Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial.

BACKGROUND: Patients with short bowel syndrome might have impaired postprandial endogenous glucagon-like peptide-2 (GLP-2) secretion, which is required for optimal intestinal adaptation. We aimed to assess the therapeutic potential of glepaglutide, a novel long-acting GLP-2 analogue, for reducing faecal output and increasing intestinal absorption in patients with short bowel syndrome. METHODS: In this single-centre, double-blind, crossover, randomised phase 2 trial, adults (aged ≥18 to ≤90 years) with short bowel syndrome and with a faecal wet weight output of 1500 g/day or more were randomly assigned to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0·1 mg; 1 mg, 10 mg; 1 mg, 0·1 mg; 0·1 mg, 10 mg; or 0·1 mg, 1 mg). Patients received daily subcutaneous injections of the first assigned dose of glepaglutide for 3 weeks, followed by a washout period of 4-8 weeks, and then the second dose of glepaglutide for 3 weeks. An unmasked statistician generated the randomisation list, and the trial investigator enrolled patients and assigned them their patient numbers. Trial investigators, patients, and other care providers were masked throughout the trial. The primary endpoint was the absolute change from baseline in faecal wet weight output, measured separately over the two treatment periods. Metabolic balance studies were done before and after each treatment period to assess the primary endpoint. Per-protocol analysis was used to assess the efficacy. Safety analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02690025, and has completed. FINDINGS: Of the 22 patients screened between Feb 5, 2016, and Jan 25, 2017, 18 patients were randomly assigned and treated with glepaglutide; 16 patients completed the trial. Treatment with 1 mg and 10 mg glepaglutide changed the adjusted mean faecal output by -592 g/day (95% CI -913 to -272; p=0·002) and -833 g/day (-1152 to -515; p=0·0002) from baseline, respectively. No changes were observed with 0·1 mg glepaglutide. Of the 18 patients who were randomly assigned to treatment, common treatment-related adverse events were stoma complications (13 [72%] patients), injection site reactions (11 [61%]), peripheral oedema (ten [56%]), nausea and abdominal pain (eight [44%] each), polyuria and fatigue (six [33%] each), abdominal distention, vomiting, and dizziness (five [28%] each); and cough and decreased appetite (four [22%] each). Related or possibly related serious adverse events were reported in two patients in the 0·1 mg dose group and two patients in the 10 mg dose group. These events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin. No patients died during the trial. INTERPRETATION: Glepaglutide was well tolerated, and was associated with improved intestinal absorption in patients with short bowel syndrome with 1 mg and 10 mg glepaglutide, but not with 0·1 mg glepaglutide. Larger phase 3 clinical trials of longer durations have been initiated to fully assess the safety and efficacy of glepaglutide. FUNDING: Zealand Pharma.

Assessment of muscle function using hybrid PET/MRI: comparison of 18F-FDG PET and T2-weighted MRI for quantifying muscle activation in human subjects.

PURPOSE: The aim of this study was to determine the relationship between relative glucose uptake and MRI T 2 changes in skeletal muscles following resistance exercise using simultaneous PET/MRI scans. METHODS: Ten young healthy recreationally active men (age 21 - 28 years) were injected with 18F-FDG while activating the quadriceps of one leg with repeated knee extension exercises followed by hand-grip exercises for one arm. Immediately following the exercises, the subjects were scanned simultaneously with 18F-FDG PET/MRI and muscle groups were evaluated for increases in 18F-FDG uptake and MRI T 2 values. RESULTS: A significant linear correlation between 18F-FDG uptake and changes in muscle T 2 (R 2 = 0.71) was found. for both small and large muscles and in voxel to voxel comparisons. Despite large intersubject differences in muscle recruitment, the linear correlation between 18F-FDG uptake and changes in muscle T 2 did not vary among subjects. CONCLUSION: This is the first assessment of skeletal muscle activation using hybrid PET/MRI and the first study to demonstrate a high correlation between 18F-FDG uptake and changes in muscle T 2 with physical exercise. Accordingly, it seems that changes in muscle T 2 may be used as a surrogate marker for glucose uptake and lead to an improved insight into the metabolic changes that occur with muscle activation. Such knowledge may lead to improved treatment strategies in patients with neuromuscular pathologies such as stroke, spinal cord injuries and muscular dystrophies.

Effects of acquisition time and reconstruction algorithm on image quality, quantitative parameters, and clinical interpretation of myocardial perfusion imaging.

BACKGROUND: Recently introduced iterative reconstruction algorithms with resolution recovery (RR) and noise-reduction technology seem promising for reducing scan time or radiation dose without loss of image quality. However, the relative effects of reduced acquisition time and reconstruction software have not previously been reported. The aim of the present study was to investigate the influence of reduced acquisition time and reconstruction software on quantitative and qualitative myocardial perfusion single photon emission computed tomography (SPECT) parameters using full time (FT) and half time (HT) protocols and Evolution for Cardiac Software. METHODS: We studied 45 consecutive, non-selected patients referred for a clinically indicated routine 2-day stress/rest (99m)Tc-Sestamibi myocardial perfusion SPECT. All patients underwent an FT and an HT scan. Both FT and HT scans were processed according to our standard procedure with both ordered-subset expectation maximization (OSEM) + filtered back projection (FBP) reconstructions and a second reconstruction of HT scans was performed with the RR software producing three datasets for each patient for visual analysis (FT-OSEM, HT-OSEM, and HT-RR) and for quantitative analysis (FT-FBP, HT-FBP, and HT-RR). The datasets were analyzed using commercially available QGS/QPS software and read by two observers evaluating image quality and clinical interpretation. Image quality was assessed on a 10-cm visual analog scale score. RESULTS: HT imaging was associated with loss of image quality that was compensated for by RR reconstruction. HT imaging was also associated with increasing perfusion defect extents, an effect more pronounced using RR than FBP reconstruction. Compared to standard FT-FBP, HT-RR significantly reduced left ventricular volumes whereas HT-FBP increased end-systolic volume. HT imaging had no effect on measured left ventricular ejections fraction or measures of reversibility. Image interpretation found a higher level of concordance between FT-OSEM and HT-RR than between FT-OSEM and HT-OSEM without any observable systematic effects. CONCLUSIONS: Use of RR reconstruction algorithms compensates for loss of image quality associated with reduced scan time. Both HT acquisition and RR reconstruction algorithm had significant effects on motion and perfusion parameters obtained with standard software, but these effects were relatively small and probably of limited clinical importance. Although no systematic effects on image interpretation were observed, the influence on diagnostic accuracy remains to be determined.

Effects of local alpha2-adrenergic receptor blockade on adipose tissue lipolysis during prolonged systemic adrenaline infusion in normal man.

During prolonged adrenaline infusion, lipolysis peaks within 30 min and thereafter tends to decline, and we hypothesized that the stimulation of local adipose tissue alpha2-adrenergic receptors accounts for this decline. The lipolytic effect of a prolonged intravenous adrenaline infusion combined with local infusion of the alpha2-blocker phentolamine in superficial and deep abdominal subcutaneous adipose tissue and in preperitoneal adipose tissue was studied in seven healthy subjects. The interstitial glycerol concentration in the three adipose tissue depots was measured by the microdialysis method. Regional adipose tissue blood flow was measured by the (133)Xe clearance technique. Regional glycerol output (lipolytic rate) was calculated from these measurements and simultaneous measurements of arterial glycerol concentrations. Adrenaline infusion increased lipolysis in all three depots (data previously published). Phentolamine infusion did not augment lipolysis in the subcutaneous depots while it increased the lipolytic rate in the preperitoneal depot. It is concluded that alpha2-adrenergic receptors do not have a significant effect on subcutaneous adipose tissue lipolysis during high circulating adrenaline concentrations, and the decrease in lipolysis in subcutaneous adipose tissue under prolonged adrenaline stimulation is thus not attributed to alpha2-adrenergic receptor inhibition of lipolysis. However, in the preperitoneal adipose tissue depot, alpha2-adrenergic receptor tone plays a role for the lipolytic rate obtained during prolonged adrenaline stimulation.

Post-exercise abdominal, subcutaneous adipose tissue lipolysis in fasting subjects is inhibited by infusion of the somatostatin analogue octreotide.

To determine whether blockade of the exercise-induced increase in growth hormone (GH) secretion may affect the regional lipolytic rate in the post-exercise recovery period, the aim of the present experiments was to study the effect of infusion of the somatostatin analogue octreotide on the s.c., abdominal adipose tissue metabolism, before, during and after exercise in healthy, fasting, young male subjects. The adipose tissue net releases of fatty acids and glycerol were measured by arterio-venous catheterizations and simultaneous measurements of adipose tissue blood flow with the local Xe-clearance method. Nine subjects were studied during 1-h basal rest, and then during continuous octreotide infusion during 1-h rest, 1-h exercise at 50% of maximal oxygen consumption and 4-h post-exercise rest. A control study on seven subjects was performed under similar conditions but without octreotide infusion. The results show that octreotide infusion during rest increased lipolysis and fatty acid release from the abdominal, s.c. adipose tissue. The exercise-induced increase in lipolysis and fatty acid release does not seem to be affected by octreotide when compared with the control study without octreotide infusion while the post-exercise increase in lipolysis is inhibited by octreotide, suggesting that the exercise-induced increase in GH secretion plays a role for the post-exercise lipolysis in s.c., abdominal adipose tissue.

Lipid mobilization from human abdominal, subcutaneous adipose tissue is independent of sex during steady-state exercise.

The aim of the study was to elucidate whether there are sex differences of significant biological importance in the human abdominal, subcutaneous adipose tissue lipid metabolism when studied by Fick's Principle during rest and exercise in steady-state conditions. The net mobilization of fatty acids and glycerol from the abdominal, subcutaneous adipose tissue was measured by arterio-venous catheterizations and simultaneous measurements of adipose tissue blood flow with the local Xe-clearance technique in 16 healthy, young normal weight men and women during rest, during 1 h of exercise at moderate intensity, and for another 60 min during post-exercise recovery. The results show that there are not significant sex differences with respect to the steady-state fatty acid and glycerol mobilizations neither during resting condition nor during exercise.

Determination of adipose tissue blood flow with local 133Xe clearance. Evaluation of a new labelling technique.

Adipose tissue blood flow was measured in six healthy, non-obese subjects with the xenon wash-out technique after labelling of the tissue by either injection of 133Xe dissolved in isotonic sodium chloride (water depot) or injection of 133Xe in gas form (gas depot). The wash-out rates were registered from four depots simultaneously. Two depots were placed above the umbilicus, and two depots were placed below the umbilicus in the abdominal, subcutaneous adipose tissue. A water depot and a gas depot were placed in the two positions, respectively. It was not possible to demonstrate any difference between the wash-out rates registered from the two depot types, and it was also not possible to demonstrate any difference between the changes in wash-out rates induced by an oral glucose load. Similarly, the tissue distribution of the water and the gas depots appeared to be similar as registered by a gamma camera. It is concluded that that the two tissue labelling modes give identical results. However, there are significant regional differences in the wash-out rates of xenon from subcutaneous, abdominal adipose tissue, the wash-out rates from infraumbilical depots being about 20% lower than from the supraumbilical depots.