Table 3.
Overall summary of adverse events to week 26 – Treated set
| Participants, n (%) | Placebo (N=53) |
Empagliflozin pooled (N=52) |
Linagliptin 5 mg (N=52) |
|---|---|---|---|
| Any adverse event | 34 (64·2) | 40 (76·9) | 37 (71·2) |
| Severe adverse event | 2 (3·8) | 1 (1·9) | 1 (1·9) |
| Drug-related adverse event (investigator-defined) | 6 (11·3) | 9 (17·3) | 9 (17·3) |
| Adverse event leading to discontinuation | 2 (3·8) | 0 (0·0) | 0 (0·0) |
| Serious adverse event | 2 (3·8) | 2 (3·8) | 2 (3·8) |
| Fatal | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Life-threatening* | 1 (1·9) | 1 (1·9) | 0 (0·0) |
| Persistent or significant disability/incapacity | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Requiring/prolonging hospitalization* | 2 (3·8) | 2 (3·8) | 0 (0·0) |
| Congenital anomaly/birth defect | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Other* | 0 (0·0) | 1 (1·9) | 2 (3·8) |
| Other significant adverse events (according to ICH E3) | 1 (1·9) | 0 (0·0) | 0 (0·0) |
| Adverse events of special interest and specific adverse events | |||
| Hypersensitivity reactions | 1 (1·9) | 4 (7·7) | 2 (3·8) |
| Skin lesions | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Pemphigoid in bullous conditions | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Pancreatitis | 1 (1·9) | 0 (0·0) | 0 (0·0) |
| Pancreatic cancer | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Hepatic injury | 1 (1·9) | 2 (3·8) | 2 (3·8) |
| Decreased renal function | 1 (1·9) | 0 (0·0) | 0 (0·0) |
| Diabetic ketoacidosis | 1 (1·9) | 0 (0·0) | 0 (0·0) |
| Increased ketone reported as AE | 2 (3·8) | 2 (3·8) | 4 (7·7) |
| Adverse events leading to lower limb amputation | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Hypoglycaemia adverse events1) | 5 (9·4) | 12 (23·1) | 10 (19·2) |
| PG <54 mg/dL | 4 (7·5) | 10 (19·2) | 8 (15·4) |
| Severe hypoglycaemia requiring assistance | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Urinary tract infection | 1 (1·9) | 3 (5·8) | 1 (1·9) |
| Genital infection | 1 (1·9) | 1 (1·9) | 2 (3·8) |
| Acute pyelonephritis or urosepsis | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Bone fracture | 0 (0·0) | 0 (0·0) | 0 (0·0) |
| Arthralgia | 1 (1·9) | 1 (1·9) | 2 (3·8) |
| Volume depletion | 1 (1·9) | 0 (0·0) | 0 (0·0) |
| Other adverse events in at least >5% of participants | |||
| Infections and infestations | 13 (24·5) | 18 (34·6) | 23 (44·2) |
| Nasopharyngitis | 3 (5·7) | 3 (5·8) | 3 (5·8) |
| Influenza | 0 (0·0) | 0 (0·0) | 3 (5.8) |
| Metabolism and nutrition disorders | 12 (22·6) | 16 (30·8) | 16 (30·8) |
| Vitamin D deficiency | 5 (9·4) | 5 (9·6) | 3 (5·8) |
| Hyperglycaemia | 3 (5·7) | 1 (1·9) | 0 (0·0) |
| Gastrointestinal disorders | 10 (18·9) | 12 (23·1) | 12 (23·1) |
| Abdominal pain | 4 (7·5) | 3 (5·8) | 4 (7·7) |
| Diarrhoea | 5 (9·4) | 2 (3·8) | 3 (5·8) |
| Vomiting | 2 (3·8) | 3 (5·8) | 5 (9·6) |
| Nausea | 3 (5·7) | 3 (5·8) | 3 (5·8) |
| Nervous system disorders | 11 (20·8) | 11 (21·2) | 10 (19·2) |
| Headache | 7 (13·2) | 8 (15·4) | 9 (17·3) |
| Dizziness | 3 (5·7) | 2 (3·8) | 1 (1·9) |
| Respiratory, thoracic and mediastinal disorders | 8 (15·1) | 2 (3·8) | 11 (21·2) |
| Cough | 4 (7·5) | 0 (0·0) | 3 (5·8) |
| Epistaxis | 0 (0·0) | 0 (0·0) | 3 (5·8) |
| Renal and urinary disorders | 3 (5·7) | 1 (1·9) | 6 (11·5) |
| Microalbuminuria | 1 (1·9) | 0 (0·0) | 3 (5·8) |
| Skin and subcutaneous tissue disorders | 1 (1·9) | 5 (9·6) | 4 (7·7) |
| Rash | 0 (0·0) | 3 (5·8) | 1 (1·9) |
| Immune system disorders | 0 (0·0) | 4 (7·7) | 0 (0·0) |
| Seasonal allergy | 0 (0·0) | 4 (7·7) | 0 (0·0) |
TS (TG1) (exposure adjusted) population; MedDRA version used for reporting: 25.0. Definition of serious adverse event includes: death, life-threatening, hospitalisation, prolongation of hospitalization, significant disability, congenital anomaly/birth defect, medical/surgical intervention. Definition of life-threatening adverse event: participant at risk of death (not an event that might cause death if more severe).
For serious adverse events defined as life-threatening, requiring/prolonging hospitalisation, or other, the following were reported. Placebo: 1 patient experienced life-threatening events requiring hospitalisation (splenic vein thrombosis, abdominal pain, pancreatitis acute, systemic inflammatory response syndrome, diabetic ketoacidosis, acute kidney injury, acute respiratory failure, hypovolaemic shock); 1 patient required hospitalisation (hyperglycaemia). Empagliflozin: 1 patient experienced life-threatening events requiring hospitalisation (suicidal ideation) and other events (road traffic accident); 1 patient required hospitalisation (skin candida). Linagliptin: 1 patient experienced other events (breast abscess); 1 patient experienced other events (pneumomediastinum).
MedDRA=Medical Dictionary for Regulatory Activities; TG=treatment groupings (see Supplementary Appendix for detailed explanation); TS=treated set.