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GLEPAGLUTIDE, A LONG-ACTING GLUCAGON-LIKE PEPTIDE-2 ANALOG, IMPROVES INTESTINAL ABSORPTION OF MACRONUTRIENTS, BODY WEIGHT AND LEAN BODY MASS IN PATIENTS WITH SHORT BOWEL SYNDROME
Mark Hvistendahl1, Rahim M. Naimi1, 3, Mark B. Hansen2, Palle B. Jeppesen1
1. Department of Medical Gastroenterology, Rigshospitalet, Copenhagen, Denmark; 2. Research & Development, Zealand Pharma, Glostrup, Denmark; 3. Clinical Development, Zealand Pharma, Glostrup, Denmark

Background & Aim
Short bowel syndrome (SBS) is a condition characterized by malassimilation in part due to reduced intestinal surface area following resection of the intestines. SBS encompasses a wide functional spectrum ranging from mild intestinal insufficiency (II) to severe intestinal failure (IF). Glucagon-like peptide-2 (GLP-2) treatment improves intestinal wet weight absorption by increasing intestinal mucosal surface area and possibly by slowing gastrointestinal emptying and reducing gastrointestinal secretions.
We aimed to evaluate the efficacy of 3 doses of glepaglutide, a long-acting GLP-2 analog, on intestinal macronutrient and energy absorption (secondary endpoint) as well as body composition (exploratory endpoint) in patients with SBS-II and SBS-IF.

Methods
This was a randomized, double-blind, proof-of-concept, dose-finding, single-center, cross-over, phase 2 study. Glepaglutide was given subcutaneously once daily to 18 patients (13 SBS-IF and 5 SBS-II; 16 with jejunostomy and 2 with ≥50% colon in continuity). Mean age was 62 years and mean short bowel length was 110 cm. In a cross-over fashion, patients received 2 of 3 doses (0.1 mg, 1 mg and 10 mg) of glepaglutide for 3 weeks. A wash-out period of 4-8 weeks separated the 2 treatment periods.
Intestinal absorption of macronutrients (nitrogen by Kjeldahl, lipid by Van de Kamer and carbohydrate by Englyst) and energy (by bomb calorimetry and sum of the 3 macronutrients) were measured during 72-hour metabolic balance studies prior to and in the end of each treatment period. Body composition was measured by dual-energy x-ray absorptiometry.

Results
Eighteen patients were randomized, and 16 patients completed the study.
Compared to baseline, significant increases in intestinal absorption of protein and lipid were observed in the 1 mg/d dose group, and carbohydrate absorption tended to increase (p=0.053). In the combined 1+10 mg/d dose group, protein and carbohydrate absorption increased significantly, while the lipid absorption did not.
Glepaglutide increased intestinal energy absorption measured by calculated sum of macronutrients in the 1 mg/d and combined 1+10 mg/d dose groups whereas energy absorption measured by bomb calorimetry did not reach statistical significant changes. The effect going from 1 to 10 mg seems neutral (Table 1).
Daily dosing of 1 and 10 mg glepaglutide significantly increased body weight (2.1 and 1.9 kg, respectively) compared to baseline. This was associated with an increase in lean body mass (Table 2). No changes were observed in fat mass or bone mineral content.

Conclusions
Glepaglutide increased intestinal protein, lipid and total energy absorption as measured by the sum of macronutrients in patients with SBS. Compared to baseline, body weight and lean body mass also increased with glepaglutide, which may reflect increases in macronutrient and fluid absorption.

Table 1. Energy absorption during 72-hour metabolic balance studies.
Changes from baseline.
Adjusted means [95% CI]
1+10 mg/day10 mg/day1 mg/day0.1 mg/day
PROTEIN
absorption
Absolute
(kJ/day)

Relative
(%)
171 [3, 339]
p=0.047

-53 [-150, 45]
p=0.258
80 [-159, 318]
p=0.473

-42 [-173, 89]
p=0.493
262 [20, 504]
p=0.037

-63 [-196, 70]
p=0.313
-174 [-425, 78]
p=0.154

-83 [-220, 55]
p=0.212
LIPID
absorption
Absolute
(kJ/day)

Relative
(%)
309 [-90, 708]
p=0.115

24 [-3, 51]
p=0.079
103 [-407, 612]
p=0.663

0.1 [-38, 39]
p=0.994
516 [3, 1029]
p=0.049

48 [9, 87]
p=0.021
-330 [-864, 205]
p=0.200

-31 [-72, 10]
p=0.122
CARBOHYDRATE
absorption
Absolute
(kJ/day)

Relative
(%)
352 [91, 613]
p=0.013

19 [2, 36]
p=0.029
336 [-31, 703]
p=0.069

21 [3, 39]
p=0.029
368 [-6, 743]
p=0.053

18 [-1, 36]
p=0.059
-11 [-399, 377]
p=0.952

-2 [-20, 17]
p=0.862
ENERGY
absorption by calculated sum of macronutrients
Absolute
(kJ/day)

Relative
(%)
822 [205, 1439]
p=0.014

18 [-2, 38]
p=0.069
544 [-317, 1406]
p=0.189

11 [-11, 34]
p=0.286
1099 [223, 1976]
p=0.019

25 [3, 47]
p=0.032
-491 [-1402, 419]
p=0.257

-10 [-33, 13]
p=0.352
ENERGY
absorption by bomb calorimetry
Absolute
(kJ/day)

Relative
(%)
511 [-62, 1084]
p=0.075

22 [-26, 71]
p=0.325
588 [-227, 1403]
p=0.139

21 [-48, 90]
p=0.506
435 [-393, 1263]
p=0.269

24 [-46, 94]
p=0.468
-377 [-1234, 481]
p=0.351

6 [-66, 78]
p=0.856
Adjusted means and [95% CI] are estimated in an ANCOVA model including treatment period, parenteral support and total oral intake at baseline as covariates. Protein is derived from a nitrogen-to-protein conversation factor (6.25 * 24 kJ/g (in vitro)).


Table 2. Body weight and body composition.
Changes from baseline.
Adjusted mean [95% CI]
10 mg/day
(n=11)
1 mg/day
(n=11)
0.1 mg/day
(n=10)
Body weight
(kg)
1.9 [1.0, 2.8]
p=0.0003
2.1 [1.1, 3.0]
p=0.0001
-0.2 [-1.2, 0.8]
p=0.633
Body composition
by DEXA scan
Total lean mass
(g)
2302 [1084, 3519]
p=0.0006
2240 [1004, 3475]
p=0.001
724 [-568, 2016]
p=0.260
Total fat mass
(g)
-524 [-1405, 358]
p=0.233
62 [-818, 942]
p=0.886
-815 [-1749, 120]
p=0.085
Total bone mineral content
(g)
-2 [-62, 57]
p=0.934
19 [-42, 79]
p=0.531
-21 [-84, 41]
p=0.487
Adjusted means and [95% CI] are estimated in an ANCOVA model including baseline, treatment period, parenteral support and total oral intake at baseline as covariates. DEXA: Dual-Energy X-ray Absorptiometry.



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