Insulin/Glucagon-Like Peptide-1 Receptor Agonist Combination Therapy for the Treatment of Type 2 Diabetes: Are Two Agents Better Than One?
Article Figures & Tables
Tables
- TABLE 1.
Overview of Trials Evaluating IDegLira and iGlarLixi in Patients With Type 2 Diabetes Uncontrolled on Basal Insulin or a GLP-1 Receptor Agonist
Population Patients With Type 2 Diabetes Uncontrolled on Basal Insulin Patients With Type 2 Diabetes Uncontrolled on a GLP-1 Receptor Agonist Trial Dual Ii (47) Dual V (48) Lixilan-L (50) Dual Iii (49) Patients Type 2 diabetes uncontrolled on basal insulin + oral agents (n = 398) Type 2 diabetes uncontrolled on basal insulin glargine U100 + metformin (n = 557) Type 2 diabetes uncontrolled on basal insulin + oral agents (n = 736) Type 2 diabetes uncontrolled on GLP-1 receptor agonist + oral agents (n = 438) Inclusion criteria Basal insulin (20–40 units for ≥3 months) + metformin ± sulfonylurea or glinides; A1C: 7.5–10.0%; BMI ≥27 kg/m2 Insulin glargine U100 (20–50 units for ≥56 days) + metformin; A1C 7.0–10.0%; BMI ≤40 kg/m2 At run-in: basal insulin ≥6 months (stable dose of 15–40 units for ≥2 months) with ≤2 oral agents (metformin sulfonylurea, glinide, SGLT2 inhibitor, DPP-4 inhibitor); FPG ≤180 mg/dL if on 2 oral agents or 1 oral agent other than metformin; ≤200 mg/dL if on metformin or 0 oral agents GLP-1 receptor agonist (maximum tolerated dose of liraglutide once daily or exenatide twice daily) + metformin ± sulfonylurea or pioglitazone; A1C 7.0–9.0%; BMI ≤40 kg/m2 At randomization: A1C 7.0–10.0%; FPG ≤140 mg/dL; insulin glargine U100 20–50 units; calcitonin ≤20 pg/mL; amylase/lipase levels <3 times ULN Treatment groups IDegLira + metformin; insulin degludec (maximum dose 50 units) + metformin IDegLira + metformin; insulin glargine U100 + metformin iGlarLixi + metformin; insulin glargine U100 + metformin IDegLira + metformin ± sulfonylurea ± pioglitazone; unchanged GLP-1 receptor agonist + metformin ± sulfonylurea ± pioglitazone Blinding Double-blinded Open-label Open-label Open-label Randomization 1:1 1:1 1:1 2:1 Duration (weeks) 26 26 Run-in: 6; after randomization: 30 26 Baseline characteristics* Age (years) 57–58 58.4–59.1 59.6–60.3 58.3–58.4 A1C (%) 8.7–8.8 8.2–8.4 8.1 7.7–7.8 BMI (kg/m2) 33.6–33.8 31.7 31.0–31.3 32.9–33.0 Diabetes duration (years) 10–11 11.3–11.6 12.0–12.1 10.4 Basal insulin dose (units) 29 31–32 35 NA Completers (%) IDegLira: 85; insulin degludec: 83 IDegLira: 89.9; insulin glargine U100: 95.0 iGlarLixi: 91.6; insulin glargine U100: 96.2 IDegLira: 94.5; unchanged GLP-1 receptor agonist: 80.1 Starting dose IDegLira: 16 units; insulin degludec: 16 units IDegLira: 16 units; insulin glargine U100: pretrial dose iGlarLixi: 20 units/10 mg (given with pen A) if the insulin glargine U100 dose was <30 units at the end of run-in or 30 units/10 mg (given with pen B) if the insulin glargine U100 dose was ≥30 units at the end of the run-in; insulin glargine U100: pretrial dose IDegLira: 16 units; unchanged GLP-1 receptor agonist: pretrial dose Titration frequency Twice weekly Twice weekly Once weekly Twice weekly FPG titration target (mg/dL) 72–90 72–90 80–100 72–90 ↵* Range of mean values across treatments.
DPP-4, dipeptidyl peptidase 4;
NA, not applicable;
SGLT2, sodium–glucose cotransporter 2;
ULN, upper limit of normal.
- TABLE 2.
Efficacy and Dose of IDegLira and iGlarLixi in Phase 3 Trials
Population Patients With Type 2 Diabetes Uncontrolled on Basal Insulin Patients With Type 2 Diabetes Uncontrolled on a GLP-1 Receptor Agonist Trial DUAL II (47) DUAL V (48) LixiLan-L (50) DUAL III (49) Treatment IDegLira Insulin degludec IDegLira Insulin glargine U100 iGlarLixi Insulin glargine U100 IDegLira Unchanged GLP-1 receptor agonist n 199 199 278 279 367 369 292 146 A1C (%) Baseline 8.7 (0.7) 8.8 (0.7) 8.4 (0.9) 8.2 (0.9) 8.1 (0.7) 8.1 (0.7) 7.8 (0.6) 7.7 (0.5) End of trial 6.9 (NR) 8.0 (NR) 6.6 (0.9) 7.1 (0.9) 6.9 (0.9) 7.5 (0.9) 6.4 (0.8) 7.4 (1.0) Change –1.9* (NR) –0.9 (NR) –1.81 (1.08) –1.13 (0.98) –1.1 (SE 0.06)* –0.6 (SE 0.06) –1.3 (0.9)* –0.3 (0.9) Responders (%) A1C <7% 60.3* 23.1 71.6* 47.0 55* 30 75* 36 A1C ≤6.5% 45.2* 13.1 55.4* 30.8 34* 14 63* 23 FPG (mg/dL) Baseline 175 (52) 173 (56) 160.6 (47.5) 159.8 (52.0) 131.5 (36.0) 133.3 (37.8) 161.7 (38.2) 169.1 (41.7) End of trial 112 (NR) 126 (NR) 109.5 (38.4) 110.2 (38.6) 122.5 (41.4) 120.7 (37.8) 108.5 (29.3) 158.4 (48.7) Change –62 (53)* –46 (60) –50.9 (NR) –49.9 (NR) –7.2 (SE 1.8) –9.0 (SE 1.8) –53.6 (41.1)* –10.7 (49.3) End of trial dose (units) 45 45 41 66 47 47 43 NA Data are mean (SD) unless otherwise stated.
↵* Significant difference between treatments in favor of IDegLira/iGlarLixi.
NA, not applicable;
NR, not reported;
SE, standard error.
- TABLE 3.
Safety of IDegLira and iGlarLixi in Phase 3 Trials
Population Patients With Type 2 Diabetes Uncontrolled on Basal Insulin Patients With Type 2 Diabetes Uncontrolled on a GLP-1 Receptor Agonist Trial DUAL II (47) DUAL V (48) LixiLan-L(50) DUAL III (49) Treatment IDegLira Insulin degludec IDegLira Insulin glargine U100 iGlarLixi Insulin glargine U100 IDegLira Unchanged GLP-1 Receptor Agonist n 199 199 278 279 365 365 292 146 Hypoglycemia (% [events/PYE]) Overall 24.1 (1.5) 24.6 (2.6) 28.4 (2.23)* 49.1 (5.05) 40.0 (3.03) 42.5 (4.22) 32 (2.82) 2.8 (0.12)† Nocturnal 6.0 (0.22) 8.5 (0.32) 6.1 (0.22)* 24.4 (1.23) NR NR 11 (0.454) 0.7 (0.015)† Severe n = 1‡ n = 0‡ n = 0‡ n = 1‡ 1.1 (0.02) 0.3 (<0.01) 0.3 (0.007) 0 (0) Body weight (kg) Baseline (SD) 95.4 (19) 93.5 (20) 88.3 (17.5) 87.3 (15.8) 87.7 (14.5) 87.1 (14.8) 95.6 (16.6) 95.5 (17.3) End of trial (SD) NR NR 86.9 (17.2) 89.1 (15.9) 87.5 (14.4) 88.0 (15.1) NR NR Change (SD) –2.7 (NR)* 0.0 (NR) –1.4 (3.5)* 1.8 (3.6) –0.7 (SE 0.2)* 0.7 (SE 0.2) 2.0 (3.9) –0.8 (3.0)† Adverse event (% [events/PYE]) 57.8 (4.0) 61.3 (3.6) 57.6 (3.43) 50.5 (2.86) 53.4 (NR) 52.3 (NR) 65.6 (4.10) 63.4 (3.64) Serious adverse event (% [events/PYE]) 3.5 (0.12) 5.5 (0.14) 1.8 (0.04) 3.2 (0.07) 5.5 (NR) 4.9 (NR) 3.1 (0.09) 2.1 (0.05) Nausea (% [events/PYE]) 6.5 (0.22) 3.5 (0.08) 9.4 (0.26) 1.1 (0.02) 10.4 (NR) 0.5 (NR) 3.1 (0.08) 4.1 (0.11) MACE (n) 1 2 1 1 similar % similar % 2 0 Pancreatitis (n) 0 0 0 0 0 0 0 0 Pancreatic carcinoma (n) 0 1 0 0 0 0 0 0 Medullary thyroid carcinoma/thyroid neoplasm (n) 0 0 0 0 NR NR 0 0
In this Issue
April 2018, 36(2)
Insulin/Glucagon-Like Peptide-1 Receptor Agonist Combination Therapy for the Treatment of Type 2 Diabetes: Are Two Agents Better Than One?
