Table 3.
Studies using the GLP-1 antagonist Exendin 9–39 to assess glycaemic outcomes in people with type 2 diabetes or postprandial hypoglycaemia after bariatric surgery.
| Author | Groups | No (F%) | Meal | Ex-9 Dose/Placebo | Age (years) | BMI before Intervention (Kg/m2) | BMI at Assessment (Kg/m2) | Time of Assessment | T2D Duration (years) |
Glucose Parameters with Ex-9 vs. Placebo |
Insulin Parameters with Ex-9 vs. Placebo | C-Peptide Parameters with Ex-9 vs. Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Studies in Population with T2D Preoperatively. | ||||||||||||
| Jorgensen 2013 [37] |
RYGB, T2D preoperatively | 9 (33%) | MMTT, 300 kcal, 50% carbs, 35% fat, 15% protein | 43,000 pmol/kg bolus and then 900 pmol/kg/min OR saline (IV) |
50 ± 3 | 37.67 (mean) | 1 week postop | 5.7 ± 1.3 | +64.6% (↑NC) AUC (0–240) +28.8% (↑NC) 2 h glucose |
−22.9% (↓NC) AUC (0–240) | −28.4% (↓NC) AUC (0–240) | |
| RYGB, T2D preoperatively | 34.03 (mean) | 3 months postop | +39.2% (↔ NC) AUC (0–240) +29.2% (↑NC) 2 h glucose |
−31.7% (↔ NC) AUC (0–240) | −25.5% (↓NC) AUC (0–240) | |||||||
| Preoperative values used as control | 39.2 ± 2.4 | Preop | +49.7 (↑) AUC (0–240) +18% (↑) 2 h glucose |
−2.9% (↔) AUC (0–240) | −2.1% (↔) AUC (0–240) | |||||||
| Vetter 2015 [140] |
RYGB, T2D preoperatively |
10 (90%) | MMTT, 240 Kcal, 55% carbs, 25% protein 20% fat |
7500 pmol/kg bolus and then 750 pmol/kg/min OR saline (IV) |
54 ± 6.6 | 43.2 ± 1.9 | 39.1 ± 1.4 | 58.9 ± 12.1 days postop | 5.2 ± 3.3 | +41.4% (↑ND) AUC (0–180) | −44.9% (↓ND) AUC (0–180) | −37.1% (↓*) AUC (0–180) |
| Intensive lifestyle modification (ILM), T2D at baseline | 10 (50%) | 51.8 ± 11.6 | 41.8 ± 1.2 | 37.3 ± 1.4 | 85.5 ± 24.4 days post-ILM initiation | 3.1 ± 2.7 | +44.4% (↑) AUC (0–180) | −10% (↔) AUC (0–180) | −5.1% (↔) AUC (0–180) |
|||
| Shah 2019 [141] | RYGB, T2D preoperatively | 22 (91%) | 75 g of oral glucose | 600 pmol/kg/min OR saline (IV) | 44.1 ± 8.6 | 42.1 ± 5.1 | 34.9 ± 4.6 | 3 months | 8.26 ± 7.6 | NR | −48.8% (↓NA) in AUC (0–180) | −51.1% (↓NA) in ISR AUC (0–180) |
| No control group | ||||||||||||
| Jimenez 2013 [139] |
RYGB, T2D remission | 8 (100%) | MMTT, 398 kcal, 50% carbs, 35% fat, 15% protein | 7500 pmol/kg bolus and then 750 pmol/kg/min OR saline (IV) |
54.1 ± 8.4 | 46.8 ± 6.6 | 30.8 ± 4.7 | NR (>24 months postop) | 2.1 ± 1.1 | +10.07% (↑NC) AUC (0–120) +NR (↑NC) 2 h glucose |
−53.8% (↓NC) AUC (0–120) | −24.9% (↓NC) in AUC (0–120) |
|
Healthy controls |
7 (NR) |
47.0 ± 10.8 |
NA |
21.1 ± 1.3 |
NA |
NA |
+9.3% (↑) AUC (0–120) +NR (↔) 2 h glucose |
−4% (↔) in AUC (0–120) |
−2.9% (↔) in AUC (0–120) |
|||
| Author | Groups | No (F%) | Meal | Ex-9 Dose/Placebo | Age (years) | BMI before Intervention (Kg/m2) | BMI at Assessment (Kg/m2) | Time of Assessment |
T2D Duration
(years) |
Glucose Parameters with
Ex-9 vs. Placebo |
Insulin Parameters with Ex-9 vs. Placebo | C-Peptide Parameters with Ex-9 vs. Placebo |
| Jimenez 2014 [142] |
SG, T2D remission | 8 (67%) | MMTT, 398 kcal, 50% carbs, 35% fat, 15% protein | 7500 pmol/kg bolus and then 750 pmol/kg/min OR saline (IV) |
49.8 ± 12.4 | 47.7 ± 5.5 | 32.7 ± 2.3 | 3.4 ± 0.9 yearspostop | 2.8 ± 1.8 | +12.4% (NR) in AUC (0–120) +23.7% (↑) in 2 h glucose |
−18.4% (↓*) in total insulin output | −39.1% (↓) in b-cell glucose sensitivity |
|
SG, without T2D preop |
6 (67%) |
52.1 ± 13.1 |
44.9 ± 5.3 |
31.1 ± 4.2 |
2.9 ± 0.9 years postop |
NA |
+2.9% (NR) in AUC (0–120) +16.7% (↔) in 2 h glucose |
−11.1% (↓*) in total insulin output |
+3.3% (NR) in b-cell glucose sensitivity |
|||
|
Healthy controls |
8 (67%) |
50 ± 13 |
NA |
23.3 ± 2.0 |
NA |
NA |
+9.4% (NR) in AUC (0–120) +12.7% (↔) in 2 h glucose |
+2.4% (↔) in total insulin output |
−33.7% (NR) in b-cell glucose sensitivity |
|||
| Studies in Populations with Postprandial Hyperinsulinaemic Hypoglycaemia | ||||||||||||
| Salehi 2014 [144] |
RYGB with established PHH | 9 (100%) | MMTT, 350 kcal, 57% carbs, 28% fat, 15% protein | 7500 pmol/kg bolus and then 750 pmol/kg/min OR saline (IV) |
44.6 ± 4.5 | 48 ± 2.6 | 30.9 ± 2.5 | 3.9 ± 0.5 years postop | NA | +67.3% (NR) in nadir levels +250.4% (↑*,**) AUC (0–180) |
−63.3% (↓*,**) AUC (0–180) | −46.8% (↓*,**) in ISR AUC (0–180) |
|
RYGB without symptoms of PHH |
7 (43%) |
47.6 ± 3.0 |
55 ± 2.6 |
33.8 ± 3.4 |
3.6 ± 0.7 years postop |
NA |
+14.3% (NR) in nadir levels +32.1% (↔ ND) AUC (0–180) |
−19.2% (↔ ND) AUC (0–180) |
−22.4% (↔ ND) in ISR AUC (0–180) |
|||
| BMI-matched controls | 8 (88%) | 33.1 ± 3.3 | NA | 32.8 ± 1.1 | NA | NA | +9.8% (NR) in nadir levels +5.4% (↔) AUC (0–180) |
−22.2% (↔) AUC (0–180) | −22.6% (↔) in ISR AUC (0–180) | |||
| Craig 2017 [143] |
RYGB with established PHH | 8 (100%) | 75 g of oral glucose | 7500 pmol/kg bolus and then 750 pmol/kg/min OR saline (IV) |
46.4 ± 4 | NR | 31.2 ± 2 | 5 years postop | NA | +69.2% (↑) in nadir levels +21.1% (↑) AUC (0–180) |
−56% (↓) in peak levels −57.1% (↓) AUC (0–180) |
−51.4% (↓) AUC (0–180) |
| BMI-matched controls | 8 (100%) | 47 ± 3 | NA | 31.0 ± 0 | NA | NA | NA | NA | NA | |||
| Craig 2018 [174] | RYGB with established PHH |
8 (100%) | 75 g of oral glucose | 0.13–0.38 mg/kg (subcut) | 45 ± 3.8 | 49 ± 2.3 | 29 ± 1.3 | 6.9 years postop | NA | +66% (↑NA) in nadir levels +72% (↑NA) AUC (90–180) |
−57% (↓) in peak levels −48% (↓) AUC (0–60) |
−44% (↓) in peak levels −31% (↓) AUC (0–60) |
| No control group | ||||||||||||
| Tan 2020 [176] |
RYGB with established PHH (treated with Lyo Ex-9) | 14 (100%) | 75 g of oral glucose | 0.05–0.46 mg/kg bd for 3 days (subcut) | 45 ± 5 | 48 ± 3 | 28 ± 4 | 8.6 years postop | NA | +39% (↑NA) in nadir levels^ +79% (↑NA) AUC (90–180)^ |
−50% (↓) in peak levels^ −47% (↓) AUC (0–60)^ |
NA NA |
|
RYGB with established PHH (treated with Liq Ex-9) |
5 (100%) |
0.38 mg/kg bd for 3 days (subcut) |
51 ± 3 |
50 ± 4 |
30 ± 4 |
10.2 years postop |
NA |
+47% (↑NA) in nadir levels +71% (↑) AUC (90–180) |
−67% (↔) in peak levels −63% (↓) AUC (0–60) |
NA NA |
||
| No control group | ||||||||||||
| Salehi 2011 [175] | RYGB without symptoms of PHH | 12 (75%) |
MMTT with clamp MMTT, 57% carbs, 15% protein, 28% fat |
7500 pmol/kg bolus and then 750 pmol/kg/min OR saline (IV) |
47 ± 2 | 52 ± 2 | 33 ± 1 | 3.3 ± 0.3 years postop | NA | 0% AUC (95–270) (clamp study) | −50% (↓*) AUC (95–270) | −28% (NR) AUC (95–270) |
|
RYGB with symptoms of PHH |
12 (92%) |
39 ± 2 |
52 ± 2 |
32 ± 2 |
3.7 ± 0.4 years postop |
NA |
0% AUC (95–270) (clamp study) |
−54% (↓*) AUC (95–270) |
−37% (NR) AUC (95–270) |
|||
|
BMI matched controls |
10 (80%) |
43 ± 3 |
33 ± 2 |
NA |
NA |
0% AUC (95–270) (clamp study) |
−16% (NR) AUC (95–270) |
−12% (NR) AUC (95–270) |
||||
Roux-en-Y gastric bypass, T2D: Type 2 Diabetes Mellitus, F: Female, MMTT: Mixed Meal Tolerance Test, SG: Sleeve Gastrectomy, PHH: Postprandial Hyperinsulinaemic Hypoglycaemia, Ex-9: Exendin 9–39, AUC: Area Under the Curve, 2 h: 2 h, ISR: Insulin Secretion Rate, bd: twice daily, NA: Not Applicable, NR: Not Reported, ↑: increased with Ex-9 vs. placebo, ↔: no change with Ex-9 vs. placebo, ↓: reduced with Ex-9 vs. placebo,*: significant difference between surgical and non-surgical group on the outcome change with Ex-9 vs. placebo, NC: no comparison performed between study groups on the outcome change with Ex-9 vs. placebo, ND: no difference between surgical and non-surgical group on the outcome change with Ex-9 vs. placebo, **: significant difference between surgical groups on the outcome change with Ex-9 vs. placebo, ^ the analysis is for a subgroup of 6 participants received ≥20 mg (≥0.35 mg/kg) of subcutaneous Lyophilized (Lyo) Ex-9, Lyo: Lyophilized Ex-9, Liq: Liquid form of Ex-9, IV: intravenous, subcut: subcutaneous.