Glucagon-like Peptide-1 Receptor Agonist Therapy Research Articles

The Impact of GLP-1 Receptor Agonists on Patients with Diabetes on Insulin Therapy

Objective: The clinical benefit of adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) to basal-bolus or very high dose insulin regimens is unclear. This study investigated the impact of adding a GLP-1RA to a spectrum of insulin regimens (basal, basal-bolus, and U-500) to determine the impact on hemoglobin A1c (HbA1c), weight loss, and total daily insulin dose (TDD) over the course of 12 months. Methods: A retrospective chart review was conducted on 113 participants with type 2 diabetes mellitus using insulin therapy. Each participant's HbA1c, body weight, and TDD were recorded prior to initiation of GLP-1RA therapy and at the 3, 6, and 12-month time points while on combination therapy. Results: Across all participants, the HbA1c values decreased significantly from a baseline of 8.9 (74 mmol/mol) ± 0.14% to 8.2 (66 mmol/mol) ± 0.14% (P<.01) in the first 3 months, 8.0 (64 mmol/mol) ± 0.12% (P<.01) at 6 months, to 8.3 (67 mmol/mol) ± 0.14% (P<.01) at 12 months. There was no significant decrease in weight or TDD with the addition of a GLP-1RA overall or in different insulin groups. However, there was a clinically significant decrease in weight over the study duration. Conclusion: The results of this study suggest that adding a GLP-1RA to various insulin regimens may help to achieve glycemic goals while avoiding the less desirable side effects of weight gain and increasing insulin regimens. However, the expected weight loss and decrease in TDD may not be as sizable in the clinical setting. Abbreviations: DCOE = Diabetes Center of Excellence; DM = diabetes mellitus; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = hemoglobin A1c; RCT = randomized controlled trial; TDD = total daily dose.

Long-term efficacy and safety of combined insulin and glucagon-like peptide-1 therapy: Evidence from the LEADER trial.

AimGlucagon‐like peptide‐1 receptor agonist (GLP‐1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long‐term data are lacking. The aim was to assess the long‐term efficacy of the GLP‐1RA liraglutide in subgroups by insulin use in the LEADER trial.Materials and MethodsLEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal‐only insulin, other insulin or no insulin). Insulin was a non‐random treatment allocation as part of standard of care therapy.ResultsAt baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal‐only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no‐insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal‐only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal‐only and no‐insulin subgroups.ConclusionsIn patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes.

Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes, lowering glycated haemoglobin (HbA1c) and weight, but are currently only approved for use as subcutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes. In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA1c of 7·0-9·5% (53-80·3 mmol/mol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in HbA1c (oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the European Clinical Trials registry, number EudraCT 2015-005210-30. Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were eligible and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 341 (48%) of 711 participants were female and the mean age was 56 years (SD 10). All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. Mean change from baseline in HbA1c at week 26 was -1·2% (SE 0·1) with oral semaglutide, -1·1% (SE 0·1) with subcutaneous liraglutide, and -0·2% (SE 0·1) with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] -0·1%, 95% CI -0·3 to 0·0; p<0·0001) and superior to placebo (ETD -1·1%, -1·2 to -0·9; p<0·0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in HbA1c than both subcutaneous liraglutide (ETD -0·2%, 95% CI -0·3 to -0·1; p=0·0056) and placebo (ETD -1·2%, -1·4 to -1·0; p<0·0001) at week 26. Oral semaglutide resulted in superior weight loss (-4·4 kg [SE 0·2]) compared with liraglutide (-3·1 kg [SE 0·2]; ETD -1·2 kg, 95% CI -1·9 to -0·6; p=0·0003) and placebo (-0·5 kg [SE 0·3]; ETD -3·8 kg, -4·7 to -3·0; p<0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (-1·5 kg, 95% CI -2·2 to -0·9; p<0·0001) and placebo (ETD -4·0 kg, -4·8 to -3·2; p<0·0001). Adverse events were more frequent with oral semaglutide (n=229 [80%]) and subcutaneous liraglutide (n=211 [74%]) than with placebo (n=95 [67%]). Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care. Novo Nordisk A/S.

545-P: The Difference in the Effects on Microalbuminuria Depending on the Order of GLP-1RA and SGLT2i Therapy in Type 2 Diabetes

Background: It has been reported that the combination therapy of Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i) decrease micro-albuminuria in type 2 diabetes (T2DM) with nephropathy. There is the possibility that protective effects on estimate glomerular filtration rate (eGFR) and micro-albuminuria are different between (1) GLP-1RA add-on therapy to SGLT2i and (2) SGLT2i to GLP-1RA. Objective: In this study, we aimed to clarify whether there are differences in the changes of eGFR and micro-albuminuria depending on the order of combination therapy between (1) and (2) in T2DM. Method: We studied 69 patients with T2DM who took GLP-1RA together with SGLT2i in Our Hospital, retrospectively. We investigated urine albumin to creatinine ratio (ACR), eGFR, body mass index (BMI), systolic blood pressure (SBP), HbA1c, UA, Na, Cl, hematocrit (Ht) and platelet (Plt) before and after six months of the therapy. Six months changes (delta:Δ) of clinical parameters were compared between each combination therapy. Result: In all subjects, HbA1c, BMI and logACR were significantly decreased with the therapies, respectively. As the comparison of Δ in each clinical factors between (1) and (2) groups, ΔHbA1c of (1) significantly showed lower levels than (2). Whereas ΔNa and ΔCl of (1) significantly showed higher levels. Multiple regression analysis including ΔPlt, ΔHt, ΔUA, ΔBMI, ΔHbA1c, and the type of combination therapy as an independent factor for eGFR, ΔUA, ΔHt and ΔHbA1c were the significant contributing factors. Multiple regression analysis including ΔBMI, ΔHDL-C, ΔHbA1c, age, sex and the type of combination therapy as an independent factor for ΔlogACR, ΔHDL-C was the significant contributing factor. The type of combination therapy was not shown as a significant associated factor for ΔlogACR. Conclusions: Both GLP-1RA add-on therapy to SGLT2i and SGLT2i to GLP-1RA equally reduce albuminuria in T2DM with nephropathy. Disclosure M. Ohara: None. K. Motoyama: None. A. Tamai: None. T. Sakura: None. Y. Yakushiji: None. M. Hosoi: Speaker's Bureau; Self; Eli Lilly and Company.

984-P: Real-World Adherence and Discontinuation of GLP-1 Receptor Agonist (GLP-1RA) Therapy in Type 2 Diabetes (T2D) Patients in the U.S.

Background: GLP-1 RAs are an incretin-based, injectable, therapeutic option for the treatment of T2D. However, there are limited data related to patients’ adherence to, or discontinuation of, GLP-1 RA therapy in the real-world. Methods: Using the Optum Research Database (2010-2016), we conducted a retrospective cohort study of U.S. T2D patients ≥ 18 years initiating GLP-1 RAs as monotherapy or as dual therapy with metformin to evaluate GLP-1 RA adherence and discontinuation. GLP-1 RA adherence was assessed using the proportion of days covered (PDC) among all GLP-1 RA initiators with two or more prescription fills. Discontinuation was defined as any GLP-1 RA therapy gap &amp;gt;90 days after end of days of supply from medication fill during follow-up. Multivariable logistic regression was used to evaluate factors associated with non-adherence and discontinuation. Results: Of 4,791 patients included, 42% were female and median age was 56 years. The proportion of patients characterized as non-adherent (PDC &amp;lt;80%) was 49.1% within 1 year. The proportion of patients who discontinued therapy was 47.7% within 1 year. Factors associated with poor adherence/discontinuation within 1 year included male sex, older age, Southern geographic region, and Medicare insurance. Conclusion: A substantial proportion of U.S. T2D patients are non-adherent to GLP-1 RA therapy and nearly half of patients discontinue GLP-1 RA therapy within a year. Further investigation on the impact of adherence on real-world effectiveness, including weight loss and HbA1c, is warranted. Disclosure T. Weiss: Employee; Self; Merck &amp; Co., Inc. K. Iglay: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. R.D. Carr: Employee; Self; Merck &amp; Co., Inc. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, Merck &amp; Co., Inc. A.P. Mishra: None. L. Yang: Employee; Self; Bristol-Myers Squibb Company, Merck &amp; Co., Inc. S. Rajpathak: None.

Management of Patients with Type 2 Diabetes with Once-Weekly Semaglutide Versus Dulaglutide, Exenatide ER, Liraglutide and Lixisenatide: A Cost-Effectiveness Analysis in the Danish Setting.

IntroductionOnce-weekly semaglutide is a novel glucagon-like peptide-1 (GLP-1) analog for the treatment of type 2 diabetes (T2D) that has been associated with greater reductions in glycated hemoglobin (HbA1c) and body weight versus GLP-1 receptor agonists dulaglutide, exenatide extended-release (ER), liraglutide and lixisenatide in the SUSTAIN trial program and a network meta-analysis (NMA). The aim of the present study was to assess the long-term cost-effectiveness of semaglutide versus all available GLP-1 receptor agonists in Denmark, using a clinically orientated treatment approach.MethodsOutcomes were projected over patient lifetimes using the IQVIA CORE Diabetes Model. Baseline characteristics and treatment effects were sourced from the corresponding SUSTAIN trials and the NMA. Patients were assumed to initiate GLP-1 receptor agonist therapy and subsequently treatment-intensify according to clinical treatment guidelines, with addition of basal insulin and switching to basal-bolus insulin occurring when HbA1c exceeded recommended targets. Patients were assumed to receive a GLP-1 receptor agonist plus basal insulin therapy once HbA1c levels reached 7.5% and a basal-bolus insulin regimen once HbA1c exceeded 8.0%. Costs were captured in 2017 Danish kroner (DKK), with future costs and outcomes discounted at 3% per annum.ResultsPrimary analyses indicated that semaglutide 0.5 mg and 1 mg were associated with improvements in quality-adjusted life expectancy of 0.11 and 0.34 quality-adjusted life years, respectively, versus dulaglutide, achieved at cost savings of DKK 289 and DKK 13,416, respectively. Supporting analyses indicated that both doses of semaglutide were either cost-effective or dominant versus exenatide ER, liraglutide 1.2 mg and 1.8 mg and lixisenatide.ConclusionSemaglutide represents a cost-effective alternative to other GLP-1 receptor agonist therapies available in Denmark, demonstrating clinical benefits versus dulaglutide, exenatide ER, liraglutide and lixisenatide for the treatment of patients with T2D.FundingNovo Nordisk A/S.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-0630-6) contains supplementary material, which is available to authorized users.

Two Cases of Mitochondrial Diabetes in Which Pancreatic Beta-Cell Function and Neuropathy Were Improved by Glucagon-Like Peptide-1 Receptor Agonist Therapy

Mitochondrial diabetes is a refractory type of diabetes mellitus where pancreas beta-cell function attenuates. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been reported for pleiotropic effects in addition to effect to glucose tolerance. In animal models, GLP-1RAs were reported to recover mitochondrial function of pancreas beta-cells and increase the growth rate of nerve cells. Our two cases appear to be the first reported cases in the literature of mitochondrial diabetes where GLP-1RAs improved insulin secretion and neuropathy. J Endocrinol Metab. 2019;9(1-2):33-36 doi: https://doi.org/10.14740/jem539

Predictors of effectiveness of glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes and obesity

Background: Type 2 diabetes mellitus (DM2), which mainly develops from visceral obesity, is a socially significant disease. Reduction of losses from DM2 is a priority in modern medicine development. Glucagon-like peptide-1 receptor agonists (aGLP-1) present one of few groups of antidiabetic drugs that allows to reduce not only glycemia, but also weight in DM2. Taking into account predictors of response to the therapy will allow to reach trearment targets with the highest probability, maintaining a safety of treatment, to optimize recommendations for administration of aGPP-1 as much as possible.&#x0D; Aims: To assess dynamics of metabolic parameters, to identify predictors of reduction in blood glucose, body weight and other metabolic parameters on aGLP-1 therapy in patients with DM2 with body mass index (BMI) 35 kg/m2.&#x0D; Materials and methods: The study involved 33 patients (10 men, 23 women), who had been treated with aGLP-1, the observation period for 24 weeks was planned. 3 patients terminated the participation before the appointed time (1 due to pancreatitis development 2 due to the lack of financial opportunity to purchase the drug). So, 30 patients (10 men, 20 women) were included in the final analysis. Examination consisted of the survey, physical examination with measurement of anthropometric, clinical parameters, filling questionnaires. Data were evaluated at baseline and after 24 weeks of treatment.&#x0D; Results: The study found that patients who achieved weight loss 5% initially had higher BMI (p = 0.028), lower GLP-1 (p = 0.036), had lower level of ghrelin after standard breakfast test (p = 0.022). There was trend (p = 0.071) to greater decrease in BMI in patients with restrictive type of eating behavior compared to patients who had a mixed type. More pronounced decrease in glycemia was noted in patients who had higher fasting plasma glucose level at inclusion (p = 0.001). Dynamics of HbA1c was better in patients with initially higher GLP-1 (p = 0.016) and higher levels of glycemia (p = 0.001). Also, we revealed the statistically significant decrease in triglycerides level, blood pressure by end of the treatment period.&#x0D; Conclusions: Results indicate the different predictors for reduction in weight, glycemia and blood pressure on aGLP-1 therapy. In addition to the metabolic parameters, level of orexigenic and anorexigenic hormones and psycho-social characteristics of patients help to estimate an expected effect of aGLP-1 therapy. When being identifying, the predictors of weight loss and the predictors of carbohydrate metabolism compensation should be studied separately. Identification of response predictors is necessary to optimize indications for this group of drugs administration in DM2.

The Effect of Early Response to GLP-1 RA Therapy on Long-Term Adherence and Persistence Among Type 2 Diabetes Patients in the United States.

Treatment adherence and persistence are crucial to achieve glycemic control in patients with type 2 diabetes (T2D). Early response to a new therapy may lead to improved treatment adherence and associated outcomes. To assess the effect of early response to glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy, as indicated by reduced hemoglobin A1c (A1c) and body weight, on long-term adherence and persistence. Adults aged ≥ 18 years with T2D initiated with GLP-1 RA therapy after January 1, 2010, were identified from the IBM Explorys Therapeutic Dataset. Patients were required to have health care utilization ≥ 6 months before and ≥ 18 months after the index prescription. Changes in A1c and body weight from baseline through 6 months were assessed for all patients; early response was defined by > 1% reduction in A1c and > 3% reduction in body weight within 3-6 months. Adherence (assessed as the proportion of days covered [PDC] ≥ 80%) and nonpersistence/discontinuation (indicated by a gap in therapy ≥ 60 days) over 18 months were evaluated among early responders versus nonresponders. Multivariable logistic regression was used to assess the effect of early response to GLP-1 RA therapy on adherence and discontinuation over 18 months. Among 8,329 identified patients, 33.3% and 31.2% experienced early response as indicated by reductions in A1c > 1% point and in body weight > 3% from baseline, respectively. Significantly higher proportions (P < 0.001) of early responders in both reduced A1c and body weight were adherent over 18 months compared with patients without an early response (A1c: 45.0% vs. 37.1%; body weight: 43.3% vs. 38.0%). Significantly lower proportions (P < 0.001) of early responders discontinued over 18 months compared with patients without an early response (A1c: 61.4% vs. 67.9%; body weight: 61.9% vs. 67.5%). After controlling for baseline demographic and clinical characteristics including baseline weight, baseline A1c, oral antidiabetes drug use, insulin use, and the presence of comorbidity of diabetes, patients were more likely to be adherent over 18 months if they had reductions in A1c > 1% (OR = 1.59, 95% CI = 1.36-1.85) or body weight reduction > 3% (OR = 1.18, 95% CI = 1.02-1.36) at 3-6 months compared with those without an early response. Similarly, the early responders had significantly lower likelihood of discontinuation compared with those without early response (A1c > 1%; OR = 0.62, 95% CI = 0.53-0.72; body weight > 3%; OR = 0.81, 95% CI = 0.70-0.94). Early response to GLP-1 RA therapy was associated with significantly increased adherence and reduced likelihood of discontinuation. Funding to conduct this study was provided to IBM Watson Health by Novo Nordisk A/S. The analysis was conducted independently by IBM Watson Health. Novo Nordisk A/S and IBM Watson Health collaborated on study design and interpretation of results. At the time of this study, Durden and Laing were employed by IBM Watson Health and received funding from Novo Nordisk to conduct this study. Fowler is employed by IBM Watson Health. Panton and Mocevic were employed by Novo Nordisk while this study was conducted. A portion of these results were presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2018; April 23-26, 2018; Boston, MA, where it was awarded with a bronze ribbon.

Evaluating the long‐term cost‐effectiveness of fixed‐ratio combination insulin degludec/liraglutide (IDegLira) for type 2 diabetes in Spain based on real‐world clinical evidence

AimTo evaluate the long‐term cost‐effectiveness of fixed‐ratio combination insulin degludec/liraglutide (IDegLira) versus comparator regimens for type 2 diabetes in Spain, based on real‐world evidence.Materials and methodsClinical data were taken from the European Xultophy Treatment Retrospective Audit (EXTRA) real‐world evidence study in which patients failing to meet glycaemic targets were switched to IDegLira. Baseline regimens (prior to IDegLira treatment) were categorized as: multiple daily insulin injections (MDI; 28%); glucagon‐like peptide‐1 (GLP‐1) receptor agonists in combination with insulin (24%); basal insulin (19%); GLP‐1 receptor agonists (10%); and non‐injectable medications (19%). The IQVIA CORE Diabetes Model was used to project long‐term outcomes for patients switching to IDegLira or continuing their baseline regimens (excluding non‐injectable regimens). Costs were accounted from a Spanish National Health System perspective. Future costs and clinical benefits were discounted at 3% annually and sensitivity analyses were performed.ResultsIDegLira was projected to reduce the incidence of diabetes‐related complications and improve quality‐adjusted life expectancy versus all four comparators. IDegLira reduced direct medical costs versus GLP‐1 receptor agonists in combination with insulin, and versus GLP‐1 receptor agonist therapy, and was therefore considered dominant (cost saving while improving outcomes). IDegLira was found to be cost‐effective versus MDI and basal insulin with incremental cost‐effectiveness ratios of EUR 3013 per quality‐adjusted life‐year (QALY) gained and EUR 6890 per QALY gained, respectively.ConclusionsLong‐term projections based on real‐world evidence indicated that IDegLira is likely to improve clinical outcomes and reduce costs or be cost‐effective compared with other injectable regimens in people with type 2 diabetes in Spain.

Hypoglycemia Abrogates the Vascular Endothelial Protective Effect of Exenatide in Type 2 Diabetes Mellitus.

Glucagon-like peptide-1 (GLP-1) receptor agonists improve postprandial glucose, lipid metabolism, and vascular endothelial function. However, little is known about the effect of hypoglycemia on vascular endothelial function in patients on GLP-1 receptor agonist therapy. The aim of the present study was to determine the effect of hypoglycemia on vascular endothelial function in patients with type 2 diabetes mellitus (T2DM) treated with exenatide. Seventeen patients with T2DM underwent a meal tolerance test to examine the changes in vascular endothelial function and in glucose metabolism, both without exenatide and after a single subcutaneous injection of 10 μg exenatide. Vascular endothelial function was evaluated using reactive hyperemia index (RHI) measured by peripheral arterial tonometry before and 120 min after the meal loading test. The primary endpoint was the difference in changes in postprandial vascular endothelial function between the baseline and exenatide test. The results were analyzed in relation to the presence of absence of hypoglycemia. The natural logarithmically scaled RHI (L_RHI) was significantly lower after the baseline meal test but not in the exenatide test. Administration of exenatide caused symptomatic hypoglycemia in two patients during the meal tolerance test. The difference in the change in L_RHI was 0.125 ± 0.085 in the non-hypoglycemic group, whereas it was lower, − 0.487 ± 0.061, in the hypoglycemic group. The results of this study also suggest that the presence of hypoglycemia induces vascular endothelial dysfunction even during GLP-1 receptor agonist therapy.Trial registration: UMIN000015699.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-0596-4) contains supplementary material, which is available to authorized users.

The Role of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes in Asia

The improvement of glycemic control in patients with type 2 diabetes (T2D) is an urgent need in Asia. East Asian T2D patients have distinct characteristics, including relatively low body weight, early impairment of islet beta cell function with reduced insulin secretion and a marked increase in postprandial blood glucose levels. Control of postprandial hyperglycemia and beta cell preservation are key elements of the therapeutic strategy for these patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce HbA1c, fasting plasma glucose, and (in particular) postprandial glucose levels, and slow gastric emptying, while minimizing the risk of hypoglycemia and weight gain. Compared with long-acting GLP-1RAs, short-acting GLP-1RAs produce greater slowing of gastric emptying (which is a key factor driving the reduction of postprandial glycemia) and induce beta cell rest rather than promoting postprandial insulin secretion when used under physiological conditions. GLP-1RAs have greater efficacy in Asian than Caucasian patients. GLP-1RA add-on therapy provides clinically meaningful reductions in HbA1c and postprandial glucose in Asians with T2D inadequately controlled by oral antidiabetic drugs (OADs) or basal insulin ± OADs. Premixed insulin is often prescribed for T2D patients in China. A short-acting GLP-1RA plus basal insulin is an alternative to premixed insulin, resulting in better efficacy and a lower risk of hypoglycemia and weight gain. In conclusion, GLP-1RAs, especially short-acting GLP-1RAs, are a practical treatment option for East Asian patients with T2D inadequately controlled by OADs or basal insulin.Funding: Sanofi.

Predictors of Effectiveness of Glucagon-Like Peptide-1 Receptor Agonist Therapy in Patients with Type 2 Diabetes and Obesity.

Rationale It is well known that diabetes mellitus (DM) exacerbates the mechanisms underlying atherosclerosis. Currently, glucagon-like peptide-1 receptor agonists (aGLP-1) have one of the most prominent cardioprotective effects among the antidiabetic agents. However, the treatment with aGLP-1 is effective only in 50-70% of the cases. Taking into account the high cost of these medications, discovery of the predictors of optimal response to treatment is required. Purpose To identify the predictors of the greater impact of aGLP-1 on HbA1c levels, weight reduction, and improvement in lipid profile. Methods The study group consisted of 40 patients with type 2 DM (T2DM) and obesity who were treated with aGLP-1. The follow-up period was 24 weeks. Patients' evaluation was conducted at baseline and after 24 weeks. In addition, it included the assessment of the hormones involved in glucose and lipid metabolism and appetite regulation. Results Patients who have initially higher BMI (body mass index), glycemia, and triglycerides (TG) had better improvement in these parameters undergoing aGLP-1 treatment. In patients with a BMI loss ≥ 5%, GLP-1 and fasting ghrelin levels were higher and ghrelin level in postnutritional status was lower. The HbA1c levels decreased more intensively in participants with higher GLP-1 levels. TG responders had lower baseline fasting glucose-dependent insulinotropic peptide (GIP) and postprandial ghrelin levels. Conclusion The evaluation of the glycemic control, lipid profile, and GLP-1, GIP, and ghrelin levels are useable for estimating the expected efficacy of aGLP-1.

Exenatide Delays Gastric Emptying in Patients with Type 2 Diabetes Mellitus but not in Those with Gastroparetic Conditions.

The effect of the treatment with glucagon-like peptide (GLP)-1 receptor agonists on gastric emptying in patients with diabetes with and without gastroparesis is analysed. Patients with type 2 diabetes mellitus subjected to GLP-1 receptor agonist therapy with exenatide were examined before and shortly after initiation of treatment. Gastric half-emptying time was determined by 13C-octanoic breath test; routine laboratory parameter as well as active GLP-1, ghrelin, leptin, insulin, proinsulin and C-peptide levels were determined in fasting state as well as postprandial secretion within 1 h after a standardised meal. Thirty patients' data sets were available for evaluation, of those 20 patients had no gastroparesis and 10 patients showed pathological results following the breath test. Gastric half-emptying time was prolonged in nearly all patients who presented without gastroparesis at initiation of treatment with GLP-1 receptor agonists, only 2 patients with pre-existing mild gastroparesis had worsening of gastric emptying. No effect was detected on leptin and ghrelin levels. Postprandial GLP-1 concentrations measured as AUC after meal decreased significantly. Fasting insulin and C-peptide levels increased significantly without effect on postprandial levels. Proinsulin levels - fasting as well as AUC - decreased non-significantly. Patients reported comparable perception of therapeutic effects. Treatment with GLP-1 receptor agonists may be applied in patients with pre-existing gastroparesis; no effect in terms of worsening of symptoms compared to those without gastroparesis was detected. Patients reported outcome was independent from underlying gastroparesis. Negative effects on gastric emptying were only detected in patients without or with mild gastroparesis.

Addition of glucagon-like peptide-1 receptor agonist therapy to insulin in C-peptide-positive patients with type 1 diabetes.

We aimed to test the hypothesis that addition of glucagon-like peptide-1 receptor agonists (GLP-1RAs) to insulin in C-peptide-positive patients with type 1 diabetes (T1D) will result in a reduction in glycated haemoglobin (HbA1c) with reduced insulin requirements and a rise in C-peptide concentrations. We conducted a retrospective analysis of 11 normal-weight patients with T1D consecutively treated with a GLP-1RA in addition to insulin. Paired t tests were used to compare the changes in HbA1c, insulin doses, body weight, body mass index, and C-peptide concentrations prior to and 12 ± 1 weeks after GLP-1RA therapy. At the end of 12 ± 1 weeks of GLP-1RA therapy, HbA1c fell from 10.74 ± 0.96% (95 ± 10.5 mmol/mol) to 7.4 ± 0.58% (58 ± 6.3mmol/mol) (P < 0.01), body weight fell from 71 ± 2.0 to 69 ± 2 kg (P = 0.06), and total insulin dose was reduced by 64% from 33 ± 6 to 11 ± 5 units (P < 0.01). Five out of 10 patients did not require any insulin. C-peptide concentrations increased significantly from 0.43 ± 0.09 ng/ml (0.14 ± 0.02 nmol/L) to 1.42 ± 0.42ng/ml (0.47 ± 0.13 nmol/L) (P = 0.01). Addition of GLP-1RA therapy to insulin in normal-weight patients with T1D led to a reduction in HbA1c with reduced insulin requirements, a 3.5-fold increase in C-peptide concentrations and freedom from insulin therapy in 50% of patients who tolerated the GLP-1RA therapy over a period of 12 ± 1 weeks.

Two Cases of Mitochondrial Diabetes in Which Pancreatic Beta-Cell Function and Neuropathy Were Improved by Glucagon-Like Peptide-1 Receptor Agonist Therapy

Two Cases of Mitochondrial Diabetes in Which Pancreatic Beta-Cell Function and Neuropathy Were Improved by Glucagon-Like Peptide-1 Receptor Agonist Therapy

Predictors of effectiveness of glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes and obesity.

Diabetes type 2 (CD2), which develops mainly against visceral obesity, is socially significant disease, reduction of losses from which is priority in development of modern medicine. Glucagon-like peptide-1 receptor agonists (aGPP-1) is one of few groups of antidiabetic drugs that allows to reduce not only glycemia, but also weight with CD2. Taking into account predictors of response to therapy will allow highest probability to reach targets while maintaining safety of treatment, optimize recommendations for appointment of aGPP-1 as much as possible. Aims: to assess dynamics of metabolic parameters, to determine predictors of reduction in blood glucose, body weight and other metabolic parameters in AGPP-1 therapy in patients with type 2 diabetes with body mass index (BMI) &gt;35 kg/m. Material and methods. Study involved 33 patients (10 men, 23 women) who had been treated with aGPP-1, planned period of observation for 24 weeks. Early termination ofparticipation of 3 patients (1 - due to development ofpancreatitis, 2 - due to lack of financial opportunity to purchase the drug). Accordingly, 30 patients (10 men, 20 women) were included in final analysis. Examination consisted of survey, physical examination with measurement of anthropometric, clinical parameters, filling questionnaires. Data were evaluated initially and after 24 weeks of treatment. Results. Study found that patients who achieved weight loss &gt; 5% initially had higher BMI (p = 0.028), lower GLP-1 (p = 0.036), had lower level of ghrelin after sample with standard breakfast (p = 0.022). There was trend (p = 0.071) to greater decrease in BMI in patients with restrictive type of eating behavior compared to patients who had mixed type. More pronounced decrease in glycemia was noted in patients who had higher fasting plasma glucose level at inclusion (p = 0.001). Dynamics of HbA1C was better in patients with initially higher GLP-1 (p = 0.016) and higher levels of glycemia (p = 0.001). Also, in examined patients, there was statistically significant decrease in level of triglycerides, blood pressure by end of treatment period. Conclusions. Results indicate that there are different predictors for weight loss, glycemia and blood pressure in aGPP-1 therapy. In addition to metabolic parameters, level of orexigenic and anorexigenic hormones and psycho-social characteristics ofpatients help to estimate expected effect of therapy for ARP1. When predictors are identified, predictors of weight loss and carbohydrate metabolism compensation should be studied separately. Identification of response predictors is necessary to optimize indications for prescribing this group of drugs with CD2.

Doubly robust estimation of the weighted average treatment effect for a target population.

The weighted average treatment effect is a causal measure for the comparison of interventions in a specific target population, which may be different from the population where data are sampled from. For instance, when the goal is to introduce a new treatment to a target population, the question is what efficacy (or effectiveness) can be gained by switching patients from a standard of care (control) to this new treatment, for which the average treatment effect for the control estimand can be applied. In this paper, we propose two estimators based on augmented inverse probability weighting to estimate the weighted average treatment effect for a well-defined target population (ie, there exists a predefined target function of covariates that characterizes the population of interest, for example, a function of age to focus on elderly diabetic patients using samples from the US population). The first proposed estimator is doubly robust if the target function is known or can be correctly specified. The second proposed estimator is doubly robust if the target function has a linear dependence on the propensity score, which can be used to estimate the average treatment effect for the treated and the average treatment effect for the control. We demonstrate the properties of the proposed estimators through theoretical proof and simulation studies. We also apply our proposed methods in a comparison of glucagon-like peptide-1 receptor agonists therapy and insulin therapy among patients with type 2 diabetes, using the UK Clinical Practice Research Datalink data.

Overview of the burden of illness and the role of once-weekly glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes

The prevalence of type 2 diabetes (T2D) is increasing globally, and as the prevalence of T2D rises, the burden of its associated comorbidities is predicted to increase. Effective treatments for T2D are required to improve diabetes control and reduce its negative impact. Glucagon-like peptide-1 receptor agonists (GLP-RAs) are effective in improving glycemic control and bodyweight, are associated with a low risk of hypoglycemia, and some have been associated with reductions in major adverse cardiovascular events (MACE). Once-weekly GLP-1RAs have been developed to overcome barriers to treatment adherence. Currently approved once-weekly GLP-1RAs include exenatide extended-release, albiglutide, and dulaglutide. Semaglutide, another once-weekly GLP-1RA, has recently been approved by the US Food and Drug Administration for the treatment of T2D. Compared with other once-weekly GLP-1RAs, semaglutide has shown greater reductions in HbA1c and weight over once-daily GLP-1RAs. This greater efficacy and improvement in MACE, combined with improvements in delivery devices and dispensing procedures, could help address the burden of T2D.

No pancreatic safety concern following glucagon-like peptide-1 receptor agonist therapies: A pooled analysis of cardiovascular outcome trials.

Evidence on the pancreatic safety of glucagon-like peptide-1 receptor agonist therapy has been limited. The objective of the study was to investigate this issue by pooling data on the incidence of acute pancreatitis and pancreatic cancer from four large-scale cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists. Data were extracted from four published cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes, and pooled analysis was performed to evaluate the risk of acute pancreatitis and pancreatic cancer associated with glucagon-like peptide-1 receptor agonist treatment. Peto OR with 95% CI was used for risk evaluation. The four cardiovascular outcome trials enrolled a total of 33457 patients with type 2 diabetes and reported 123 patients with acute pancreatitis and 70 patients with pancreatic cancer during the median follow-ups of 2.1 to 3.8years. There was no increased risk of either acute pancreatitis (Peto OR 0.89 [95% CI 0.63, 1.27]) or pancreatic cancer (Peto OR 0.84 [95% CI 0.53, 1.35]) associated with glucagon-like peptide-1 receptor agonists compared with placebo when added to standard care. Combined analysis of the four cardiovascular outcome trials showed that treatment with glucagon-like peptide-1 receptor agonists was not associated with an increased risk of either acute pancreatitis or pancreatic cancer in patients with type 2 diabetes. Our new analysis further supports the previously reported results.