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Trial profile. ITT, intention-to-treat principle.
Source publication
Objective:
To investigate whether addition of three different doses of liraglutide to insulin in patients with type 1 diabetes (T1D) results in significant reduction in glycemia, body weight, and insulin dose.
Research design and methods:
We randomized 72 patients (placebo = 18, liraglutide = 54) with T1D to receive placebo and 0.6, 1.2, and 1.8...
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Aim:
To evaluate the efficacy and safety of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide in African-American/black people with Type 2 diabetes.
Methods:
Analyses were performed on patient-level data from individuals self-defined as African-American/black or non-African-American/black in seven phase III studies. Endpoints incl...
Background
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) act by increasing insulin secretion, decreasing glucagon secretion, slowing gastric emptying, and increasing satiety.
Objective
Published evidence directly comparing GLP-1RAs with other approved treatments for type 2 diabetes (T2D) was systematically reviewed.
Methods
A literature se...
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assessment of the efficiency of new therapies. The aim of this study is to examine the clinical features and treatment satisfaction with liraglutide in insulin-dependent obese patients having uncontrolled dia...
Background:
Closed-loop (CL) systems aims to outperform usual treatments in blood glucose control and continuous glucose monitors (CGM) are a key component in such systems. Meals represents one of the main disturbances in blood glucose control, and postprandial period (PP) is a challenging situation for both CL system and CGM accuracy.
Methods:...
Aims/introduction:
This phase 3, randomized, double-blind 24-week study with extension to 1 year assessed efficacy and safety of albiglutide compared with placebo in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by diet and exercise with or without a single oral antidiabetic drug.
Materials and methods:
Patients...
Citations
... Varying doses of liraglutide decreased SBP modestly with statistical significance compared to placebo, but their effects were not significantly different compared to each other. This suggests that modest SBP reduction may be attained by using a dose as low as 0.6 mg, as Kuhadiya et al. (2016) 35 has shown this statistically significant but clinically modest treatment effect on SBP using this dose, with decrease of SBP by 2.50 mmHg (95% CI -4.97 to -0.03). ...
... Varying doses of liraglutide decreased SBP modestly with statistical significance compared to placebo, but their effects were not significantly different compared to each other. This suggests that modest SBP reduction may be attained by using a dose as low as 0.6 mg, as Kuhadiya et al. (2016) 35 has shown this statistically significant but clinically modest treatment effect on SBP using this dose, with decrease of SBP by 2.50 mmHg (95% CI -4.97 to -0.03). ...
Background
The cardiovascular benefits provided by glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond weight reduction and glycemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP lowering effect by GLP1-RAs.
Methods
A comprehensive database search for placebo-controlled randomized controlled trials (RCTs) on GLP-1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with mean difference (MD) in millimeters mercury (mmHg) and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic and diastolic BP. Subgroup analyses and meta-regression were done to account for covariates.
Results
Compared to placebo, GLP-1RAs modestly reduced SBP (semaglutide: MD −3.40, [95% CI −4.22 to −2.59, p<0.001], liraglutide: MD −2.61, [95% CI −3.48 to −1.74, p<0.001], dulaglutide: MD −1.46, [95% CI −2.20 to −0.72, p<0.001] and exenatide: MD −3.36, [95% CI - 3.63 to −3.10, p<0.001]). This benefit consistently increased with longer treatment duration. Established people with type 2 diabetes experienced less SBP lowering with semaglutide. DBP reduction was only significant in the exenatide group (MD −0.94, [95% CI −1.78 to −0.1], p=0.03). Among semaglutide cohorts, mean change in hemoglobin A1c and mean change in body mass index were directly associated with SBP reduction.
Conclusion
Patients on GLP-1RA experienced modest SBP lowering compared to placebo. Only exenatide reduced DBP. Further studies are needed to clarify the mechanisms and the clinical benefit of GLP-1RA effects in BP reduction.
... hypoglycemia and ketoacidosis observed in T1D studies with SGLT2 inhibitors, these agents are not currently approved for use in T1D in the U.S. or European Union (143). GLP-1RAs have similarly been studied for glycemic control and weight loss in T1D, but their long-term effect on kidney and CV risk has not yet been evaluated (144)(145)(146). Three upcoming trials will study new therapies for T1D and CKD. ...
Diabetes is the leading cause of chronic kidney disease (CKD) and kidney failure worldwide. CKD frequently coexists with heart failure and atherosclerotic cardiovascular disease in the broader context of cardio-kidney-metabolic syndrome. Diabetes and CKD are associated with increased risk of all-cause and cardiovascular death as well as decreased quality-of-life. The role of metabolic and hemodynamic abnormalities has long been recognized as important contributors to the pathogenesis and progression of CKD in diabetes, while a more recent and growing body of evidence support activation of both systemic and local inflammation as important contributors. Current guidelines recommend therapies targeting pathomechanisms of CKD in addition to management of traditional risk factors such as hyperglycemia and hypertension. Sodium-glucose cotransporter-2 inhibitors are recommended for treatment of patients with CKD and type 2 diabetes (T2D) if eGFR is >20 ml/min/173m2 on a background of renin-angiotensin system inhibition. For patients with T2D, CKD, and atherosclerotic cardiovascular disease, a glucagon-like peptide-1 receptor agonist is recommended as additional risk-based therapy. A non-steroidal mineralocorticoid receptor antagonist is also recommended as additional risk-based therapy for persistent albuminuria in patients with T2D already treated with renin-angiotensin system inhibition. Implementation of guideline directed medical therapies is challenging in the face of rapidly accumulating knowledge, high cost of medications, and lack of infrastructure for optimal healthcare delivery. Furthermore, studies of new therapies have focused on T2D and CKD. Clinical trials are now planned to inform the role of these therapies in people with T1D and CKD.
... Four hundred and fifty-nine articles were initially screened, and 16 were ultimately included in this review [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Of these, 15 were RCTs in type 1 diabetes [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], and one was a randomised crossover study in MODY [29]. ...
... Four hundred and fifty-nine articles were initially screened, and 16 were ultimately included in this review [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Of these, 15 were RCTs in type 1 diabetes [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], and one was a randomised crossover study in MODY [29]. Owing to the dearth of literature regarding the impact of incretins on diabetes types other than type 1 diabetes, we focused the review on type 1 diabetes. ...
... Ten articles described various metabolic endpoints and five studies focused on various mechanistic endpoints of liraglutide or exenatide in type 1 diabetes, all of which are summarised here [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. One of the 16 included articles was a randomised crossover study in patients with MODY, discussed in the Discussion section [29]. ...
Incretin-based therapies, in particular glucagon-like peptide-1 (GLP-1) receptor agonists, have been evaluated in other forms of diabetes, but randomised controlled trials are mainly limited to people living with type 1 diabetes. In this review we present the evidence issuing from these trials and discuss their clinical implications as well as the difficulties in interpreting the data. In type 1 diabetes, the addition of GLP-1 receptor agonists to intensive insulin therapy lowers weight and required insulin doses compared with placebo, but the effects on glucose control (HbA1c, risk of hypoglycaemia) are dependent on the different study protocols. Side effects are limited to the gastrointestinal complaints of nausea, vomiting and diarrhoea. We briefly discuss the potential for using GLP-1 receptor agonists as (adjunct) therapies in other forms of diabetes, where the evidence to date is scarce.
Graphical Abstract
... Insulin dose reduction was based on the treating physician's judgment and individual patient requirements. The physicians were aware that avoiding excessive insulin dose reductions after initiating adjunct dapagliflozin therapy may mitigate the risk of DKA [16,17,27]. All SGLT2i indirectly augments β-cell function in type 2 diabetes by reversing glucotoxicity, thus improving insulin sensitivity and weight loss [28]. ...
Objective:
This study evaluated whether adding sodium-glucose cotransporter-2 inhibitors (SGLT2i) and/or glucagon-like peptide-1 receptor agonists (GLP1-RA) to insulin reduced weight and glycemia in people with type 1 diabetes.
Methods:
This retrospective analysis of electronic health records evaluated 296 people with type 1 diabetes over 12 months after medications were first prescribed. Four groups were defined: control n = 80, SGLT2i n = 94, GLP1-RA n = 82, and combination of drugs (Combo) n = 40. We measured changes at 1 year in weight and glycated hemoglobin (HbA1c).
Results:
The control group did not have changes in weight or glycemic control. The mean (SD) percentage weight loss after 12 months was 4.4% (6.0%), 8.2% (8.5%), and 9.0% (8.4%) in the SGLT2i, GLP1-RA, and Combo groups, respectively (p < 0.001). The Combo group lost the most weight (p < 0.001). The HbA1c reduction was 0.4% (0.7%), 0.3% (0.7%), and 0.6% (0.8%) in the SGLT2i, GLP1-RA, and Combo groups, respectively (p < 0.001). The Combo group had the biggest improvements in glycemic control and total and low-density lipoprotein cholesterol compared with baseline (all p < 0.01). Severe adverse events were similar between all the groups, with no increased risk of diabetic ketoacidosis.
Conclusions:
The SGLT2i and GLP1-RA agents on their own improved body weight and glycemia, but combining the medications resulted in more weight loss. Treatment intensification appears to result in benefits with no difference in severe adverse events.
... Furthermore, another randomized placebo-controlled, 12-week clinical trial in 72 overweight individuals and individuals with obesity, all of which had type 1 diabetes as comorbidity, showed that the addition of an either high (1.2 and 1.8 mg) or low (0.6 mg) liraglutide dose to insulin therapy resulted in significant weight reduction (NCT01722266) [29]. ...
We evaluated the quality of evidence from phase III/IV clinical trials of drugs against obesity using the principles of Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool. Our systematic review evaluates the quality of clinical evidence from existing clinical trials and not the pharmacological efficacy of anti-obesity therapies. A literature search using select keywords in separate was performed in PubMed and ClinicalTrials.gov databases for phase III/IV clinical trials during the last ten years. Our findings indicate that the quality of existing clinical evidence from anti-obesity trials generally ranges from low to moderate. Most trials suffered from publication bias. Less frequently, trials suffered from the risk of bias mainly due to lack of blindness in the treatment. Our work indicates that additional higher-quality clinical trials are needed to gain more confidence in the estimate of the effect of currently used anti-obesity medicines, to allow more informed clinical decisions, thus reducing the risk of implementing potentially ineffective or even harmful therapeutic strategies.
... Liraglutide treatment has also reduced the cardiovascular risk in patients with T2D (5,6). Driven by these beneficial effects in T2D patients, several studies have investigated the impact of liraglutide treatment in type 1 diabetes (T1D) patients (7)(8)(9)(10)(11)(12)(13)(14)(15), and beneficial effects on metabolic control have been observed in some (8,(16)(17)(18), but not all, studies (19)(20)(21). ...
Context
The effect of liraglutide in C-peptide positive (C-pos) type 1 diabetes (T1D) patients during hypoglycaemia remains unclear.
Objective
To investigate the effect of a 12-week liraglutide-treatment on the body glucose fluxes during a hypoglycaemic clamp in C-pos T1D patients and its impact on the alpha and beta cell responses during hypoglycaemia.
Design
This was a randomized, double-blind, cross-over study. Each C-pos T1D patient was allocated to the treatment-sequence liraglutide/placebo or placebo/liraglutide with daily injections for 12 weeks adjunct to insulin-treatment, separated by a 4-week wash-out period.
Setting and Participants
14 T1D patients with fasting C-peptide ≥ 0.1 nmol/l.
Intervention(s)
All patients underwent a hyperinsulinaemic-stepwise-hypoglycaemic clamp with isotope tracer [plasma glucose (PG)-plateaus: 5.5, 3.5, 2.5 and 3.9 mmol/l] after a 3-month-liraglutide- (1.2 mg) or placebo-treatment.
Main Outcome Measure(s)
The responses of endogenous glucose production (EGP) and rate of peripheral glucose disposal (Rd) were similar for liraglutide- and placebo-treatment during the clamp.
Results
The numbers of hypoglycaemic events were similar in both groups. At the clamp, mean glucagon levels were significantly lower at PG-plateau 5.5 mmol/l in the liraglutide- than in the placebo-group, but showed similar responses to hypoglycaemia in both groups. Mean C-peptide levels were significantly higher at PG-plateaus 5.5 and 3.5 mmol/l after liraglutide-treatment, but this effect was not reflected in EGP and Rd. HbA1c and body weight were lower and a trend for reduced insulin was seen after liraglutide-treatment.
Conclusions
The results indicate that three months liraglutide-treatment does not promote or prolong hypoglycaemia in C-pos T1D patients.
... Adverse events were higher in the liraglutide groups and were mainly related to the gastrointestinal system. Higher doses of liraglutide (1.2 and 1.8 mg), which were administered over 12 weeks in C-peptide-negative and overweight persons with T1D, were associated with a modest reduction in mean glucose levels and insulin doses, as well as significant weight loss [64]. ...
Background: In Type 1 diabetes (T1D), according to the most recent guidelines, the everyday glucose-lowering treatment is still restricted to the use of subcutaneous insulin, while multiple therapeutic options exist for Type 2 diabetes (T2D). Methods: For this narrative review we unsystematically screened PubMed and Embase to identify clinical trials which investigated glucose-lowering agents as an adjunct to insulin treatment in people with T1D. Published studies up to March 2022 were included. We discuss the safety and efficacy in modifying cardiovascular risk factors for each drug, the current status of research, and provide a clinical perspective. Results: For several adjunct agents, in T1D, the scientific evidence demonstrates improvements in HbA1c, reductions in the risk of hypoglycemia, and achievements of lower insulin requirements, as well as positive effects on cardiovascular risk factors, such as blood lipids, blood pressure, and weight. As the prevalence of obesity, the major driver for double diabetes, is rising, weight and cardiovascular risk factor management is becoming increasingly important in people with T1D. Conclusions: Adjunct glucose-lowering agents, intended to be used in T2D, bear the potential to beneficially impact on cardiovascular risk factors when investigated in the T1D population and are suggested to be more extensively considered as potentially disease-modifying drugs in the future and should be investigated for hard cardiovascular endpoints.
... 36 While Liraglutide is registered as a treatment for patients with type 2 diabetes, the application of Liraglutide in patients with type 1 diabetes has been studied as well. [37][38][39] These studies reveal a decrease in insulin dose requirement and modest improvements in glycaemic control. While we omitted insulin treatment due to our focus on Liraglutide treatment, including insulin treatment in future studies is warranted to address the interplay between Liraglutide, insulin and microvascular dysfunction. ...
Background:
Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon-like peptide-1 analogue, inhibited NOX2 and adhesion molecules in isolated endothelial cells. Here we have studied how Liraglutide affects advanced glycation, NOX expression and inflammation of the cardiac, cerebral and renal microvasculature in diabetic rats.
Methods:
DM was induced in Sprague-Dawley rats (n=15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg body weight). 10 control rats remained non-diabetic. From day 9 post-STZ injection, Liraglutide (200 μg/kg bodyweight; n=7) or vehicle (n=8) was injected subcutaneously daily until termination on day 29. The advanced glycation end-product N-ε-(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM-1 and VCAM-1 were subsequently immunohistochemically analysed and quantified to compare Liraglutide treatment to placebo.
Results:
In the heart, Liraglutide treatment significantly reduced the DM-increased scores/cm2 for CML in both ventricles (from 253±53 to 72±12; p=0.003) and atria (343±29 to 122±8; p=0.0001) as well as for NOX2, ICAM-1 and VCAM-1, but not for NOX4. Also in the cerebrum and cerebellum of the brain, Liraglutide significantly reduced the scores/cm2 for CML (to 60±7 (p=0.0005) and 47±13 (p=0.02) respectively) as well as for NOX2 and NOX4. In the kidney the DM-induced expression of ICAM-1 and VCAM-1 was decreased in the blood vessels and glomeruli by Liraglutide treatment. Liraglutide did not affect blood glucose levels or body weight.
Conclusions:
Our study implies that Liraglutide protects the cardiac, cerebral and renal microvasculature against diabetes-induced dysfunction, independent of lowering blood glucose in a type 1 diabetes rat model.
... According to the different degree and severity of cognitive impairment (6)(7), the degree of cognitive impairment can be divided into three levels (8-9) from light to heavy: mild cognitive impairment, amnesia and dementia, which can be manifested as memory loss, psychomotor block, dementia, delirium, fine motor coordination difficulties and advanced cognitive impairment (10)(11). Liraglutide is a biosynthetic GLP-1 analog (12)(13) developed by danmeno and Nord pharmaceutical companies, and it is also a receptor agonist of GLP-1 (14). Its protein sequence is highly homologous with GLP-1 (15), and only two amino acid positions are modified (16). ...
At present, there is not enough research about the application of liraglutide nano preparations in perioperative neurocognitive dysfunction. Therefore, the purpose of this study is the mechanism of the effect of liraglutide nano preparations on perioperative neurocognitive dysfunction in aged mice. In this study, 140 male SD rats aged 6-8 weeks were used as the research object, and were divided into 4 groups (n=24) according to the random number table method, which were group C (control group), group S (model group), and treatment. Group (low-dose liraglutide pretreated control group) and DS2 group (high-dose liraglutide pretreated control group) were treated with liraglutide anesthesia to establish a cognitive dysfunction model. Morris water maze experiment was conducted 4 days after anesthesia to compare the escape latency and the number of crossings of the original platform in each group; after 4 days of anesthesia, 18 old mice were randomly selected from each group for fluorescence quantitative polymerase chain reaction (RealTimePCR) and protein Western blotting (Western.Blot) was used to determine the mRNA and protein levels of Caspase-3, Bax and Bcl-2 in the hippocampus; the remaining 6 old mice in each group were taken to observe the pathological changes of the hippocampus neurons by transmission electron microscopy . Compared with saline-treated group, the levels of NF-KB, TNF-a and IL-1β protein in mice treated with liraglutide decreased and IkB increased significantly (p<0.05). Liraglutide intervention may alleviate non-alcoholic fatty liver in diabetic mice by reducing the expression of inflammatory genes in liver tissue, thereby improving neurocognitive dysfunction in mice.
... From observation, it appears that the greatest glycaemic benefit arose from a study involving suboptimally controlled, overweight CSII users who received more conservative titrations, 38 compared to other studies. 31,32,[34][35][36][37] Although liraglutide alone showed a clinically relevant HbA1c-lowering effect of approximately 0.5% (À5.5 mmol/mol), the improvement observed with placebo often diluted the treatment effect; whether this is driven by continuous intensive insulin optimization or other aspects of study designs is uncertain. ...
Exogenous insulin has been the mainstay treatment for individuals living with type 1 diabetes (T1D). Although there has been tremendous growth in both pharmacological and technological advancements, insulin monotherapy has proven to be insufficient for maintaining optimal glycaemic targets for most adults with T1D. At present, there is still no breakthrough for the treatment of T1D. Adjunctive pharmacotherapies might therefore complement insulin management to achieve better glycaemic control, while possibly offering additional benefits. Recent interest in re-purposing glucagon-like peptide-1 receptor agonists (GLP-1RAs), a leading antihyperglycaemic medication class approved for type 2 diabetes, has prompted the field to seek extended potential for the T1D population. The adjunctive use of GLP-1RAs has been at the forefront of T1D research, albeit with some conflicting trial findings to date. However, the potential of GLP-1 agonism for T1D may have been underestimated, possibly from missed opportunities or categorized effects. Moreover, some GLP-1RAs have demonstrated extra-pancreatic potential with emerging multi-organ protection involving the heart, kidneys, liver and brain in varied cohorts, which may bode well for the growing T1D profile of comorbid complications. This narrative review aims to summarize and critically appraise the current evidence-based literature from large-scale randomized controlled trials and closed-loop system pilot studies that examined GLP-1RAs as adjunctive therapy for T1D. Furthermore, we outline uncharted opportunities with GLP-1 agonism using versatile approaches in selected T1D populations that may inspire and re-direct future research in this field.This article is protected by copyright. All rights reserved.
