This Phase 3 randomized, double-blind study in adults with T2DM (A1C 7.0-10.5%) on MET monotherapy (≥1500 mg/day ≥8 weeks) included a 26 week placebo (PBO)-controlled period followed by a 78 week extension where non-rescued PBO pts with fasting finger-stick glucose ≥110 mg/dL received blinded glimepiride (GLIM). Efficacy, safety and effect on bone mineral density (BMD) of ertugliflozin (ERTU) 5 mg and 15 mg QD at week 104 are reported.
Pts (N=621) had baseline mean ± SD: age 56.6 ± 8.8 y; T2DM duration 8.0 ± 6.0 y; BMI 31.1 ± 4.7 kg/m2; A1C 8.1 ± 0.9%. 41% were post-menopausal women. At week 104, ERTU 5 mg and ERTU 15 mg reduced A1C, FPG, body weight (BW) and blood pressure (BP) compared to baseline, and increased the proportion of pts with A1C <7% (Table).
Incidence of female genital mycotic infections was higher in ERTU 5 mg (7.3%; p=0.017) and 15 mg (9.8%; p=0.003) vs. PBO/GLIM (0.9%). Symptomatic hypoglycemia was lower in ERTU 5 mg (5.8%; p=0.009) and 15 mg (5.9%; p=0.009) vs. PBO/GLIM (13.4%). ERTU had no impact on BMD vs. PBO/GLIM, except total hip where BMD reduction was greater for ERTU 15 mg (Table). Fractures occurred in 3, 2 and 7 pts in ERTU 5 mg, 15 mg and PBO/GLIM, respectively.
ERTU added to MET in pts with inadequately controlled T2DM improved glycemic control, BW and BP over 104 weeks. ERTU was well tolerated with no clinically meaningful impact on BMD.
Table: Change in efficacy (vs baseline) and bone mineral density (vs PBO/GLIM) endpoints
| ERTU 5 mg | ERTU 15 mg | ||
| Efficacy endpointsa (change vs baseline) | |||
| Change from baseline at Wk 104: LS mean (95% CI)b | A1C (%) | -0.5 (-0.6, -0.4) | -0.8 (-0.9, -0.6) |
| FPG (mg/dL) | -17.0 (-22.7, -11.3) | -26.7 (-32.5, -21.0) | |
| Body weight (kg) | -3.6 (-4.2, -3.0) | -3.5 (-4.1, -2.9) | |
| SBP (mmHg) | -3.9 (-5.8, -2.0) | -2.8 (-4.8, -0.9) | |
| DBP (mmHg) | -2.3 (-3.6, -1.1) | -1.2 (-2.5, 0.0) | |
| Proportion of subjects with A1C <7%c | 27.1% | 36.6% | |
| BMD endpointsd (change vs PBO/GLIM) | |||
| Percent change from baseline at Wk 104: Difference in LS mean (95% CI) vs PBO/GLIMb | Lumbar spine | -0.3 (-1.1, 0.5) | -0.2 (-1.0, 0.6) |
| Femoral neck | 0.1 (-0.7, 0.9) | 0.3 (-0.6, 1.1) | |
| Total hip | -0.5 (-1.1, 0.1) | -0.8 (-1.4, -0.2) | |
| Distal forearm | 0.2 (-0.5, 0.9) | -0.1 (-0.8, 0.7) | |
| ERTU 5 mg | ERTU 15 mg | ||
| Efficacy endpointsa (change vs baseline) | |||
| Change from baseline at Wk 104: LS mean (95% CI)b | A1C (%) | -0.5 (-0.6, -0.4) | -0.8 (-0.9, -0.6) |
| FPG (mg/dL) | -17.0 (-22.7, -11.3) | -26.7 (-32.5, -21.0) | |
| Body weight (kg) | -3.6 (-4.2, -3.0) | -3.5 (-4.1, -2.9) | |
| SBP (mmHg) | -3.9 (-5.8, -2.0) | -2.8 (-4.8, -0.9) | |
| DBP (mmHg) | -2.3 (-3.6, -1.1) | -1.2 (-2.5, 0.0) | |
| Proportion of subjects with A1C <7%c | 27.1% | 36.6% | |
| BMD endpointsd (change vs PBO/GLIM) | |||
| Percent change from baseline at Wk 104: Difference in LS mean (95% CI) vs PBO/GLIMb | Lumbar spine | -0.3 (-1.1, 0.5) | -0.2 (-1.0, 0.6) |
| Femoral neck | 0.1 (-0.7, 0.9) | 0.3 (-0.6, 1.1) | |
| Total hip | -0.5 (-1.1, 0.1) | -0.8 (-1.4, -0.2) | |
| Distal forearm | 0.2 (-0.5, 0.9) | -0.1 (-0.8, 0.7) | |
a All efficacy analyses were based on the full analysis set and excluding data after initiation of glycemic rescue therapy. 23 (11.1%), 22 (10.7%) and 51 (24.4%) pts in the ERTU 5 mg, 15 mg and PBO/GLIM groups, respectively, received glycemic rescue through Wk 104 (out of all pts randomized and treated).
b Based on constrained longitudinal data analysis (cLDA) model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another antihyperglycemic medication), baseline eGFR (continuous), menopausal status (men, premenopausal women, women perimenopausal or <3 years postmenopausal, women ≥3 years postmenopausal) and the interaction of time by treatment. Time was treated as a categorical variable.
c Missing data imputed using the cLDA model fitted with fixed effects as in the primary analysis. Ten imputed values were created for each missing value. A pt with missing data was considered to have an A1C <7.0% if at least 6 of 10 imputed values were <7.0%.
d BMD analyses were based on raw data, and excluding data after initiation of bone rescue therapy. 1 pt in the ERTU 5 mg group and 1 pt in the ERTU 15 mg group received bone rescue.
S. Gallo: Employee; Self; Pfizer Inc. B. Charbonnel: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi, Takeda Development Centre Europe Ltd. A. Goldman: Stock/Shareholder; Self; Merck & Co., Inc.. Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. H. Shi: Employee; Self; Pfizer Inc. S. Huyck: Employee; Self; Merck & Co., Inc. A. Darekar: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc. S. Terra: Employee; Self; Pfizer Inc..
