In most patients with T1D, adequate glycemic control is not achieved with insulin therapy alone, and intensifying insulin therapy can increase the risk of hypoglycemia. Sotagliflozin (SOTA) is a dual SGLT1 and SGLT2 inhibitor, which blunts and delays postprandial hyperglycemia and reduces renal glucose reabsorption. In two 52 weeks phase 3 studies adults with T1D were randomized 1:1:1 to placebo + insulin (PBO), SOTA 200 mg + insulin or SOTA 400 mg + insulin, once daily, after 6 weeks of insulin therapy optimization. HbA1c change over 52 weeks, along with change of daily insulin dose and safety, were assessed using a pooled analysis. Significant HbA1c reductions were observed with SOTA 200 or 400 vs. PBO at week 24 and sustained to 52 weeks, with a concomitant decrease in total daily insulin dose, mainly due to reduction in bolus insulin (BI), as 70-80% of the total insulin reduction was from BI for both SOTA doses. At 52 weeks, patients in SOTA groups had a lower incidence of severe hypo (SH) but more genital mycotic infections, DKA and diarrhea than PBO.
In conclusion, SOTA demonstrated additional and sustained reduction of HbA1c on top of optimized insulin while reducing total daily insulin dose (mainly BI doses), with less incidence of SH. This may be an additional therapy for patients with T1D without good glycemic control despite optimized insulin therapy.
Pooled Efficacy and Safety Results from Randomization to Week 52 on a Background of Optimized Insulin Therapy inTandem1 and 2 (inTandem1, NCT02384941 and inTandem2, NCT02421510)
| Placebo n = 526 | SOTA 200 mg n = 524 | SOTA 400 mg n = 525 | |
| Baseline Characteristics | |||
| Age (mean [s.d]) | 42.5 (13.3) | 44.4 (13.7) | 44.0 (13.4) |
| BMI mg/m2 (mean [s.d.]) | 28.54 (5.28) | 28.89 (5.56) | 28.74 (5.18) |
| HbA1c (%) (mean [s.d.]) | 7.66 (0.81) | 7.68 (0.77) | 7.64 (0.78) |
| Total insulin dose (IU) (mean [s.d.]) | 64.4 (36.6) | 62.7 (36.6) | 62.8 (33.5) |
| Bolus insulin dose (IU) (mean [s.d.]) | 31.9 (23.4) | 30.7 (20.8) | 31.3 (21.1) |
| Basal insulin dose (IU) (mean [s.d.]) | 32.5 (17.5) | 32.0 (20.5) | 31.4 (16.9) |
| Efficacy: HbA1c change from Baseline | |||
| Week 24 Treatment Comparison LS Mean (SE), a % (p-value) | N/A | -0.36 (p<0.001) | -0.38 (p<0.001) |
| Week 52 Treatment Comparison LS Mean (SE), a % (p-value) | N/A | -0.23 (p<0.001) | -0.32 (p<0.001) |
| Insulin Change from Baseline at Week 52 | |||
| Total insulin - Percent change (%) from Baseline LS Mean (SE), p-value Treatment Comparison vs. Placebo LS Mean (SE), p-value - Absolute change (IU) LS Mean (SE), p-value | 2.12 (0.959), p=0.028 N/A 0.18 (0.657), p=0.78 | -4.98 (0.955), p<0.001 -7.10 (1.301), p<0.001 -3.51 (0.654), p<0.001 | -8.21 (0.958), p<0.001 -10.33 (1.303), p<0.001 -5.86 (0.656), p<0.001 |
| Bolus insulin - Percent change (%) from Baseline LS Mean (SE), p-value Treatment Comparison vs. placebo LS Mean (SE), p-value - Absolute change (IU) LS Mean (SE), p-value - Proportion of insulin reduction attributable to bolus insulinb | 5.14 (2.338), p=0.028 N/A -1.45 (0.511), p=0.004 N/A | -1.48 (2.332), p=0.52 -6.63 (3.182), p=0.037 -3.08 (0.508), p<0.001 82.8% | -8.58 (2.338), p<0.001 -13.73 (3.187), p<0.001 -4.28 (0.510), p<0.001 71.3% |
| Basal insulin - Percent change (%) from Baseline LS Mean (SE), p-value Treatment Comparison vs. PBO LS Mean (SE), p-value - Absolute change (IU) LS Mean (SE), p-value - Proportion of insulin reduction attributable to basal insulinb | 4.75 (1.137), p<0.001 N/A 1.58 (0.337), p<0.001 N/A | -2.36 (1.136), p=0.038 -7.11 (1.554), p<0.001 -0.64 (0.336), p=0.055 17.2% | -4.50 (1.136), p<0.001 -9.25 (1.554), p<0.001 -1.72 (0.336), p<0.001 28.7% |
| Patients with Safety Event through 52 Weeks | |||
| Any TEAE, n (%) | 374 (71.1) | 393 (75.0) | 390 (74.3) |
| DKA,c,d n (%) | 1 (0.2) | 15 (2.9) | 20 (3.8) |
| Severe hypoglycemia,c n (%) | 39 (7.4) | 30 (5.7) | 23 (4.4) |
| Diarrhea,e n (%) | 27 (5.1) | 34 (6.5) | 46 (8.8) |
| Genital mycotic infection, n (%) | 15 (2.9) | 48 (9.2) | 63 (12.0) |
| Placebo n = 526 | SOTA 200 mg n = 524 | SOTA 400 mg n = 525 | |
| Baseline Characteristics | |||
| Age (mean [s.d]) | 42.5 (13.3) | 44.4 (13.7) | 44.0 (13.4) |
| BMI mg/m2 (mean [s.d.]) | 28.54 (5.28) | 28.89 (5.56) | 28.74 (5.18) |
| HbA1c (%) (mean [s.d.]) | 7.66 (0.81) | 7.68 (0.77) | 7.64 (0.78) |
| Total insulin dose (IU) (mean [s.d.]) | 64.4 (36.6) | 62.7 (36.6) | 62.8 (33.5) |
| Bolus insulin dose (IU) (mean [s.d.]) | 31.9 (23.4) | 30.7 (20.8) | 31.3 (21.1) |
| Basal insulin dose (IU) (mean [s.d.]) | 32.5 (17.5) | 32.0 (20.5) | 31.4 (16.9) |
| Efficacy: HbA1c change from Baseline | |||
| Week 24 Treatment Comparison LS Mean (SE), a % (p-value) | N/A | -0.36 (p<0.001) | -0.38 (p<0.001) |
| Week 52 Treatment Comparison LS Mean (SE), a % (p-value) | N/A | -0.23 (p<0.001) | -0.32 (p<0.001) |
| Insulin Change from Baseline at Week 52 | |||
| Total insulin - Percent change (%) from Baseline LS Mean (SE), p-value Treatment Comparison vs. Placebo LS Mean (SE), p-value - Absolute change (IU) LS Mean (SE), p-value | 2.12 (0.959), p=0.028 N/A 0.18 (0.657), p=0.78 | -4.98 (0.955), p<0.001 -7.10 (1.301), p<0.001 -3.51 (0.654), p<0.001 | -8.21 (0.958), p<0.001 -10.33 (1.303), p<0.001 -5.86 (0.656), p<0.001 |
| Bolus insulin - Percent change (%) from Baseline LS Mean (SE), p-value Treatment Comparison vs. placebo LS Mean (SE), p-value - Absolute change (IU) LS Mean (SE), p-value - Proportion of insulin reduction attributable to bolus insulinb | 5.14 (2.338), p=0.028 N/A -1.45 (0.511), p=0.004 N/A | -1.48 (2.332), p=0.52 -6.63 (3.182), p=0.037 -3.08 (0.508), p<0.001 82.8% | -8.58 (2.338), p<0.001 -13.73 (3.187), p<0.001 -4.28 (0.510), p<0.001 71.3% |
| Basal insulin - Percent change (%) from Baseline LS Mean (SE), p-value Treatment Comparison vs. PBO LS Mean (SE), p-value - Absolute change (IU) LS Mean (SE), p-value - Proportion of insulin reduction attributable to basal insulinb | 4.75 (1.137), p<0.001 N/A 1.58 (0.337), p<0.001 N/A | -2.36 (1.136), p=0.038 -7.11 (1.554), p<0.001 -0.64 (0.336), p=0.055 17.2% | -4.50 (1.136), p<0.001 -9.25 (1.554), p<0.001 -1.72 (0.336), p<0.001 28.7% |
| Patients with Safety Event through 52 Weeks | |||
| Any TEAE, n (%) | 374 (71.1) | 393 (75.0) | 390 (74.3) |
| DKA,c,d n (%) | 1 (0.2) | 15 (2.9) | 20 (3.8) |
| Severe hypoglycemia,c n (%) | 39 (7.4) | 30 (5.7) | 23 (4.4) |
| Diarrhea,e n (%) | 27 (5.1) | 34 (6.5) | 46 (8.8) |
| Genital mycotic infection, n (%) | 15 (2.9) | 48 (9.2) | 63 (12.0) |
BMI, body mass index; DKA, diabetic ketoacidosis; IU, international units; LS (SE), least square means and standard error; N/A, not applicable; TEAE, Treatment-emergent adverse event.
aStatistical comparisons of each SOTA arm to placebo were preplanned and performed using a generalized linear model with repeated measures statistics.
bProportion of insulin reduction attributable to bolus or basal insulin was calculated by LS Mean of absolute bolus or basal insulin dose change (IU) from BL over bolus + basal absolute dose change from baseline (IU), number of patients on which the raw means and LS means are not the same for each type of insulin.
cAdjudicated event of special interest.
dDKA cases were adjudicated as “yes with certainty,” “yes, probably,” “no, unlikely,” “no with certainty,” “unclassifiable,” and “insufficient data.” Positively adjudicated cases were classified as either “with certainty” or “probably.”
eDiscontinuation of drug due to diarrhea was: 0.4% placebo, 0.4% SOTA 200 mg, and 0.8% SOTA 400 mg.
J. Pettus: Advisory Panel; Self; Sanofi, Novo Nordisk Inc.. Consultant; Self; MannKind Corporation. Advisory Panel; Self; Insulet Corporation. Consultant; Self; Senseonics. S.A. Weinzimer: Speaker's Bureau; Self; Medtronic MiniMed, Inc., Insulet Corporation. Consultant; Self; Sanofi. Stock/Shareholder; Self; InsuLine Medical Ltd. R.J. Mccrimmon: Advisory Panel; Self; Novo Nordisk Foundation, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK. Other Relationship; Self; Elsevier. F. Ampudia Blasco: Advisory Panel; Self; Abbott, Eli Lilly and Company, GlaxoSmithKline plc., LifeScan, Inc., Medtronic, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis. J.A. Stewart: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. P. Strumph: Employee; Self; Lexicon Pharmaceuticals, Inc.. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.. Board Member; Self; College Diabetes Network. J.H. Oliveira: Employee; Self; Sanofi R&D. Employee; Spouse/Partner; Eli Lilly and Company. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc.. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc., Merck & Co., Inc. R. Castro: Employee; Self; Sanofi US.
