Monday, June 5, 2023
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Director, Banting and Best Diabetes Centre; Professor of Medicine, Samuel Lunenfeld Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
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The first glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes, exenatide (Byetta, Amylin Pharmaceuticals; San Diego, California), has been used clinically in the United States since April 2005. There is ongoing interest in the development of novel long-acting GLP-1 receptor agonists. The following summary discusses new information on GLP-1 analogs other than exenatide presented at the American Diabetes Association (ADA) 68th Scientific Sessions.
The long-acting GLP-1 receptor agonist albiglutide is a recombinant human serum albumin (HSA)-GLP-1 hybrid protein. As the GLP-1 epitopes are fused to the larger HSA molecule, albiglutide exhibits a pharmacokinetic profile resembling that of albumin in the circulation. Preclinical studies have demonstrated that albiglutide is able to mimic the entire range of GLP-1 actions.[1] The pharmacokinetic (PK) and pharmacodynamic (PD) profiles, safety, and tolerability of albiglutide were evaluated in 39 healthy volunteers using a single-blind, randomized, placebo-controlled, sequential, escalating-dose study.[2] Subjects were randomized to either placebo treatment or to 5 cohorts (C1-C5) that received escalating subcutaneous (SC) injections of albiglutide on days 1 and 8 as follows: C1: 0.25/1 mg; C2: 3/6 mg; C3: 16/24 mg; C4: 48/60 mg; C5: 80/104 mg. Albiglutide injections were given 30 minutes before breakfast. All subjects were followed until day 56. PK data from these studies indicated that the half-life of albiglutide was similar for all doses and ranged from 6 to 8 days, making it suitable for once-weekly dosing. PD data revealed no significant changes in glucagon, insulin, C-peptide, or free fatty acid concentrations on days 2 and 9. Individuals in the C5 cohort had significantly reduced plasma glucose and fructosamine levels compared with the placebo group. Reductions in fructosamine were also observed for C2 through C4 cohorts. Albiglutide appeared to be safe and well tolerated, with the incidence and severity of adverse events (AEs) similar to placebo.
PK and PD profiles, safety, and tolerability of albiglutide were also evaluated in 2 clinical studies in subjects with type 2 diabetes.[3] In the first study, the PK properties of albiglutide, as well as its effects on fasting plasma glucose (FPG) and 24-hour glucose profile, were examined in patients with type 2 diabetes who were either diet-controlled or had withdrawn from metformin, sulfonylurea (SU), or combination metformin/SU therapy 2 weeks prior to the study. Placebo or albiglutide (9 mg, 16 mg, or 32 mg) were administered via SC injection on days 1 and 8. PK data showed that the half-life of albiglutide ranged from 6 to 7 days in these patients. On day 9, compared with placebo, all doses of albiglutide were associated with reductions in baseline-adjusted FPG and mean 24-hour glucose control. In the second study, PK and PD data were obtained following a single SC injection of either 16 mg or 64 mg of albiglutide into the arm, thigh, or abdomen. This non-placebo-controlled study was carried out in individuals with type 2 diabetes who were either diet-controlled or being treated with metformin or a thiazolidinedione. The half-life of albiglutide in this study was 4 to 6 days and was consistent for all injection sites. FPG and post-prandial glucose (PPG) levels were measured on day 3 (the day albiglutide reaches maximum postdosing concentration). Both doses of albiglutide reduced FPG levels compared with baseline. Significant reductions in PPG relative to baseline were achieved with the 64-mg dose. In both studies, there were no significant changes in glucagon, insulin, C-peptide, insulin:glucose, or insulin:glucagon associated with albiglutide treatment. Albiglutide exhibited a favorable safety profile and was well tolerated. AEs were generally mild and similar to placebo for both studies.
AVE0010 is an exendin-4-based GLP-1 receptor agonist that exhibits 4-fold greater affinity for the human GLP-1 receptor compared with native GLP-1.[4] The efficacy, safety, tolerability, PK, and PD of AVE0010 were examined in a 28-day, randomized, multicenter, placebo-controlled, parallel-group study of 64 patients with type 2 diabetes on a stable treatment regimen of metformin and/or SU.[5] Patients received SC injections of placebo or stepwise increasing doses of AVE0010 either once or twice a day while continuing their metformin and/or SU therapy. AVE0010 was started at a dose of 5 micrograms (mcg)/injection and increased by 2.5 mcg increments every fifth day (based on tolerability) to a maximum dose of 20 mcg/injection. Some patients did form antibodies to AVE0010, and PK data were reported only for those individuals who were antibody-negative (n = 59). The half-life of AVE0010 ranged from 2.7 to 4.3 hours and was slightly longer in the groups that received twice-daily dosing. The 20-mcg dose of AVE0010 (both once a day and twice a day) produced significant reductions in placebo-subtracted changes from baseline for PPG, FPG, mean 7-point plasma glucose profile, postprandial glucagon, and glycated hemoglobin (A1C) levels. AVE0010 was reported to be safe and well tolerated, with a low incidence of nausea and vomiting.
The dose-response effect of AVE0010 was determined in a 13-week, multicenter, randomized, placebo-controlled, parallel group study of 542 patients with type 2 diabetes who were inadequately controlled on metformin monotherapy. Patients received SC injections of placebo or 5, 10, 20, or 30 mcg of AVE0010 (once or twice daily). The 20- and 30-mcg doses of AVE0010 were administered in escalating doses during the first 4 weeks of the study. All AVE0010 groups had significantly greater improvements in change in A1C from baseline compared with placebo. A dose-response relationship for A1C level was observed for both the once-daily and twice-daily dosing regimens of AVE0010. AVE0010 treatment also resulted in dose-dependent increases in the percentage of patients achieving an A1C < 7.0 % (ADA target) or < 6.5 % (International Diabetes Federation and American College of Endocrinology target), reductions in body weight from baseline, and decreases in FPG, PPG, and mean plasma glucose. The most frequent AEs associated with AVE0010 included transient dose-dependent nausea, diarrhea, and vomiting.
The effects of AVE0010 on glucose-stimulated insulin secretion (GSIS) and beta-cell function were evaluated using pancreatic islets isolated from 8 human donors who did not have diabetes.[6] Islets were cultured either (A) acutely (1 hour) under physiologic conditions at low (2.8 mmol/L) or high (20 mmol/L) glucose concentrations, or (B) chronically (48 hours) under lipotoxic conditions, followed by a 1-hour incubation at low or high glucose concentration. Under physiologic conditions, AVE0010 dose-dependently increased GSIS in human islets and was more potent than GLP-1. Chronic lipotoxic stress conditions led to increases in triglyceride content, decreases in insulin content, and reductions in GSIS in untreated human islets. Although AVE0010 and GLP-1 had no effect on triglyceride content, both peptides were able to prevent lipid-induced insulin depletion. Moreover, AVE0010 and GLP-1 were able to preserve the beta-cell response to glucose in human islets.
R1583 (taspoglutide) is a long-acting GLP-1 analog in which amino acids 8 and 35 of the native GLP-1 peptide are substituted with aminoisobutyric acid to prevent DPP-IV- and protease-mediated cleavage at the N- and C-terminus, respectively.[7] R1583 is formulated as a zinc-based drug to prolong its PK activity. The safety, tolerability, PK profile, and PD effects of single doses of R1583 were examined in a randomized, double-blind, placebo-controlled, sequential-dose-escalating study in 48 subjects with type 2 diabetes inadequately controlled with metformin.[8] Participants were given a single SC injection of placebo or 1, 8, or 30 mg of R1583. Plasma levels of R1583 were detectable for up to 14, 28, or 35 days after administration of the 1-, 8-, or 30-mg dose, respectively. There was a dose-dependent decrease in body weight, FPG, PPG, and mean 24-hour blood glucose area under the curve values with all doses of R1583 after 14 days, relative to placebo. However, these parameters only reached statistical significance with the 30-mg dose. Plasma fructosamine values were also decreased at postinjection days 21 and 28 with the 30-mg dose of R1583 compared with placebo. The most common AEs associated with R1583 were gastrointestinal in nature, dose-dependent, and transient. There was no evidence of anti-GLP-1 antibody formation in this study.
The safety and tolerability of escalating doses of R1583 were assessed in a randomized, double-blind, placebo-controlled phase 2 clinical study of patients with type 2 diabetes who had not achieved sufficient glucose control on metformin.[7] Weekly SC injections of placebo or 20 mg of R1583 were given to 133 patients for 4 weeks. After 4 weeks, patients were either maintained on the 20-mg dose of R1583 (20/20), or were titrated up to 30 mg (20/30) or 40 mg (20/40) of R1583 weekly for an additional 4 weeks. All patients underwent a 4-week follow-up period subsequent to the last dose of R1583. FPG levels were reduced, and the percentage of patients achieving A1C levels ≤ 7% was increased by all dose combinations of R1583 compared with placebo. The 20/20 dose of R1583 was as efficacious as either the 20/30 or 20/40 dose, with respect to reductions in A1C, suggesting that up-titrating the dose of R1583 after an initiation period adds no additional benefit to glucose control. The most common AEs reported were mild-moderate nausea, diarrhea, and vomiting. These were dose-dependent and transient. Low titer antibodies were detected in 3 of 90 patients.
The efficacy, safety, and tolerability of R1583 were evaluated in a second randomized, double-blind, placebo-controlled phase 2 clinical study of 306 patients with type 2 diabetes who had inadequate glucose control on metformin.[9] Patients underwent 8 weeks of treatment with SC injection of placebo or 5, 10, or 20 mg of R1583 administered weekly, or 10 or 20 mg of R1583 administered biweekly, and were followed for an additional 4 weeks after the last R1583 injection. Compared with placebo, A1C levels were significantly decreased by 8 weeks for all R1583 dosing regimens. In addition, the percentage of individuals who attained A1C levels ≤ 7% was significantly greater for all R1583 groups vs placebo. Progressive, dose-dependent reductions in body weight (compared with baseline values) were observed in the 10- and 20-mg weekly and 20-mg biweekly treatment groups. The drug was reported to be safe and well tolerated. AEs included mild-moderate nausea, vomiting, and diarrhea, which were dose-related and transient. Antibodies were detected in a small fraction of R1583-treated patients.
Liraglutide is a DPP-IV-resistant GLP-1analog that has been modified by 2 amino acid changes (one addition and one substitution) and by the addition of a fatty acid group that enables it to form a noncovalent bond with serum albumin following SC administration, thus reducing its renal clearance and increasing its PK profile. The half-life of liraglutide in humans is approximately 12 hours, thus requiring only 1 injection per day.[10]
The efficacy and safety of liraglutide as a monotherapy were compared with the safety and efficacy of glimepiride monotherapy in a 52-week, double-blind, parallel-group study of 746 patients with type 2 diabetes treated with either diet and exercise or less than half-maximal doses of a single oral antidiabetic agent (OAD).[11] Patients were randomized to receive daily SC injections of 1.2 or 1.8 mg of liraglutide, or oral administration of 8 mg glimepiride. Liraglutide injections were dose escalated on a weekly basis from 0.6 to 1.8 mg/day for the first 2 weeks of treatment. Both doses of liraglutide significantly reduced A1C values from baseline compared with glimepiride, with the 1.8 mg dose of liraglutide exhibiting greater efficacy relative to the 1.2 mg dose. A greater proportion of liraglutide patients achieved A1C levels ≤ 7% with either dose of liraglutide vs glimepiride. FPG and PPG levels were significantly reduced for both doses of liraglutide compared with glimepiride. Patients in both liraglutide treatment groups lost weight, whereas individuals who received glimepiride gained weight. Systolic blood pressure (BP) was also reported to be significantly reduced in the liraglutide-treated patients compared with those treated with glimepiride. Liraglutide was well tolerated, exhibited low long-term incidence of nausea, and had a lower rate of hypoglycemia than glimepiride.
Data from three 26-week phase 3 clinical studies entitled LEAD (Liraglutide Effect and Action in Diabetes) were also presented. These were randomized, double-blind trials with both placebo and active control groups. The main objective of the LEAD studies was to evaluate the efficacy of once-daily administration of liraglutide on glycemic control in patients with type 2 diabetes treated with either a single OAD or OAD combination therapy, for a minimum of 3 months. In LEAD 1 studies, 1041 patients were randomized to receive 4 mg/day of glimepiride alone or in combination with liraglutide (0.6, 1.2, or 1.8 mg/day) or rosiglitazone (4 mg/day).[12] In LEAD 2 studies, 1091 patients were randomized to receive 2 mg/day of metformin alone or in combination with liraglutide (0.6, 1.2, or 1.8 mg/day) or glimepiride (4 mg/day).[13] In LEAD 5 studies, 581 patients were randomized to receive both glimepiride and metformin alone or in combination with either 1.8 mg/day liraglutide or insulin glargine.[14] In all 3 LEAD studies, all doses of liraglutide significantly reduced A1C values from baseline relative to active control and/or placebo, reduced FPG levels compared with placebo, and produced significant reductions in body weight vs placebo and/or active control. Liraglutide was generally well tolerated in these studies, and the most common AEs noted were mild-moderate hypoglycemia and transient mild nausea. The percentage of patients with detectable levels of liraglutide antibodies ranged from 0% to 12.7% across all 3 studies. Antibody formation was reported to have no clinical impact in LEAD 5.
An analysis of beta-cell function was also carried out in the 3 LEAD studies using the homeostatic model of assessment (HOMA) index of beta-cell function and measurement of proinsulin:insulin ratios.[15] Liraglutide in combination with OAD treatment significantly increased HOMA index of beta-cell function and reduced proinsulin:insulin ratios from baseline to end of treatment in all 3 LEAD studies.
The impact of liraglutide treatment on systolic and diastolic BP was also examined in the LEAD studies.[16] The combination of liraglutide plus OAD reduced systolic BP from baseline in all 3 trials and reached statistical significance in LEAD 2 and 5. Reductions in systolic BP were observed at the first assessment point, which was measured after 2 weeks of treatment. Although body weight was reduced in all liraglutide plus OAD treatment groups compared with active controls, time-effect profiles indicated that reductions in systolic BP could not be accounted for by changes in body weight alone. No significant changes in diastolic BP were observed in any group.
The cardiovascular actions of liraglutide were also evaluated in a preclinical study that examined the effects of liraglutide on cardiomyocyte survival in mice.[17] Nondiabetic mice were treated with saline or liraglutide twice-daily for 7 days and then underwent experimental coronary artery occlusion. Survival rate and cardiac function were increased, while infarct size, cardiac rupture, and matrix metallopeptidase 9 activity were significantly reduced in liraglutide-treated vs saline-treated mice. Moreover, liraglutide increased the expression and/or activity of genes that play a protective role against injury in the heart, including Akt, GSK3beta, Nrf2, and HO-1. Pair-feeding studies confirmed that the improved survival effect of liraglutide was independent of weight loss.
Although exenatide has been approved for clinical use, it requires twice-daily injections to be effective. Consequently, GLP-1 receptor agonist development has evolved with the generation of longer-acting GLP-1 mimetic agents that require less frequent dosing, ranging from daily to weekly to biweekly administration. A large number of preclinical and clinical studies with these agents were presented at this year's ADA meeting, thus underscoring the continued interest in the therapeutic application of GLP-1 receptor agonists for the treatment of type 2 diabetes. Data from these studies demonstrate that long-acting mimetics are well tolerated and can effectively improve glycemic control and beta-cell function and reduce body weight in patients with type 2 diabetes when used as monotherapy or in combination with conventional diabetes therapies. Whether GLP-1 receptor agonists will continue to exhibit efficacy and an acceptable safety profile over long periods of time remains to be determined. In addition, head-to-head studies are required to identify potential differences among the various long-acting agents.
