# Abstract

 

## Introduction In a previous pooled analysis of 19 double-blind clinical studies conducted by Merck, which included data available as of July 2009 on 10,246 patients with type 2 diabetes (T2DM), treatment with sitagliptin was shown to be generally well tolerated compared with treatment with control agents. As the sitagliptin clinical development program continues, additional studies with sitagliptin have been completed. The present analysis updates the safety and tolerability assessment of sitagliptin by examining pooled data from 25 double-blind clinical studies. 

## Methods The present analysis included data from 14,611 patients in 25 studies with T2DM who received either sitagliptin 100 mg/day (*n* = 7,726; sitagliptin group) or a comparator agent (*n* = 6,885; non-exposed group). These studies represent all randomized, double-blind trials conducted by Merck that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years, and for which results were available as of December 2011. These studies assessed sitagliptin, versus comparator agents, taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or metformin + pioglitazone or rosiglitazone). Patient-level data from each study were used to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events (AEs). 

## Results Overall incidence rates of AEs and drug-related AEs were higher in the non-exposed group compared with the sitagliptin group. Incidence rates of specific AEs were generally similar between the two groups, except for higher incidence rates of hypoglycemia related to the greater use of a sulfonylurea and diarrhea related to the greater use of metformin in the non-exposed group, and of constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events, malignancy, or pancreatitis. 

## Conclusion In this updated pooled safety analysis of data from 14,611 patients with T2DM, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration. # Results 

## Patient Characteristics and Exposure In the entire 25-study cohort, patients (55% male) had an mean age of 54 years (range 19--91 years; 17% ≥65 years), a mean duration of diabetes of 5.1 years, and a mean glycosylated hemoglobin (HbA1c) of 8.4% at baseline (with 29% of patients having a baseline HbA1c ≥9.0%) (Table [1](#)). The majority of patients were White (61%), with 18% Asian and 6% Black. At baseline, 10% of patients had a history of cardiovascular disease, and 81% had additional cardiovascular risk factors besides type 2 diabetes mellitus and cardiovascular disease, including hypertension (53%), history of dyslipidemia/hypercholesterolemia (49%), and history of smoking (39%). There were no meaningful differences between groups in these baseline characteristics. ::::table-wrap

::: caption
Baseline characteristics
:::

Characteristic Sitagliptin (*n* = 7,726) Non-exposed (*n* = 6,885) Total (*n* = 14,611)

______________________________________________________________________

Gender, *n* (%)\
Male 4,196 (54) 3,788 (55) 7,984 (54.6)
Age, years 54.0 ± 10.3 54.4 ± 10.5 54.2 ± 10.4
Race, *n* (%)\
White 4,674 (60) 4,227 (61) 8,901 (61)
Black 427 (6) 384 (6) 811 (6)
Asian 1,436 (19) 1,227 (18) 2,663 (18)
Multiracial 462 (6) 427 (6) 889 (6)
Other or unknown 727 (9) 620 (9) 1,347 (9)
Body weight, kg 85.0 ± 19.6 85.8 ± 20.1 85.3 ± 19.8
Body mass index, kg/m^2^ 30.5 ± 5.7 30.7 ± 5.8 30.6 ± 5.7
HbA~1c~, % 8.4 ± 1.3 8.4 ± 1.3 8.4 ± 1.3
Duration of T2DM^a^, years 5.1 ± 5.4 5.1 ± 5.3 5.1 ± 5.4
On antihyperglycemic therapy, *n* (%) 3,001 (38.8) 2,773 (40.3) 5,774 (39.5)
History of CVD, *n* (%) 793 (10) 691 (10) 1,484 (10)
Patients with known CV risk factors other than T2DM and history of CVD, *n* (%)^b^ 5,828 (81) 5,269 (82) 11,097 (81)
History of dyslipidemia, *n* (%) 3,862 (50) 3,356 (49) 7,218 (49)
History of hypertension, *n* (%) 4,110 (53) 3,666 (53) 7,776 (53)
History of smoking, *n* (%)^b^ 2,712 (38) 2,539 (39) 5,251 (39)

Data are expressed as mean (± standard deviation) or frequency \[*n*
(%)\], unless otherwise indicated

*CV* cardiovascular, *CVD* cardiovascular disease, *HbA1c* glycosylated
hemoglobin, *T2DM* type 2 diabetes mellitus

^a^Excludes 16 patients (11 sitagliptin, 5 non-exposed) with unknown
duration of diabetes

^b^Denominator is 7,177 for sitagliptin group and 6,451 for non-exposed
group because history of smoking was not collected in all patients from
Protocols 010, 014 and 074, and 11 patients from other studies did not
provide information on smoking history:::: The mean exposure to study drug was slightly greater in the sitagliptin group relative to the non-exposed group: 284 dosing days (range 1--791) and 264 dosing days (range 1--801), respectively. In the sitagliptin group, 2,457 (32%) patients were treated for at least 1 year, with 584 (8%) of these patients treated for 2 years; the corresponding numbers of patients in the non-exposed group were 1,775 (26%) and 470 (7%). The proportions of patients discontinuing treatment were 27.2% in the sitagliptin group and 28.8% in the non-exposed group. 

## Summary Measures of Adverse Events The incidence rate of patients reporting one or more adverse events was higher in the non-exposed group compared with the sitagliptin group (Table [2](#)). The incidence rate of drug-related adverse events was also higher in the non-exposed group, as was the incidence of patient discontinuations due to a drug-related adverse event; this was primarily due to the greater incidence rate of adverse events of drug-related hypoglycemia reported for the non-exposed group (data not shown). The incidence of serious adverse events was similar for the two groups, both overall (Table [2](#)) and by SOC category (data not shown). The incidence of adverse events resulting in death, overall, was similar in the two treatment groups; for the Neoplasms SOC, however, the incidence of adverse events resulting in death was lower in the sitagliptin group compared with the non-exposed group (one event in 6,388 patient-years of follow-up compared with six events in 5,378 patient-years of follow-up, respectively, with a difference in rates of −0.1 events per 100-patient-years (95% CI −0.2, −0.0). ::::table-wrap
::: caption
Adverse event summary
:::

```
                                                              Incidence rate per 100 patient-years^a^                                                                
```

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Sitagliptin Non-exposed Difference between sitagliptin and non-exposed (95% CI)^b^\
≥1 adverse events 142.8 151.1 −7.6 (−13.9, −1.3)
With one or more drug-related^c^ adverse events 19.1 25.5 −5.9 (−7.8, −4.1)
With one or more serious adverse events 7.3 6.9 0.4 (−0.6, 1.4)
With one or more serious drug-related^c^ adverse events 0.4 0.2 0.1 (−0.1, 0.4)
Deaths 0.3 0.4 −0.1 (−0.4, 0.1)
Discontinuations due to adverse events 4.5 4.9 −0.5 (−1.3, 0.3)
Discontinuations due to drug-related^c^ adverse event 1.6 2.2 −0.5 (−1.0, −0.0)
Discontinuations due to serious adverse event 1.7 1.4 0.2 (−0.2, 0.7)
Discontinuations due to serious drug-related^c^ adverse event 0.2 0.1 0.1 (−0.0, 0.3)

^a^100 × (number of patients with ≥1 event/patient-years of follow-up
time)

^b^Between-group difference and 95% CI based on stratified analysis.
Positive differences indicate that the incidence rate for the
sitagliptin group is higher than the incidence rate for the non-exposed
group. "−0.0" represents rounding of values that were slightly less than
zero

^c^As determined by the investigator:::: Incidence rates for adverse events in each SOC are in Table [3](#). There were three SOCs (Metabolism and nutrition disorders; Neoplasms benign, malignant, and unspecified; and Skin and subcutaneous tissue disorders) for which the 95% CI for the between-group difference in incidence rates excluded 0. The between-group difference in the incidence rates of adverse events in the Metabolism and nutrition disorders SOC was primarily due to a higher incidence rate of hypoglycemia in the non-exposed group. The between-group difference in the Neoplasms benign, malignant, and unspecified SOC was related to a higher incidence rate in the sitagliptin group for non-malignant adverse events within the Neoplasms benign, malignant, and unspecified SOC, and was not the result of an imbalance in any single adverse event or any group of biologically related adverse events. The incidence rates of malignancy were similar for the two groups: 0.90 per 100 patient-years in the sitagliptin group and 0.93 per 100 patient-years in the non-exposed group [between-group difference of −0.05 (95% CI −0.41, 0.30)]. For the Skin and subcutaneous disorders SOC, the three most common adverse events were rash, pruritus, and urticaria; the 95% CI included zero for all three of these adverse events. ::::table-wrap
::: caption
Summary of adverse event system organ classes
:::

System organ class Incidence rate per 100 patient-years^a^

______________________________________________________________________

Sitagliptin 100 mg Non-exposed Difference between sitagliptin and non-exposed (95% CI)^b^\
Blood and lymphatic system disorders 1.2 0.9 0.2 (−0.1, 0.6)
Cardiac disorders 3.7 3.8 −0.2 (−0.9, 0.5)
Congenital, familial, and genetic disorders 0.2 0.2 −0.0 (−0.2, 0.1)
Ear and labyrinth disorders 1.6 1.9 −0.4 (−0.9, 0.1)
Endocrine disorders 0.3 0.4 −0.2 (−0.4, 0.0)
Eye disorders 3.8 3.9 −0.1 (−0.9, 0.6)
Gastrointestinal disorders 24.3 24.6 0.3 (−1.7, 2.3)
General disorders and administration site conditions 8.3 9.2 −0.9 (−2.1, 0.2)
Hepatobiliary disorders 1.2 0.9 0.2 (−0.1, 0.6)
Immune system disorders 0.9 0.9 −0.1 (−0.4, 0.3)
Infections and infestations 45.5 45.7 0.3 (−2.5, 3.1)
Injury, poisoning and procedural complications 8.8 8.8 0.3 (−0.9, 1.4)
Investigations 14.0 14.9 −1.3 (−2.7, 0.2)
Metabolism and nutrition disorders 11.1 17.5 −6.4 (−7.9, −4.9)
Musculoskeletal and connective tissue disorders 19.3 18.5 0.7 (−1.0, 2.4)
Neoplasms benign, malignant and unspecified 2.0 1.5 0.6 (−0.0, 1.2)
Nervous system disorders 15.1 14.7 0.3 (−1.1, 1.8)
Pregnancy, puerperium, and perinatal conditions 0.0 0.1 −0.0 (−0.1, 0.1)
Psychiatric disorders 4.3 4.5 −0.1 (−0.9, 0.6)
Renal and urinary disorders 2.8 2.6 0.1 (−0.5, 0.7)
Reproductive system and breast disorders 2.6 2.8 −0.2 (−0.8, 0.4)
Respiratory, thoracic and mediastinal disorders 7.9 8.0 −0.1 (−1.2, 0.9)
Skin and subcutaneous tissue disorders 7.8 6.7 1.1 (0.1, 2.1)
Social circumstances 0.0 0.0 −0.0^c^
Surgical and medical procedures 0.0 0.0 0.0^c^
Vascular disorders 5.4 5.3 −0.1 (−1.0, 0.7)

*SOC* system organ class

^a^100 × (number of patients with ≥1 event in the SOC/patient-years of
follow-up time)

^b^Between-group difference and 95% CI based on stratified analysis.
Positive differences indicate that the incidence rate for the
sitagliptin group is higher than the incidence rate for the non-exposed
group. "0.0" and "−0.0" represent rounding for values that are slightly
greater and slightly less than zero, respectively

^c^95% CI were not computed for events that occurred in fewer than four
patients in both groups, because the CI would necessarily have included
0:::: 

## Adverse Events of Interest 

### Hypoglycemia The incidence rates of hypoglycemia were based on symptomatic reports of hypoglycemia, regardless of a concurrent glucose measurement. The predefined analysis for hypoglycemia (i.e., excluding data after initiation of glycemic rescue therapy) showed a between-group difference of −6.2 events per 100 patient-years (95% CI −7.6, −5.0), favoring the sitagliptin group. The difference observed for hypoglycemia was mainly due to the use of a sulfonylurea as a comparator agent in three studies of up to 2 years in duration, as well as a study in which patients were switched from placebo to a sulfonylurea during a double-blind continuation period (P020 in Table [6](#) in Appendix). Results from some individual studies included in this pooled analysis (in which sitagliptin was added to either a sulfonylurea with or without metformin or to insulin with or without metformin) demonstrated an increased risk for hypoglycemia with sitagliptin used in combination with these agents relative to placebo. In a separate pooled analysis of hypoglycemia in which confounding effects of a sulfonylurea or insulin as either background or comparator therapies were removed, the incidence rates of hypoglycemia were 5.6 and 5.1 per 100 patient-years in the sitagliptin (*n* = 5,956) and non-exposed (*n* = 5,122) groups, respectively, with a between-group difference of 0.5 events per 100 patient-years (95% CI −0.7, 1.6). 

### GI Symptoms The primary analysis of select GI adverse events demonstrated similar incidence rates for the pooled select GI terms, the composite of abdominal pain terms, nausea, and vomiting (Table [4](#)). The incidence rate of the adverse event of constipation was higher in the sitagliptin group (2.3) than in the non-exposed group (1.8). For the specific adverse event of diarrhea, a lower incidence was observed in the sitagliptin group. The differences observed for diarrhea mainly reflected the use of metformin as a comparator; when the confounding effects of initiation of metformin were removed, the incidence rates were 4.3 and 4.9 per 100 patient-years in the sitagliptin (*n* = 5,940) and non-exposed (*n* = 5,122) groups, respectively. ::::table-wrap
::: caption
Summary of composite adverse events/adverse events of interest
:::

System organ class Incidence rate per 100 patient-years^a^

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Sitagliptin 100 mg Non-exposed Difference between sitagliptin and non-exposed (95% CI)^b^\
Acute renal failure (narrow SMQ) 0.2 0.1 0.0 (−0.1, 0.2)
Acute renal failure (broad SMQ) 2.1 1.6 0.4 (−0.1, 0.9)
Atrial fibrillation/flutter 0.4 0.2 0.2 (−0.0, 0.4)
Bronchitis 4.0 3.5 0.5 (−0.2, 1.2)
Gastrointestinal adverse event composite 14.6 15.6 −0.5 (−2.0, 1.0)
Abdominal pain composite 3.7 4.0 −0.3 (−1.1, 0.4)
Constipation 2.3 1.8 0.6 (0.0, 1.1)
Diarrhea 6.6 8.4 −1.4 (−2.5, −0.4)
Nausea 2.8 3.2 −0.2 (−0.9, 0.4)
Vomiting 1.8 1.6 0.3 (−0.2, 0.8)
Pancreatitis 0.1 0.1 −0.0 (−0.2, 0.1)
Pancreatitis (including chronic pancreatitis) 0.1 0.1 0.0 (−0.1, 0.2)
Proteinuria 0.5 0.4 0.1 (−0.2, 0.3)
Pneumonia 0.9 0.8 0.2 (−0.2, 0.5)
Rash 1.7 1.1 0.6 (0.2, 1.1)
Upper respiratory infection 8.2 8.9 −0.6 (−1.7, 0.5)
Urinary tract infection 4.4 4.8 −0.3 (−1.1, 0.4)

*SMQ* standardized MedDRA queries

^a^100 × (number of patients with ≥1 event/person years of follow-up
time)

^b^Between-group difference and 95% CI based on stratified analysis.
Positive differences indicate that the incidence rate for the
sitagliptin group is higher than the incidence rate for the non-exposed
group. "0.0" and "−0.0" represent rounding for values that are slightly
greater and slightly less than zero, respectively:::: 

### MACE Detailed description of the analyses of MACE has been previously published \[[12](#)\]. The exposure-adjusted incidence of MACE was 0.65 per 100 patient-years in the sitagliptin group, and 0.74 per 100 patient-years in the non-exposed group, with an adjusted incidence rate ratio of 0.83 (95% CI 0.53, 1.30). 

### Neoplasms As noted above, the analysis of all events of malignancies revealed similar incidences in the two treatment groups: 0.90 per 100 patient years in the sitagliptin group and 0.93 per 100 patient-years in the non-exposed group [between-group difference of −0.05 (95% CI −0.41, 0.30)]. Low incidence rates of a wide range of specific malignancies were reported, with similar rates in both treatment groups; the 95% CI did not exclude zero for any of the specific malignancies that were reported. The most common malignancies observed were basal cell carcinoma, prostate cancer, and breast cancer (Table [8](#) in Appendix). Analyses were performed for the pool of terms representing the category of pancreatic cancer (adenocarcinoma of pancreas, pancreatic carcinoma, pancreatic carcinoma metastatic). The exposure-adjusted incidence rates for the pooled terms related to the category of pancreatic cancer were similar in the two treatment groups (0.05 and 0.06 events per 100 patient-years in the sitagliptin and non-exposed groups, respectively). The number of adverse events (three in each group) was below the pre-defined threshold for calculating a 95% CI. The incidence rate of adverse events in the Neoplasms benign, malignant, and unspecified SOC overall was 2.03 per 100 patient-years in the sitagliptin group and 1.52 per 100 patient-years in the non-exposed group [between-group difference of 0.52 (95% CI 0.03, 1.01)]. The higher rate in the sitagliptin group was related to a higher rate of non-malignant neoplasms in the Neoplasms benign, malignant, and unspecified SOC [incidence rates of 1.18 and 0.60 per 100 patient-years in the sitagliptin and non-exposed groups, respectively; between-group difference of 0.60 (95% CI 0.25, 0.96)]. This difference was not the result of an imbalance in any single adverse event or any group of biologically related adverse events. The most common non-malignant neoplasm adverse event terms observed were uterine leiomyoma/leiomyoma, lipoma, and skin papilloma. The only term for which the 95% CI around the between-group difference excluded zero was lipoma [between-group difference 0.15 (95% CI 0.02, 0.29)]. A sensitivity analysis, performed to assess the incidence of non-malignant neoplasms across any SOC, revealed a similar pattern, with incidences of 1.58 and 1.12 per 100 patient-years in the sitagliptin and non-exposed groups, respectively [between-group difference of 0.45 (95% CI 0.02, 0.89)]; in this sensitivity analysis, the adverse event term "colonic polyp" was the most common, with similar incidences in the two treatment groups (0.25 and 0.26 per 100-patient years, respectively). 

### Angioedema At baseline, 29.4% and 28.1% of sitagliptin-treated and non-exposed patients, respectively, were treated with ACE inhibitors. In the subgroup defined by ACE inhibitor use, the exposure-adjusted incidence of events was 0.99 per 100-patient-years in the sitagliptin group and 1.35 per 100-patient-years in the non-exposed group; for those patients not treated with ACE inhibitors, the incidence rates were 1.14 and 1.16, respectively. 

### Other Composite Endpoints The following composite endpoints, primarily of interest due to theoretical mechanistic concerns and/or post-marketing case reports, were analyzed. For the composite endpoint of pancreatitis (which included the MedDRA terms "pancreatitis" and "pancreatitis acute"), the incidence rates were similar for both groups (Table [4](#)), with a difference in rate of −0.0 (95% CI −0.2, 0.1). A similar pattern was observed with an expanded composite that included the MedDRA term "pancreatitis chronic". The incidence of acute renal failure was assessed using both the narrow SMQ and the broad SMQ (Table [4](#)); low and similar rates were observed in both treatment groups for both composite endpoints, as well as for the composite endpoint of proteinuria, which comprised the MedDRA terms "albumin urine present" or "protein urine present". Separate analyses were done on the composite endpoints of bronchitis, pneumonia, and upper respiratory infection (Table [4](#)). Similar incidences were seen in both treatment groups for all three of these infection composites. Similar incidence rates were also observed for the composite endpoint of urinary tract infections (with or without cystitis). The incidence of the composite endpoint of rash was higher in the sitagliptin group compared with the non-exposed group (Table [4](#)). The difference in the composite endpoint was primarily related to a higher incidence of the individual terms "rash" and "rash macular". The incidence of the individual adverse event term "atrial fibrillation" was higher in the sitagliptin group (Table [4](#)). For the predefined composite endpoint of atrial fibrillation/atrial flutter, the between-group difference was 0.2 event per 100 patient-years, and the 95% CI did not exclude zero (95% CI −0.0, 0.4). 

## Specific Adverse Events for which CI Excluded Zero The incidences of adverse events for which the 95% CI excluded zero are depicted in Table [5](#). There were 17 specific adverse events in which the incidence was higher in the sitagliptin group, and 23 specific adverse events in which the incidence was higher in the non-exposed group. For those adverse events in which the between-group difference was ≥0.5 events per 100 patient-years, there were two (constipation and dyspepsia) and seven (diarrhea, fatigue, edema peripheral, blood glucose decreased, hypoglycemia, blood glucose increased, and weight increased) in which the incidences were higher in the sitagliptin and non-exposed groups, respectively. Apart from the adverse event of hypoglycemia, the between-group differences in adverse events for which the 95% CI excluded zero were all less than 1.5 events per 100 patient-years. ::::table-wrap
::: caption
Adverse events for which the 95% confidence intervals around the
difference in incidence rates excludes zero
:::

Adverse event Incidence rate per 100 patient-years^a^

______________________________________________________________________

Sitagliptin 100 mg Non-exposed Difference between sitagliptin and non-exposed (95% CI)^b^\
Sitagliptin > non-exposed\
Acne 0.2 0.0 0.1 (0.0, 0.3)
Atrial fibrillation^c^ 0.4 0.2 0.2 (0.0, 0.4)
Chest discomfort 0.3 0.1 0.2 (0.0, 0.4)
Constipation 2.3 1.8 0.6 (0.0, 1.1)
Dermatitis contact 0.6 0.3 0.3 (0.0, 0.6)
Dyspepsia 2.0 1.4 0.6 (0.0, 1.1)
Gilbert's syndrome 0.1 0.0 0.1 (0.0, 0.2)
Hepatomegaly 0.1 0.0 0.1 (0.0, 0.3)
Ischemic cardiomyopathy 0.1 0.0 0.1 (0.0, 0.2)
Lipoma 0.2 0.0 0.1 (0.0, 0.3)
Micturition urgency 0.1 0.0 0.1 (0.0, 0.2)
Ovarian cyst 0.1 0.0 0.1 (0.0, 0.2)
Periodontitis 0.3 0.1 0.2 (0.0, 0.3)
Rash macular 0.2 0.0 0.1 (0.0, 0.3)
Rash vesicular 0.1 0.0 0.1 (0.0, 0.2)
Tibia fracture 0.1 0.0 0.1 (0.0, 0.2)
Vaginal hemorrhage 0.1 0.0 0.1 (0.0, 0.2)
Non-exposed > sitagliptin\
Albumin urine present 0.0 0.2 −0.1 (−0.3, −0.0)
Blood glucose decreased 0.7 1.3 −0.5 (−0.9, −0.1)
Blood glucose increased 2.0 3.1 −1.1 (−1.8, −0.6)
Blood triglycerides increased 0.5 0.7 −0.3 (−0.6, −0.0)
Bradycardia 0.0 0.2 −0.2 (−0.3, −0.1)
Diarrhea 6.6 8.4 −1.4 (−2.5, −0.4)
Fatigue 1.6 2.1 −0.5 (−1.1, −0.0)
Hypoglycemia 6.7 13.0 −6.3 (−7.6, −5.1)
Hypoesthesia 0.7 1.0 −0.4 (−0.7, −0.0)
Neck pain 0.6 0.9 −0.3 (−0.7, −0.0)
Neurodermatitis 0.0 0.1 −0.1 (−0.2, −0.0)
Peripheral edema 2.2 3.0 −0.8 (−1.4, −0.2)
Pharyngeal erythema 0.0 0.1 −0.1 (−0.2, −0.0)
Sepsis 0.0 0.1 −0.1 (−0.2, −0.0)
Sinus headache 0.1 0.3 −0.2 (−0.4, −0.1)
Suicidal ideation 0.0 0.1 −0.1 (−0.2, −0.0)
Thrombophlebitis 0.0 0.2 −0.1 (−0.3, −0.0)
Urine ketone body present 0.0 0.1 −0.1 (−0.3, −0.0)
Weight increased 0.8 1.4 −0.6 (−1.0, −0.2)
White blood cell count increased 0.1 0.3 −0.2 (−0.4, −0.0)
Upper airway cough syndrome 0.0 0.1 −0.1 (−0.3, −0.0)
Vitreous detachment 0.0 0.1 −0.1 (−0.2, −0.0)
Wheezing 0.0 0.1 −0.1 (−0.3, −0.0)

^a^100 × (number of patients with ≥1 event/patient-years of follow-up
time)

^b^Between-group difference and 95% CI based on stratified analysis.
Positive differences indicate that the incidence rate for the
sitagliptin group is higher than the incidence rate for the non-exposed
group. "0.0" and "−0.0" represent rounding for values that are slightly
greater and slightly less than zero, respectively

^c^When atrial fibrillation and atrial flutter were combined, the
between-group difference was 0.2 (95% CI −0.0, 0.4). Incidence rates for
atrial flutter were 0.0 and 0.1 for the sitagliptin and the non-exposed
groups, respectively, with a between-group difference of −0.1 (95% CI
−0.2, 0.0):::: 

## Predefined Laboratory Abnormality Criteria 

### Liver Enzymes The proportions of patients in the sitagliptin and non-exposed groups with their last measurement (obtained either at the time of discontinuation or at the final scheduled study visit) of AST ≥3 times the upper limit of normal (ULN) were both 0.3% [between-group difference 0.0 (95% CI −0.2, 0.2)]; the proportion of patients whose last ALT measurement was ≥3 times the ULN were 0.8% and 0.6%, respectively [between-group difference 0.0 (95% CI −0.0, 0.5)]. One patient in each group had a last value of ALT or AST ≥3 times the ULN with a simultaneous elevation of the total serum bilirubin ≥2 times the ULN. 

### Serum Creatinine Similar proportions of patients had a last measurement of serum creatinine with an increase of ≥0.3 mg/dL (1.8% and 1.7% in the sitagliptin and the non-exposed groups, respectively). The proportions of patients who met the predefined criterion of two or more consecutive serum creatinine measurements with an increase from baseline of ≥0.3 mg/dL, or an increase from baseline of ≥50% were also similar in the two groups (0.8% and 0.6%, respectively).


Extracted trial result:
Outcome: The incidence rates of malignancy (binary)
Intervention: sitagliptin 100 mg/day
Comparator: comparator agent
Intervention events: 6953
Intervention group size: 7726
Comparator events: 6403
Comparator group size: 6885
Notes: Used incidence rate per 100 to get the binary events.