original article
Dose response of continuous subcutaneous infusion of recombinant glucagon-like peptide-1 in combination with metformin and sulphonylurea over 12 weeks in patients with type 2 diabetes mellitus S. S. Torekov1,2 , J. J. Holst1,2 & M. R. Ehlers3,4 1 Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 2 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 3 Restoragen, Inc., Lincoln, NE, USA 4 Immune Tolerance Network, UCSF, San Francisco, CA, USA
Aims: Any differences observed between natural glucagon-like peptide-1 (GLP-1) and studies obtained with analogues might call for renewed considerations concerning the use and design of such analogues. Thus, we aimed to evaluate the dose–response relationship of recombinant glucagon-like peptide-1 (7–36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes. Methods: We compared the efficacy and safety of three doses of recombinant GLP-1, ranging from 1.25 to 5.0 pmol/kg/min (pkm) and placebo, given by continuous subcutaneous infusion over 3 months in combination with metformin and sulphonylurea (SU), to lower haemoglobin A1c (HbA1c), fasting plasma glucose and weight in 95 type 2 diabetes patients with inadequate glycaemic control. Results: The mean decreases in HbA1c at endpoint (week 12) were significantly greater for all three rGLP-1 dose groups when each was compared with the placebo group, with the greatest decrease occurring in the 5.0 pkm dose group (−1.3%, s.d. ± 0.18, p < 0.001). The mean decreases in fasting plasma glucose from baseline to endpoint were significantly greater for all three rGLP-1 dose groups than for the placebo group, with the greatest decrease occurring in the 5.0 pkm dose group (−26.0 mg/dl, s.d. ± 8.5, p = 0.02). Body weight was significantly reduced by 1.8 kg (s.d. ± 1.3) in the 1.25 pkm dose group only (p = 0.04). Conclusions: Administration of rGLP-1 by CSCI over a 12-week period in combination with metformin and an SU had a dose dependent effect in lowering HbA1c and fasting plasma glucose. However, administration of rGLP-1 by CSCI may be less effective with respect to lowering of body weight compared with the daily and once weekly analogues. Keywords: antidiabetic drug, antiobesity drug, clinical trial, dose–response relationship, GLP-1, GLP-1 analogue Date submitted 6 September 2013; date of first decision 15 October 2013; date of final acceptance 12 November 2013
Introduction Glucagon-like peptide-1 (7–36) amide (GLP-1) and its analogues represent a new class of type 2 diabetes drugs that potentiates glucose-dependent insulin secretion, suppresses glucagon release and exerts protective effects on pancreatic β-cells [1]. It is now recognized that the optimal therapeutic effect of GLP-1 is achieved with regimens that provide sustained plasma levels of active peptide [2,3]. Such regimens include continuous subcutaneous infusion (CSCI) of GLP-1 (7–36) amide [4–6], and once or twice daily or weekly injections of GLP-1 analogues with extended plasma stability [7–9]. Long term data on the dose–response range for GLP-1 administered by CSCI have been sparse, but would be useful to evaluate Correspondence to: Signe S. Torekov, Assistant Prof., PhD, Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. E-mail: [email protected]
the dose dependence with respect to continued efficacy and tolerability. In addition, any differences observed between natural GLP-1 and studies obtained with analogues might be due to the modification introduced for prolonged GLP-1 action and might therefore call for renewed considerations concerning the use and design of such analogues. Recombinant glucagon-like peptide-1 (rGLP-1) is produced by recombinant technology and is identical in sequence to the native and synthetic GLP-1 [6]. In this study, we compared the safety and efficacy of three doses of recombinant GLP-1, ranging from 1.25 to 5.0 pmol/kg/min (pkm) and placebo, given by CSCI over 3 month in combination with metformin and sulphonylurea (SU), to lower haemoglobin A1c (HbA1c), fasting plasma glucose and weight in 95 type 2 diabetes patients with inadequate glycaemic control. In view of the gastrointestinal (GI) side-effects observed with an intravenous infusion rate of 4.8 pkm, which appears to correspond to CSCI at approximately 9.6 pkm [2,4,5], and with continuous subcutaneous infusion 8.5 pkm [10], we decided not to include even higher doses in this study.
original article
Diabetes, Obesity and Metabolism 16: 451–456, 2014. © 2013 John Wiley & Sons Ltd
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Materials and Methods
Test Product, Dose and Mode of Administration
Study Design
rGLP-1 is a 30-residue human GLP-1(7–36) amide with a calculated molecular weight (MW) of 3298.7 Da manufactured by recombinant technology. Recombinant GLP-1 drug product was formulated as a 0.5 mg/ml (1.25 pkm dose group), 1.0 mg/ml (2.5 pkm dose group) or 2.0 mg/ml (5.0 pkm group) solution in 10 mM acetic acid [adjusted to pH 4.5 with sodium hydroxide (NaOH)] containing 5.07% (weight/volume) dmannitol, filled into depyrogenated 5-ml vials at 3.3 ml per vial. Recombinant GLP-1 was delivered by CSCI (24 h/day) via a mini-pump for a duration of 12 weeks. The flow rate of study drug infusion was determined by the patient’s weight. On the basis of weight and available infusion rates, subjects in the 1.25 pkm dose group received a dose in the range 1.08–1.44 pkm; the 2.5 pkm group received 2.16–2.89 pkm; and the 5.0 group received 4.33–5.77 pkm. Placebo (delivery vehicle) was delivered by CSCI via a mini-pump for a duration of 12 weeks. The rate of infusion was determined by the patient’s weight.
This was a randomized, double-blind, parallel-group, placebo controlled, efficacy and safety study of rGLP-1 in combination with metformin and SU in patients with type 2 diabetes mellitus who had failed to achieve adequate glycaemic control with metformin plus an SU alone. This study was designed to include a 2-week screening period, a 12-week treatment period and a 1-week follow-up period for a total duration of 15 weeks. Eligible patients with type 2 diabetes had been receiving metformin plus an SU for their treatment in addition to diet and exercise. Following the initial screening visit (visit 1), patients were enrolled in a 2-week screening period during which patients continued taking their prior dose of metformin (≥1000 mg and ≤2550 mg/day) and SU (at a dose of at least 50% of the highest recommended dose in the package insert). After the 2-week screening period, patients who met the entry criteria were randomized to study drug at the baseline visit (visit 2). After randomization, study drug was administered by CSCI via a mini-pump (MiniMed 506, Medtronic MiniMed Inc, Northridge, CA, US) for 12 weeks in combination with oral metformin plus an SU. At the week 12 visit, study drug was discontinued and the patient returned 1 week later for the follow-up visit.
Diagnosis and Key Criteria for Inclusion Male or female patients, between 25 and 75 years of age, with type 2 diabetes mellitus with inadequate glycaemic control (HbA1c ≥ 7.5 and ≤12%) on combination therapy with metformin (≥1000 mg and ≤2550 mg/day) and an SU (at a dose of at least 50% of the highest recommended dose in the package insert). Patient demographics’ and baseline values are described in Table 1.
Ethics This study was conducted in accordance with the ethical principles included in the ‘Recommendations Guiding Investigators in Biomedical Research Involving Human Patients’ adopted by the 18th World Medical Assembly (WMA), Helsinki, Finland, June 1964; as amended at the 52nd WMA, Edinburgh, Scotland, October 2000. The study was also in accordance with local legal and regulatory requirements. Written informed consent was given by each patient prior to entering the study, in accordance with US Title 21 Code of Federal Regulations (CFR) Parts 50.20–50.27, the current edition of the Declaration of Helsinki, and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. The content was in compliance with Food and Drug Administration (FDA) regulations (21 CFR 50.25) and the ICH document ‘Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance’ dated April 1996.
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Laboratory Evaluations All blood samples were drawn after patients had fasted for at least 8 h but before they took their normal dose of metformin and/or SU. All patient samples were shipped to Pacific Biometrics (PBI, Seattle, WA, USA) for analysis, and included clinical chemistry, haematology, urinalysis and pregnancy testing. Efficacy tests (HbA1c and fasting plasma glucose) were performed by PBI.
Criteria for Evaluation The primary efficacy endpoint was the change in HbA1c from baseline after 12 weeks of therapy. The secondary efficacy endpoints were: (i) change in fasting plasma glucose values during 12 weeks of therapy and (ii) change in weight from baseline after 12 weeks of therapy. The fasting plasma glucose results were obtained from blood samples drawn at baseline and after 12 weeks of therapy. Body weights were measured at baseline and at the week 12 visit. Safety and tolerability were assessed by adverse experiences and by comparing changes from baseline in vital sign measurements and laboratory data.
Statistical Methods The primary efficacy analysis was performed for the intent-totreat population, which consisted of all randomized patients who received study drug and had a baseline and at least one post-baseline efficacy assessment. The primary efficacy analysis dataset was a last-observation-carried-forward dataset. Analysis of the efficacy variables was based on the a priori null hypothesis that the combination of rGLP-1 plus metformin and SU was not superior to placebo plus metformin and SU. The hypothesis test was derived from an analysis of covariance (ancova) model with terms for treatment (all dose groups), centre effects, and baseline HbA1c values. In addition, pairwise comparisons were made for each rGLP-1 dosage group against the control group using a step-down procedure.
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Table 1. Demographic and baseline characteristics. rGLP-1 (pkm) Characteristic Age (years) Mean (s.d.) Median Range Gender [n (%)] Male Female Race [n (%)] Caucasian Black Asian Hispanic American Indian Other Height (cm) Mean (s.d.) Median Range Weight (kg) Mean (s.d.) Median Range Body mass index (kg/m2 ) Mean (s.d.) Median Range Duration of diabetes (years) Mean (s.d.) Median Range
Placebo N = 23
1.25 N = 21
2.5 N = 25
5.0 N = 26
Combined N = 72
Overall N = 95
52 (9) 51 32–71
56 (10) 57 40–77
52 (9) 52 39–74
52 (8) 53 37–65
53 (9) 53 37–77
53 (9.2) 53 32–77
12 (52.2) 11 (47.8)
15 (71.4) 6 (28.6)
15 (60.0) 10 (40.0)
11 (42.3) 15 (57.7)
41 (56.9) 31 (43.1)
53 (55.8) 42 (44.2)
17 (73.9) 3 (13.0) 0 2 (8.7) 1 (4.3) 0
14 (66.7) 6 (28.6) 0 1 (4.8) 0 0
18 (72.0) 2 (8.0) 0 5 (20.0) 0 0
19 (73.1) 3 (11.5) 0 3 (11.5) 0 1 (3.8)
51 (70.8) 11 (15.3) 0 9 (12.5) 0 1 (1.4)
68 (71.6) 14 (14.7) 0 11 (11.6) 1 (1.1) 1 (1.1)
171 (9) 172 154–188
174 (8) 177 154–188
169 (8) 170 152–183
169 (9) 168 152–188
171 (9) 170 152–188
170 (9) 172 152–188
100 (16) 100 75–131
97 (14) 95 63–127
93 (19) 87 61–128
93 (14) 91 65–125
94 (16) 92 61–128
95 (16) 93 61–131
34.0 (4.3) 34.6 27.2–44.3
32.0 (4.6) 33.0 24.5–39.2
32.4 (5.7) 32.8 21.9–40.6
32.6 (3.6) 32.4 25.4–40.7
32.3 (4.7) 32.6 21.9–40.7
32.7 (4.6) 32.8 21.9–44.3
7.8 (4.2) 6.3 2.3–17.2
8.0 (3.8) 9.0 1.2–17.1
9.0 (5.6) 8.3 0.8–27.3
8.2 (4.9) 8.0 0.3–16.6
8.4 (4.8) 8.6 0.3–27.3
8.2 (4.7) 8.1 0.3–27.3
s.d., standard deviation; range, minimum–maximum; pkm, pmol/kg/min.
A similar comparison was performed between the combination of rGLP-1 and metformin plus SU groups and the metformin plus SU group for the variables of changes in fasting plasma glucose and weight. Sample size was based on the assumption that an absolute decrease in HbA1c of 1.0% from baseline would be seen after 12 weeks of therapy with rGLP-1. A one-sided step-down analysis was used to choose a sample size that was sufficient to have 80% power to detect an absolute decrease of 1% in HbA1c compared with the control group at a 5% significance level. On the basis of these assumptions and prior experience with rGLP-1, the number of patients per treatment group was set at 21.
Results Patient Disposition and Baseline Demographics A total of 188 patients with type 2 diabetes who had failed to achieve glycaemic control with metformin plus SU alone were screened at 28 study centres. Following the 2-week screening period, 95 patients from 26 centres were randomized to receive double-blind study drug. Of the 95 randomized patients 81 completed the study. Baseline demographics are presented in Table 1. The four treatment groups were matched for mean age, gender, race, body mass index (BMI) and duration of disease (p > 0.05).
Efficacy Results Safety Analyses. Safety analyses were performed for the safety population, which consisted of all randomized patients who received study drug. Adverse experiences were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse experiences were reported by primary body system and preferred term. Counting for tabulation was performed by patient and not by event; that is, a patient reporting the same event more than once had that event counted only once. A p value < 0.05 was considered significant.
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The primary efficacy variable was the change in HbA1c from baseline after 12 weeks of therapy. Overall, there was a significant decrease in HbA1c following treatment with rGLP1 compared with placebo (p < 0.001). The mean decreases in HbA1c at endpoint (week 12) were significantly greater for all three rGLP-1 dose groups when each was compared with the placebo group (p = 0.020, p = 0.001 and p < 0.001 for the 1.25, 2.5 and 5.0 pkm dose groups, respectively; Figure 1). While these values remained relatively stable in the placebo group,
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10
110 105
* **
***
8
Weight [kg]
HbA1c %
9
*
100 95 90 85
7 Placebo
1.25
2.5
5.0
80
Dose of rGLP-1 Infused (pmol / kg / min) Baseline
Placebo
3 months
1.25 Baseline
Figure 1. Dose–response effect of recombinant glucagon-like peptide1 (rGLP-1) infusion on haemoglobin A1c (HbA1c). HbA1c level at baseline (pre-treatment) and after 3 months rGLP-1 treatment. Pairwise comparisons were made for each rGLP-1 dosage group against the control group. Data are means (s.e.). * p < 0.05, ** p < 0.005 and *** p < 0.0005.
there were notable decreases in all three rGLP-1 dose groups by week 4 and HbA1c continued to decrease for patients in all three rGLP-1 dose groups throughout the study. The greatest mean decrease in HbA1c occurred in the 5.0 pkm dose group (−1.3%, s.d. ± 0.18, p < 0.001). The mean decreases in fasting plasma glucose from baseline to endpoint were significantly greater for all three rGLP-1 dose groups than for the placebo group (1.25 pkm, p = 0.02; 2.5 pkm, p = 0.01; and 5.0 pkm, p = 0.02), with the greatest mean decrease in FPG occurring in the 5.0 pkm dose group (−26.0 mg/dl, s.d. ± 8.52; Figure 2). Body weight was significantly reduced by 1.8 kg (s.d. ±1.3) only in the 1.25 pkm dose group (p = 0.04, Figure 3).
Fasting Plasma Glucose [mg/dl]
230 220 210 200
*
190
*
2.5
5.0
Dose of rGLP-1 Infused (pmol / kg / min)
*
180
3 months
Figure 3. Dose–response effect of recombinant glucagon-like peptide-1 (rGLP-1) infusion on body weight. Body weight at baseline (pre-treatment) and after 3 months rGLP-1 treatment. Pairwise comparisons were made for each rGLP-1 dosage group against the control group. Data are means (s.e.); * p < 0.05.
Safety Results Safety results are summarized in Table 2. Other than hypoglycaemia, the adverse experiences reported by the highest percentage of patients were injection site reaction (rGLP-1, 18.1%; placebo, 4.3%), nausea (rGLP-1, 18.1%; placebo, 0%), diarrhoea (rGLP-1, 15.3%; placebo, 4.3%) and headache (rGLP-1, 11.1%; placebo, 4.3%). Among the three rGLP-1 dose groups, only nausea appeared to be dose-dependent while injection site reaction, diarrhoea and headache were not. Sixteen (22.2%) patients in the rGLP1 group and three (13.0%) patients in the placebo group reported hypoglycaemic experiences. Among the three rGLP1 dose groups, 26.9%, 24.0% and 14.3% of patients in the 5.0, 2.5 and 1.25 pkm dose groups, respectively, reported hypoglycaemic experiences; all were mild or moderate in intensity and resolved with oral nutrition or discontinuation of a companion medication. Only one patient discontinued study drug as a result of hypoglycaemia; this patient was in the 5.0 pkm dose group. Of the patients who reported hypoglycaemia and had fingerstick glucose values available, two had associated blood glucose values 5.0% of patients in any dose group.
Number (%) of patients* rGLP-1 (pkm) Body systemMedDRA term
Placebo N = 23
1.25 N = 21
2.5 N = 25
5 N = 26
Combined N = 72
Any AEs GI disorders Constipation Diarrhoea NOS Dyspepsia Eructation Nausea General disorders Oedema lower limb Fatigue Injection site reaction NOS Infections/infestations Nasopharyngitis Metabolism/nutritional disorders Anorexia Hypertriglyceridemia Hypoglycaemia NOS Musculoskeletal/connective tissue disorder Neck Pain Nervous system disorders Dizziness (excluding vertigo) Headache NOS Tremor Renal/urinary disorders Urinary frequency Skin/SC tissue disorders Sweating increased
15 (65.2) 3 (13.0) 0 1 (4.3) 0 0 0 5 (21.7) 0 2 (8.7) 1 (4.3) 3 (13.0) 0 4 (17.4) 0 0 3 (13.0) 0 0 1 (4.3) 0 1 (4.3) 0 1 (4.3) 0 2 (8.7) 0
14 (66.7) 5 (23.8) 0 2 (9.5) 1 (4.8) 0 2 (9.5) 6 (28.6) 0 1 (4.8) 5 (23.8) 3 (14.3) 0 5 (23.8) 0 0 3 (14.3) 2 (9.5) 0 2 (9.5) 0 2 (9.5) 0 2 (9.5) 2 (9.5) 1 (4.8) 0
19 (76.0) 8 (32.0) 0 5 (20.0) 0 0 4 (16.0) 10 (40.0) 2 (8.0) 3 (12.0) 5 (20.0) 7 (28.0) 2 (8.0) 7 (28.0) 0 0 6 (24.0) 2 (8.0) 0 4 (16.0) 1 (4.0) 3 (12.0) 1 (4.0) 0 0 3 (12.0) 0
21 (80.8) 10 (38.5) 2 (7.7) 4 (15.4) 2 (7.7) 2 (7.7) 7 (26.9) 4 (15.4) 0 1 (3.8) 3 (11.5) 7 (26.9) 2 (7.7) 12 (46.2) 3 (11.5) 2 (7.7) 7 (26.9) 3 (11.5) 2 (7.7) 7 (26.9) 3 (11.5) 3 (11.5) 3 (11.5) 1 (3.8) 0 4 (15.4) 2 (7.7)
54 (75.0) 23 (31.9) 2 (2.8) 11 (15.3) 3 (4.2) 2 (2.8) 13 (18.1) 20 (27.8) 2 (2.8) 5 (6.9) 13 (18.1) 17 (23.6) 4 (5.6) 24 (33.3) 3 (4.2) 2 (2.8) 16 (22.2) 7 (9.7) 2 (2.8) 13 (18.1) 4 (5.6) 8 (11.1) 4 (5.6) 3 (4.2) 2 (2.8) 8 (11.1) 2 (2.8)
AE, adverse experience; GI, gastrointestinal; NOS, not otherwise specified; MedDRA, Medical Dictionary for Regulatory Activities; rGLP-1, recombinant glucagon-like peptide-1; SC, subcutaneous; pkm, pmol/kg/min. *Patients who experienced more than one episode of a particular AE were counted only once for that experience. Patients who had more than one AE within a body system category were counted only once in that body system total.
effective than the 2.5 pkm dose in terms of both parameters of glycaemic control that were studied: HbA1c and fasting plasma glucose. It is notable that the patients in this study were relatively poorly controlled on oral agents and therefore can be expected to have had significantly impaired β-cell function. Our data suggest, therefore, that higher doses of GLP-1 by CSCI may be more effective in improving glycaemic control towards the normal range in poorly controlled type 2 diabetes. Although the 5.0 pkm dose of rGLP-1 was clearly more effective in reducing plasma glucose than the lower doses, this dose also elicited the highest incidence of nausea. However, a previously published study showed that although a dose as high a 8.5 pkm gave the highest incidence of nausea, this adverse effect (AE) most commonly appeared during the first 48–72 h of administration and then abated [10], suggesting a form of tachyphylaxis of the GI effects of GLP-1; this has also been noted with both exenatide and liraglutide [7,8]. Furthermore, dose-escalation of exenatide has been shown to limit GI sideeffects [11]. Thus, with proper titration a dose of 8.5 pkm may
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be tolerable for longer term use and give even greater efficacy results, as no ceiling effect was observed in this study. We found the maximal lowering of HbA1c at 12 weeks treatment with the highest dose (−1.3%). This reduction is comparable to the studies with the daily and once weekly GLP-1 analogues, where an HbA1c reduction of 0.5–1.5% is obtained in 12 weeks in patients with a baseline HbA1c similar to our study group [12]. The only significant weight change was observed in the low dose GLP-1 group, which also had the highest baseline weight. As the effect of GLP-1 on weight loss is greater with increasing weight, our results on weight change may reflect the baseline weight of the treatment groups. In addition, the reduction in weight was only minor in our study; and this observation is in agreement with a previously published study showing limiting effect in weight reduction when GLP-1 is continuously administered in contrast to the greater effect seen with prandial subcutaneous administration [13]. The previous study showed that a 5-day treatment of rGLP-1 by prandial subcutaneous
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original article administration promptly slowed gastric emptying and reduced food intake with an ensuing weight loss in contrast to no significant change in gastric emptying, food intake and weight during continuous subcutaneous administration [13]. Most likely, differences in the plasma profiles of GLP-1 during continuous versus prandial administration, explain these differences. In addition, tachyphylaxis of the GLP-1-induced delay in gastric emptying caused by continuous administration [14] may play a role. In this context, it is tempting to speculate whether short acting GLP-1 analogues given before every major meal more effectively would reduce weight in contrast to the modest effect on weight loss of GLP-1 analogues given at greater intervals and not before every meal. Some concerns have been raised that continuous infusion of GLP-1 (7–36) amide would lead to sustained elevation of the metabolite generated by dipeptidyl-peptidase 4 metabolism of GLP-1 [the (9–36) peptide] and that this would antagonize the effect. However, an earlier study showed that at similar concentrations of intact GLP-1, but with widely ranging metabolite concentrations, the effect on plasma glucose levels was equal, indicating that the presence of the metabolite does not antagonize or otherwise influence the glucose-lowering effect of GLP-1 [15]. On the other hand, the effect of accumulation of the metabolite on weight loss is unknown and may contribute to explain the very modest effect on weight loss in our study. Twelve weeks of CSCI therapy with rGLP-1 in combination with metformin and SU were generally well tolerated, with no serious adverse effects (SAEs) and AEs mild to moderate during the double-blind treatment period. The episodes of hypoglycaemia where most likely due to the combination with SU treatment, as SU uncouple the glucose dependence of the actions of GLP-1 [16], and this has also been observed in trials testing the combination of a GLP-1 analogue with an SU. Previous studies in which GLP-1 peptides were administered to patients after all other antidiabetic drugs were withdrawn have not shown an increase in hypoglycaemia [5,8]. In conclusion, administration of rGLP-1 by CSCI over a 12-week period in combination with metformin and an SU had a dose dependent effect in lowering HbA1c and fasting plasma glucose. However, administration of rGLP-1 by CSCI does not seem to be superior in lowering HbA1c and may even be less effective with respect to lowering of body weight compared with the daily and once weekly analogues.
Acknowledgements This study was supported by Restoragen. We thank Roberta L. Schneider, Richard E. Harley, Annette L. Mathisen, Ron Brazg, Boas Gonen and Steven E. Kahn for their advice on the study design, trial conduct and statistical analysis.
Conflict of Interest M. R. E. was employed by Restoragen. S. S. T. and J. J. H have no conflict of interest. S. S. T., J. J. H. and M.R.E. were involved in the writing of the manuscript and analysis of the study. J. J. H. and M. R. E.
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designed the study. M. R. E. contributed to data collection and conduction of the study.
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Dose response of continuous subcutaneous infusion of recombinant glucagon-like peptide-1 in combination with metformin and sulphonylurea over 12 weeks in patients with type 2 diabetes mellitus S. S. Torekov1,2 , J. J. Holst1,2 & M. R. Ehlers3,4 1 Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 2 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 3 Restoragen, Inc., Lincoln, NE, USA 4 Immune Tolerance Network, UCSF, San Francisco, CA, USA
Aims: Any differences observed between natural glucagon-like peptide-1 (GLP-1) and studies obtained with analogues might call for renewed considerations concerning the use and design of such analogues. Thus, we aimed to evaluate the dose–response relationship of recombinant glucagon-like peptide-1 (7–36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes. Methods: We compared the efficacy and safety of three doses of recombinant GLP-1, ranging from 1.25 to 5.0 pmol/kg/min (pkm) and placebo, given by continuous subcutaneous infusion over 3 months in combination with metformin and sulphonylurea (SU), to lower haemoglobin A1c (HbA1c), fasting plasma glucose and weight in 95 type 2 diabetes patients with inadequate glycaemic control. Results: The mean decreases in HbA1c at endpoint (week 12) were significantly greater for all three rGLP-1 dose groups when each was compared with the placebo group, with the greatest decrease occurring in the 5.0 pkm dose group (−1.3%, s.d. ± 0.18, p < 0.001). The mean decreases in fasting plasma glucose from baseline to endpoint were significantly greater for all three rGLP-1 dose groups than for the placebo group, with the greatest decrease occurring in the 5.0 pkm dose group (−26.0 mg/dl, s.d. ± 8.5, p = 0.02). Body weight was significantly reduced by 1.8 kg (s.d. ± 1.3) in the 1.25 pkm dose group only (p = 0.04). Conclusions: Administration of rGLP-1 by CSCI over a 12-week period in combination with metformin and an SU had a dose dependent effect in lowering HbA1c and fasting plasma glucose. However, administration of rGLP-1 by CSCI may be less effective with respect to lowering of body weight compared with the daily and once weekly analogues. Keywords: antidiabetic drug, antiobesity drug, clinical trial, dose–response relationship, GLP-1, GLP-1 analogue Date submitted 6 September 2013; date of first decision 15 October 2013; date of final acceptance 12 November 2013
Introduction Glucagon-like peptide-1 (7–36) amide (GLP-1) and its analogues represent a new class of type 2 diabetes drugs that potentiates glucose-dependent insulin secretion, suppresses glucagon release and exerts protective effects on pancreatic β-cells [1]. It is now recognized that the optimal therapeutic effect of GLP-1 is achieved with regimens that provide sustained plasma levels of active peptide [2,3]. Such regimens include continuous subcutaneous infusion (CSCI) of GLP-1 (7–36) amide [4–6], and once or twice daily or weekly injections of GLP-1 analogues with extended plasma stability [7–9]. Long term data on the dose–response range for GLP-1 administered by CSCI have been sparse, but would be useful to evaluate Correspondence to: Signe S. Torekov, Assistant Prof., PhD, Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. E-mail: [email protected]
the dose dependence with respect to continued efficacy and tolerability. In addition, any differences observed between natural GLP-1 and studies obtained with analogues might be due to the modification introduced for prolonged GLP-1 action and might therefore call for renewed considerations concerning the use and design of such analogues. Recombinant glucagon-like peptide-1 (rGLP-1) is produced by recombinant technology and is identical in sequence to the native and synthetic GLP-1 [6]. In this study, we compared the safety and efficacy of three doses of recombinant GLP-1, ranging from 1.25 to 5.0 pmol/kg/min (pkm) and placebo, given by CSCI over 3 month in combination with metformin and sulphonylurea (SU), to lower haemoglobin A1c (HbA1c), fasting plasma glucose and weight in 95 type 2 diabetes patients with inadequate glycaemic control. In view of the gastrointestinal (GI) side-effects observed with an intravenous infusion rate of 4.8 pkm, which appears to correspond to CSCI at approximately 9.6 pkm [2,4,5], and with continuous subcutaneous infusion 8.5 pkm [10], we decided not to include even higher doses in this study.
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Diabetes, Obesity and Metabolism 16: 451–456, 2014. © 2013 John Wiley & Sons Ltd
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Materials and Methods
Test Product, Dose and Mode of Administration
Study Design
rGLP-1 is a 30-residue human GLP-1(7–36) amide with a calculated molecular weight (MW) of 3298.7 Da manufactured by recombinant technology. Recombinant GLP-1 drug product was formulated as a 0.5 mg/ml (1.25 pkm dose group), 1.0 mg/ml (2.5 pkm dose group) or 2.0 mg/ml (5.0 pkm group) solution in 10 mM acetic acid [adjusted to pH 4.5 with sodium hydroxide (NaOH)] containing 5.07% (weight/volume) dmannitol, filled into depyrogenated 5-ml vials at 3.3 ml per vial. Recombinant GLP-1 was delivered by CSCI (24 h/day) via a mini-pump for a duration of 12 weeks. The flow rate of study drug infusion was determined by the patient’s weight. On the basis of weight and available infusion rates, subjects in the 1.25 pkm dose group received a dose in the range 1.08–1.44 pkm; the 2.5 pkm group received 2.16–2.89 pkm; and the 5.0 group received 4.33–5.77 pkm. Placebo (delivery vehicle) was delivered by CSCI via a mini-pump for a duration of 12 weeks. The rate of infusion was determined by the patient’s weight.
This was a randomized, double-blind, parallel-group, placebo controlled, efficacy and safety study of rGLP-1 in combination with metformin and SU in patients with type 2 diabetes mellitus who had failed to achieve adequate glycaemic control with metformin plus an SU alone. This study was designed to include a 2-week screening period, a 12-week treatment period and a 1-week follow-up period for a total duration of 15 weeks. Eligible patients with type 2 diabetes had been receiving metformin plus an SU for their treatment in addition to diet and exercise. Following the initial screening visit (visit 1), patients were enrolled in a 2-week screening period during which patients continued taking their prior dose of metformin (≥1000 mg and ≤2550 mg/day) and SU (at a dose of at least 50% of the highest recommended dose in the package insert). After the 2-week screening period, patients who met the entry criteria were randomized to study drug at the baseline visit (visit 2). After randomization, study drug was administered by CSCI via a mini-pump (MiniMed 506, Medtronic MiniMed Inc, Northridge, CA, US) for 12 weeks in combination with oral metformin plus an SU. At the week 12 visit, study drug was discontinued and the patient returned 1 week later for the follow-up visit.
Diagnosis and Key Criteria for Inclusion Male or female patients, between 25 and 75 years of age, with type 2 diabetes mellitus with inadequate glycaemic control (HbA1c ≥ 7.5 and ≤12%) on combination therapy with metformin (≥1000 mg and ≤2550 mg/day) and an SU (at a dose of at least 50% of the highest recommended dose in the package insert). Patient demographics’ and baseline values are described in Table 1.
Ethics This study was conducted in accordance with the ethical principles included in the ‘Recommendations Guiding Investigators in Biomedical Research Involving Human Patients’ adopted by the 18th World Medical Assembly (WMA), Helsinki, Finland, June 1964; as amended at the 52nd WMA, Edinburgh, Scotland, October 2000. The study was also in accordance with local legal and regulatory requirements. Written informed consent was given by each patient prior to entering the study, in accordance with US Title 21 Code of Federal Regulations (CFR) Parts 50.20–50.27, the current edition of the Declaration of Helsinki, and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. The content was in compliance with Food and Drug Administration (FDA) regulations (21 CFR 50.25) and the ICH document ‘Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance’ dated April 1996.
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Laboratory Evaluations All blood samples were drawn after patients had fasted for at least 8 h but before they took their normal dose of metformin and/or SU. All patient samples were shipped to Pacific Biometrics (PBI, Seattle, WA, USA) for analysis, and included clinical chemistry, haematology, urinalysis and pregnancy testing. Efficacy tests (HbA1c and fasting plasma glucose) were performed by PBI.
Criteria for Evaluation The primary efficacy endpoint was the change in HbA1c from baseline after 12 weeks of therapy. The secondary efficacy endpoints were: (i) change in fasting plasma glucose values during 12 weeks of therapy and (ii) change in weight from baseline after 12 weeks of therapy. The fasting plasma glucose results were obtained from blood samples drawn at baseline and after 12 weeks of therapy. Body weights were measured at baseline and at the week 12 visit. Safety and tolerability were assessed by adverse experiences and by comparing changes from baseline in vital sign measurements and laboratory data.
Statistical Methods The primary efficacy analysis was performed for the intent-totreat population, which consisted of all randomized patients who received study drug and had a baseline and at least one post-baseline efficacy assessment. The primary efficacy analysis dataset was a last-observation-carried-forward dataset. Analysis of the efficacy variables was based on the a priori null hypothesis that the combination of rGLP-1 plus metformin and SU was not superior to placebo plus metformin and SU. The hypothesis test was derived from an analysis of covariance (ancova) model with terms for treatment (all dose groups), centre effects, and baseline HbA1c values. In addition, pairwise comparisons were made for each rGLP-1 dosage group against the control group using a step-down procedure.
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Table 1. Demographic and baseline characteristics. rGLP-1 (pkm) Characteristic Age (years) Mean (s.d.) Median Range Gender [n (%)] Male Female Race [n (%)] Caucasian Black Asian Hispanic American Indian Other Height (cm) Mean (s.d.) Median Range Weight (kg) Mean (s.d.) Median Range Body mass index (kg/m2 ) Mean (s.d.) Median Range Duration of diabetes (years) Mean (s.d.) Median Range
Placebo N = 23
1.25 N = 21
2.5 N = 25
5.0 N = 26
Combined N = 72
Overall N = 95
52 (9) 51 32–71
56 (10) 57 40–77
52 (9) 52 39–74
52 (8) 53 37–65
53 (9) 53 37–77
53 (9.2) 53 32–77
12 (52.2) 11 (47.8)
15 (71.4) 6 (28.6)
15 (60.0) 10 (40.0)
11 (42.3) 15 (57.7)
41 (56.9) 31 (43.1)
53 (55.8) 42 (44.2)
17 (73.9) 3 (13.0) 0 2 (8.7) 1 (4.3) 0
14 (66.7) 6 (28.6) 0 1 (4.8) 0 0
18 (72.0) 2 (8.0) 0 5 (20.0) 0 0
19 (73.1) 3 (11.5) 0 3 (11.5) 0 1 (3.8)
51 (70.8) 11 (15.3) 0 9 (12.5) 0 1 (1.4)
68 (71.6) 14 (14.7) 0 11 (11.6) 1 (1.1) 1 (1.1)
171 (9) 172 154–188
174 (8) 177 154–188
169 (8) 170 152–183
169 (9) 168 152–188
171 (9) 170 152–188
170 (9) 172 152–188
100 (16) 100 75–131
97 (14) 95 63–127
93 (19) 87 61–128
93 (14) 91 65–125
94 (16) 92 61–128
95 (16) 93 61–131
34.0 (4.3) 34.6 27.2–44.3
32.0 (4.6) 33.0 24.5–39.2
32.4 (5.7) 32.8 21.9–40.6
32.6 (3.6) 32.4 25.4–40.7
32.3 (4.7) 32.6 21.9–40.7
32.7 (4.6) 32.8 21.9–44.3
7.8 (4.2) 6.3 2.3–17.2
8.0 (3.8) 9.0 1.2–17.1
9.0 (5.6) 8.3 0.8–27.3
8.2 (4.9) 8.0 0.3–16.6
8.4 (4.8) 8.6 0.3–27.3
8.2 (4.7) 8.1 0.3–27.3
s.d., standard deviation; range, minimum–maximum; pkm, pmol/kg/min.
A similar comparison was performed between the combination of rGLP-1 and metformin plus SU groups and the metformin plus SU group for the variables of changes in fasting plasma glucose and weight. Sample size was based on the assumption that an absolute decrease in HbA1c of 1.0% from baseline would be seen after 12 weeks of therapy with rGLP-1. A one-sided step-down analysis was used to choose a sample size that was sufficient to have 80% power to detect an absolute decrease of 1% in HbA1c compared with the control group at a 5% significance level. On the basis of these assumptions and prior experience with rGLP-1, the number of patients per treatment group was set at 21.
Results Patient Disposition and Baseline Demographics A total of 188 patients with type 2 diabetes who had failed to achieve glycaemic control with metformin plus SU alone were screened at 28 study centres. Following the 2-week screening period, 95 patients from 26 centres were randomized to receive double-blind study drug. Of the 95 randomized patients 81 completed the study. Baseline demographics are presented in Table 1. The four treatment groups were matched for mean age, gender, race, body mass index (BMI) and duration of disease (p > 0.05).
Efficacy Results Safety Analyses. Safety analyses were performed for the safety population, which consisted of all randomized patients who received study drug. Adverse experiences were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse experiences were reported by primary body system and preferred term. Counting for tabulation was performed by patient and not by event; that is, a patient reporting the same event more than once had that event counted only once. A p value < 0.05 was considered significant.
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The primary efficacy variable was the change in HbA1c from baseline after 12 weeks of therapy. Overall, there was a significant decrease in HbA1c following treatment with rGLP1 compared with placebo (p < 0.001). The mean decreases in HbA1c at endpoint (week 12) were significantly greater for all three rGLP-1 dose groups when each was compared with the placebo group (p = 0.020, p = 0.001 and p < 0.001 for the 1.25, 2.5 and 5.0 pkm dose groups, respectively; Figure 1). While these values remained relatively stable in the placebo group,
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10
110 105
* **
***
8
Weight [kg]
HbA1c %
9
*
100 95 90 85
7 Placebo
1.25
2.5
5.0
80
Dose of rGLP-1 Infused (pmol / kg / min) Baseline
Placebo
3 months
1.25 Baseline
Figure 1. Dose–response effect of recombinant glucagon-like peptide1 (rGLP-1) infusion on haemoglobin A1c (HbA1c). HbA1c level at baseline (pre-treatment) and after 3 months rGLP-1 treatment. Pairwise comparisons were made for each rGLP-1 dosage group against the control group. Data are means (s.e.). * p < 0.05, ** p < 0.005 and *** p < 0.0005.
there were notable decreases in all three rGLP-1 dose groups by week 4 and HbA1c continued to decrease for patients in all three rGLP-1 dose groups throughout the study. The greatest mean decrease in HbA1c occurred in the 5.0 pkm dose group (−1.3%, s.d. ± 0.18, p < 0.001). The mean decreases in fasting plasma glucose from baseline to endpoint were significantly greater for all three rGLP-1 dose groups than for the placebo group (1.25 pkm, p = 0.02; 2.5 pkm, p = 0.01; and 5.0 pkm, p = 0.02), with the greatest mean decrease in FPG occurring in the 5.0 pkm dose group (−26.0 mg/dl, s.d. ± 8.52; Figure 2). Body weight was significantly reduced by 1.8 kg (s.d. ±1.3) only in the 1.25 pkm dose group (p = 0.04, Figure 3).
Fasting Plasma Glucose [mg/dl]
230 220 210 200
*
190
*
2.5
5.0
Dose of rGLP-1 Infused (pmol / kg / min)
*
180
3 months
Figure 3. Dose–response effect of recombinant glucagon-like peptide-1 (rGLP-1) infusion on body weight. Body weight at baseline (pre-treatment) and after 3 months rGLP-1 treatment. Pairwise comparisons were made for each rGLP-1 dosage group against the control group. Data are means (s.e.); * p < 0.05.
Safety Results Safety results are summarized in Table 2. Other than hypoglycaemia, the adverse experiences reported by the highest percentage of patients were injection site reaction (rGLP-1, 18.1%; placebo, 4.3%), nausea (rGLP-1, 18.1%; placebo, 0%), diarrhoea (rGLP-1, 15.3%; placebo, 4.3%) and headache (rGLP-1, 11.1%; placebo, 4.3%). Among the three rGLP-1 dose groups, only nausea appeared to be dose-dependent while injection site reaction, diarrhoea and headache were not. Sixteen (22.2%) patients in the rGLP1 group and three (13.0%) patients in the placebo group reported hypoglycaemic experiences. Among the three rGLP1 dose groups, 26.9%, 24.0% and 14.3% of patients in the 5.0, 2.5 and 1.25 pkm dose groups, respectively, reported hypoglycaemic experiences; all were mild or moderate in intensity and resolved with oral nutrition or discontinuation of a companion medication. Only one patient discontinued study drug as a result of hypoglycaemia; this patient was in the 5.0 pkm dose group. Of the patients who reported hypoglycaemia and had fingerstick glucose values available, two had associated blood glucose values 5.0% of patients in any dose group.
Number (%) of patients* rGLP-1 (pkm) Body systemMedDRA term
Placebo N = 23
1.25 N = 21
2.5 N = 25
5 N = 26
Combined N = 72
Any AEs GI disorders Constipation Diarrhoea NOS Dyspepsia Eructation Nausea General disorders Oedema lower limb Fatigue Injection site reaction NOS Infections/infestations Nasopharyngitis Metabolism/nutritional disorders Anorexia Hypertriglyceridemia Hypoglycaemia NOS Musculoskeletal/connective tissue disorder Neck Pain Nervous system disorders Dizziness (excluding vertigo) Headache NOS Tremor Renal/urinary disorders Urinary frequency Skin/SC tissue disorders Sweating increased
15 (65.2) 3 (13.0) 0 1 (4.3) 0 0 0 5 (21.7) 0 2 (8.7) 1 (4.3) 3 (13.0) 0 4 (17.4) 0 0 3 (13.0) 0 0 1 (4.3) 0 1 (4.3) 0 1 (4.3) 0 2 (8.7) 0
14 (66.7) 5 (23.8) 0 2 (9.5) 1 (4.8) 0 2 (9.5) 6 (28.6) 0 1 (4.8) 5 (23.8) 3 (14.3) 0 5 (23.8) 0 0 3 (14.3) 2 (9.5) 0 2 (9.5) 0 2 (9.5) 0 2 (9.5) 2 (9.5) 1 (4.8) 0
19 (76.0) 8 (32.0) 0 5 (20.0) 0 0 4 (16.0) 10 (40.0) 2 (8.0) 3 (12.0) 5 (20.0) 7 (28.0) 2 (8.0) 7 (28.0) 0 0 6 (24.0) 2 (8.0) 0 4 (16.0) 1 (4.0) 3 (12.0) 1 (4.0) 0 0 3 (12.0) 0
21 (80.8) 10 (38.5) 2 (7.7) 4 (15.4) 2 (7.7) 2 (7.7) 7 (26.9) 4 (15.4) 0 1 (3.8) 3 (11.5) 7 (26.9) 2 (7.7) 12 (46.2) 3 (11.5) 2 (7.7) 7 (26.9) 3 (11.5) 2 (7.7) 7 (26.9) 3 (11.5) 3 (11.5) 3 (11.5) 1 (3.8) 0 4 (15.4) 2 (7.7)
54 (75.0) 23 (31.9) 2 (2.8) 11 (15.3) 3 (4.2) 2 (2.8) 13 (18.1) 20 (27.8) 2 (2.8) 5 (6.9) 13 (18.1) 17 (23.6) 4 (5.6) 24 (33.3) 3 (4.2) 2 (2.8) 16 (22.2) 7 (9.7) 2 (2.8) 13 (18.1) 4 (5.6) 8 (11.1) 4 (5.6) 3 (4.2) 2 (2.8) 8 (11.1) 2 (2.8)
AE, adverse experience; GI, gastrointestinal; NOS, not otherwise specified; MedDRA, Medical Dictionary for Regulatory Activities; rGLP-1, recombinant glucagon-like peptide-1; SC, subcutaneous; pkm, pmol/kg/min. *Patients who experienced more than one episode of a particular AE were counted only once for that experience. Patients who had more than one AE within a body system category were counted only once in that body system total.
effective than the 2.5 pkm dose in terms of both parameters of glycaemic control that were studied: HbA1c and fasting plasma glucose. It is notable that the patients in this study were relatively poorly controlled on oral agents and therefore can be expected to have had significantly impaired β-cell function. Our data suggest, therefore, that higher doses of GLP-1 by CSCI may be more effective in improving glycaemic control towards the normal range in poorly controlled type 2 diabetes. Although the 5.0 pkm dose of rGLP-1 was clearly more effective in reducing plasma glucose than the lower doses, this dose also elicited the highest incidence of nausea. However, a previously published study showed that although a dose as high a 8.5 pkm gave the highest incidence of nausea, this adverse effect (AE) most commonly appeared during the first 48–72 h of administration and then abated [10], suggesting a form of tachyphylaxis of the GI effects of GLP-1; this has also been noted with both exenatide and liraglutide [7,8]. Furthermore, dose-escalation of exenatide has been shown to limit GI sideeffects [11]. Thus, with proper titration a dose of 8.5 pkm may
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be tolerable for longer term use and give even greater efficacy results, as no ceiling effect was observed in this study. We found the maximal lowering of HbA1c at 12 weeks treatment with the highest dose (−1.3%). This reduction is comparable to the studies with the daily and once weekly GLP-1 analogues, where an HbA1c reduction of 0.5–1.5% is obtained in 12 weeks in patients with a baseline HbA1c similar to our study group [12]. The only significant weight change was observed in the low dose GLP-1 group, which also had the highest baseline weight. As the effect of GLP-1 on weight loss is greater with increasing weight, our results on weight change may reflect the baseline weight of the treatment groups. In addition, the reduction in weight was only minor in our study; and this observation is in agreement with a previously published study showing limiting effect in weight reduction when GLP-1 is continuously administered in contrast to the greater effect seen with prandial subcutaneous administration [13]. The previous study showed that a 5-day treatment of rGLP-1 by prandial subcutaneous
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original article administration promptly slowed gastric emptying and reduced food intake with an ensuing weight loss in contrast to no significant change in gastric emptying, food intake and weight during continuous subcutaneous administration [13]. Most likely, differences in the plasma profiles of GLP-1 during continuous versus prandial administration, explain these differences. In addition, tachyphylaxis of the GLP-1-induced delay in gastric emptying caused by continuous administration [14] may play a role. In this context, it is tempting to speculate whether short acting GLP-1 analogues given before every major meal more effectively would reduce weight in contrast to the modest effect on weight loss of GLP-1 analogues given at greater intervals and not before every meal. Some concerns have been raised that continuous infusion of GLP-1 (7–36) amide would lead to sustained elevation of the metabolite generated by dipeptidyl-peptidase 4 metabolism of GLP-1 [the (9–36) peptide] and that this would antagonize the effect. However, an earlier study showed that at similar concentrations of intact GLP-1, but with widely ranging metabolite concentrations, the effect on plasma glucose levels was equal, indicating that the presence of the metabolite does not antagonize or otherwise influence the glucose-lowering effect of GLP-1 [15]. On the other hand, the effect of accumulation of the metabolite on weight loss is unknown and may contribute to explain the very modest effect on weight loss in our study. Twelve weeks of CSCI therapy with rGLP-1 in combination with metformin and SU were generally well tolerated, with no serious adverse effects (SAEs) and AEs mild to moderate during the double-blind treatment period. The episodes of hypoglycaemia where most likely due to the combination with SU treatment, as SU uncouple the glucose dependence of the actions of GLP-1 [16], and this has also been observed in trials testing the combination of a GLP-1 analogue with an SU. Previous studies in which GLP-1 peptides were administered to patients after all other antidiabetic drugs were withdrawn have not shown an increase in hypoglycaemia [5,8]. In conclusion, administration of rGLP-1 by CSCI over a 12-week period in combination with metformin and an SU had a dose dependent effect in lowering HbA1c and fasting plasma glucose. However, administration of rGLP-1 by CSCI does not seem to be superior in lowering HbA1c and may even be less effective with respect to lowering of body weight compared with the daily and once weekly analogues.
Acknowledgements This study was supported by Restoragen. We thank Roberta L. Schneider, Richard E. Harley, Annette L. Mathisen, Ron Brazg, Boas Gonen and Steven E. Kahn for their advice on the study design, trial conduct and statistical analysis.
Conflict of Interest M. R. E. was employed by Restoragen. S. S. T. and J. J. H have no conflict of interest. S. S. T., J. J. H. and M.R.E. were involved in the writing of the manuscript and analysis of the study. J. J. H. and M. R. E.
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designed the study. M. R. E. contributed to data collection and conduction of the study.
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