Background
Methods
Study | Study Design | Sitagliptin 100 mg/day Group (N = 5429) | n | Non-exposed Group (N = 4817) | n | Reference* |
---|---|---|---|---|---|---|
P010: twice-daily dose-range finding study | 106-week active-controlled period | Sitagliptin 50 mg b.i.d. switched to Sitagliptin 100 mg q.d. | 122 | Glipizide | 123 | [11] |
P014: once-daily dose-range finding study | 12-week placebo-controlled period and 94-week active- controlled period | -Sitagliptin 100 mg q.d. -Sitagliptin 50 mg b.i.d. switched to Sitagliptin 100 mg q.d. | 110 111 | Placebo (12 weeks) switched to metformin (94 weeks) | 111 | [12] |
P019: placebo-controlled add-on to pioglitazone study | 24-week placebo-controlled period | Sitagliptin 100 mg q.d. + pioglitazone | 175 | Placebo + pioglitazone | 178 | [48] |
P020: placebo-controlled add-on to metformin study | 24-week placebo-controlled period and 80-week active- controlled period | Sitagliptin 100 mg q.d. + metformin | 464 | Placebo + metformin (24 weeks) switched to glipizide + metformin (80 weeks) | 237 | [49] |
P021: placebo-controlled monotherapy study | 24-week placebo-controlled period | Sitagliptin 100 mg q.d. | 238 | Placebo | 253 | [50] |
P023: placebo-controlled monotherapy study | 18-week placebo-controlled period and 36-week active- controlled period | Sitagliptin 100 mg q.d. | 205 | Placebo (18 weeks) switched to pioglitazone (36 weeks) | 110 | [51] |
P024: active-comparator controlled add-on to metformin study | 104-week active-controlled period | Sitagliptin 100 mg q.d. + metformin | 588 | Glipizide + metformin | 584 | |
P035: placebo-controlled add-on to glimepiride, alone or in combination with metformin study | 24-week placebo-controlled period and 30-week active- controlled period | Sitagliptin 100 mg q.d. + glimepiride (± metformin) | 222 | Placebo + glimepiride (± metformin) (24 weeks) switched to pioglitazone + glimepiride (± metformin) (30 weeks) | 219 | [25] |
P036: placebo- and active-controlled study of initial combination use of sitagliptin and metformin | 24-week placebo-controlled period; 80-week active-controlled period | -Sitagliptin 100 mg q.d. -Sitagliptin 50 mg b.i.d./metformin 500 mg b.i.d. -Sitagliptin 50 mg b.i.d./metformin 1000 mg b.i.d. | 179 190 182 | -Placebo (24 weeks) switched to metformin (80 weeks) -Metformin 500 mg b.i.d. -Metformin 1000 mg b.i.d. | 176 182 182 | |
P040: placebo-controlled monotherapy study | 18-week placebo-controlled period | Sitagliptin 100 mg q.d. | 352 | Placebo | 178 | [54] |
P047: placebo-controlled monotherapy study in elderly patients | 24-week placebo-controlled period | Sitagliptin 100 mg q.d | 91 | Placebo | 92 | [55] |
P049: active-comparator controlled monotherapy study | 24-week active-controlled period | Sitagliptin 100 mg q.d | 528 | Metformin | 522 | [56] |
P051: placebo-controlled add-on to insulin, alone or in combination with metformin study | 24-week placebo-controlled period | Sitagliptin 100 mg q.d + insulin (± metformin) | 322 | Placebo + insulin ± metformin | 319 | [26] |
P052: placebo-controlled add-on to metformin and rosiglitazone study | 54-week placebo-controlled period | Sitagliptin 100 mg q.d. + metformin and rosiglitazone | 170 | Placebo + metformin and rosiglitazone | 92 | [57] |
P053: placebo-controlled add-on to metformin study | 30-week placebo-controlled period | Sitagliptin 100 mg q.d. + metformin | 96 | Placebo + metformin | 94 | [58] |
P061: placebo- and active-controlled mechanism of action factorial study | 12-week placebo-controlled period | -Sitagliptin 100 mg q.d. -Sitagliptin 100 mg q.d. + pioglitazone | 52 52 | -Pioglitazone -Placebo | 54 53 | [28] |
P064: active-comparator controlled study of initial combination use of sitagliptin and pioglitazone | 54-week active-controlled period | Sitagliptin 100 mg q.d + pioglitazone | 261 | Placebo + pioglitazone | 259 | [29] |
P079: active-comparator controlled study of initial combination use of sitagliptin/metformin FDC (MK-0431A) | 44-week active-controlled period | Sitagliptin 50 mg + metformin 1000 mg b.i.d. (FDC) | 625 | Metformin 1000 mg b.i.d. | 621 | |
P801: placebo- and active-controlled add-on to metformin study | 18-week placebo-controlled period | Sitagliptin 100 mg q.d. | 94 | -Rosiglitazone -Placebo | 87 91 | [59] |
Adverse Events of Interest
Cardiovascular
Malignancy
Bone Fracture
Infection
Angioedema
Liver Function Tests
Results
Patient Characteristics and Exposure
Sitagliptin 100 mg | Non-exposed | |
---|---|---|
RANDOMIZED, N | 5429 | 4817 |
n (%) | n (%) | |
DISCONTINUED | 1818 (33.5) | 1694 (35.2) |
Reason for discontinuation | ||
Adverse event | 239 (4.4) | 216 (4.5) |
Lack of efficacy* | 614 (11.3) | 520 (10.8) |
Lost to follow-up | 222 (4.1) | 180 (3.7) |
Protocol violation | 98 (1.8) | 99 (2.1) |
Protocol-specific criteria | 61 (1.1) | 55 (1.1) |
Withdrawal of consent | 336 (6.2) | 367 (7.6) |
Other reasons†
| 248 (4.6) | 257 (5.3) |
Safety and Tolerability
Incidence Rate per 100 Patient-years†
| |||
---|---|---|---|
Sitagliptin 100 mg | Non-exposed | Difference between Sitagliptin and Non-exposed (95% CI)* | |
With one or more adverse events | 153.5 | 162.6 | -7.6 (-15.6, 0.3) |
With drug-related‡ adverse events | 20.0 | 26.8 | -6.4 (-8.7, -4.1) |
With serious adverse events | 7.8 | 7.9 | -0.1 (-1.3, 1.1) |
With serious drug-related‡ adverse events | 0.4 | 0.3 | 0.1 (-0.1, 0.4) |
Who died | 0.3 | 0.5 | -0.2 (-0.5, 0.1) |
Discontinued due to adverse events | 4.8 | 5.2 | -0.5 (-1.5, 0.4) |
Discontinued due to drug-related‡ adverse events | 1.7 | 2.3 | -0.5 (-1.1, 0.1) |
Discontinued due to serious adverse events | 1.7 | 1.7 | -0.0 (-0.6, 0.5) |
Discontinued due to serious drug-related‡ adverse events | 0.2 | 0.1 | 0.1 (-0.1, 0.3) |
Incidence Rate per 100 Patient-years†
| |||
---|---|---|---|
System Organ Class | Sitagliptin 100 mg | Non-exposed | Difference between Sitagliptin and Non-exposed (95% CI)* |
Blood and Lymphatic System Disorders | 1.1 | 0.6 | 0.4 (0.0, 0.8) |
Cardiac Disorders | 4.2 | 4.3 | -0.2 (-1.1, 0.7) |
Congenital, Familial, and Genetic Disorders | 0.2 | 0.3 | -0.0 (-0.3, 0.2) |
Ear And Labyrinth Disorders | 1.7 | 2.0 | -0.4 (-1.0, 0.2) |
Endocrine Disorders | 0.3 | 0.5 | -0.2 (-0.5, 0.1) |
Eye Disorders | 4.0 | 4.3 | -0.2 (-1.1, 0.6) |
Gastrointestinal Disorders | 26.0 | 27.7 | -1.2 (-3.7, 1.2) |
General Disorders And Administration Site Conditions | 8.8 | 9.3 | -0.6 (-1.9, 0.8) |
Hepatobiliary Disorders | 1.3 | 1.1 | 0.2 (-0.3, 0.7) |
Immune System Disorders | 1.0 | 1.1 | -0.1 (-0.6, 0.3) |
Infections And Infestations | 49.2 | 48.1 | 1.8 (-1.7, 5.3) |
Injury, Poisoning And Procedural Complications | 9.7 | 9.4 | 0.7 (-0.7, 2.1) |
Investigations | 15.1 | 15.7 | -1.2 (-3.0, 0.6) |
Metabolism And Nutrition Disorders | 9.3 | 16.3 | -6.8 (-8.5, -5.2) |
Musculoskeletal And Connective Tissue Disorders | 20.3 | 19.4 | 1.0 (-1.1, 3.0) |
Neoplasms Benign, Malignant And Unspecified | 2.2 | 1.7 | 0.6 (-0.0, 1.2) |
Nervous System Disorders | 15.4 | 15.5 | -0.2 (-2.0, 1.6) |
Pregnancy, Puerperium, and Perinatal Conditions | 0.0 | 0.1 | -0.0** |
Psychiatric Disorders | 4.6 | 4.7 | 0.0 (-0.9, 1.0) |
Renal And Urinary Disorders | 3.0 | 3.0 | -0.1 (-0.8, 0.7) |
Reproductive System And Breast Disorders | 2.8 | 3.2 | -0.3 (-1.1, 0.5) |
Respiratory, Thoracic And Mediastinal Disorders | 8.8 | 8.6 | 0.2 (-1.2, 1.4) |
Skin And Subcutaneous Tissue Disorders | 8.6 | 7.3 | 1.3 (0.1, 2.5) |
Social Circumstances | 0.0 | 0.1 | -0.0** |
Surgical and Medical Procedures | 0.1 | 0.1 | 0.0** |
Vascular Disorders | 5.8 | 5.8 | -0.2 (-1.2, 0.9) |
Adverse Event | Incidence Rate per 100 Patient-years†
| ||
---|---|---|---|
Sitagliptin 100 mg | Non-exposed | Difference between Sitagliptin and Non-exposed (95% CI)* | |
Gastrointestinal disorders SOC
| |||
Abdominal pain‡^
| 1.3 | 1.7 | -0.5 (-1.0, 0.0) |
Constipation | 2.6 | 1.9 | 0.8 (0.1, 1.4) |
Diarrhea‡
| 6.9 | 9.6 | -2.3 (-3.6, -1.0) |
Dyspepsia | 2.0 | 1.6 | 0.4 (-0.1, 1.0) |
Gastritis | 1.2 | 1.5 | -0.3 (-0.8, 0.2) |
Gastroesophageal reflux disease | 1.1 | 0.8 | 0.3 (-0.1, 0.8) |
Nausea‡
| 3.0 | 3.8 | -0.5 (-1.3, 0.3) |
Toothache | 1.2 | 1.3 | -0.2 (-0.7, 0.3) |
Vomiting‡
| 1.8 | 1.9 | 0.0 (-0.6, 0.6) |
General disorders and administration site conditions SOC
| |||
Fatigue | 1.8 | 2.5 | -0.6 (-1.3, -0.0) |
Peripheral Edema | 2.4 | 2.4 | -0.0 (-0.7, 0.6) |
Infections and infestations SOC
| |||
Bronchitis | 4.2 | 3.8 | 0.4 (-0.4, 1.3) |
Cellulitis | 0.8 | 1.0 | -0.2 (-0.6, 0.2) |
Gastroenteritis | 2.0 | 1.9 | 0.1 (-0.5, 0.7) |
Gastroenteritis Viral | 1.0 | 1.0 | 0.0 (-0.4, 0.5) |
Influenza | 4.5 | 5.2 | -0.7 (-1.7, 0.2) |
Nasopharyngitis | 7.7 | 7.0 | 0.9 (-0.3, 2.1) |
Pharyngitis | 1.5 | 1.4 | 0.1 (-0.4, 0.6) |
Sinusitis | 2.7 | 2.7 | 0.1 (-0.6, 0.8) |
Upper respiratory tract infection | 8.6 | 9.0 | -0.3 (-1.6, 1.0) |
Urinary tract infection | 4.1 | 4.2 | -0.2 (-1.1, 0.6) |
Viral infection | 1.1 | 0.9 | 0.2 (-0.2, 0.7) |
Injury, poisoning, and procedural complications SOC
| |||
Contusion | 1.0 | 0.8 | 0.1 (-0.3, 0.5) |
Muscle strain | 0.9 | 1.0 | -0.1 (-0.6, 0.3) |
Investigations SOC
| |||
ALT increased | 1.5 | 1.4 | 0.1 (-0.4, 0.6) |
AST increased | 1.0 | 1.0 | 0.0 (-0.4, 0.4) |
Blood glucose decreased | 0.5 | 1.0 | -0.5 (-0.9, -0.1) |
Blood glucose increased | 2.3 | 3.6 | -1.3 (-2.1, -0.6) |
Blood uric acid increased | 1.0 | 0.8 | 0.2 (-0.2, 0.6) |
Weight increased | 0.8 | 1.0 | -0.2 (-0.7, 0.2) |
Metabolism and nutrition disorders SOC
| |||
Hyperglycemia | 1.2 | 1.4 | -0.2 (-0.7, 0.3) |
Hypoglycemia‡
| 5.2 | 12.1 | -6.8 (-8.3, -5.5) |
Musculoskeletal and connective tissue disorders SOC
| |||
Arthralgia | 3.4 | 3.7 | -0.3 (-1.2, 0.5) |
Back pain | 4.3 | 4.1 | 0.1 (-0.8, 1.0) |
Muscle spasms | 1.2 | 1.5 | -0.3 (-0.8, 0.2) |
Musculoskeletal pain | 1.6 | 1.6 | -0.1 (-0.6, 0.5) |
Myalgia | 1.2 | 1.2 | -0.0 (-0.5, 0.4) |
Neck pain | 0.7 | 1.0 | -0.3 (-0.7, 0.1) |
Osteoarthritis | 1.6 | 1.1 | 0.5 (-0.0, 1.0) |
Pain in extremity | 2.8 | 2.1 | 0.7 (0.1, 1.4) |
Nervous system disorders SOC
| |||
Dizziness | 2.8 | 2.7 | 0.1 (-0.6, 0.9) |
Headache | 5.8 | 5.6 | 0.4 (-0.7, 1.4) |
Hypoesthesia | 0.7 | 1.1 | -0.4 (-0.8, 0.0) |
Paraesthesia | 1.0 | 1.2 | -0.2 (-0.7, 0.3) |
Psychiatric disorders SOC
| |||
Anxiety | 0.9 | 1.0 | -0.1 (-0.5, 0.3) |
Depression | 1.4 | 1.2 | 0.3 (-0.2, 0.8) |
Insomnia | 1.5 | 1.4 | 0.0 (-0.5, 0.6) |
Respiratory, thoracic, and mediastinal disorders SOC
| |||
Cough | 2.7 | 2.6 | 0.0 (-0.7, 0.7) |
Oropharyngeal pain | 1.3 | 1.2 | 0.1 (-0.4, 0.6) |
Skin and subcutaneous tissue disorders SOC
| |||
Rash | 1.3 | 0.9 | 0.4 (-0.1, 0.8) |
Vascular disorders SOC
| |||
Hypertension | 3.6 | 3.6 | -0.1 (-1.0, 0.7) |
Adverse Event | Incidence Rate per 100 Patient-years†
| ||
---|---|---|---|
Sitagliptin 100 mg | Non-exposed | Difference between Sitagliptin and Non-exposed (95% CI)* | |
Sitagliptin > Non-exposed
| |||
Atrial fibrillation‡
| 0.4 | 0.2 | 0.3 (0.0, 0.6) |
Constipation | 2.6 | 1.9 | 0.8 (0.1, 1.4) |
Protein urine present^
| 0.5 | 0.2 | 0.3 (0.0, 0.5) |
Pain in extremity | 2.8 | 2.1 | 0.7 (0.1, 1.4) |
Dermatitis Contact | 0.7 | 0.3 | 0.5 (0.1, 0.8) |
Non-exposed > Sitagliptin
| |||
Diarrhea#
| 6.9 | 9.6 | -2.3 (-3.6, -1.0) |
Fatigue | 1.8 | 2.5 | -0.6 (-1.3, -0.0) |
Blood glucose decreased | 0.5 | 1.0 | -0.5 (-0.9, -0.1) |
Blood glucose increased | 2.3 | 3.6 | -1.3 (-2.1, -0.6) |
Blood triglycerides increased | 0.5 | 0.8 | -0.4 (-0.7, -0.0) |
Hypoglycemia#
| 5.2 | 12.1 | -6.8 (-8.3, -5.5) |
Sinus headache | 0.1 | 0.3 | -0.3 (-0.5, -0.1) |
Adverse Event | Incidence Rate per 100 Patient-years†
| ||
---|---|---|---|
Sitagliptin 100 mg | Non-exposed | Difference between Sitagliptin and Non-exposed (95% CI)* | |
Gastrointestinal disorders SOC
| |||
Abdominal discomfort | 0.3 | 0.3 | 0.0 (-0.3, 0.3) |
Abdominal distension | 0.3 | 0.2 | 0.1 (-0.1, 0.3) |
Abdominal pain | 0.1 | 0.5 | -0.5 (-0.8, -0.2) |
Abdominal pain upper | 0.5 | 0.8 | -0.2 (-0.6, 0.1) |
Constipation | 0.8 | 0.5 | 0.4 (0.1, 0.8) |
Diarrhea | 2.4 | 4.5 | -1.8 (-2.7, -1.0) |
Dry mouth | 0.1 | 0.3 | -0.1 (-0.4, 0.1) |
Dyspepsia | 0.5 | 0.5 | 0.0 (-0.3, 0.3) |
Flatulence | 0.3 | 0.5 | -0.1 (-0.4, 0.2) |
Gastritis | 0.1 | 0.5 | -0.3 (-0.6, -0.1) |
Gastroesophageal reflux disease | 0.2 | 0.1 | 0.1 (-0.1, 0.3) |
Nausea | 1.3 | 1.8 | -0.4 (-1.0, 0.1) |
Vomiting | 0.4 | 0.4 | -0.0 (-0.3, 0.3) |
General disorders and administration site conditions SOC
| |||
Fatigue | 0.6 | 0.7 | -0.2 (-0.6, 0.2) |
Peripheral Edema | 0.4 | 0.6 | -0.2 (-0.5, 0.1) |
Infections and infestations SOC
| |||
Upper respiratory tract infection | 0.4 | 0.3 | 0.2 (-0.1, 0.5) |
Urinary tract infection | 0.3 | 0.1 | 0.1 (-0.1, 0.3) |
Investigations SOC
| |||
ALT increased | 0.5 | 0.4 | 0.0 (-0.3, 0.3) |
AST increased | 0.3 | 0.4 | -0.2 (-0.5, 0.1) |
Blood creatine phosphokinase increased | 0.2 | 0.1 | 0.1 (-0.0, 0.3) |
Blood glucose decreased | 0.3 | 0.5 | -0.2 (-0.5, 0.0) |
Blood glucose increased | 0.3 | 0.5 | -0.2 (-0.5, 0.1) |
Blood uric acid increased | 0.3 | 0.2 | 0.1 (-0.2, 0.3) |
Creatinine renal clearance decreased | 0.3 | 0.3 | 0.0 (-0.2, 0.2) |
Glycosylated hemoglobin increased | 0.1 | 0.2 | -0.1 (-0.3, 0.1) |
Weight decreased | 0.2 | 0.1 | 0.1 (-0.1, 0.3) |
Weight increased | 0.2 | 0.5 | -0.3 (-0.6, -0.0) |
Metabolism and nutrition disorders SOC
| |||
Decreased appetite | 0.2 | 0.2 | 0.1 (-0.1, 0.3) |
Hyperglycemia | 0.1 | 0.2 | -0.1 (-0.4, 0.0) |
Hypoglycemia | 3.5 | 7.5 | -3.8 (-5.0, -2.8) |
Musculoskeletal and connective tissue disorders SOC
| |||
Arthralgia | 0.2 | 0.2 | -0.0 (-0.3, 0.2) |
Muscle spasms | 0.1 | 0.2 | -0.1 (-0.3, 0.1) |
Myalgia | 0.1 | 0.2 | -0.1 (-0.3, 0.1) |
Nervous system disorders SOC
| |||
Dizziness | 0.6 | 0.5 | 0.1 (-0.2, 0.4) |
Headache | 1.2 | 1.1 | 0.1 (-0.4, 0.6) |
Paraesthesia | 0.1 | 0.3 | -0.2 (-0.4, -0.0) |
Psychiatric disorders SOC
| |||
Insomnia | 0.2 | 0.1 | 0.1 (-0.1, 0.3) |
Respiratory, thoracic, and mediastinal disorders SOC
| |||
Cough | 0.2 | 0.1 | 0.0 (-0.2, 0.2) |
Skin and subcutaneous tissue disorders SOC
| |||
Pruritus | 0.2 | 0.2 | -0.0 (-0.3, 0.2) |
Rash | 0.4 | 0.2 | 0.2 (-0.0, 0.5) |
Urticaria | 0.1 | 0.2 | -0.1 (-0.3, 0.1) |
Vascular disorders SOC
| |||
Hypertension | 0.3 | 0.2 | 0.1 (-0.1, 0.3) |
CI = confidence interval Adverse Event | Incidence Rate per 100 Patient-years†
| ||
---|---|---|---|
Sitagliptin 100 mg | Non-exposed | Difference between Sitagliptin and Non-exposed (95% CI)* | |
Cardiac disorders SOC
| |||
Acute myocardial infarction | 0.1 | 0.2 | -0.1 (-0.3, 0.0) |
Angina pectoris | 0.2 | 0.1 | 0.1 (-0.1, 0.3) |
Coronary artery disease | 0.2 | 0.4 | -0.2 (-0.5, 0.0) |
Myocardial infarction | 0.2 | 0.2 | 0.0 (-0.2, 0.2) |
Myocardial ischemia | 0.0 | 0.2 | -0.2 (-0.4, -0.1) |
General disorders and administration site conditions SOC
| |||
Non-cardiac chest pain | 0.1 | 0.3 | -0.1 (-0.4, 0.1) |
Infections and Infestations SOC
| |||
Pneumonia | 0.2 | 0.2 | 0.1 (-0.2, 0.3) |
Neoplasms benign, malignant and unspecified SOC
| |||
Basal cell carcinoma | 0.2 | 0.2 | 0.0 (-0.2, 0.2) |
Breast cancer‡
| 0.3 | 0.2 | 0.1 (-0.2, 0.5) |
Prostate cancer‡
| 0.2 | 0.2 | -0.0 (-0.3, 0.3) |
Nervous system disorders SOC
| |||
Cerebrovascular accident | 0.1 | 0.2 | -0.1 (-0.3, 0.1) |
Transient ischemia attack | 0.0 | 0.2 | -0.1 (-0.3, 0.0) |
Adverse Events of Interest
Hypoglycemia
Adverse Event | Incidence Rate per 100 Patient-years†
| ||
---|---|---|---|
Sitagliptin 100 mg | Non-exposed | Difference between Sitagliptin and Non-exposed (95% CI)* | |
Gastrointestinal disorders SOC
| |||
One or more select event (abdominal pain‡, diarrhea, nausea, vomiting) | 14.0 | 17.2 | -2.9 (-4.8, -1.1) |
Abdominal pain‡
| 4.1 | 4.7 | -0.7 (-1.7, 0.3) |
Diarrhea | 7.1 | 10.0 | -2.5 (-3.9, -1.1) |
Nausea | 3.1 | 4.0 | -0.7 (-1.6, 0.2) |
Vomiting | 1.9 | 1.9 | 0.0 (-0.6, 0.6) |
Metabolism and nutrition disorders SOC
| |||
Hypoglycemia | 4.9 | 11.7 | -6.7 (-8.2, -5.3) |
Gastrointestinal Symptoms
Cardiovascular
Malignancy
Adverse Event | n/patient-years of exposure (Incidence Rate per 100 Patient-years†) | ||
---|---|---|---|
Sitagliptin 100 mg | Non-exposed | Difference between Sitagliptin and Non-exposed (95% CI)* | |
Any malignancy | 46/4690 (1.0) | 40/3930 (1.0) | -0.0 (-0.5, 0.4) |