding data after glycemic rescue therapy) were generally consistent with those that included data after rescue therapy and with those examining the event rates per 100 patient-years (data not shown).

Summary measures of the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups (Table 3). Drug-related adverse experiences and discontinuations due to drug-related adverse experiences were higher in non-exposed patients, primarily due to hypoglycemia in sulfonylurea-treated patients. In a few SOCs, there were small differences in the incidence rates of adverse experiences (Table 4). For the "Blood and Lymphatic System Disorders" SOC, a slightly higher incidence rate of the adverse experience of anemia in the sitagliptin group compared to the non-exposed group (0.4% vs. 0.1%, respectively; between-group difference [95% CI] = 0.3% [-0.0, 0.6]) accounted for a majority of the between-group difference. The between-group difference in incidence rate in the "Metabolism and Nutrition Disorders" SOC was primarily due to a higher incidence rate of hypoglycemia in the non-exposed group (10.9%) (primarily seen in sulfonylurea-treated patients) relative to the sitagliptin group (3.4%) (Table 5). For the "Investigations" SOC, 3 adverse experiences (blood glucose increased, blood glucose decreased, and weight increased) accounted for the higher incidence rate in the non-exposed group relative to the sitagliptin group (Table 6).

The most commonly reported adverse experiences in either group were hypoglycemia, upper respiratory tract infection, and nasopharyngitis (Table 6). Of these events, only nasopharyngitis occurred more frequently in the sitagliptin group, although the 95% CI around the between-group difference included 0 (between-group difference [95% CI] = 1.2% [-0.1, 2.4]. For specific clinical adverse experiences reported more frequently in a treatment group and for which the 95% CI around the between-group difference excluded 0, there were 7 specific adverse experiences that were higher in the sitagliptin group and 11 that were higher in the non-exposed group (Table 5). The largest between-group difference (7.4%) was observed for the adverse experience of hypoglycemia, which occurred at a higher incidence rate in the non-exposed group; otherwise the between-group differences in incidence rates were small (< 1%; Table 5). In the development program for sitagliptin, an episode of hypoglycemia was defined as an episode with symptoms of hypoglycemia assessed by the investigator as a clinical adverse experience of hypoglycemia based upon review of the patient's hypoglycemia log. Incidence rates of hypoglycemia were based upon all reports of hypoglycemia; a concurrent fingerstick glucose was not required. The incidence rates of hypoglycemia were driven largely by the use of a sulfonylurea as a comparator agent or as background therapy. Of the 296 patients in the non-exposed group having at least one episode of hypoglycemia, 239 (81%) had an episode while treated with a sulfonylurea. For the patients not treated with a sulfonylurea, the incidence rates for hypoglycemia were 2.6% (n/N: 87/3298) and 2.3% (50/2428) in the sitagliptin and non-exposed groups, respectively. The incidence rates of specific clinical adverse experiences occurring in at least 1% of patients in either group are listed in Table 6.

The incidence rate of drug-related clinical adverse experiences overall was higher in the non-exposed group (17.7%) compared with the sitagliptin group (12.9%), primarily due to reports of hypoglycemia and blood glucose decreased. Drug-related adverse experiences that occurred at an incidence rate of at least 0.5% in either group are listed in Table 7.

The incidence rate of serious clinical adverse experiences overall was approximately 7% in each treatment group. A review of specific serious clinical adverse experiences irrespective of the relationship to study drug that occurred at an incidence rate of at least 0.2% did not reveal any notable between-group differences (Table 8).

The incidence rates of GI adverse experiences did not meaningfully differ between groups (Tables 4, 5, 6). For the pre-specified GI adverse experiences (diarrhea, nausea, vomiting and abdominal pain [including upper and lower abdominal pain and abdominal/stomach discomfort]), the incidence rates were generally similar between groups (Table 6). In the sitagliptin and non-exposed groups, the incidence rates of pancreatitis (0.1% and 0%, respectively), acute pancreatitis (0% and 0.1%, respectively) and chronic pancreatitis (0.1% and 0%, respectively) were low and not meaningfully different between the groups.

The overall incidence rates and intensity of adverse experiences of infection were similar in the two treatment groups, as, in general, were the frequencies and particular types of infections reported (Table 4 and Table 6). Further, the incidence rates of adverse experiences of infection that were reported as serious or that led to discontinuation were similar between groups. In addition, there was no evident increase in the frequency of specific types of infections suggestive of immune suppression (e.g., herpes zoster) between groups. As noted above, the incidence rate of the adverse experience of nasopharyngitis was slightly higher in the sitagliptin group, but in both treatment groups the events were generally mild in intensity and similar in duration, generally occurring as isolated events and after similar time periods following study initiation, and did not recur more frequently in patients in the sitagliptin group relative to those in the non-exposed group.

The overall incidence rate of adverse experiences in the "Skin and Subcutaneous Tissue Disorders" SOC was not meaningfully different between groups (Table 4). Two adverse experiences (acne and contact dermatitis [with approximately half of the events being "poison ivy/oak"]) were reported more frequently in the sitagliptin group compared with the non-exposed group, whereas hyperkeratosis was reported more frequently in the non-exposed group (Table 5). Rash was the only skin-related adverse experience reported by at least 1% of the patients in either group (Table 6), with an incidence rate of 1.0% in the sitagliptin group and 0.9% in the non-exposed group. No adverse experiences of Stevens-Johnson syndrome were reported in patients in the clinical trials that were pooled for this report; one event of erythema multiforme was reported for a patient in the non-exposed group. No adverse experiences consistent with the lesions observed during the preclinical development of some other (non-sitagliptin) DPP-4 inhibitors were reported.

For the analysis of angioedema-related events and the relationship of these events to concurrent treatment with ACE inhibitors, approximately 33% of patients were on an ACE inhibitor at baseline and approximately 36% were on an ACE inhibitor at any time during the studies (for a total of 1,023 and 779 patient-years on an ACE inhibitor for the sitagliptin and non-exposed groups, respectively). Among the 6139 patients included in this pooled analysis, there were 54 incident angioedema-related events, 16 of which occurred in patients concurrently taking an ACE inhibitor. The number of incident angioedema-related events per 100 patient-years while a patient was on an ACE inhibitor was the same (0.9) in both groups. The total numbers of angioedema-related events per 100 patient-years while a patient was on an ACE inhibitor were also similar in the sitagliptin (1.1) and non-exposed (0.9) groups. For patients not on an ACE inhibitor, the numbers of incident angioedema-related events per 100 patient-years were 1.1 in the sitagliptin group and 1.3 in the non-exposed group.

The incidence rates of overall and serious adverse experiences in the "Cardiac Disorders" SOC were similar between groups (Table 4), with the overall incidence rates of serious adverse experiences in this SOC being 1.2% in the sitagliptin group and 1.5% in the non-exposed group (between-group difference [95% CI] = -0.3% [-1.0, 0.3]). In an analysis in which ischemia-related adverse experiences overall were assessed, the incidence rates were 2.0% in the sitagliptin group and 2.3% in the non-exposed group (between-group difference [95% CI] = -0.2% [-1.0, 0.5]). For the serious ischemia-related adverse experiences, the incidence rates were 1.1% in the sitagliptin group and 1.5% in the non-exposed group (between-group difference [95% CI] = -0.4% [-1.0, 0.2]). There were 3 patients (0.09%) in the sitagliptin group (2 with ischemic stroke and 1 with myocardial infarction) with a fatal ischemic event compared with 7 patients (0.26%) in the non-exposed group (4 with myocardial infarction, 1 with myocardial ischemia, and 2 with sudden cardiac death).

Summary measures of the incidence rates of laboratory adverse experiences overall, serious laboratory adverse experiences, and discontinuations due to laboratory adverse experiences were similar in the two groups (Table 9). There were no meaningful between-group differences in the number of laboratory adverse experiences reported with an incidence rate of at least 1% (Table 10). For hepatic transaminases, the proportions of patients in the sitagliptin and non-exposed groups with their last measurement (obtained either at time of discontinuation or at the final scheduled study visit) of ALT > 3 times the upper limit of normal (3xULN) were 0.7% and 0.8%, respectively; the proportions with last AST measurement > 3xULN were 0.4% and 0.2%, respectively. The number of patients meeting the definition of Hy's Rule (i.e., an ALT and/or AST measurement > 3xULN and a bilirubin > 2xULN) at any time during the study was 2 in the sitagliptin group (with both cases resolving while continuing treatment; 1 patient had suspected concurrent bacteremia and a history of steatohepatitis, and the other had elevated ALT/AST and alkaline phosphatase prior to randomization) and 1 in the non-exposed group (in a patient with concurrent diagnosis of a liver abscess).