Introduction
Methods
Compliance with Ethics Guidelines
Indication and Use
Formulation and Pharmacokinetics
Antibody Formation
Clinical effects
Study [Reference] | Study design | Sample size | Weeks | Background therapy | Baseline HbA1c (%) |
---|---|---|---|---|---|
Kim et al. [4] | Randomized double-blind, phase 2, dose-finding vs. placebo | Placebo: 16 ExeOW 0.8 mg: 16 ExeOW 2.0 mg: 15 | 15 | Diet/exercise ± MET | Placebo: 8.6 ExeOW 0.8 mg: 8.6 ExeOW 2 mg: 8.3 |
DURATION-1 [8] | Randomized, open label, comparative vs ExeBID | 295 ExeOW: 148 ExeBID: 147 | 30 | Diet/exercise ± MET, SFU, or TZD (or combos) | ExeOW: 8.3 ExeBID: 8.3 |
DURATION-1 1-year follow-up [22] | Uncontrolled, open label | ExeOW: 258 (130 from ExeBID arm) | 52 | Diet/exercise ± MET, SFU, or TZD (or combos) | ExeOW: 8.3 ExeBID: 8.2 |
DURATION-1 3-year follow-up [23] | Uncontrolled, open label | ExeOW: 194 | 156 | Diet/exercise ± MET, SFU, or TZD (or combos) | 8.2 |
DURATION-1 6-year follow-up [17] | Uncontrolled, open label | ExeOW:136 | 312 | Diet/exercise ± MET, SFU, or TZD (or combos) | 8.1 |
DURATION-2 [12] | Randomized, prospective, double blind, double dummy, comparative vs. SITA vs. PIO | 514 (491) ExeOW: 170 (160) SITA: 172 (166) PIO: 172 (165) | 26 | MET | ExeOW 8.6 SITA: 8.5 PIO: 8.5 |
DURATION-3 [13] | Randomized, prospective, open label comparative vs GLAR | 456 ExeOW: 233 GLAR: 223 | 26 | MET ± SFU | ExeOW: 8.3 GLAR: 8.3 |
DURATION-3 3-year follow-up [18] | As above | ExeOW: 140 GLAR: 147 | 156 | MET ± SFU | ExeOW: 8.2 GLAR: 8.3 |
DURATION-4 [11] | Randomized, prospective, double blind, double dummy, comparative vs. MET, PIO, and SITA | 820 (696) ExeOW: 248 MET: 246 PIO: 163 SITA: 163 | 26 | Diet/exercise | ExeOW: 8.5 MET: 8.6 PIO: 8.5 SITA: 8.5 |
DURATION-5 [14] | Randomized, prospective, open label, comparative vs. ExeBID | 252 ExeOW: 129 ExeBID: 123 | 24 | Diet/exercise ± MET, SFU, or TZD (or combos) | ExeOW: 8.5 ExeBID: 8.4 |
DURATION-6 [15] | Randomized, prospective, open label, non-inferiority vs. LIRA 1.8 mg | 911 ExeOW: 461 LIRA: 450 | 26 | Diet/exercise ± MET, SFU, or TZD (or combos) | ExeOW: 8.5 LIRA: 8.4 |
DURATION-8 [16] | Multicenter, double-blind, randomized, active-controlled phase 3 trial | 695 ExeOW + DAPA: 231 ExeOW alone: 231 DAPA alone: 233 | 28 | Diet/exercise ± MET | ExeOW + DAPA: 9.3 ExeOW: 9.3 DAPA: 9.3 |
Study [Reference] | HbA1c mean decrease from baseline (%) | Patients achieving HbA1c <7% (%) | Patients achieving HbA1c <6.5% (%) | Baseline FPG mean (mmol/L) | FPG mean decrease from baseline (mmol/L) |
---|---|---|---|---|---|
Kim et al. [4] | Placebo: +0.4 ExeOW 0.8 mg: −1.4 ExeOW 2: −1.7 p < 0.0001 | Placebo: 0 ExeOW 0.8 mg: 36 ExeOW 2 mg: 86 | NR | Placebo: 10.2 ExeOW 0.8 mg: 10.3 ExeOW 2 mg: 9.3 | Placebo: + 1.0 ExeOW 0.8 mg: −2.4 ExeOW 2 mg: −2.2 p < 0.001 |
DURATION-1 [8] | ExeOW: −1.9* Exe BID: −1.5* p = 0.0023 | ExeOW: 77 Exe BID: 61 | ExeOW: 49 ExeBID: 25 | ExeOW: 9.6 ExeBID: 9.2 | ExeOW: −2.3* ExeBID: −1.4* p < 0.0001 |
DURATION-1 1-year follow-up [22] | From ExeOW: −2.0* (vs. −2.1* at week 30) pts from Exe BID: −2.0* | 71 | 54 | Pts from ExeOW: 9.6 pts from Exe BID: 9.2 | From ExeOW: −2.6* from Exe BID: −2.4* |
DURATION-1 3-year follow-up [23] | −1.6* | 55 | 33 | 9.3 | −1.8* |
DURATION-1 6-year follow-up [17] | −1.6%* | 46.3 | 33 | 9.1 | −1.5 |
DURATION-2 [12] | ExeOW: −1.5* SITA: −0.9* PIO: −1.2*
p < 0.001 vs. SITA p = 0.0165 vs. PIO | ExeOW: 59 SITA: 30 PIO: 43
p < 0.0001 vs. SITA p < 0.0015 vs. PIO | ExeOW: 40 SITA: 17 PIO: 28
p < 0.0001 vs. SITA
p < 0.0120 vs. PIO | ExeOW: 9.2 SITA: 9.1 PIO: 9.1 | ExeOW: −1.8* SITA: −0.9* PIO: −1.5*
p = 0.0038 vs. SITA p = NS vs. PIO |
DURATION-3 [13] | ExeOW: −1.5* GLAR: −1.3*
p = 0.017 | ExeOW: 60 GLAR: 48
p = 0.01 | ExeOW: 35 GLAR: 23
p = 0.004 | ExeOW: 9.9 GLAR: 9.7 | ExeOW: −2.1* GLAR: −2.8* (p = 0.001) |
DURATION-3 3-year follow-up [18] | ExeOW: −1.09* GLAR: −0.88*
p = 0.02 | ExeOW: 40 GLAR: 33
p = NS | ExeOW: 24 GLAR: 15
p = 0.023 | ExeOW: 9.6 GLAR: 9.7 | ExeOW: −1.73* GLAR: −2.65* (p = 0.001) |
DURATION-4 [11] | ExeOW: −1.53* MET: −1.48* PIO: −1.63* SITA: −1.15*
p = NS vs. MET
p = NS vs. PIO
p = <0.001 vs. SITA | ExeOW: 63 MET: 55 PIO: 61 SITA: 43
p = NS vs. MET
p = NS vs. PIO
p < 0.002 vs. SITA | ExeOW: 49 MET: 36 PIO:42 SITA: 26
p = 0.004 vs. MET
p = NS vs. PIO
p < 0.002 vs. SITA | ExeOW: 9.9 MET: 10.0 PIO: 9.8 SITA: 9.7 | ExeOW: −2.3* MET: −2.0* PIO: −2.6* SITA: −1.1*
p = NS vs. MET
p = NS vs. PIO
p = <0.001 vs. SITA |
DURATION-5 [14] | ExeOW: −1.6* ExeBID: −0.9*
p = 0.0001 | ExeOW: 58 ExeBID: 30
p < 0.0001 | ExeOW: 41 ExeBID: 16
p < 0.0001 | ExeOW: 9.6 ExeBID: 9.3 | ExeOW: −1.9* ExeBID: −0.7*
p = 0.0008 |
DURATION-6 [15] | ExeOW: −1.28 LIRA: −1.48 (p = 0.02) Tx difference 0.21% (95% CI = 0.08–0.33%) | ExeOW: 9.6 LIRA: 9.8 | ExeOW: −1.8 LIRA: −2.1 (p = 0.0001) | ||
DURATION-8 [16] | ExeOW + DAPA: −2.0 ExeOW: −1.6 DAPA: −1.4 | ExeOW + DAPA: 45 ExeOW: 27 DAPA: 19 | ExeOW + DAPA: 30 ExeOW: 19 DAPA: 10 | ExeOW + DAPA: 11.0 ExeOW: 10.8 DAPA: 10.9 | ExeOW + DAPA: −2.30 ExeOW: −1.19 DAPA: −1.46 |
Effects on Glycemic Control
ExeOW as Monotherapy
ExeOW as Add-on to Other Antidiabetic Therapies
ExeOW Compared to ExeBID
ExeOW Compared to Pioglitazone and Sitagliptin
ExeOW Compared to Insulin
ExeOW Compared to Liraglutide
ExeOW in Combination with Dapagliflozin
Non-Glycemic Effects
Effects on Body Weight
Effects on Cardiovascular System
Changes of Biochemical Indicators of Cardiovascular Risk
Study [Reference] | Baseline TG mean (mmol/L) | TG mean decrease from baseline (%) (mmol/L) | Baseline T-CHOL (mmol/L) | T-CHOL mean decrease from baseline (mmol/L) | Baseline HDL Mean (mmol/L) | HDL mean decrease from baseline (mmol/L) |
---|---|---|---|---|---|---|
DURATION-1 [8] | ExeOW: 1.88 ExeBID: 1.78 | ExeOW: 15%* ExeBID: −11%* | ExeOW: 4.49 ExeBID: 4.72 | ExeOW: −0.31* ExeBID: −0.1* | ExeOW: 1.14 ExeBID: 1.20 | ExeOW: −0.02* ExeBID: −0.03* |
DURATION-1 1-year follow-up [22] | ExeOW: 1.88 ExeBID: 1.78 | ExeOW: −15%* ExeBID: −13%* | ExeOW: 4.39 ExeBID: 4.65 | ExeOW: −0.25* ExeBID: −0.23* | ExeOW: 1.13 ExeBID: 1.18 | ExeOW: −0.01* ExeBID: −0.04* |
DURATION-1 3-year follow-up [23] | 1.7 | −12%* | 4.5 | −0.26* | 1.2 | +0.03* |
DURATION-1 6-year follow-up [17] | 1.7 | −5.2%* | 4.5 | −0.26* | 1.2 | +0.07* |
DURATION-2 [12] | ExeOW: 1.9 SITA: 1.9 PIO: 2.2 | ExeOW: −5% SITA: −5% PIO: −16% (p = 0.006) | ExeOW: 4.5 SITA: 4.6 PIO: 4.9 | Exe-LAR: → SITA: ↑ PIO: ↑ +0.16* | ExeOW: 1.1 SITA: 1.1 PIO: 1.1 | ExeOW: +0.05* SITA: +0.05* PIO: +0.16* |
DURATION-3 [13] | ExeOW: 1.85 GLAR: 1.82 | ExeOW: −4% GLAR: −11% | ExeOW: 4.82 GLAR: 4.81 | ExeOW: −0.12* GLAR: −0.04* p < 0.05 | ExeOW: 1.2 GLAR: 1.19 | ExeOW: 0.0 GLAR: −0.01 p = NS |
DURATION-3 3-year follow-up [18] | ExeOW: 1.86 GLAR: 1.81 | ExeOW: + 2% GLAR: −3% p = NS | ExeOW: 4.82 GLAR: 4.81 | ExeOW: −0.13* GLAR: −0.07* p = NS | ExeOW: 1.20 GLAR: 1.19 | ExeOW: +0.05 GLAR: +0.05 p = NS |
DURATION-4 [11] | NR | No significant change | NR | No significant change | NR | No significant change |
DURATION-5 [14] | ExeOW: 1.9 ExeBID: 1.7 | ExeOW: (−0.011*) ExeBID: (−0.10*) | ExeOW: 4.7 ExeBID: 5.0 | ExeOW:−0.39* ExeBID: +0.01* | ExeOW: 1.11 ExeBID: 1.18 | ExeOW: 0* ExeBID: + 0.03* |
DURATION-6 [15] | NR | NR | ExeOW: 4.5 LIRA: 4.6 | ExeOW: −0.06* LIRA: −0.15* | ExeOW: 1.1 LIRA: 1.2 | ExeOW: +0.02* LIRA: +0.02* |
Study [Reference] | Baseline LDL-C mean (mmol/L) | LDL-C mean decrease from baseline (mmol/L) | Baseline SBP mean (mmHg) | SBP mean decrease from baseline (mmHg) | Baseline DBP mean (mmHg) | DBP mean decrease from baseline (mmHg) |
---|---|---|---|---|---|---|
DURATION-1 [8] | ExeOW: 2.37 ExeBID: 2.6 | ExeOW: −0.13 ExeBID: +0.03 | ExeOW: 127.8 ExeBID: 129.5 | ExeOW: −4.7* ExeBID: −3.4* | ExeOW: 77.7 ExeBID: 79.6 | ExeOW: −1.7* ExeBID: −1.7* |
DURATION-1 1-year follow-up [22] | ExeOW: 2.3 ExeBID: 2.53 | ExeOW: −0.08* ExeBID: −0.07* | NR | ExeOW: −6.2* ExeBID: −3.8* | NR | ExeOW: −2.8* ExeBID: −1.8* |
DURATION-1 3-year follow-up [23] | 2.4 | −0.18* | 129 | −2.14* | 78 | −2.0* (p < 0.05) |
DURATION-1 6-year follow-up [17] | 2.4 | −0.25* | 129 | +1.7* | 78 | −1.2* |
DURATION-2 [12] | ExeOW: 2.7 SITA: 2.7 PIO: 2.9 | No significant differences between the 3 groups | ExeOW: 126 SITA: 126 PIO: 127 | ExeOW vs. SITA: p = 0.005 (Normal BP)
p = 0.009 (hypertensive pts) | NR | No significant differences between the 3 groups |
DURATION-3 [13] | ExeOW: 2.68 GLAR: 2.68 | ExeOW −0.05 GLAR +0.04 p = NS | ExeOW: 135 GLAR: 133 | ExeOW: −3 GLAR: −1
p = 0.05 | ExeOW: 81 GLAR: 80 | ExeOW: −1 GLAR: −1
p = NS |
DURATION-3 3-year follow-up [18] | ExeOW: 2.68 GLAR: 2.68 | ExeOW −0.17 GLAR −0.13 p = NS | ExeOW: 135 GLAR: 133 | ExeOW: −2 GLAR: +2 | ExeOW: 81 GLAR: 80 | ExeOW: −2 GLAR: −2 |
DURATION-4 [11] | NR | No significant change | NR | ExeOW: −1.3* MET: NR PIO −1.7* SITA −1.8* | NR | ExeOW: NR MET: NR PIO: −2.5 SITA: NR |
DURATION-5 [14] | ExeOW: 2.7 ExeBID: 3.1 | ExeOW: −0.16 ExeBID: +0.07 | Abnorm Bas. BP ExeOW: 142 ExeBID: 139 Normal Bas. BP ExeOW: 118 ExeBID: 118 | Abnorm. Bas. BP ExeOW: −7.9* ExeBID: −7.7* Normal Bas. BP ExeOW: + 1.6* ExeBID: +5.0* | Abnorm. Bas. BP ExeOW: 81 ExeBID: 82 Normal Bas. BP ExeOW: 74 ExeBID: 74 | Abnorm. Bas. BP ExeOW: −0.4* ExeBID: −2.3* Normal Bas. BP ExeOW: +0.6* ExeBID: +1.8* |
DURATION-6 [15] | ExeOW: 2.5 LIRA: 2.5 | ExeOW: −0.05* LIRA: −0.09* | ExeOW: 132 LIRA: 134 | ExeOW: −2.5* LIRA: −3.4* | ExeOW: 79 LIRA: 80 | ExeOW: −0.5* LIRA: −0.5* |
Hemodynamic Effects
Cardioprotective Effects
Tolerability
ExeOW Study | LS mean body weight decrease (kg) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
ExeOW | ExeBID | SITA | PIO | GLAR | MET | PIO | SITA | LIRA | DET | |
DURATION-1 [8] | −3.7 | −3.6 | ||||||||
DURATION-2 [12] | −2.3 | −0.3 § | 2.8 ¶ | |||||||
DURATION-3 [13] | −2.6 | 1.4* | ||||||||
DURATION-4 [11] | −2 | −2 | 1.5* | 0.3* | ||||||
DURATION-5 [14] | −2.3 | −1.4 | ||||||||
DURATION-6 [15] | −2.7 | −3.6 |
Study [Ref] | Adverse event (%) | Withdrawal rate (%) | |||||||
---|---|---|---|---|---|---|---|---|---|
Txs | Nausea | Vomiting | Diarrhea | Injection site reactions | Upper respiratory infections | Minor hypoglycemia | Due to AE | Overall | |
DURATION-1 [8] | ExeOW | 26.4 | 10.8 | 13.3 | 22.3 | 8.1 | 5.4 | 6.1 | 13.5 |
ExeBID | 34.5 | 18.6 | 13.1 | 11.7 | 17.2 | 6.2 | 4.8 | 11.6 | |
DURATION-2 [12] | ExeOW | 24 | 11 | 18 | 10 | 7 | 1 | 6.3 | 25.3 |
SITA | 10 | 2 | 10 | 10 | 16 | 3 | 3.0 | 16.3 | |
PIO | 5 | 3 | 10 | 7 | 20 | 1 | 3.6 | 23.8 | |
DURATION-3 [13] | ExeOW | 13 | 4 | 9 | 13 | n/a | 8 | 5 | 10.3 |
GLAR | 1 | 1 | 4 | 2 | n/a | 26 | 1 | 6.3 | |
DURATION-4 [11] | ExeOW | 11.3 | 4.8 | 10.9 | 10.5 | 7.7 | 5.2 | 2.4 | 15.3 |
MET | 6.9 | 3.3 | 12.6 | 10.2 | 4.5 | 4 | 2.4 | 13.1 | |
SITA | 3.7 | 1.8 | 5.5 | 6.7 | 9.8 | 1 | 0.6 | 14.1 | |
PIO | 4.3 | 3.1 | 3.7 | 3.7 | 8.6 | 3.1 | 3.1 | 18.4 | |
DURATION-5 [14] | ExeOW | 14 | 4.7 | 9.3 | 13 | 7 | 3.9 | 5 | 15.5 |
ExeBID | 35 | 8.9 | 4.1 | 10 | 4.1 | 3.3 | 5 | 22.8 | |
DURATION-6 [15] | ExeOW | 9 | 4 | 6 | 10 | 3 | 10.8 | 2.6 | NR |
LIRA | 21 | 11 | 13 | 1 | 3 | 8.9 | 5.3 | NR | |
DAVIES et al. [22] | ExeOW | 18 | 14 | 17 | 1 | NR | 6 | 11 | NR |
DET | 2 | 9 | 11 | 0 | NR | 7 | 5 | NR | |
INAGAKI et al. [81] | ExeOW | 27 | 18 | 8.8 | 34.9 | 25.6 | 9.8 | 5.1 | NR |
GLAR | 3 | 4 | 2.4 | 0 | 21.2 | 20.8 | 2.8 | NR |
Adverse event | 30-Week annual event rate (%) | Week 312 annual event rate (%) |
---|---|---|
Nausea | 84.6 | 7.6 |
Injection site pruritus | 51.0 | 1.6 |
Diarrhea | 37.3 | 10.2 |
Vomiting | 36.1 | 6.9 |
Urinary tract infection | 22.4 | 7.6 |
Constipation | 19.9 | 2.8 |
Nasopharyngitis | 18.7 | 16.0 |
Upper respiratory infection | 16.2 | 17.2 |
Viral gastroenteritis | 14.9 | 3.3 |
Arthralgia | 12.4 | 6.7 |
Sinusitis | 8.7 | 10.4 |
Back pain | 8.7 | 5.7 |
Hypertension | 6.2 | 4.3 |
Cough | 6.2 | 3.2 |
Bronchitis | 5.0 | 4.7 |
Pain in extremity | 2.5 | 5.0 |
Muscoloskeletal pain | 2.5 | 4.2 |