Once-daily Glucagon-like Peptide-1 Receptor Agonist Research Articles

Investigation the impact of liraglutide on the thyroid function tests

Aim: Liraglutide is a once-daily glucagon-like peptide-1 receptor agonist (GLP‑1 RA) which is an incretin hormone secreted from intestinal L cells in response to nutritional intake and stimulates glucose-dependent insulin secretion, decreases hepatic glucagon secretion, slows gastric emptying, provides a feeling of satiety and is the first GLP‑1 RA to be indicated for weight loss treatment for obesity. The impact of liraglutide on thyroid function tests is unknown and to the best of our knowledge, there are no studies on this regard. Our aim is to compare thyroid function tests, other biochemical and hemogram parameters before and 6 months after liraglutide treatment.
 Material and Methods: The patients, 18-65 years old, who used liraglutide for at least 6 months due to obesity treatment between January 2021 and January 2023 in Burdur State Hospital were included.
 Results: There were 51 patients (39 female, 12 male) using liraglutide without thyroid disease during the study period. Twelve patients discontinued liraglutide use before the 6th month of treatment was completed. Weight, body mass index (BMI), fasting plasma glucose (FPG), hemoglobin A1C (HbA1c), low-density lipoprotein (LDL), triglyceride and thyroid-stimulating hormone (TSH) values were significantly lower at the 6th month of treatment. Free thyroxine (FT4) and free triiodothyronine (FT3) values were similar. and there was no difference other biochemical and hemogram parameters between before and 6 months after treatment
 Conclusion: We found a significant decrease in TSH values and improvement in metabolic parameters, but no change in thyroid hormone levels.

A brief review on newer Glucagon like Peptide-1 analogues

GLP-1 (Glucagon like Peptide-1) receptor agonists have been shown to be effective in the treatment of type 2 diabetes mellitus (T2DM). Although the first GLP-1 receptor agonist, Exenatide, was approved in the year 2000, other agents with a longer duration of action that do not require twice-daily dosing are now being developed. Indeed, Liraglutide, a once-daily GLP-1 receptor agonist, was approved in 2010, a once-weekly extended-release formulation of Exenatide (Exenatide ER) was approved in 2011 and now more recently Semaglutide, an oral GLP 1 receptor agonist was approved for medical use in the United States in September 2019 and in the European Union in April 2020. The importance of GLP-1 itself and the use of GLP-1 receptor agonists in T2DM are discussed. An overview of the clinical development of the GLP-1 receptor agonists (Exenatide ER, Liraglutide, Lixisenatide, Albiglutide, Taspoglutide and Semaglutide) is provided and their mechanism of action, efficacy in terms of glycaemic control, weight loss and tolerability are reviewed. Keywords: GLP1 receptor agonist; Liraglutide; Exenatide ER; Lixisenatide; Semaglutide

Achieving postprandial glucose control with lixisenatide improves glycemic control in patients with type 2 diabetes on basal insulin: a post-hoc analysis of pooled data

BackgroundTo examine the impact on glycemic control of achieving postprandial glucose (PPG) target with lixisenatide, a once-daily glucagon-like peptide-1 receptor agonist approved in the US, in patients with uncontrolled type 2 diabetes (T2D) on basal insulin, an agent that primarily targets fasting plasma glucose.MethodsA post hoc pooled analysis was conducted using clinical trial data extracted from the intent-to-treat subpopulation of patients with T2D who participated in the 24-week, phase 3, randomized, double-blind, placebo-controlled, 2-arm parallel-group, multicenter GetGoal-L (NCT00715624), GetGoal-Duo 1 (NCT00975286) and GetGoal-L Asia trials (NCT00866658).ResultsData from 587 lixisenatide-treated patients and 484 placebo-treated patients were included. Patients on lixisenatide were more likely to achieve a PPG target of < 10 mmol/L (< 180 mg/dL) than placebo-treated patients (P < 0.001), regardless of baseline fasting plasma glucose (FPG) levels. More importantly, those who reached the PPG target experienced a significantly greater reduction in mean HbA1c, were more likely to achieve HbA1c target of < 53 mmol/mol (< 7.0%), and experienced weight loss. Those outcomes were achieved with no significant differences in the risk of symptomatic hypoglycemia compared with placebo.ConclusionCompared with placebo, addition of lixisenatide to basal insulin improved HbA1c and reduced PPG, without increasing hypoglycemia risk. These findings highlight the importance of PPG control in the management of T2D, and provide evidence that adding an agent to basal insulin therapy that also impacts PPG has therapeutic value for patients who are not meeting glycemic targets.Trial registrationNCT00715624. Registered 15 July 2008, NCT00975286. Registered 11 September 2009, NCT00866658. Registered 20 March 2009.

Lixisenatide: A New Member of the Glucagon-Like Peptide 1 Receptor Agonist Class of Incretin Therapies.

In Brief In the past decade, various incretin-based therapies have emerged in clinical practice. These drugs, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists lower A1C with weight-neutral or weight-lowering effects and a relatively lower risk of hypoglycemia. This article provides a review of lixisenatide, a once-daily GLP-1 receptor agonist for the treatment of type 2 diabetes.

The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease.

Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer’s disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by amyloid plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of amyloid-β plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD.

Efficacy and Clinical Characteristics of Liraglutide in Japanese Patients With Type 2 Diabetes.

BackgroundLiraglutide was first released in Japan as a long-acting once-daily glucagon-like peptide-1 receptor agonist. The maximum dose in Japan is 0.9 mg/day, which is half of that used in the United States and the European Union (1.8 mg/day). The efficacy of this maximum allowable dose of liraglutide for Japanese patients and the profiles of those patients for whom this agent should be recommended remain unclear.MethodsThis study aimed to examine the effective use of liraglutide in Japanese type 2 diabetic patients. We administered liraglutide to 60 patients, who had been managed with oral hypoglycemic agents or diet and exercise therapy only, during a period of 6 months.ResultsThough HbA1c levels significantly decreased, by approximately 1.5%, after 6 months of liraglutide administration, no significant changes in body weights were observed. The 0.6 mg dose was effective in approximately 40% of patients. In contrast, the effects of a dose increase from 0.6 mg to 0.9 mg were small. The greatest efficacy, as shown by a 2.5% HbA1c decrease, was achieved in non-obese patients. Thus, efficacy decreased as the degree of obesity increased. In addition, efficacy was higher in patients who had a diabetes duration of less than 10 years and was also higher in the group that had a low sulfonylurea (SU) index, when we define the SU index as mg/glimepiride × years of treatment.ConclusionsAs appetite suppressions and associated decreases in body weights were not observed in obese patients, the efficacy of liraglutide at 0.9 mg did not appear to be high. Rather, it appeared to be highly effective for patients who were non-obese and for whom amelioration of blood glucose elevations could be anticipated via the stimulation of insulin secretion. Therefore, we found that liraglutide at doses of 0.9 mg was highly effective in non-obese patients who were in the early stages of diabetes and was particularly effective in patients who had not yet been administered SU agents.

Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double‐blind, placebo‐controlled, 24‐week trial (GetGoal‐M‐Asia)

This study assessed the efficacy and safety of the once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin ± sulfonylurea. In this 24-week, double-blind, placebo-controlled, multinational study, patients were randomized to lixisenatide 20 µg once daily or placebo. The primary endpoint was absolute change in glycated haemoglobin (HbA1c ) from baseline to week 24. A total of 391 patients were randomized. Lixisenatide significantly reduced HbA1c levels compared with placebo (LS mean difference: -0.36%, p = 0.0004). A significantly higher proportion of lixisenatide-treated patients achieved HbA1c targets of <7% (p = 0.003) and ≤6.5% (p = 0.001) versus placebo. Lixisenatide was associated with a statistically significant reduction in 2-h postprandial plasma glucose after a standardized breakfast versus placebo (LS mean difference: -4.28 mmol/L, p < 0.0001) and a significant reduction in fasting plasma glucose (p = 0.0109). There was no difference in weight loss versus placebo, with a modest reduction in body weight reported for both groups (lixisenatide: -1.50 kg, placebo: -1.24 kg; p = 0.296). The incidence of treatment-emergent adverse events (TEAEs) was 64.3% with lixisenatide versus 47.4% with placebo, with serious TEAEs reported in 1.5% versus 2.1% of patients, respectively. The most common TEAE in the lixisenatide group was nausea (16.3% vs 2.6% with placebo). The incidence of symptomatic hypoglycaemia was 5.6% with lixisenatide treatment and 2.6% with placebo (p = 0.1321), with no severe symptomatic hypoglycaemia events reported. In Asian patients with type 2 diabetes mellitus insufficiently controlled on metformin ± sulfonylurea, lixisenatide significantly improved glycaemic control and was well tolerated during the 24-week study.

Lixisenatide Significantly Increases the Probability of a A1C Response in Patients Not Adequately Controlled on Oral Antihyperglycemic Agents

To evaluate the response to lixisenatide, a novel once-daily glucagon-like peptide-1 receptor agonist, as add on to 1 oral antihyperglycemic agent (OAA) and 2 OAAs in patients with type 2 diabetes mellitus (T2DM) and the patient characteristics that may predict a response. Data were extracted from 5 randomized, 24-week, double-blind, placebo-controlled trials of the efficacy and safety of lixisenatide in patients with T2DM with inadequate glycemic control: GetGoal-M, -F1, -S, -P and -M Asia. Response was defined as the proportion of patients achieving A1C <7% or an A1C reduction of ≥1%. Evaluated predictors of response were age, gender, race, diabetes duration and baseline A1C. Significantly more patients achieved A1C <7% with lixisenatide + 1 OAA vs. placebo (43.0 vs. 23.0%, respectively; p<0.0001) and with lixisenatide + 2 OAAs vs. placebo (42.1 vs. 18.0%, respectively; p<0.0001). Significantly more patients achieved a response with lixisenatide + 1 OAA vs. placebo (59.8 vs. 35.4%, respectively; p<0.0001) and lixisenatide + 2 OAAs vs. placebo (60.2% vs. 27.5%, respectively; p<0.0001). No baseline characteristics were a strong predictor of response. In multivariable regression analysis, lixisenatide + 1 OAA and lixisenatide + 2 OAAs was 4.17 times (95% CI: 3.21, 5.41) and 2.81 times (95% CI: 2.14, 3.70) more likely to produce a A1C response vs. placebo, respectively. Lixisenatide added to 1 OAA or 2 OAAs significantly improved A1C and led to a higher proportion of patients reaching A1C <7% or an A1C reduction of ≥1% vs. placebo.

Once-Daily Lixisenatide in Combination with Basal Insulin ± Oral Antihyperglycemic Agents in Patients with Type 2 Diabetes Selectively Reduces Postprandial Hyperglycemic Daytime Exposure

To investigate the efficacy of the once-daily glucagon-like peptide-1 receptor agonist lixisenatide* on basal hyperglycemia (BHG) and persisting postprandial hyperglycemia (PPHG) in patients with type 2 diabetes mellitus (T2DM). Patient-level data were pooled from 3 randomized, phase III studies evaluating lixisenatide + standard of care (SOC; basal insulin ± oral agents) vs. placebo + SOC. Glucose profile exposures (AUC24h) were calculated for BHG, defined as the 24-hour area under the curve above 5.6 mmol/L and below fasting level, as well as the incremental PPHG, defined as the area above fasting and below self-monitored 7-point plasma glucose profiles. Mean baseline characteristics for a pool of 753 subjects were: age 57 years; body mass index 29.8 kg/m2, duration of diabetes 12 years, A1C 8.2% and fasting glucose 7.5 mmol/L. Mean baseline BHG and PPHG exposures were 49.2 and 55.1 mmol/L/hour, respectively. Mean baseline BHG and PPHG contributions to hyperglycemia were 42% and 58%, respectively. After 24 weeks of treatment, mean A1C reduced by –0.7% for lixisenatide group vs. –0.2% for placebo (p<0.0001). BHG exposures for lixisenatide and placebo groups were similar at 24 weeks. PPHG exposure was significantly reduced with lixisenatide vs. placebo (mean change –18 vs. –4 mmol/L/hour, respectively, p<0.0001). Mean BHG and PPHG contributions to hyperglycemia at the end of the study were 46% and 54% with lixisenatide vs. 39% and 61% with placebo. Once-daily lixisenatide complements the effects of basal insulin on glycemic control in T2DM, decreasing A1C mainly by reducing PPHG.

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin

OBJECTIVETo examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA1c).RESEARCH DESIGN AND METHODSWe conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA1c reduction from baseline was the primary end point.RESULTSMean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA1c at end point was 7.8%. HbA1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, –3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, –1.3 kg; P < 0.0001) and insulin dosage (–3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo.CONCLUSIONSBy improving HbA1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options.

Liraglutide: from clinical trials to clinical practice

Liraglutide, a once-daily glucagon-like peptide-1 receptor agonist, is approved for use as monotherapy in the USA and Japan (but not in Europe or Canada) and in combination with selected oral agents (all regions) for the treatment of patients with type 2 diabetes. Guidance from local advisory bodies is emerging on the most appropriate place for liraglutide in the treatment pathway. It is apparent from its phase 3 clinical trial programme that liraglutide provides superior glycaemic control compared with that achieved with other antidiabetic agents used early in the treatment pathway (e.g. glimepiride and sitagliptin). Key additional benefits include a low incidence of hypoglycaemia and clinically relevant weight loss, although these benefits may be ameliorated by concomitant sulphonylurea (SU) treatment and, in the case of hypoglycaemia, reduction of the SU dose may be necessary. Overall, the profile of liraglutide is similar and, in some aspects, superior to twice-daily exenatide. The implementation of liraglutide therapy is straightforward, with simple dose titration from the starting dose of 0.6 to 1.2 mg/day after 1 week; some patients may benefit from additional titration to 1.8 mg/day. Treatment is self-administered by subcutaneous injection. This contrasts with other agents used early in the treatment pathway, but clinical data suggest patients' overall treatment satisfaction with liraglutide is similar (1.2 mg) or better (1.8 mg) than that with sitagliptin despite differing administration methods. Some patients may experience nausea when initiating liraglutide treatment, but the titration regimen is designed to improve tolerability and clinical data indicate nausea is transient.

Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial.

AimsTo evaluate the dose–response relationship of lixisenatide (AVE0010), a glucagon-like peptide-1 (GLP-1) receptor agonist, in metformin-treated patients with Type 2 diabetes.MethodsRandomized, double-blind, placebo-controlled, parallel-group, 13 week study of 542 patients with Type 2 diabetes inadequately controlled [glycated haemoglobin (HbA1c) ≥ 7.0 and < 9.0% (≥ 53 and < 75 mmol/mol)] on metformin (≥ 1000 mg/day) treated with subcutaneous lixisenatide doses of 5, 10, 20 or 30 μg once daily or twice daily or placebo. The primary end-point was change in HbA1c from baseline to 13 weeks in the intent-to-treat population.ResultsLixisenatide significantly improved mean HbA1c from a baseline of 7.55% (59.0 mmol/mol); respective mean reductions for 5, 10, 20 and 30 μg doses were 0.47, 0.50, 0.69 and 0.76% (5.1, 5.5, 7.5 and 8.3 mmol/mol), on once-daily and 0.65, 0.78, 0.75 and 0.87% (7.1, 8.5, 8.2 and 9.5 mmol/mol) on twice-daily administrations vs. 0.18% (2.0 mmol/mol) with placebo (all P< 0.01 vs. placebo). Target HbA1c < 7.0% (53 mmol/mol) at study end was achieved in 68% of patients receiving 20 and 30 μg once-daily lixisenatide vs. 32% receiving placebo (P< 0.0001). Dose-dependent improvements were observed for fasting, postprandial and average self-monitored seven-point blood glucose levels. Weight changes ranged from −2.0 to −3.9 kg with lixisenatide vs. −1.9 kg with placebo. The most frequent adverse event was mild-to-moderate nausea.ConclusionsLixisenatide significantly improved glycaemic control in mildly hyperglycaemic patients with Type 2 diabetes on metformin. Dose–response relationships were seen for once- and twice-daily regimens, with similar efficacy levels, with a 20 μg once-daily dose of lixisenatide demonstrating the best efficacy-to-tolerability ratio. This new, once-daily GLP-1 receptor agonist shows promise in the management of Type 2 diabetes to be defined further by ongoing long-term studies.