Introduction
Methods and Materials
Study Design
Key Inclusion Criteria
Monotherapy
Combination Therapy
Key Exclusion Criteria
Study Procedures and Treatment
Rescue Criteria
Outcome Measures
Results
Monotherapy (n = 249) | All combination therapies (n = 479) | |
---|---|---|
Age, years, mean (SD) | 58.1 (10.4) | 57.2 (10.1) |
Sex, male, n (%) | 146 (58.6) | 268 (55.9) |
Seated SBP, mmHg, mean (SD) | 127.5 (13.7) | 125.8 (14.1) |
Seated DBP, mmHg, mean (SD) | 79.1 (9.5) | 76.2 (9.8) |
Weight, kg, mean (SD) | 67.8 (13.4) | 67.4 (14.5) |
BMI, mg/m2, mean (SD) | 25.7 (4.2) | 25.6 (4.4) |
Waist circumference, cm, mean (SD) | 88.3 (10.7) | 88.3 (11.1) |
Duration of T2DM, years, mean (SD) | 3.8 (4.0) | 6.9 (6.1) |
HbA1c, %, mean (SD) | 7.5 (0.8) | 7.8 (0.9) |
FPG, mg/dL [mmol/L], mean (SD) | 140.3 (25.4) [7.8 (1.4)] | 147.4 (29.1) [8.2 (1.6)] |
eGFR (mL/min/1.73 m2), mean (SD) | 68.6 (12.2) | 70.5 (13.5) |
eGFR <45 mL/min/1.73 m2, n (%) | 0 (0) | 0 (0) |
eGFR ≥45–60 mL/min/1.73 m2, n (%) | 61 (24.5) | 97 (20.3) |
eGFR ≥60–90 mL/min/1.73 m2, n (%) | 175 (70.3) | 347 (72.4) |
eGFR ≥90 mL/min/1.73 m2, n (%) | 13 (5.2) | 35 (7.3) |
Baseline use of antidiabetic medications n (%) | ||
Sulfonylurea (n = 122, 25.5%) | ||
Glimepiride | ||
0.5 mg, n (%) | – | 2/122 (1.6) |
1 mg, n (%) | – | 67/122 (54.9) |
1.5 mg, n (%) | – | 3/122 (2.5) |
2 mg, n (%) | – | 23/122 (18.9) |
2.5 mg, n (%) | – | 1/122 (0.8) |
3 mg, n (%) | – | 14/122 (11.5) |
4 mg, n (%) | – | 5/122 (4.1) |
5 mg, n (%) | – | 1/122 (0.8) |
6 mg, n (%) | – | 6/122 (4.9) |
Dipeptidyl peptidase-4 inhibitors (n = 62, 12.9%) | ||
Sitagliptin | ||
25 mg, n (%) | – | 2/62 (3.2) |
50 mg, n (%) | – | 46/62 (74.2) |
100 mg, n (%) | – | 14/62 (22.6) |
α-glucosidase inhibitors (n = 61, 12.7%) | ||
Acarbose | ||
150 mg, n (%) | – | 1/61 (1.6) |
300 mg, n (%) | – | 2/61 (3.3) |
Miglitol | ||
150 mg, n (%) | – | 23/61 (37.7) |
225 mg, n (%) | – | 3/61 (4.9) |
Voglibose | ||
0.6 mg, n (%) | – | 16/61 (26.2) |
0.9 mg, n (%) | – | 16/61 (26.2) |
Metformin (n = 71, 14.8%) | ||
500 mg | – | 18/71 (25.4) |
750 mg | – | 38/71 (53.5) |
1,000 mg | – | 3/71 (4.2) |
1,500 mg | – | 12/71 (16.9) |
Thiazolidinediones (n = 64, 13.4%) | ||
Pioglitazone | ||
15 mg | – | 32/64 (50.0) |
30 mg | – | 31/64 (48.4) |
45 mg | – | 1/64 (1.6) |
Glinide (n = 49, 10.2%) | ||
Mitiglinide | ||
30 mg | – | 22/49 (44.9) |
Nateglinide | ||
270 mg | – | 27/49 (55.1) |
Glucagon-like peptide-1 analogs (n = 50, 10.4%) | ||
Liraglutide | ||
0.6 mg | – | 7/50 (14.0) |
0.9 mg | – | 43/50 (86.0) |
Safety
Monotherapy (n = 249) | All combination therapies (n = 479) | |
---|---|---|
At least 1 AE, n (%) | 197 (79.1) | 347 (72.4) |
At least 1 serious AE, n (%) | 14 (5.6) | 15 (3.1) |
At least 1 episode of hypoglycemia, n (%) | 6 (2.4) | 19 (4.0) |
Deaths, n
| 0 | 0 |
Events of urinary tract infection, n (%)a
| 9 (3.6) | 11 (2.3) |
Events of genital infection, n (%)a
| 7 (2.8) | 12 (2.5) |
Fractures, n (%) | 6 (2.4) | 6 (1.3) |
Malignant and unspecified neoplasms, n (%) | 5 (2.0) | 2 (0.4) |
Mean change in eGFR mL/min/1.73 m2 (SE) | 0.2 (0.6) | 0.1 (0.5) |
Renal impairment, n (%) | 5 (2.0) | 16 (3.3) |
Volume-related events, n (%) | 3 (1.2) | 2 (0.4) |
Most common AEs (≥4%), n (%) | ||
Nasopharyngitis | 63 (25.3) | 116 (24.2) |
Pollakiuria | 13 (5.2) | 13 (2.7) |
Upper respiratory tract infection | 12 (4.8) | 10 (2.1) |
Constipation | 9 (3.6) | 22 (4.6) |
Eczema | 11 (4.4) | 12 (2.5) |
Back pain | 10 (4.0) | 21 (4.4) |
Thirst | 10 (4.0) | 8 (1.7) |
Dental caries | 10 (4.0) | 11 (2.3) |
Monotherapy (n = 249) | All combination therapies (n = 479) | |
---|---|---|
Mean (SE) | Mean (SE) | |
Albumin, g/dL [g/L] | 0.02 (0.01) [0.20 (0.14)] | 0.01 (0.01) [0.10 (0.09)] |
Cystatin C, mg/L [nmol/L] | −0.01 (0.01) [−1.05 (0.41)] | −0.01 (0.00) [−0.97 (0.28)] |
Hematocrit, % | 2.17 (0.14) | 2.00 (0.11) |
Inorganic phosphorous, mg/dL [mmol/L] | −0.01 (0.03) [0.00 (0.01)] | 0.01 (0.02) [0.00 (0.01)] |
Magnesium, mEq/L [mmol/L] | 0.05 (0.01) [0.03 (0.00)] | 0.05 (0.01) [0.03 (0.00)] |
Parathyroid hormone, pg/mL [ng/L] | 0.80 (1.22) [0.80 (1.22)] | 5.00 (0.94) [5.00 (0.94)] |
Serum calcium, mg/dL [mmol/L] | −0.02 (0.02) [−0.01 (0.01)] | −0.06 (0.02) [−0.02 (0.00)] |
Serum creatinine, mg/dL [µmol/L] | 0.00 (0.01) [0.00 (0.47)] | −0.01 (0.00) [−0.53 (0.35)] |
Serum potassium, mEq/L | −0.03 (0.02) [−0.03 (0.02)] | −0.03 (0.02) [−0.03 (0.02)] |
Serum sodium, mEq/L [mmol/L] | 0.30 (0.16) [0.30 (0.16)] | 0.10 (0.12) [0.10 (0.12)] |
Serum uric acid, mg/dL [μmol/L] | −0.61 (0.06) [−36.29 (3.44)] | −0.50 (0.04) [−29.74 (2.22)] |
Total protein, g/dL [g/L] | 0.04 (0.02) [0.40 (0.24)] | 0.03 (0.02) [0.30 (0.17)] |
Urine glucose, mg/dL [mmol/L] | 2,545.40 (122.98) [141.27 (6.83)] | 2,839.50 (93.90) [157.59 (5.21)] |
Urine albumin, mg/L | −22.40 (9.45) | −25.00 (5.56) |
Urine sodium, mEq/L [mmol/L] | −2.40 (3.46) [−2.40 (3.46)] | −11.10 (2.60) [−11.10 (2.60)] |
Efficacy
Monotherapy (n = 249) | All combination therapies (n = 477) | |
---|---|---|
HbA1c, % | ||
Baseline mean (SD) | 7.5 (0.8) | 7.8 (0.9) |
Mean change from baseline (95% CI) | −0.7 (−0.8 to −0.6) | −0.7 (−0.8 to −0.6) |
Proportion of patients achieving HbA1c <7% | ||
n with HbA1c ≥7.0% at baseline | 189 | 396 |
Baseline mean (SD) HbA1c, % | 7.8 (0.7) | 8.1 (0.8) |
Responders, % (95% CI) | 53.4 (46.1 to 60.7) | 35.1 (30.4 to 40.0) |
Total body weight, kg | ||
Baseline mean (SD) | 67.8 (13.4) | 67.4 (14.5) |
Mean change from baseline (95% CI) | −2.6 (−2.9 to −2.3) | −2.1 (−2.3 to −1.8) |
Proportion of patients achieving body weight reduction ≥5% at week 52 | ||
Baseline mean (SD) body weight, kg | 67.8 (13.4) | 67.4 (14.5) |
Responders, % (95% CI) | 33.7 (27.9 to 40.0) | 24.1 (20.3 to 28.2) |
Mean BMI, mg/m2
a
| ||
Baseline mean (SD) | 25.7 (4.2) | 25.8 (4.4) |
Mean change from baseline (95% CI) | −1.0 (−1.1 to −0.9) | −0.9 (−1.0 to −0.8) |
Waist circumference, cma
| ||
Baseline mean (SD) | 88.1 (10.8) | 88.6 (11.1) |
Mean change from baseline (95% CI) | −2.1 (−2.7 to −1.6) | −2.0 (−2.4 to −1.6) |
FPG, mg/dL [mmol/L] | ||
Baseline mean (SD) | 140.1 (24.8) [7.8 (1.4)] | 147.3 (29.0) [8.2 (1.6)] |
Mean change from baseline (95% CI) | −14.3 (−17.0 to −11.6) [−0.8 (−0.9 to −0.6)] | −17.4 (−19.8 to −15.0) [−1.0 (−1.1 to −0.8)] |
Mean SBP, mmHga
| ||
Baseline mean (SD) | 127.5 (13.8) | 125.8 (14.1) |
Mean change from baseline (95% CI) | −5.2 (−6.8 to −3.7) | −3.9 (−5.2 to −2.6) |
Mean DBP, mmHga
| ||
Baseline mean (SD) | 79.1 (9.5) | 76.2 (9.9) |
Mean change from baseline (95% CI) | −2.9 (−4.0 to −1.9) | −2.1 (−2.9 to −1.2) |
Proportion of patients achieving SBP <130 mmHg at week 52, % (95% CI) | ||
n
b
| 110 | 180 |
Baseline mean (SD) SBP, mmHg | 139.6 (7.4) | 140.1 (8.0) |
Responders, % (95% CI) | 47.3 (37.7 to 57.0) | 53.3 (45.8 to 60.8) |
Fasting insulin, IU/mL [pmol/L]a
| ||
Baseline mean (SD) | 7.3 (6.6) [50.8 (45.5)] | 7.1 (8.6) [49.1 (59.7)] |
Mean change from baseline (95% CI) | −2.1 (−2.6 to −1.6) [−14.6 (−18.1 to −11.1)] | −2.0 (−2.6 to −1.4) [−13.9 (−18.1 to −9.7)] |
Fasting C-peptide, ng/mL [nmol/L]a
| ||
Baseline mean (SD) | 2.0 (1.0) [0.7 (0.3)] | 1.9 (1.0) [0.6 (0.3)] |
Mean change from baseline (95% CI) | −0.2 (−0.3 to −0.2) [−0.1 (−0.1 to −0.1)] | −0.1 (−0.2 to −0.1) [0.0 (−0.1 to 0.0)] |
Total cholesterol, mg/dL [mmol/L]a
| ||
Baseline mean (SD) | 204.8 (33.7) [5.3 (0.9)] | 197.3 (35.1) [5.1 (0.9)] |
Mean percent change from baseline (95% CI) | 3.7 (2.1 to 5.4) | 3.5 (2.2 to 4.8) |
LDL, mg/dL [mmol/L]a
| ||
Baseline mean (SD) | 116.2 (30.9) [3.0 (0.8)] | 110.2 (29.9) [2.9 (0.8)] |
Mean percent change from baseline (95% CI) | 4.4 (1.5 to 7.3) | 3.1 (1.1 to 5.3) |
HDL, mg/dL [mmol/L]a
| ||
Baseline mean (SD) | 59.9 (17.1) [1.6 (0.4)] | 58.8 (15.1) [1.5 (0.4)] |
Mean percent change from baseline (95% CI) | 9.7 (7.7 to 11.8) | 8.7 (7.3 to 10.2) |
Triglyceride, mg/dL [mmol/L]a
| ||
Baseline mean (SD) | 150.2 (113.5) [1.7 (1.3)] | 145.7 (134.6) [1.7 (1.5)] |
Mean percent change from baseline (95% CI) | −8.8 (−13.6 to −3.6) | −7.6 (−11.0 to −4.0) |
Free fatty acid, mg/dL [mmol/L]a
| ||
Baseline mean (SD) | 12.7 (4.9) [0.5 (0.2)] | 12.2 (5.0) [0.4 (0.2)] |
Mean percent change from baseline (95% CI) | 6.0 (−0.2 to 12.7) | 9.2 (4.2 to 14.6) |