Abstract
Background:
No meta-analysis has holistically analyzed and summarized the therapeutic efficacy and safety of albiglutide in type 2 diabetes (T2D). This meta-analysis addresses this knowledge gap.
Methods:
Randomized controlled trials involving patients with T2D receiving albiglutide in the intervention arm and either a placebo or an active comparator in the control arm were searched through electronic databases. The primary outcome was the change from baseline (CFB) in glycated hemoglobin (HbA1c); secondary outcomes included CFB in fasting plasma glucose, body weight, and adverse events (AE).
Results:
From 443 initially screened articles, data from 12 randomized controlled trials involving 6423 subjects were analyzed. Albiglutide, at both doses, outperformed placebo in terms of HbA1c reductions (for albiglutide 30 mg: mean differences −1.04%, 95% confidence interval [CI] [−1.37–−0.72], P < .00001, I2 = 89%; and for albiglutide 50 mg: mean differences −1.10%, 95% CI [−1.45–−0.75], P < .00001, I2 = 90%). Higher proportions of subjects achieved HbA1c < 7% in the albiglutide arm than in placebo (for albiglutide 30 mg: odds ratio 6.26, 95% CI [2.50–15.70], P < .0001, I2 = 82%; and for albiglutide 50 mg: odds ratio 5.57, 95% CI [2.25–13.80], P = .0002, I2 = 84%). Albiglutide had glycemic efficacy comparable to other glucose-lowering drugs. CFB in body weight was similar with albiglutide and placebo. AE profile, including gastrointestinal AE, was identical with albiglutide and placebo, except for higher drug-related AE and injection-site reaction with albiglutide.
Conclusion:
Albiglutide provides reassuring data on good glycemic efficacy, tolerability, and safety over an extended period of clinical use in patients with T2D. Albiglutide 30 mg has comparable efficacy and safety profiles to albiglutide 50 mg.
Keywords: albiglutide, glucagon-like peptide-1 receptor agonists, glycated hemoglobin, hypoglycemia, meta-analysis, type 2 diabetes
1. Introduction
Glucagon-like peptide-1 receptor agonists (GLP-1RAs), a relatively newer class of anti-hyperglycemic drugs, have garnered interest for their cardiovascular (CV) and renal advantages in patients with type 2 diabetes (T2D). GLP-1RAs control blood glucose levels by increasing hyperglycemia-induced insulin secretion, suppressing glucagon secretion at hyper- or euglycemia, slowing gastric emptying, and reducing calorie intake and body weight.[1] Before basal insulin, GLP-1RAs are the preferred injectable glucose-lowering therapy for T2D due to their similar, if not superior, effectiveness in lowering glycated hemoglobin (HbA1c) with weight loss and no intrinsic risk of hypoglycemia episodes.[2] CV outcome trials involving GLP-1RAs have demonstrated their efficacy in preventing CV events such as acute myocardial infarction, stroke, and associated mortality.[3] Therefore, guidelines recommend GLP-1RAs for glycemic management and comprehensive CV risk reduction in patients with established or high risk of atherosclerotic CV disease, regardless of glycemic control status.[2,4–6] GLP-1RAs may also help prevent renal complications of T2D.[7] Gastrointestinal (GI) adverse events (AE) are the most commonly reported AE of GLP-1RAs.[8] Exenatide, liraglutide, dulaglutide, albiglutide, lixisenatide, and semaglutide are GLP-1RAs approved by the US Food and Drug Administration for T2D treatment.[9] Each GLP-1RA exhibits variations in pharmacokinetics, effectiveness, incidence of adverse reactions, and dose requirements.[10]
On April 15, 2014, the Food and Drug Administration approved albiglutide (Tanzeum; GlaxoSmithKline plc, Brentford, Middlesex, United Kingdom) subcutaneous injection to improve glycemic control in adult T2D patients, in addition to diet and exercise.[11] The recommended starting dose is 30 mg once weekly subcutaneously, which can be increased to 50 mg once weekly in patients who require additional glycemic control.[12] The efficacy and safety of albiglutide in patients with T2D have been assessed in a series of 8 phase 3 clinical trials, referred to as the HARMONY program. The trials included almost 5000 patients, 2000 of whom received albiglutide.[13–20] In addition to the HARMONY program, albiglutide has undergone several phase 2 and 3 trials.[21–26]
During the phase 2 and 3 trials, albiglutide exhibited substantial glycemic effectiveness.[11] Nevertheless, significant variations in the effectiveness and safety results of albiglutide were observed in the trials. Fisher et al have published a meta-analysis on the CV safety of albiglutide in the HARMONY program.[27] An integrated safety analysis of the HARMONY phase 3 trials and another pooled analysis of GI safety across the albiglutide development program have also been published.[28,29] However, no meta-analysis of albiglutide’s efficacy and safety in patients with T2D exists. This meta-analysis uses the newest evidence to assess albiglutide’s effectiveness and safety in T2D management.
2. Materials
This meta-analysis complied with the guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklists.[30] The meta-analysis was registered with PROSPERO, bearing the registration number CRD42024532105, and the protocol summary is accessible online. Since ethical approval was already granted for the individual studies, there was no need for additional approval for this meta-analysis.
A thorough investigation was conducted by searching multiple databases and registers, such as MEDLINE (via PubMed), Scopus, Google Scholar, Cochrane Central Register, International Clinical Trials Registry Platform, and ClinicalTrials.gov. The search covered these sources’ inception until March 20, 2024. The search strategy utilized a Boolean approach with the terms (albiglutide) AND (type 2 diabetes); the search terms were applied to titles only. A thorough and careful search was conducted to find any recently published or unpublished clinical trials in English. This search included examining references within the clinical trials included in this study and relevant journals.
The selection of clinical trials for this meta-analysis was based on the PICOS criteria. The patient population (P) consisted of individuals with T2D; the intervention (I) was the administration of albiglutide for managing T2D; the control (C) included individuals receiving either a placebo or another approved glucose-lowering drug (GLD); the outcomes (O) included HbA1c; and the study type (S) included the randomized controlled trials (RCTs). This analysis included RCTs with a minimum 12-week duration with study subjects aged ≥18 years and a diagnosis of T2D. The trials had at least 2 treatment arms/groups, with 1 receiving albiglutide as monotherapy or as part of a standard diabetes treatment regimen and the other receiving a placebo or alternative GLD, alone or in combination. Clinical trials involving animals or healthy humans, nonrandomized trials, RCTs < 12 weeks in duration, retrospective studies, pooled analyses of clinical trials, conference proceedings, letters to editors, case reports, and articles lacking data with outcomes of interest were excluded.
The primary outcome of this meta-analysis was the change from baseline (CFB) in HbA1c levels. Additional outcomes encompassed the percentage of study subjects achieving HbA1c < 6.5%, <7.0%, and <7.5% at the end of the trial and CFB in fasting plasma glucose (FPG), body weight, baseline to the end of the trial, and AE. The analyses of the outcomes were stratified according to whether the control group received a placebo or an active comparator, including oral anti-hyperglycemic drugs (OADs), other GLP-1RA, or insulin. The outcome analyses were further stratified according to the dose of albiglutide (30 mg or 50 mg).
Data extraction was independently conducted by 4 review authors using standardized data extraction forms, with details provided elsewhere.[31] The handling of missing data has also been elaborated upon in the same source.[31] Four authors independently performed the risk of bias assessment using the risk of bias tool in Review Manager (RevMan) computer program, version 7.2.0 (The Cochrane Collaboration, 2024. Available at revman.cochrane.org). Specific biases have been outlined in the same source.[31]
Outcomes were expressed as mean differences (MD) for continuous variables. For analysis, HbA1c levels were presented as percentages (%); the International System of Units was used for other variables. The results were reported as odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) for binary outcomes. The data was aggregated, employing random effect models to analyze the primary and secondary outcomes. The RevMan computer program version, 7.2.0 (The Cochrane Collaboration, 2024. Available at revman.cochrane.org) enabled the comparison of MD for both primary and secondary outcomes between the albiglutide (experimental drug) and control groups in the included studies. The results were reported as 95% CIs. Forest plots, created using RevMan web software, portrayed outcomes, with the left side favoring albiglutide and the right side favoring the control group. A significance level of P < .05 was used. The results included forest plots incorporating data from at least 2 RCTs.
The evaluation of heterogeneity was initially performed by analyzing forest plots. Afterward, a Chi2 test was conducted with N-1 degrees of freedom and a significance level of 0.05 to ascertain the statistical significance. Additionally, the I2 test was utilized in the further analysis.[32] The details of interpreting I2 values have already been elaborated elsewhere.[31]
The Grading of Recommendations Assessment, Development and Evaluation methodology assessed the quality of evidence about each meta-analysis outcome.[33] The process of creating the summary of findings table and evaluating the quality of evidence as “high,” “moderate,” “low,” or “very low” has been previously described.[31] Publication bias was evaluated using funnel plots, in which studies falling outside the inverted funnel plot indicated the presence of substantial publication bias.[34]
3. Results
3.1. Search results
The study selection process is illustrated in Figure 1. Initially, 443 articles were identified; following the screening of titles and abstracts and subsequent full-text reviews, the number of studies considered for this meta-analysis was narrowed to 19. Detailed evaluation led to the inclusion of 12 RCTs involving 6423 subjects with T2D, which met all the inclusion criteria.[13–24] Seven studies were excluded; among them, 1 was a retrospective database analysis using administrative claims data,[35] 1 assessed CV outcomes of albiglutide without assessing glycemic efficacy outcomes,[25] 1 was an extension study of Rosenstock 2014,[36] 2 were pharmacokinetics and pharmacodynamics studies with short duration,[37,38] 1 was nonrandomized, open-label, phase 3 study without a placebo group;[26] the other study compared the efficacy and safety of albiglutide from a ready-to-use, single dose, autoinjector system with the lyophilized product without a placebo group.[39]
Figure 1.
Flowchart on study retrieval and inclusion in the meta-analysis.
3.2. Study characteristics
Two of the 12 RCTs included in this meta-analysis were phase 2 studies,[21,22] and the remaining 10 were phase 3 studies.[13–20,23,24] Two studies were conducted in multiple centers in 1 country,[22,23] and others were multicenter studies conducted in 2 or more countries.[13–21,24] Three studies included a placebo,[13,14,22] 5 studies included an active comparator,[16,18–20,24] and the rest 4 studies included both placebo and active comparators in the control groups.[15,17,21,23] OADs (sitagliptin, glimepiride, and pioglitazone) were used as active comparators in 3 studies,[15,17,20] other GLP-1RAs (liraglutide and exenatide twice a day) in 3 studies[19,21,23] and insulins (insulin lispro and insulin glargine) in 3 studies.[16,18,24] Only 1 study had a single arm of albiglutide 30 mg once a week (QW),[13] and 7 studies had single arms of albiglutide 50 mg QW (initiated as albiglutide 30 mg and titrated to 50 mg)[15–20,24]; 2 studies had both albiglutide 30 mg QW and 50 mg QW arms.[14,23] The 2 phase 2 studies had 3 or more arms of albiglutide, among which only the albiglutide 30 mg QW arm was considered for analysis.[21,22] Two studies had 16 weeks duration,[21,22] 1 had 24 weeks,[23] 2 had 26 weeks,[18,24] 1 had 32 weeks,[19] and 5 studies had 52 weeks duration[13,14,16,17,20]; the other had a duration of 104 weeks.[15] Table 1 and Supplementary Table S1, Supplemental Digital Content, http://links.lww.com/MD/M882, respectively, present the details of the included and excluded studies.
Table 1.
The basic characteristics of the included randomized controlled trials and participants.
| Study name, ID [Ref. no.], trial reg. no., trial name, phase of study, study place |
Major baseline characteristics of the study subjects | Study arms | N | Age (yr, mean ± SD) | Male (%) | Diabetes duration (yr, mean ± SD) | Baseline HbA1c (%, mean ± SD) | Baseline BW (kg, mean ± SD) | Duration of RCT (wk) |
|---|---|---|---|---|---|---|---|---|---|
| HARMONY 1, Reusch 2014,[13] NCT00849056, Phase 3, Multicenter, Multi-country |
- Background AHA: TZD ± Metformin. - HbA1c 7–10%. - BMI 20–45 kg/m2. - Fasting C-peptide ≥ 0.8 ng/mL. - Creatinine clearance > 60 mL/min. |
Albiglutide 30 mg QW | 150 | 55.2 ± 9.98 | 61.3 | 8.0 ± 5.6 | 8.1 ± 1.0 | 97.6 ± 22.0 | 52 |
| Placebo | 151 | 54.9 ± 9.4 | 58.3 | 7.9 ± 6.1 | 8.1 ± 0.9 | 100.2 ± 23.1 | |||
| HARMONY 2, Nauck 2016,[14] NCT00849017, Phase 3, Multicenter in USA and Mexico |
- Background AHA: none. - HbA1c 7–10%. - BMI 20–45 kg/m2. |
Albiglutide 30 mg QW | 101 | 53.6 ± 10.9 | 57.4 | 3.4 ± 3.7 | 8.0 ± 0.8 | 95.8 ± 19.6 | 52 |
| Albiglutide 50 mg QW | 99 | 52.0 ± 11.8 | 50.5 | 4.2 ± 4.6 | 8.2 ± 0.9 | 97.1 ± 17.8 | |||
| Placebo | 101 | 53.1 ± 11.7 | 57.4 | 4.3 ± 4.0 | 8.0 ± 0.9 | 95.4 ± 19.9 | |||
| HARMONY 3, Ahrén, 2014,[15] NCT00838903, Phase 3, Multicenter, Multi-country |
- Background AHA: metformin (≥1.5 gm/day or MTD). - HbA1c 7–10%. - BMI 20–45 kg/m2. - Creatinine clearance > 60 mL/min. |
Albiglutide 30 → 50 mg QW | 302 | 54.3 ± 10.1 | 44.7 | 6.0 ± 4.3 | 8.1 ± 0.8 | 89.6 ± 18.4 | 104 |
| Sitagliptin 100 mg QD | 302 | 54.3 ± 9.8 | 46.0 | 5.8 ± 4.8 | 8.1 ± 0.8 | 90.3 ± 19.1 | |||
| Glimepiride 2 → 4 mg QD | 307 | 54.4 ± 10.0 | 51.5 | 6.0 ± 4.8 | 8.1 ± 0.8 | 91.8 ± 20.4 | |||
| Placebo | 101 | 56.1 ± 10.0 | 49.5 | 6.7 ± 6.6 | 8.2 ± 0.9 | 91.6 ± 19.3 | |||
| HARMONY 4, Weissman 2014,[16] NCT00838916, Phase 3, Multicenter, Multi-country |
- Background AHA: Metformin ± SU. - HbA1c 7–10%. - BMI 20–45 kg/m2. - Fasting C-peptide ≥ 0.8 ng/mL. - Creatinine clearance > 60 mL/min. |
Albiglutide 30 → 50 mg QW | 504 | 55.8 ± 9.3 | 56.7 | 8.9 ± 6.5 | 8.28 ± 0.9 | 95.1 ± 19.7 | 52 |
| Insulin glargine QD | 241 | 54.7 ± 9.8 | 54.8 | 8.4 ± 5.7 | 8.36 ± 0.95 | 94.6 ± 19.1 | |||
| HARMONY 5, Home 2015,[17] NCT00839527, Phase 3, Multicenter, Multi-country |
- Background AHA: metformin (≥1.5 gm or MTD) and glimepiride (≥4 mg/day). - HbA1c 7–10%. - BMI 20–45 kg/m2. - Creatinine clearance > 60 mL/min. |
Albiglutide 30 → 50 mg QW | 271 | 54.5 ± 9.5 | 49.8 | 8.5 ± 6.3 | 8.19 ± 0.91 | 89.9 ± 18.8 | 52 |
| Pioglitazone 30 → 45 mg/day | 277 | 55.7 ± 9.4 | 53.4 | 9.2 ± 6.1 | 8.29 ± 0.88 | 91.0 ± 21.2 | |||
| Placebo | 115 | 55.7 ± 9.6 | 60.9 | 9.3 ± 6.1 | 8.26 ± 0.98 | 90.9 ± 20.2 | |||
| HARMONY 6, Rosenstock 2014,[18] NCT00976391, Phase 3, Multicenter, Multi-country |
- Background AHA: insulin glargine or other intermediate- or long-acting insulin ± OADs. - HbA1c 7–10.5%. - BMI 20–40 kg/m2. - Fasting C-peptide ≥ 0.8 ng/mL. - Creatinine clearance > 60 mL/min. |
Albiglutide 30 → 50 mg QW | 285 | 54.8 ± 9.1 | 46 | 11 ± 7 | 8.5 ± 0.9 | 92.5 ± 21.5 | 26 |
| Insulin lispro TID | 281 | 56.3 ± 8.9 | 48 | 11 ± 6 | 8.4 ± 0.9 | 91.6 ± 21.0 | |||
| HARMONY 7, Pratley 2014,[19] NCT01128894, Phase 3, Multicenter, Multi-country |
- Background AHA: metformin, TZD, SU, or any combination of these. - HbA1c 7–10%. - BMI 20–45 kg/m2. - Fasting C-peptide ≥ 0.8 ng/mL. |
Albiglutide 30 → 50 mg QW | 404 | 55.4 ± 10 | 47 | 8.4 ± 6.1 | 8.18 ± 0.89 | 91.7 ± 21.2 | 32 |
| Liraglutide 0.6 → 1.8 mg/day | 408 | 55.8 ± 10 | 53 | 8.3 ± 5.6 | 8.15 ± 0.84 | 92.8 ± 22.1 | |||
| HARMONY 8, Leiter 2014,[20] NCT01098539, Phase 3, Multicenter, Multi-country |
- Background AHA: metformin, SUs, TZD. - HbA1c 7–10%. - BMI 20–45 kg/m2. - eGFR 15–89 mL/min. |
Albiglutide 30 → 50 mg QW | 249 | 63.2 ± 8.37 | 54.6 | 10.83 ± 7.4 | 8.13 ± 1.04 | 83.2 ± 19.9 | 52 |
| Sitagliptin, dose as per eGFR | 246 | 63.5 ± 9.02 | 52.8 | 11.62 ± 8.5 | 8.23 ± 0.94 | 82.8 ± 20.6 | |||
| Rosenstock 2009,[21] NCT00518115, Phase 2, Multicenter in Chile, and Dominican Republic |
- Background AHA: None or Metformin monotherapy. - HbA1c 7–10%. - BMI 20–40 kg/m2. |
Albiglutide 4 mg QW | 35 | 50.4 ± 10.25 | 42.9 | 4.4 ± 4.1 | 8.1 ± 1.0 | 97.6 ± 23.7 | 16 |
| Albiglutide 15 mg QW | 35 | 55.5 ± 10.48 | 51.4 | 4.7 ± 4.6 | 8.0 ± 0.9 | 88.4 ± 14.9 | |||
| Albiglutide 30 mg QW | 31 | 54.2 ± 9.66 | 25.8 | 5.2 ± 5.4 | 8.0 ± 0.9 | 88.1 ± 13.9 | |||
| Albiglutide 15 mg bi-weekly | 33 | 52.5 ± 9.55 | 42.4 | 4.3 ± 4.3 | 8.2 ± 1.0 | 88.9 ± 19.4 | |||
| Albiglutide 30 mg bi-weekly | 32 | 55.5 ± 9.87 | 50.0 | 5.5 ± 4.5 | 8.0 ± 1.0 | 88.0 ± 14.1 | |||
| Albiglutide 50 mg bi-weekly | 35 | 51.1 ± 10.25 | 54.3 | 5.2 ± 5.5 | 8.0 ± 0.7 | 92.3 ± 15.5 | |||
| Albiglutide 50 mg monthly | 35 | 54.1 ± 11.30 | 48.6 | 5.3 ± 3.7 | 7.9 ± 0.8 | 91.3 ± 15.3 | |||
| Albiglutide 100 mg monthly | 34 | 54.4 ± 9.89 | 55.9 | 4.3 ± 3.7 | 8.0 ± 1.0 | 92.2 ± 21.1 | |||
| Exenatide 5–10 mg BID | 35 | 53.7 ± 9.38 | 45.7 | 6.4 ± 5.4 | 8.0 ± 0.9 | 94.2 ± 23.2 | |||
| Placebo | 51 | 54.0 ± 10.62 | 54.9 | 3.9 ± 3.0 | 7.9 ± 0.9 | 91.1 ± 18.8 | |||
| Seino 2014,[22] NCT01098461, Phase 2, Multicenter in Japan |
- Background AHA: None or single OAD. - HbA1c 7–10%. - BMI 18–40 kg/m2. - Fasting C-peptide ≥ 0.8 ng/mL. |
Albiglutide 15 mg QW | 52 | 53.3 ± 10.3 | 61.5 | 6.3 ± 4.6 | 8.54 ± 0.82 | 68.6 ± 12.7 | 16 |
| Albiglutide 30 mg QW | 54 | 58.0 ± 9.3 | 70.4 | 7.8 ± 5.4 | 8.54 ± 0.86 | 67.4 ± 12.0 | |||
| Albiglutide 30 mg bi-weekly | 53 | 59.1 ± 8.5 | 77.4 | 7.2 ± 5.6 | 8.54 ± 0.81 | 68.2 ± 13.0 | |||
| Placebo | 53 | 57.5 ± 11.1 | 69.8 | 6.7 ± 7.8 | 8.57 ± 0.79 | 66.3 ± 11.2 | |||
| Nino 2018,[23] NCT01733758, Phase 3, Multicenter in Japan |
- Background AHA: single OAD. - HbA1c 7–10%. - BMI 17–40 kg/m2. - Creatinine clearance > 30 mL/min. |
Albiglutide 30 mg QW | 160 | 59.6 ± 9.0 | 78.1 | 7.2 ± 6.22 | 8.07 ± 0.78 | 69.3 ± 13.5 | 24 |
| Albiglutide 50 mg QW | 150 | 57.7 ± 9.52 | 76.0 | 6.9 ± 6.21 | 8.15 ± 0.83 | 71.5 ± 12.9 | |||
| Liraglutide 0.9 mg/day (open-label) | 103 | 58.4 ± 9.72 | 78.6 | 5.8 ± 4.34 | 8.07 ± 0.79 | 72.7 ± 13.8 | |||
| Placebo | 77 | 57.3 ± 11.27 | 67.5 | 6.7 ± 5.38 | 8.16 ± 0.88 | 68.7 ± 12.1 | |||
| Rosenstock 2020,[24] NCT02229227, Phase 3, Multicenter, Multi-country |
- Background AHA: basal-bolus insulin (TDD ≤ 140 U) ± metformin. - HbA1c 7–9%. - BMI ≤ 40 kg/m2. - Fasting C-peptide ≥ 0.8 ng/mL. |
Albiglutide 30 → 50 mg QW | 402 | 58.0 ± 9.4 | 43.3 | 15.2 ± 7.7 | 7.7 ± 0.6 | 87.8 ± 17.3 | 26 |
| Insulin lispro TID | 412 | 58.1 ± 9.5 | 48.1 | 14.7 ± 7.2 | 7.7 ± 0.6 | 89.8 ± 17.8 |
AHA = anti-hyperglycemic agents, BID = twice a day, BMI = body mass index, BW = body weight, HbA1c = hemoglobin A1c, IQR = interquartile range, QD = once a day, QW = once a week, RCT = randomized controlled trial, SD = standard deviation, SGLT-2i = sodium-glucose cotransporter-2 inhibitors, SU = sulphonylureas, TDD = total daily dose, TID = thrice a day, TZD = thiazolidinedione.
3.3. Risk of bias in the included studies
Supplementary Figure S1, Supplemental Digital Content, http://links.lww.com/MD/M884 depicts the bias risk across the 12 RCTs included in the meta-analysis. All (100%) were assessed as having low risks of bias in terms of random sequence generation (selection bias), allocation concealment (selection bias), and selective reporting (reporting bias). The assessment of performance bias (blinding of participants and investigators) and detection bias (blinding of outcome assessors) indicated high risks for one-third (33.3%) of the studies. Two-thirds (66.7%) of the studies had high risks of incomplete outcome data (attrition bias). All (100%) also had high risks of other biases. Publication bias was assessed through funnel plots given in Supplementary Figure S2, Supplemental Digital Content, http://links.lww.com/MD/M885.
3.4. Grading of the results
The grades for the certainty of evidence of the key outcomes of this meta-analysis are given in the summary of findings table (Supplementary Table S2, Supplemental Digital Content, http://links.lww.com/MD/M883).
3.5. Effect of albiglutide on the glycemic parameters
3.5.1. HbA1c
Five studies (n = 915) with albiglutide 30 mg versus placebo and 4 (n = 1192) with albiglutide 50 mg versus placebo reported CFB in HbA1c. Albiglutide, at both doses, outperformed placebo in terms of HbA1c reductions; for albiglutide 30 mg: MD −1.04%, 95% CI (−1.37–−0.72), P < .00001, I2 = 89%, low certainty of evidence; and for albiglutide 50 mg: MD −1.10%, 95% CI (−1.45–−0.75), P < .00001, I2 = 90%, low certainty of evidence (Fig. 2A).
Figure 2.
Forest plot highlighting the (A) change from baseline (CFB) in HbA1c, albiglutide versus placebo; (B) CFB in HbA1c, albiglutide versus OADs; (C) CFB in HbA1c, albiglutide versus GLP-1 RAs; (D) CFB in HbA1c, albiglutide versus insulins. GLP-1 RAs = glucagon-like peptide-1 receptor agonists, HbA1c = hemoglobin A1c, OADs = oral anti-hyperglycemic drug.
The CFB in HbA1c was comparable with albiglutide and OADs (MD −0.02%, 95% CI [−0.33–0.29], P = .88, I2 = 91%) (Fig. 2B), with albiglutide and GLP-1RAs (for albiglutide 30 mg: MD −0.07%, 95% CI [−0.50–0.35], P = .74, I2 = 77%; and for albiglutide 50 mg: MD 0.04%, 95% CI [−0.29–0.38], P = .79, I2 = 90% [Fig. 2C]), and with albiglutide and insulins (MD −0.00%, 95% CI [−0.15–0.14], P = .96, I2 = 68%) (Fig. 2D).
In subgroup analysis, albiglutide 30 mg and albiglutide 50 mg were equally effective in CFB in HbA1c in the placebo- and GLP-1RA-controlled trials (Figs. 2A and C). Comparable reductions in HbA1c were reported in phase 2 trials and phase 3 trials (Supplementary Figure S3A, Supplemental Digital Content, http://links.lww.com/MD/M886), as well as in trials with durations of <52 weeks and ≥52 weeks in the placebo-controlled studies (Supplementary Figure S3B, Supplemental Digital Content, http://links.lww.com/MD/M886).
3.5.2. HbA1c < 6.5%, <7.0%, and <7.5%
The percentages of subjects achieving HbA1c < 7.0% were also higher in the albiglutide arm than in the placebo arm; for albiglutide 30 mg: OR 6.26, 95% CI (2.50–15.70), P < .0001, I2 = 82%, very low certainty of evidence; and for albiglutide 50 mg: OR 5.57, 95% CI (2.25–13.80), P = .0002, I2 = 84%, very low certainty of evidence. Albiglutide was also superior to placebo in reducing HbA1c to <6.5% and <7.5%. Albiglutide was similarly effective to other active comparators in reducing HbA1c to <6.5%, <7.0%, and <7.5% (Table 2). Albiglutide 30 mg and albiglutide 50 mg were equally effective in achieving HbA1c < 6.5% and <7.0 reduction in the placebo- and GLP-1RA-controlled trials. Achievement HbA1c < 7.5% was similar to albiglutide 30 mg and albiglutide 50 mg in the placebo-controlled trials (Table 2).
Table 2.
Summary of secondary efficacy outcome findings.
| Outcome variables | Albiglutide arm | Control arm | Number of RCTs (participants) | Pooled effect size, OR/MD (95% CI) |
I 2 (%) | P | Subgroup difference (albiglutide 30 vs 50 mg), P |
|---|---|---|---|---|---|---|---|
| Participants achieving HbA1c < 6.5% | Albiglutide 30 mg | Placebo | 5 (915) | 6.96 (3.17–15.26) | 44 | <.00001 | .25 |
| Albiglutide 50 mg | Placebo | 4 (1192) | 3.73 (1.81–7.67) | 47 | .0004 | ||
| Albiglutide 50 mg | OADs | 3 (1697) | 1.07 (0.74–1.53) | 41 | .73 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (325) | 1.43 (0.23–8.67) | 85 | .70 | .57 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1053) | 0.82 (0.45–1.50) | 73 | .52 | ||
| Albiglutide 50 mg | Insulins | 3 (2102) | 0.98 (0.74–1.30) | 27 | .88 | NA | |
| Participants achieving HbA1c < 7.0% | Albiglutide 30 mg | Placebo | 5 (915) | 6.26 (2.50–15.70) | 82 | <.0001 | .86 |
| Albiglutide 50 mg | Placebo | 4 (1192) | 5.57 (2.25–13.80) | 84 | .0002 | ||
| Albiglutide 50 mg | OADs | 3 (1697) | 1.17 (0.78–1.75) | 71 | .44 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (325) | 0.76 (0.47–1.21) | 0 | .25 | .79 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1053) | 0.83 (0.51–1.34) | 63 | .44 | ||
| Albiglutide 50 mg | Insulins | 3 (2102) | 1.02 (0.85–1.23) | 0 | .84 | NA | |
| Participants achieving HbA1c < 7.5% | Albiglutide 30 mg | Placebo | 2 (496) | 3.51 (2.23–5.54) | 32 | <.00001 | .75 |
| Albiglutide 50 mg | Placebo | 3 (965) | 3.85 (2.81–5.26) | 0 | <.00001 | ||
| Albiglutide 50 mg | OADs | 2 (1422) | 1.08 (0.48–2.40) | 92 | .85 | NA | |
| CFB in FPG (mmol/L) | Albiglutide 30 mg | Placebo | 5 (918) | −1.82 (−2.10–−1.54) | 0 | <.00001 | .96 |
| Albiglutide 50 mg | Placebo | 4 (1202) | −1.83 (−2.30–−1.37) | 62 | <.00001 | ||
| Albiglutide 50 mg | OADs | 3 (1923) | 0.07 (−0.96–1.11) | 94 | .89 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (325) | −0.04 (−0.84–0.76) | 53 | .92 | .59 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1055) | 0.22 (−0.28–0.72) | 74 | .39 | ||
| Albiglutide 50 mg | Insulins | 3 (1988) | 0.04 (−1.14–1.22) | 95 | .95 | NA | |
| CFB in body weight (kg) | Albiglutide 30 mg | Placebo | 5 (916) | 0.28 (−0.24–0.80) | 49 | .30 | .83 |
| Albiglutide 50 mg | Placebo | 4 (1202) | 0.21 (−0.17–0.58) | 0 | .28 | ||
| Albiglutide 50 mg | OADs | 3 (1924) | −2.44 (−4.84–−0.03) | 98 | .05 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (325) | 0.70 (0.17–1.24) | 0 | .01 | .72 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1055) | 0.95 (−0.31–2.22) | 90 | .14 | ||
| Albiglutide 50 mg | Insulins | 3 (1996) | −2.88 (−4.60–−1.16) | 96 | .001 | NA |
CFB = change from baseline, CI = confidence interval, FPG = fasting plasma glucose, GLP-1 RA = glucagon-like peptide-1 receptor agonists, HbA1c = hemoglobin A1c, MD = mean difference, NA = not applicable, OAD = oral anti-hyperglycemic drug, OR = odds ratio, RCTs = randomized controlled trials.
3.5.3. FPG
Albiglutide, at both doses, was superior to placebo in terms of FPG reductions; for albiglutide 30 mg: MD −1.82 mmol/L, 95% CI (−2.10–−1.54), P < .00001, I2 = 0%; and for albiglutide 50 mg: MD −1.83 mmol/L, 95% CI (−2.30–−1.37), P < .00001, I2 = 62% (Table 2). The CFB in FPG was comparable with albiglutide and OADs, with albiglutide (30 and 50 mg) and GLP-1 RAs, and with albiglutide and insulins (Table 2). Albiglutide 30 and 50 mg were equally effective in CFB in FPG in the placebo- and GLP-1RA-controlled trials (Table 2).
3.6. Body weight
CFB in body weight was similar with albiglutide compared to placebo; for albiglutide 30 mg: MD 0.28 kg, 95% CI (−0.24–0.80), P = .30, I2 = 49%; and for albiglutide 50 mg: MD 0.21 kg, 95% CI (−0.17–0.58), P = .28, I2 = 0%. Body weight change was also similar in albiglutide and OAD arms. Albiglutide 50 mg was comparable, and albiglutide 30 mg was inferior to other GLP-1RAs regarding CFB in body weight. Albiglutide was superior to insulins for the same purpose (Table 2). Albiglutide 30 mg and albiglutide 50 mg were equally effective in CFB in body weight in the placebo- and GLP-1RA-controlled trials (Table 2).
3.7. AE
3.7.1. Albiglutide versus placebo
Albiglutide 30 mg had a similar risk of any AE, whereas albiglutide 50 mg had a higher risk than placebo. Compared to placebo, both albiglutide 30 mg and 50 mg had higher risks of drug-related AE and injection-site reaction. Albiglutide 30 mg, not albiglutide 50 mg, imparted a greater risk for diabetic retinopathy (DR) compared to placebo. The risks of other enlisted AE, including hypoglycemia and GI AE, were identical in the albiglutide and placebo arms. In the placebo-controlled trials, the risks of all the above-listed AE were similar with albiglutide 30 mg and 50 mg except for injection-site reaction, which was higher with albiglutide 50 mg (Table 3).
Table 3.
Summary of safety outcome findings.
| Outcome variables | Albiglutide arm | Control arm | Number of RCTs (participants) | Pooled effect size, RR (95% CI) |
I 2 (%) | P | Subgroup difference (albiglutide 30 vs 50 mg), P |
|---|---|---|---|---|---|---|---|
| Any AE | Albiglutide 30 mg | Placebo | 5 (929) | 1.09 (0.95–1.25) | 61 | .20 | .51 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 1.15 (1.06–1.26) | 26 | .001 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.03 (0.98–1.08) | 0 | .21 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 1.09 (0.97–1.23) | 0 | .14 | .43 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 1.02 (0.91–1.15) | 62 | .72 | ||
| Albiglutide 50 mg | Insulins | 3 (2124) | 1.07 (1.01–1.13) | 0 | .02 | NA | |
| Drug-related AE | Albiglutide 30 mg | Placebo | 3 (740) | 1.35 (1.01–1.81) | 14 | .04 | .11 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 1.84 (1.44–2.34) | 0 | <.00001 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.62 (1.37–1.91) | 0 | <.00001 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 2.25 (1.73–2.92) | 0 | <.00001 | NA | |
| Serious AE | Albiglutide 30 mg | Placebo | 5 (929) | 1.37 (0.47–4.03) | 66 | .56 | .67 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 1.07 (0.70–1.63) | 0 | .76 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 0.97 (0.68–1.38) | 42 | .86 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 7.63 (1.44–40.31) | 0 | .02 | .29 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 1.80 (0.22–14.80) | 59 | .58 | ||
| Albiglutide 50 mg | Insulins | 3 (2124) | 0.93 (0.68–1.27) | 0 | .66 | NA | |
| AE leading to withdrawal | Albiglutide 30 mg | Placebo | 3 (740) | 1.01 (0.51–2.02) | 0 | .98 | .40 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 1.57 (0.73–3.37) | 44 | .24 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.04 (0.64–1.69) | 51 | .87 | NA | |
| Albiglutide 50 mg | Insulins | 3 (2124) | 3.10 (1.40–6.86) | 33 | .005 | NA | |
| Hypoglycemia (any) | Albiglutide 30 mg | Placebo | 4 (822) | 1.61 (0.83–3.13) | 0 | .16 | .55 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 1.21 (0.62–2.35) | 61 | .57 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 0.83 (0.47–1.46) | 89 | .51 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 1.38 (0.41–4.60) | 0 | .60 | .41 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 0.82 (0.62–1.09) | 0 | .18 | ||
| Albiglutide 50 mg | Insulins | 3 (2124) | 0.74 (0.62–0.88) | 67 | .0009 | NA | |
| Documented symptomatic hypoglycemia | Albiglutide 30 mg | Placebo | 2 (503) | 1.43 (0.32–6.48) | 17 | .64 | .79 |
| Albiglutide 50 mg | Placebo | 3 (989) | 1.12 (0.43–2.95) | 43 | .82 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 0.68 (0.27–1.75) | 89 | .42 | NA | |
| Albiglutide 50 mg | Insulins | 3 (2124) | 0.65 (0.57–0.76) | 29 | <.00001 | NA | |
| Severe hypoglycemia | Albiglutide 30 mg | Placebo | 2 (503) | 5.03 (0.24–103.96) | NA | .30 | .54 |
| Albiglutide 50 mg | Placebo | 3 (989) | 1.28 (0.05–31.18) | NA | .88 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 0.29 (0.06–1.39) | 0 | .12 | NA | |
| Albiglutide 50 mg | Insulins | 3 (2124) | 0.44 (0.21–0.88) | 0 | .02 | NA | |
| Any GI AE | Albiglutide 50 mg | Placebo | 2 (586) | 1.48 (0.88–2.50) | 65 | .14 | NA |
| Albiglutide 50 mg | OADs | 2 (1043) | 1.28 (1.05–1.55) | 0 | .01 | NA | |
| Nausea | Albiglutide 30 mg | Placebo | 5 (929) | 1.09 (0.62–1.89) | 26 | .77 | .69 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 1.25 (0.81–1.94) | 1 | .32 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.73 (1.23–2.43) | 0 | .002 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 0.58 (0.30–1.12) | 0 | .11 | .83 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 0.69 (0.14–3.37) | 86 | .65 | ||
| Albiglutide 50 mg | Insulins | 3 (2124) | 4.26 (2.50–7.25) | 29 | <.00001 | NA | |
| Vomiting | Albiglutide 30 mg | Placebo | 4 (692) | 1.73 (0.75–3.97) | 0 | .20 | .53 |
| Albiglutide 50 mg | Placebo | 2 (586) | 3.01 (0.65–13.88) | 0 | .16 | ||
| Albiglutide 50 mg | OADs | 3 (1043) | 1.39 (0.56–3.42) | 0 | .48 | NA | |
| Albiglutide 50 mg | Insulins | 3 (2124) | 2.71 (0.83–8.82) | 80 | .10 | NA | |
| Decreased appetite | Albiglutide 30 mg | Placebo | 2 (383) | 1.11 (0.25–4.86) | 8 | .89 | NA |
| Dyspepsia | Albiglutide 30 mg | Placebo | 3 (585) | 1.03 (0.42–2.53) | 0 | .94 | .59 |
| Albiglutide 50 mg | Placebo | 3 (989) | 1.59 (0.44–5.73) | 28 | .48 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.60 (0.53–4.82) | 68 | .40 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 3.33 (0.44–25.29) | 72 | .24 | NA | |
| Abdominal pain | Albiglutide 30 mg | Placebo | 4 (692) | 0.47 (0.20–1.09) | 0 | .08 | .27 |
| Albiglutide 50 mg | Placebo | 3 (989) | 1.67 (0.20–13.78) | 75 | .63 | ||
| Albiglutide 50 mg | OADs | 3 (1459) | 1.66 (0.82–3.33) | 38 | .16 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 1.92 (0.25–14.49) | 70 | .53 | NA | |
| GERD | Albiglutide 30 mg | Placebo | 3 (585) | 2.67 (0.50–14.18) | 39 | .25 | .37 |
| Albiglutide 50 mg | Placebo | 3 (989) | 1.15 (0.53–2.49) | 1 | .73 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 0.84 (0.46–1.54) | 17 | .57 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 1.60 (0.77–3.29) | 0 | .21 | NA | |
| Diarrhea | Albiglutide 30 mg | Placebo | 5 (929) | 1.01 (0.53–1.93) | 41 | .98 | .54 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 1.28 (0.85–1.95) | 1 | .24 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.49 (1.12–2.00) | 0 | .007 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 0.52 (0.21–1.29) | 7 | .16 | .13 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 1.10 (0.80–1.52) | 0 | .56 | ||
| Albiglutide 50 mg | Insulins | 3 (2124) | 2.04 (1.45–2.88) | 0 | <.0001 | NA | |
| Constipation | Albiglutide 30 mg | Placebo | 5 (929) | 1.88 (0.86–4.10) | 0 | .11 | .21 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 0.93 (0.42–2.05) | 60 | .85 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.75 (1.15–2.68) | 0 | .009 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 1.17 (0.51–2.64) | 0 | .71 | .82 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 1.02 (0.43–2.41) | 65 | .97 | ||
| Albiglutide 50 mg | Insulins | 2 (1311) | 2.56 (1.27–5.20) | 0 | .009 | NA | |
| Injection-site reaction | Albiglutide 30 mg | Placebo | 5 (929) | 1.83 (1.03–3.23) | 0 | .04 | .03 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 4.87 (2.43–9.76) | 0 | <.00001 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 3.53 (2.33–5.36) | 6 | <.00001 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 5.03 (0.61–41.28) | 0 | .13 | .86 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 6.15 (2.52–15.02) | 0 | <.0001 | ||
| Albiglutide 50 mg | Insulins | 3 (2124) | 4.25 (2.13–8.47) | 0 | <.0001 | NA | |
| Diabetic retinopathy | Albiglutide 30 mg | Placebo | 2 (503) | 3.68 (1.04–13.03) | 0 | .04 | .25 |
| Albiglutide 50 mg | Placebo | 2 (586) | 1.34 (0.42–4.24) | 0 | .62 | ||
| Albiglutide 50 mg | OADs | 2 (1043) | 0.87 (0.40–1.87) | 45 | .72 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1379) | 0.47 (0.16–1.45) | 70 | .19 | NA | |
| Hypertension | Albiglutide 30 mg | Placebo | 4 (692) | 0.97 (0.57–1.66) | 0 | .91 | .83 |
| Albiglutide 50 mg | Placebo | 3 (989) | 1.05 (0.67–1.64) | 0 | .84 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 0.90 (0.65–1.23) | 0 | .49 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 0.90 (0.58–1.38) | 0 | .62 | NA | |
| Peripheral edema | Albiglutide 30 mg | Placebo | 3 (610) | 1.17 (0.53–2.60) | 0 | .70 | .37 |
| Albiglutide 50 mg | Placebo | 2 586) | 0.71 (0.33–1.49) | 3 | .36 | ||
| Albiglutide 50 mg | OADs | 3 (1043) | 0.70 (0.13–3.91) | 91 | .69 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 0.67 (0.32–1.40) | 61 | .29 | NA | |
| Headache | Albiglutide 30 mg | Placebo | 4 (692) | 1.05 (0.56–1.97) | 27 | .88 | .71 |
| Albiglutide 50 mg | Placebo | 2 (586) | 0.81 (0.24–2.69) | 72 | .73 | ||
| Albiglutide 50 mg | OADs | 3 (1043) | 0.82 (0.51–1.31) | 0 | .40 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 1.19 (0.61–2.32) | 55 | .61 | NA | |
| Cough | Albiglutide 30 mg | Placebo | 3 (585) | 0.92 (0.47–1.81) | 0 | .81 | .69 |
| Albiglutide 50 mg | Placebo | 3 (989) | 1.09 (0.68–1.76) | 0 | .73 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.18 (0.82–1.69) | 0 | .37 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 0.66 (0.41–1.06) | 0 | .09 | NA | |
| Sinusitis | Albiglutide 30 mg | Placebo | 3 (585) | 1.65 (0.82–3.32) | 0 | .16 | NA |
| Albiglutide 50 mg | Insulins | 2 (1311) | 1.04 (0.57–1.19) | 34 | .89 | NA | |
| Nasopharyngitis | Albiglutide 30 mg | Placebo | 5 (929) | 1.04 (0.74–1.47) | 0 | .81 | 1.00 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 1.04 (0.76–1.43) | 0 | .79 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 1.00 (0.60–1.65) | 65 | .99 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 1.18 (0.79–1.78) | 0 | .42 | .32 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 0.90 (0.64–1.27) | 0 | .57 | ||
| Albiglutide 50 mg | Insulins | 2 (1311) | 1.16 (0.78–1.73) | 0 | .45 | NA | |
| Upper RTI | Albiglutide 30 mg | Placebo | 4 (822) | 1.04 (0.65–1.69) | 0 | .86 | .71 |
| Albiglutide 50 mg | Placebo | 4 (1216) | 0.91 (0.53–1.56) | 47 | .73 | ||
| Albiglutide 50 mg | OADs | 3 (1954) | 0.94 (0.45–1.96) | 88 | .86 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 1.24 (0.48–3.24) | 0 | .66 | .77 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 1.07 (0.77–1.49) | 0 | .70 | ||
| Albiglutide 50 mg | Insulins | 3 (2124) | 0.95 (0.70–1.30) | 10 | .77 | NA | |
| UTI | Albiglutide 30 mg | Placebo | 3 (585) | 1.05 (0.47–2.35) | 0 | .91 | .69 |
| Albiglutide 50 mg | Placebo | 2 (586) | 1.29 (0.68–2.47) | 0 | .44 | ||
| Albiglutide 50 mg | OADs | 2 (1043) | 0.93 (0.63–1.35) | 0 | .70 | NA | |
| Albiglutide 50 mg | Insulins | 3 (2124) | 1.09 (0.78–1.51) | 0 | .62 | NA | |
| Arthralgia | Albiglutide 30 mg | Placebo | 3 (585) | 1.36 (0.53–3.51) | 21 | .53 | .71 |
| Albiglutide 50 mg | Placebo | 2 (586) | 1.10 (0.60–2.00) | 0 | .76 | ||
| Albiglutide 50 mg | OADs | 2 (1043) | 1.05 (0.66–1.65) | 0 | .85 | NA | |
| Albiglutide 50 mg | Insulins | 2 (1311) | 0.90 (0.33–2.49) | 71 | .84 | NA | |
| Back pain | Albiglutide 30 mg | Placebo | 5 (929) | 1.64 (0.88–3.05) | 0 | .12 | .36 |
| Albiglutide 50 mg | Placebo | 3 (813) | 1.10 (0.60–1.99) | 0 | .76 | ||
| Albiglutide 50 mg | OADs | 2 (1043) | 0.90 (0.56–1.45) | 0 | .67 | NA | |
| Albiglutide 30 mg | GLP-1 RAs | 2 (329) | 2.07 (0.63–6.85) | 0 | .23 | .17 | |
| Albiglutide 50 mg | GLP-1 RAs | 2 (1065) | 0.82 (0.45–1.49) | 0 | .51 | ||
| Albiglutide 50 mg | Insulins | 2 (1311) | 0.78 (0.52–1.19) | 0 | .25 | NA | |
| Thyroid cancer | Albiglutide 50 mg | Placebo | 2 (789) | 0.38 (0.04–3.62) | 0 | .40 | NA |
| Albiglutide 50 mg | OADs | 2 (1945) | 1.10 (0.09–11.08) | NA | .99 | NA |
AE = adverse events, CI = confidence interval, GERD = gastroesophageal reflux disease, GI = gastrointestinal, GLP-1 RA = glucagon-like peptide-1 receptor agonists, HbA1c = hemoglobin A1c, NA = not applicable, OAD = oral anti-hyperglycemic drug, RCTs = randomized controlled trials, RR = risk ratio, RTI = respiratory tract infection, UTI = urinary tract infection.
3.7.2. Albiglutide versus OADs
Compared to OADs, albiglutide 50 mg had higher risks of drug-related AE, any GI AE, nausea, diarrhea, constipation, and injection-site reaction. Other AE were similar in the 2 groups (Table 3).
3.7.3. Albiglutide versus GLP-1RAs
Albiglutide 30 mg (not albiglutide 50 mg) was associated with a higher risk of serious AE compared to other GLP-1RAs, and albiglutide 50 mg (not albiglutide 30 mg) was associated with a higher risk of injection-site reaction compared to other GLP-1RAs. The risks of other AE were similar across the groups. There was no statistical difference between albiglutide 30 mg and 50 mg in terms of risks of AE in the GLP-1RA-controlled trials (Table 3).
3.7.4. Albiglutide versus insulins
Albiglutide 50 mg had a higher risk of any AE, drug-related AE, or AE leading to withdrawal, nausea, diarrhea, constipation, and injection-site reaction than insulins. Risks of any hypoglycemia, documented symptomatic hypoglycemia, and severe hypoglycemia were lower with albiglutide 50 mg than with insulins. Other AE risks were comparable in the 2 groups (Table 3).
4. Discussion
The present meta-analysis incorporated the results of the most recent RCTs of albiglutide in T2D. It highlights the glycemic efficacy and AE of albiglutide compared to placebo and other GLDs as monotherapy and combination therapy. Albiglutide demonstrated superior efficacy compared to placebo and comparable efficacy to other GLDs in decreasing HbA1c levels. The albiglutide and placebo groups had similar AE profiles, except for a greater risk of drug-related AE and injection-site reactions in the albiglutide group.
Albiglutide comprises a GLP-1 dimer fused to human albumin and is resistant to dipeptidyl peptidase-4 enzyme. The fusion extends the drug’s half-life and makes it convenient for once-weekly dosing. Its elimination half-life is 5 to 8 days, with peak plasma levels achieved in 2.3 to 5 days.[40] This meta-analysis demonstrated 1.04% and 1.10% greater reductions in HbA1c from the baseline with albiglutide 30 mg and 50 mg, respectively, than the placebo. Moreover, the CFB in HbA1c was comparable with albiglutide and other GLDs, including OADs, other GLP-1RAs, and insulins. In a network meta-analysis of RCTs comparing once-weekly GLP-1RAs and placebo, placebo-subtracted standardized MD of HbA1c were −1.06% (95% CI: −1.48–−0.63) for exenatide 2.0mg, −0.75% (95% CI: −1.01–−0.49) for dulaglutide 0.75mg, −0.91% (95% CI: −1.13–−0.69) for dulaglutide 1.5mg, −1.11% (95% CI: −1.40–−0.82) for semaglutide 0.5mg, −1.44% (95% CI: −1.69%, −1.19%) for semaglutide 1.0mg.[41] Albiglutide was also effective in FPG reductions (MD vs placebo was −1.82 mmol/L for 30 mg and −1.83 mmol/L for 50 mg). The FPG-reducing potentials of other once-weekly GLP-1RAs were −2.07 mmol/L for exenatide 2.0mg, −1.45 mmol/L for dulaglutide 0.75mg, −1.71 mmol/L for dulaglutide 1.5mg, −1.87 mmol/L for semaglutide 0.5mg and −2.51 mmol/L for semaglutide 1.0mg.[41] Thus, except for semaglutide 1.0mg, the glycemic efficacy of albiglutide is comparable, if not better, than the other competitor GLP-1RAs administered once weekly.
One of the therapeutic effects of GLP-1RAs is their weight loss potential when used in individuals with T2D and even in those without T2D.[10] As weight loss, even modest, is associated with glycemic improvement, GLP-1RAs are GLDs preferred in individuals with T2D having excess weight.[2] Unlike other GLP-1RAs, albiglutide was not better than placebo in weight loss in individuals with T2D, as found in this meta-analysis. A possible explanation is that, as a large fusion protein (~73 kDa), albiglutide cannot cross the blood-brain barrier to reach the hypothalamus and modulate appetite and satiety as efficiently as smaller molecules.[11,42]
The meta-analysis provides quite reassuring safety data for albiglutide, evidenced by no differences in the risks of serious AE, AE leading to withdrawal, hypoglycemia, any GI AE, nausea, vomiting, decreased appetite, dyspepsia, abdominal pain, GERD, diarrhea, constipation, and thyroid cancer in the albiglutide and placebo arms. Thus, albiglutide sets itself apart from other GLP-1RAs, all of which are associated with GI AE, including nausea, vomiting, and diarrhea.[10,41] Differences in GI tolerability within the therapeutic class may relate to differences in pharmacokinetics, brain penetration, and/or effects on gastric emptying. The mechanisms underlying the placebo-like GI AE of albiglutide may include its structural properties and extended duration of action. As discussed earlier, as a fusion protein, albiglutide’s molecular structure may prevent its reach to brain regions like the area postrema (vomiting center of the brain) as easily as smaller molecules. Such structural property may also result in a slower rate of absorption and metabolism, potentially leading to a more gradual and sustained effect on GLP-1 receptors, which may be associated with fewer GI AE.[11,29,42] Moreover, hypoglycemia risk was similar with albiglutide and placebo. The glucose-lowering effects of GLP-1RAs are mediated through potentiating glucose-dependent insulin secretion and inhibiting glucagon secretion in islet cells; thus, they have minimal hypoglycemic potentials.[1] In this meta-analysis, albiglutide was associated with greater risks of injection-site reaction compared to placebo. However, such events were generally mild in intensity, short duration, and infrequently associated with withdrawal from the studies. Albiglutide has high homology to native human GLP-1 and has a low immunogenic potential.[11] Systemic allergic reactions are very infrequent with albiglutide.[17,18,20] In this meta-analysis, the greater risk for DR in the placebo-controlled trials was not consistent across the albiglutide dose. This outcome was described only in 2 RCTs with albiglutide 30 mg and 2 with albiglutide 50 mg. The number of study subjects with the outcome was also small. Moreover, a recently published meta-analysis incorporating data from 20 RCTs encompassing 24,832 patients with T2D reassured that across all included trials, randomization to GLP-1RA treatment did not demonstrate an increased risk of DR.[43] The present meta-analysis also reassures us about the safety of albiglutide for thyroid cancer.
However, in August 2017, GlaxoSmithKline announced that it intended to withdraw the drug from the worldwide market by July 2018 for economic reasons. Although there was a warning on the label for the risk of anaphylactic reactions and a boxed warning for thyroid C-cell tumors, the manufacturer discontinued the drug not for safety issues but for limited prescribing and declining sales, even though it was priced lower than its rivals, dulaglutide (Trulicity; Eli Lilly and Company, Lilly Corporate Center, Indianapolis) and Liraglutide (Victoza; Novo Nordisk A/S, Bagsværd, Denmark).[44,45] As per our analysis, the drug has good efficacy and safety data compared to peer GLP-1RAs. Moreover, albiglutide reduced the risk of major adverse CV events when added to standard care in patients with T2D and established CV disease.[25] Availability in the market for clinical use involves many licensing and marketing issues, which are beyond the scope of this article. There is no reason why this drug should not be available for clinical use, and the pharmaceutical industry should relook.
4.1. Strengths and limitations
This is the first meta-analysis summarizing the efficiency and safety of albiglutide in T2D. The main strength of this meta-analysis is the inclusion of a large population from a fairly good number of studies. The general quality of the included trials was good; all were RCTs, and most were double-blind trials. We have separately analyzed the outcomes comparing albiglutide (at doses 30 mg and 50 mg) with placebo and active comparators. Moreover, sub-analyses of CFB in HbA1c with albiglutide compared to placebo were done for the trial phases and study durations. Furthermore, the meta-analysis included results of all RCTs available to date. There are also several limitations. High heterogeneity was observed for the HbA1c, and the certainty of evidence generated was low for HbA1c.
5. Conclusion
This meta-analysis on the efficacy and safety of albiglutide provides reassuring data on good glycemic efficacy, tolerability, and safety over an extended period of clinical use in a diverse group of patients with T2D. Albiglutide 30 mg has comparable efficacy and safety profiles to albiglutide 50 mg; hence, the 30 mg dose might be the most optimal dose to manage T2D. Albiglutide does not offer a weight-loss benefit like other GLP-1RAs but offers good GI tolerability.
Author contributions
Conceptualization: A.B.M. Kamrul-Hasan, Deep Dutta, Sanjay Kalra.
Data curation: A.B.M. Kamrul-Hasan, Lakshmi Nagendra, Saptarshi Bhattacharya.
Formal analysis: A.B.M. Kamrul-Hasan, Deep Dutta.
Investigation: A.B.M. Kamrul-Hasan, Lakshmi Nagendra, Rajiv Singla.
Methodology: A.B.M. Kamrul-Hasan, Lakshmi Nagendra, Rajiv Singla, Sanjay Kalra.
Project administration: A.B.M. Kamrul-Hasan, Saptarshi Bhattacharya, Sanjay Kalra.
Resources: A.B.M. Kamrul-Hasan, Deep Dutta, Lakshmi Nagendra, Saptarshi Bhattacharya, Rajiv Singla, Sanjay Kalra.
Software: A.B.M. Kamrul-Hasan, Rajiv Singla.
Supervision: A.B.M. Kamrul-Hasan, Sanjay Kalra.
Validation: A.B.M. Kamrul-Hasan.
Visualization: Deep Dutta, Lakshmi Nagendra, Saptarshi Bhattacharya, Rajiv Singla, Sanjay Kalra.
Writing – original draft: A.B.M. Kamrul-Hasan.
Writing – review & editing: A.B.M. Kamrul-Hasan, Deep Dutta, Lakshmi Nagendra, Saptarshi Bhattacharya, Rajiv Singla, Sanjay Kalra.
Supplementary Material
Abbreviations:
- AE
- adverse event
- CFB
- change from baseline
- CI
- confidence interval
- CV
- cardiovascular
- DR
- diabetic retinopathy
- FPG
- fasting plasma glucose
- GI
- gastrointestinal
- GLD
- glucose-lowering drug
- GLP-1RA
- glucagon-like peptide-1 receptor agonist
- HbA1c
- glycated hemoglobin
- MD
- mean difference
- OAD
- oral anti-hyperglycemic drug
- OR
- odds ratio
- QW
- once a week
- RCT
- randomized controlled trial
- RR
- risk ratio
- T2D
- type 2 diabetes
The authors have no funding and conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Supplemental Digital Content is available for this article.
How to cite this article: Kamrul-Hasan ABM, Dutta D, Nagendra L, Bhattacharya S, Singla R, Kalra S. Efficacy and safety of albiglutide, a once-weekly glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes: A systematic review and meta-analysis. Medicine 2024;103:25(e38568).
Contributor Information
Deep Dutta, Email: deepdutta2000@yahoo.com.
Lakshmi Nagendra, Email: drlakshminagendra@gmail.com.
Saptarshi Bhattacharya, Email: saptarshi515@gmail.com.
Rajiv Singla, Email: docrajivsingla@gmail.com.
Sanjay Kalra, Email: brideknl@gmail.com.
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