Until recently, the medical treatment options in short bowel patients with intestinal insufficiency or failure were based on antidiarrhoeals (codeine, opium, and loperamide) and anti-secretory agents (
Eleven SBS patients (3 female, 8 male;
Patient characteristics at baseline.
Patient ID | Gender/Age (years)/Diagnosis | Body mass index ( | Small bowel (cm) | Colon-in-cont. (%) | Time since last surgery (years) | Wet weight intake (kg/d) | Fecal wet weight excretion (kg/d) | Parenteral fluid (L/d) | Diet energy intake (MJ/d) | Fecal energy excretion (MJ/d) | Patenteral energy (MJ/d) | Duration of HPN (years) | Time on GLP-2 (days of |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
HRM | F/47/CD | 21.3 | 150 | 0 | 2.5 | 5.2 | 3.7 | 1.0 | 13.5 | 7.1 | 0.8 | 2.5 | |
LM | M/27/CD | 21.0 | 70 | 75 | 2.5 | 3.9 | 2.3 | 2.3 | 11.8 | 6.0 | 6.4 | 2.5 | |
OB | M/49/CD | 25.5 | 150 | 0 | 11.6 | 3.1 | 1.3 | 0.5 | 13.2 | 4.6 | 0.0 | 11.6 | |
GL | M/53/CD | 17.3 | 180 | 0 | 20.6 | 3.2 | 1.6 | no | 16.8 | 4.4 | no | no | |
JP | M/24/CD | 20.4 | 130 | 100 | 2.3 | 3.1 | 0.7 | 1.8 | 16.4 | 4.6 | 4.5 | 2.3 | |
EFP | F/55/CD | 17.5 | 50 | 0 | 0.5 | 2.2 | 4.9 | 3.1 | 8.0 | 7.1 | 5.5 | 1.7 | |
JE | M/44/UC compl. | 27.2 | 200 | 0 | 1.6 | 5.9 | 3.9 | no | 13.8 | 5.5 | no | no | |
JHJ | M/55/UC compl. | 22.2 | 200 | 0 | 2.3 | 4.6 | 1.9 | 1.3 | 17.8 | 2.8 | 0.4 | 2.3 | |
UDJ | F/50/UC compl | 25.8 | 150 | 0 | 0.9 | 2.8 | 2.2 | 2.9 | 8.8 | 2.2 | 2.7 | 2.9 | |
JV | M/67/CD | 22.6 | 180 | 0 | 12.1 | 8.7 | 7.1 | no | 28.2 | 18.1 | no | no | |
FVL | M/59/CD | 20.1 | 290 | 0 | 5.8 | 3.1 | 1.2 | no | 7.8 | 1.3 | no | no |
M
Over the two years, the patients were admitted at least eight times to the hospital for 72-hour evaluations. After the baseline evaluations, the patients were given native GLP-2, 400 mcg TID, subcutaneous, for one year. For these studies we employed synthetic human GLP-2, corresponding to human proglucagon 126–158, custom-synthesized by PolyPeptide Laboratories GmbH, Wolfenbüttel, Germany, as described previously [
The patients were asked to fill in deviations from their daily medical and parenteral prescriptions in a patient diary, and GLP-2 compliance was evaluated and crosschecked by counting returned empty vials. The patients also described effects and side effects of GLP-2 treatment in this diary. During the 72-hour admissions, the patients were monitored for safety (adverse events, physical exams, injection site examinations, and standard laboratory results).
During admissions, the patients were instructed to fill in three validated questionnaires regarding quality of life: The Sickness Impact Profile (SIP) [
The SIP measures sickness-related dysfunction and is designed to cover patient perception of performance in areas of activity in everyday life. It contains 136 items in two main dimensions and 5 independent categories in areas of activity; Physical (ambulation and mobility, body care and movement), psychosocial (social interaction, alertness and emotional behavior, communication), and independent categories (sleep and rest, eating, work, home keeping, recreation, and pastimes). Patients were asked to endorse or check those statements that were in accordance with their present situation. No positive answers were equivalent to no behavioral dysfunction. The SIP percent scores of the dimensions and categories were obtained by summing the number of positive statements to the items in each dimension and category, dividing that sum by the total sum of the possible values and multiplying the quotient by 100. Zero percent indicates the best possible function (absence of dysfunction), whereas 100% indicates presence of all possible dysfunctional behavior. At the end of the SIP questionnaire patients were asked to mark their overall quality of life on a 9 cm visual analogue scale (VAS). At the left at 0 cm a miserable quality of life was indicated, whereas an ideal quality of life was indicated at 9 cm at the right end of the scale.
The SF 36 measures eight multi-item variables: physical functioning (10 items), role limitations due to physical problems (four items), pain (two items), general perception of health (five items), social functioning (two items), role limitations due to emotional problems (three items), mental health (five items), and energy and vitality (four items). For each variable items, scores are coded summed, and transformed on to a scale from 0 (worst possible health state measured by the questionnaire) to 100 (best possible health state). The physical component summary includes the four first items and the mental component summary includes the last four items.
The 32-item IBDQ questionnaire examines four aspects of patients’ lives: symptoms directly related to the primary bowel disturbance (10 questions), systemic symptoms (5 questions), emotional (12 questions), and social function (5 questions). The response options for each question were framed as a seven-point scale at which 7 represented best function and 1 represented worst function. The scores of each aspect have been given as mean on the 7-point scale.
In addition to the three validated questionnaires regarding quality of life, an evaluation-form containing questions regarding treatment satisfaction in relation to GLP-2 treatment was given to the patients after the two years of GLP-2 treatment. At week 26 during the second year of GLP-2 treatment, where the patients also received oral bile acid replacement therapy, the patients were questioned weather they preferred subcutaneous GLP-2 (400
The Ethics Committee for Medical Research in Copenhagen, Denmark, (KF 01-235/98) approved the protocol. Procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 1983. Patients signed informed consent before entrance to the study.
The differences between admissions periods were tested with a Friedman repeated measures analysis of variance on ranks on using the SigmaStat for Windows Version 2.0 (Copyright® 1992–1995, Jandel Corporation, Erkrath, Germany) in patients completing the study. For comparisons of admission periods to the baseline period, the Dunnett method was used as the post hoc test. The frequencies of confirmatory answers in the SIP questionnaire were compared by the chi-square, alternatively Fisher exact test. A value of
The compliance reflects the tradeoff between the clinical benefits of receiving GLP-2 or possible secondary benefits perceived by the patient in relation to participating in the study versus the side effects, discomforts (from injections, frequent admissions, study-related invasive procedures, etc.), and potential risks in relation to treatment. In this respect 3 of the 11 patients did not complete the study.
Patient O. B. chose to discontinue GLP-2 after 232 days of treatment due to aggravation of chronic, intermittent, abdominal pain and nausea. A barium follow-through did not reveal a small bowel obstruction, and the patient had no clinical or biochemical evidence of activity in his Crohn’s disease. The condition improved in relation to discontinuation of treatment. The patient had a compliance of 93% of injections prior to discontinuing GLP-2 treatment.
Patient J. P. discontinued GLP-2 treatment at day 160 during the second year of the study due to signs of bowel obstruction. A barium follow-through revealed a short-segment relative obstruction at the jejuno-ascendo-anastomosis. An elective resection of a fibrostenotic lesion of less than 5 cm at the anastomosis was performed. There were no macroscopic or microscopic signs of active Crohn’s disease. Compliance was 100% the first year and 94% until treatment was discontinued the second year. The patient did not want to continue GLP-2 treatment after the resection.
Patient E. F. P. was excluded from the study by the investigator after 174 days of GLP-2 treatment during the second year of the study. The patient could not account for the dispensed GLP-2 vials and admitted to disposing them instead of returning them. At this point, it became evident that she had stopped filling in the patient diary, and that her reliability could be questioned due to an escalating abuse of analgesics. As evaluated by the returned vials and the diary, the compliance was 100% the first year of treatment. According to the patient, she had taken “most injections” during the second year of treatment until exclusion. She discontented with the decision to exclude her, since she had experienced positive effects of GLP-2.
In the remaining eight patients, who completed the study, the compliance was more than 94% during both years of GLP-2 treatment.
Two study-related serious adverse events occurred. Patient G. L. experienced a distal bowel perforation following study-related biopsies taken through the ileostomy, prior to the initiation of GLP-2 treatment. A new ileostomy was created after resection of 5 cm of small bowel. After time for recovery from surgery, the patient insisted on inclusion in the study, but he refused the biopsy scheduled for week 52. Patient J. H. J. experienced prolonged venous bleeding from the stoma after having biopsies taken at week 52. In contrary to instructions, the patient had taken a GLP-2 injection just prior to having the biopsies taken. The bleeding stopped spontaneously, but the patient was given two transfusions due to a drop in hemoglobin from 7.2 mmol
Other adverse events included a transient tender abdomen in relation to the initiation of GLP-2 treatment described in 5 of 11 patients (Patients H. R. M., O. B., J. P., E. F. P., J. E., and U. D. J.). Reduced appetite and peripheral edema was described in 2 of 11 patients (Patients H. R. M. and E. F. P.). Six out of 11 patient reported, that they urinated more than habitually in relation to GLP-2 treatment (Patients H. R. M., L. M., J. P., E. F. P., J. E., and J. H. J.). Nine of 11 patients described a reduction in their fecal excretions leading to a reduction in their frequency of defecation or emptying of their stoma bags (all, except patients O. B., and F. V. L.). Over the two years of treatment 5 of the 7 HPN patients (Patients H. R. M., J. P., E. F. P., J. H. J., and U. D. J.) experienced 16 episodes of catheter-related bacteremia. Seven of these episodes were seen in the patient E. F. P., who had an escalating abuse of analgesics, and who was excluded from the study due to the failure to document compliance.
The most consistent finding during physical exams in relation to GLP-2 treatment was enlargement of the stoma nipple seen in all the 9 patients with a stoma. In general, the patients detected the enlargement within a week after initiation of GLP-2 treatment, and it persisted throughout the treatment periods. The enlargement reversed toward normal size within a week after discontinuation of GLP-2 treatment.
There were no generalized skin reactions in relation to GLP-2 treatment, and in only two cases, local injection site reactions appearing as small hematomas were seen at admissions in relation to the GLP-2 injections (Patients H. R. M., and J. H. J.).
No significant changes were seen regarding the following standard laboratory results in relation to GLP-2 treatment: hemoglobin, erythrocyte volume fraction, thrombocytes, leucocytes, sedimentation, albumin, protein, C-reactive protein, alanin-aminotransferases, alkaline phosphatases, amylase, bilirubin, urea, sodium, potassium, total or ionized calcium, and magnesium. Plasma creatinine decreased at all timepoints in relation to GLP-2 treatment (range
The effect of GLP-2 on quality of life evaluated by SIP is presented in Table
Sickness impact profile, SIP (0%
( | 1st year | 2nd year | |||||||
---|---|---|---|---|---|---|---|---|---|
Baseline | Week 13 | Week 26 | Week 52 | Washout | Week 13 | Week 26 | Week 52 | ||
Treatment | None | GLP-2 | GLP-2 | GLP-2 | None | GLP-2 | GLP-2 + Cholyl-sarcosine | GLP-2 | — |
Overall | — | ||||||||
Body care and movement | — | ||||||||
Mobility | — | ||||||||
Ambulation | — | ||||||||
Physical Dimension | — | ||||||||
Emotional behaviour | — | ||||||||
Social interaction | — | ||||||||
Alertness behaviour | — | ||||||||
Communication | — | ||||||||
Psychosocial Dimension | — | ||||||||
Sleep and rest | — | ||||||||
Home management | — | ||||||||
Work | — | ||||||||
Recreation and pastimes | — | ||||||||
Eating | — | ||||||||
Independent Categories | — | ||||||||
QOL VAS-score, 0–9 cm, 9 cm | 0.01 |
QOL VAS-score
The effect of GLP-2 on quality of life evaluated by SF-36 is presented in Table
Short form 36, SF-36 (100%
( | 1st year | 2nd year | |||||||
---|---|---|---|---|---|---|---|---|---|
Baseline | Week 13 | Week 26 | Week 52 | Washout | Week 13 | Week 26 | Week 52 | ||
Treatment | None | GLP-2 | GLP-2 | GLP-2 | None | GLP-2 | GLP-2 + Cholyl-sarcosine | GLP-2 | |
Physical Function | 0.51 | ||||||||
Limitation based on Physical Function | 0.34 | ||||||||
Physical Pain | 0.19 | ||||||||
General Well-being | 0.84 | ||||||||
0.83 | |||||||||
Energy | 0.10 | ||||||||
Social Function | 0.44 | ||||||||
Limitation based on Mental Function | 0.28 | ||||||||
Mental Function | 0.02 | ||||||||
0.02 |
*
Numerically, the overall IBDQ scores were significantly better at all treatment points during the two years of GLP-2 treatment (
Inflammatory Bowel Disease Questionnaire, IBDQ (7
( | 1st year | 2nd year | |||||||
---|---|---|---|---|---|---|---|---|---|
Baseline | Week 13 | Week 26 | Week 52 | Washout | Week 13 | Week 26 | Week 52 | ||
Treatment | None | GLP-2 | GLP-2 | GLP-2 | None | GLP-2 | GLP-2 + Cholyl-sarcosine | GLP-2 | |
Overall | 0.007 | ||||||||
Bowel Symptoms | 0.61 | ||||||||
Systemic Symptoms | 0.03 | ||||||||
Emotional Function | 0.44 | ||||||||
Social Function | 0.03 |
*
The results of the treatment satisfaction questionnaire are given in Table
Evaluation of treatment satisfaction.
1 | ( |
---|---|
1. GLP-2 allows me to do, what I please to do. | |
2. I would definitely recommend the GLP-2 medication to others who share my symptoms. | |
3. I am not satisfied with the medication I current receive for my symptoms. | |
4. I am satisfied with the rapid onset of action of GLP-2. | |
5. I feel, that GLP-2 is the best medication available on the market for me. | |
6. I am satisfied with the GLP-2 medication that I have received for my symptoms. | |
7. The medication enables med to eat and drink whatever I please. |
Patients with intestinal failure frequently require life-long parenteral nutrition. Although providing good nutritional recovery, the complex technology of home parenteral nutrition may reduce the quality of life [
It has been speculated that GLP-2 could enhance small bowel adaptation and absorption, thereby possibly increasing the quality of life by reducing fecal excretions, the need for parenteral nutrition, and the incidence of HPN-related complications. Preliminary results from “proof of concept,” short-term studies have demonstrated clinically meaningful increases in intestinal absorption in relation to 35 days of treatment with native GLP-2 [
The physiological effects of long-term GLP-2 treatment in the patients included in this study are presented separately. However, in summary, the GLP-2 treatment reduced fecal wet weight losses with around 1000 mL/day, whereby the patients needed to drink less, since the parenteral support was kept constant. The effects on energy and macronutrient absorption were minor. This enabled the patients to maintain their intestinal fluid and electrolyte absorption at lower oral intakes. A reduction in the amplitude of the daily fluctuations in the fluid-balance in relation to GLP-2 treatment may explain the beneficial effects on renal function.
GLP-2 treatment was safe and well tolerated as demonstrated by the high compliance in the SBS patients completing this study (
Considering the safety, one of the patients with Crohn’s disease required elective surgery due to the evolvement of a fibrostenotic lesion at the neoterminal anastomosis. It is uncertain, whether it was induced by the GLP-2 treatment or simply reflected the natural history of the Crohn’s disease in this patient. Nevertheless, it seems that caution should be taken, when prescribing GLP-2 or analogs to patients with a relative intestinal stenosis, a narrow stoma, or a history of abdominal pain. GLP-2 treatment could cause a manifest condition of bowel obstruction. In the patient O. B., aggravation of chronic abdominal pain lead to discontinuation of GLP-2 treatment. In this respect, the reversibility of the treatment effect and the short half-life of GLP-2 are appreciated. However, all patients should be informed, that mild, but normally transient, abdominal tenderness is likely to occur when introducing GLP-2 treatment. Patients with an ostomy should also be advised to enlarge the access connection to their ostomy bags, since the stoma nipple will enlarge in relation to GLP-2 treatment. The cause of this enlargement is unknown, but it could relate to increased intestinal blood flow and blood congestion in the stoma nipple [
The occurrence of two serious adverse events in relation to study-related biopsy procedures highlights that caution should be taken when obtaining biopsies from the small bowel through ostomies and questions their necessity in the presence of better non-invasive clinical endpoints.
The general reports in the safety diaries of reductions in fecal output and increases in the need to urinate simply reflect the positive effects of GLP-2 on intestinal fluid absorption. These positive effects may, if the parenteral fluid support or the oral intake is not reduced accordingly, lead to peripheral edema (as evidenced in patients H. R. M., and E. F. P.) and theoretically to cardiac insufficiency and failure in susceptible patients.
A high incidence of catheter-related bacteremia was recorded during GLP-2 treatment (16 episodes during two years in the 7 patients receiving H. P. N.). However, excluding the seven episodes in patient E. F. P., who could no longer manage either study medication or HPN independently, the incidence approached what is described in the Danish HPN cohort [
Surveillance of standard laboratory tests obtained during the two years of GLP-2 treatment did not raise concerns. As described separately, the reduction in plasma creatinine and the increase in
To describe changes in quality in life in relation to GLP-2 treatment, we used the validated global, SIP and SF-36 questionnaires, and a more disease-specific, IBDQ, questionnaire. However, not even the IBDQ questionnaire is designed to focus on specific disabilities in relation to living with a stoma and the need for parenteral support. Furthermore, a uniform response to GLP-2 treatment is unlikely to occur. In some patients, the physiological benefits of GLP-2 on intestinal function may improve their social life, whereas others may focus on the effects on physical function. In general, GLP-2 improved the overall SIP scores and VAS-scores, and numerical, but nonsignificant, improvements were also detected regarding the SF-36 and IBDQ scores. It seems that the effects of GLP-2 are most pronounced in the psychosocial and mental domains, whereas the effects on bowel symptoms and general physical functions are less pronounced. The high compliance and treatment satisfaction (Table
The patients preferred to take GLP-2 injections TID compared to consuming Cholylsarcosine capsules TID. According to all patients, long-term acceptance of 8 capsules TID would be difficult, and the clinical applicability of long-term oral Cholylsarcosine treatment in the present form and dose therefore seems limited.
In conclusion, the main effect of GLP-2 treatment in patients with short bowel syndrome is a reduction in fecal losses of fluid and electrolytes, whereas effects on energy and macronutrient absorption are minor. This enables the patients to maintain their intestinal fluid and electrolyte absorption at lower oral intakes. Although side-effects, that is, abdominal pain and intestinal stenosis, lead to discontinuation of treatment in two patients in this study, the high compliance, treatment satisfaction, and positive trends in measures of quality of life over two years indicate that the reduction in fecal wet weight excretion of around 1000 g per day and a reduction in the need to compensate by hyperphagia/hyperdipsia in the same magnitude is desirable from a patients perspective and outdo the discomforts of injections. An alternative strategy for the HPN patients is maintaining hyperphagia/hyperdipsia in order to reduce their need for parenteral support. In this respect, the patients near both sides of the limit between intestinal insufficiency and intestinal failure are likely to achieve the largest improvements in quality of life, since treatment will either get them off or keep them off parenteral support. Based on evaluations of the HPN volumes needed in the Danish HPN-cohort, theoretically approximately 10–15% of short bowel patients with intestinal failure may be able to regain intestinal autonomy, may be weaned from H. P. N., and may have their central line removed in relation to treatment with GLP-2, 400 ug TID, provided that they are able to maintain their hyperphagia. According to most patients in this study, the benefits of GLP-2 are welcome in the limited treatments armamentarium of the short bowel syndrome.
The technical assistance of Jette Christiansen, Dorte Christensen, Hardi Hansen, and Jan Borg Rasmussen is greatly appreciated.