Glucagon-like Peptide-1 Receptor Agonist Therapy Research Articles

Real-world outcomes of addition of insulin glargine 300 U/mL (Gla-300) to glucagon-like peptide-1 receptor agonist (GLP-1RA)therapy in people with type 2 diabetes: The DELIVER-G study.

To provide real-world data on the addition of basal insulin (BI) in people with type 2 diabetes mellitus (PWD2) suboptimally controlled with glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy. However, real-world data on the addition of BI to GLP-1RA therapy are limited. We used a US electronic medical record data source (IBM® Explorys®) that includes approximately 4 million PWD2 to assess the real-world impact of adding the second-generation BI analogue insulin glargine 300 U/mL (Gla-300) to GLP-1RA therapy. Insulin-naïve PWD2 receiving GLP-1RAs who also received Gla-300 between March 1, 2015 and September 30, 2019 were identified; participants were required to have data for ≥12 months before, and ≥6 months after, addition of Gla-300. The mean (standard deviation [SD]) age of participants (N=271) was 57.9 (10.8) years. Baseline glycated haemoglobin (HbA1c) was 9.16% and was significantly reduced (-0.97 [SD 1.60]%; P< 0.0001) after addition of Gla-300; a significant increase in the proportion of PWD2 achieving HbA1c control was observed after addition of Gla-300 (HbA1c <7.0%: 4.80% vs. 22.14%, P< 0.0001; HbA1c <8.0%: 19.56% vs. 51.29%, P< 0.0001). The incidence of overall (8.49% vs. 9.59%; P= 0.513) and inpatient/emergency department (ED)-associated hypoglycaemia (0.37% vs. 0.74%; P= 1.000), as well as overall (0.33 vs. 0.46 per person per year [PPPY]; P= 0.170) and inpatient/ED-associated hypoglycaemia events (0.01 vs. 0.04 PPPY; P= 0.466) were similar before and after addition of Gla-300. In US real-world clinical practice, adding Gla-300 to GLP-1RA significantly improved glycaemic control without significantly increasing hypoglycaemia in PWD2. Further research into the effect of adding Gla-300 to GLP-1RA therapy is warranted.

The time-varying cardiovascular benefits of glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes mellitus: Evidence from large multinational trials.

AimsTo evaluate the time‐varying cardio‐protective effect of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) using pooled data from eight contemporary cardiovascular outcome trials using the difference in the restricted mean survival time (ΔRMST) as the effect estimate.Material and MethodsData from eight multinational cardiovascular outcome randomized controlled trials of GLP‐1RAs for type 2 diabetes mellitus were pooled. Flexible parametric survival models were fit from published Kaplan‐Meier plots. The differences between arms in RMST (ΔRMST) were calculated at 12, 24, 36 and 48 months. ΔRMST values were pooled using an inverse variance‐weighted random‐effects model; heterogeneity was tested with Cochran's Q statistic. The endpoints studied were: three‐point major adverse cardiovascular events (MACE), all‐cause mortality, stroke, cardiovascular mortality and myocardial infarction.ResultsWe included eight large (3183‐14 752 participants, total = 60 080; median follow‐up range: 1.5 to 5.4 years) GLP‐1RA trials. Among GLP‐1RA recipients, we observed an average delay in three‐point MACE of 0.03, 0.15, 0.37 and 0.63 months at 12, 24, 36 and 48 months, respectively. At 48 months, while cardiovascular mortality was comparable in both arms (pooled ΔRMST 0.163 [−0.112, 0.437]; P = 0.24), overall survival was higher (ΔRMST = 0.261 [0.08‐0.43] months) and stroke was delayed (ΔRMST 0.22 [0.15‐0.33]) in patients receiving GLP‐1RAs.ConclusionsGlucagon‐like peptide‐1 receptor agonists may delay the occurrence of MACE by an average of 0.6 months at 48 months, with meaningfully larger gains in patients with cardiovascular disease. This metric may be easier for clinicians and patients to interpret than hazard ratios, which assume a knowledge of absolute risk in the absence of treatment.

Glucagon-like peptide-1 (GLP-1) receptor agonists and cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of double-blind, randomized, placebo-controlled clinical trials

BackgroundThe cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.MethodsPubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.ResultsWe included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83–0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77–0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 – 1.01; P = 0.06).ConclusionWe concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.

Disutility of injectable therapies in obesity and type 2 diabetes mellitus: general population preferences in the UK, Canada, and China

IntroductionOnce-daily and once-weekly injectable glucagon-like peptide-1 receptor agonist therapies (GLP-1 RAs) are established in obesity and type 2 diabetes mellitus (T2DM). In T2DM, both once-daily and once-weekly insulin are expected to be available. This study elicited utilities associated with these treatment regimens from members of the general public in the UK, Canada, and China, to quantify administration-related disutility of more-frequent injectable treatment, and allow economic modelling.MethodsTwo anchor states (no pharmacological treatment), and seven treatment states (daily oral tablet and generic injectable regimens of variable frequency), with identical outcomes were tested A broadly representative sample of the general public in each country participated (excluding individuals with diabetes or pharmacologically treated obesity). An adapted Measurement and Valuation of Health protocol was administered 1:1 in web-enabled interviews by trained moderators: visual analogue scale (VAS) as a “warm-up”, and time trade-off (TTO) using a 20-year time horizon for utility elicitation.ResultsA total of 310 individuals participated. The average disutility of once-daily versus once-weekly GLP-1 RA was − 0.048 in obesity and − 0.033 in T2DM; the corresponding average disutility for insulin was − 0.064. Disutilities were substantially greater in China, relative to UK and Canada.DiscussionWithin obesity and T2DM, more-frequent treatment health states had lower utility. Scores by VAS also followed a logical order. The generated utility values are suitable for use in modelling injectable therapy regimens in obesity and T2DM, due to the use of generic descriptions and assumption of equal efficacy. Future research could examine the reasons for greater administration-related disutility in China.

Abstract #1155435: Use of Glucagon-like Peptide 1 Receptor Agonist Therapy for Inpatients with Type II Diabetes and Chronic Kidney Disease: A Retrospective Analysis

The use and overall benefit of non-insulin glucose lowering agents for hospitalized patients is unclear due to limited data. Our study aims to determine the impact and safety of GLP-1 receptor agonist therapy in hospitalized diabetes patients with chronic kidney disease.

The Efficacy of Treatment Intensification by Quadruple Oral Therapy Compared to GLP-1RA Therapy in Poorly Controlled Type 2 Diabetes Mellitus Patients: A Real-world Data Study.

We compared the glycemic efficacy of treatment intensification between quadruple oral antidiabetic drug therapy and once-weekly glucagon-like peptide-1 receptor agonist (GLP-1RA)-based triple therapy in patients with poorly controlled type 2 diabetes mellitus refractory to triple oral therapy. For 24 weeks, changes in glycosylated hemoglobin (HbA1c) from baseline were compared between the two treatment groups. Of all 96 patients, 50 patients were treated with quadruple therapy, and 46 were treated with GLP-1RA therapy. Reductions in HbA1c for 24 weeks were comparable (in both, 1.1% reduction from baseline; P=0.59). Meanwhile, lower C-peptide level was associated with a lower glucose-lowering response of GLP-1RA therapy (R=0.3, P=0.04) but not with quadruple therapy (R=-0.13, P=0.40). HbA1c reduction by GLP-1RA therapy was inferior to that by quadruple therapy in the low C-peptide subgroup (mean, -0.1% vs. -1.3%; P=0.04). Treatment intensification by switching to quadruple oral therapy showed similar glucose-lowering efficacy to weekly GLP-1RA-based triple therapy. Meanwhile, the therapeutic response was affected by C-peptide levels in the GLP-1RA therapy group but not in the quadruple therapy group.

Decreased Risk of Anxiety in Diabetic Patients Receiving Glucagon-like Peptide-1 Receptor Agonist: A Nationwide, Population-Based Cohort Study

Background: Previous findings on using Glucagon-like peptide-1 receptor agonist (GLP1-RA) as an antidepressant were conflicting, lacking large-scale studies. We used population-based data to investigate depression and anxiety risk in diabetic patients receiving the medication. Methods: From claims records of the National Health Insurance Research Database (NHIRD) of Taiwan, we identified cohorts of 10,690 GLP1-RA users and 42,766 propensity score-matched patients without GLP1-RA use from patients with diabetes mellitus (DM) diagnosed in 2011–2017, matched by age, gender, index year, occupation, urbanization, comorbidities, and medications. Incidence, hazard ratios (HR) and 95% confidence interval (CI) of depression and/or anxiety were estimated by the end of 2017. Results: The overall combined incidence of anxiety and/or depression was lower in GLP1-RA users than in non-users (6.80 versus 9.36 per 1,000 person-years), with an adjusted HR adjusted hazard ratio (aHR) of 0.8 (95% CI: 0.67–0.95) after controlling for covariates. The absolute incidence reduction was greater in anxiety (2.13 per 1,000 person-years) than in depression (0.41 per 1,000 person-years). The treatment effectiveness was significant for women. Patients taking GLP1-RA for longer than 180 days had the incidence of anxiety reduced to 2.93 per 1,000 person-years, with an aHR of 0.41 (95%CI: 0.27–0.61), compared to non-users. Dulaglutide could significantly decrease risks of both anxiety and depression. Conclusion: Patients with DM receiving GLP1-RA therapy have a greater reduction of the risk of anxiety than that of depression. Our findings strengthen previous research that advocated possible anti-depressant or anxiolytic effects of GLP1-RA and may lead to improved treatment adherence among patients with DM.

Comparative effectiveness of SGLT2i versus GLP1-RA on cardiovascular outcomes in routine clinical practice

BackgroundTo investigate the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular outcomes in routine clinical practice, which have never been directly compared in head-to-head outcome trials. MethodsWe compared outcomes of adults who newly started SGLT2i or GLP1-RA therapy in Stockholm, Sweden, during 2013–2019. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular (CV) death, myocardial infarction and stroke. Secondary outcomes included the individual MACE components and hospitalization for heart failure. Cox regression with propensity score overlap weighting was used to estimate hazard ratios (HRs) with 95% confidence intervals and adjust for 57 covariates. ResultsWe included 12,375 individuals, of which 5489 initiated SGLT2i and 6886 GLP1-RA therapy, followed for median 1.6 years. Mean age was 61 years and 37.6% were women. Compared with GLP1-RA, SGLT2i new users had similar risk of MACE risk (adjusted HR 1.04; 95% CI 0.83–1.31). The adjusted HRs (95% CI) for SGLT2i vs. GLP1-RA were 0.80 (0.59–1.09) for heart failure hospitalization, 0.95 (0.58–1.55) for cardiovascular death, 0.91 (0.67–1.24) for myocardial infarction and 1.71 (1.14–2.59) for ischemic stroke (5-year absolute risk difference for stroke 1.9% [95% CI 0.8–3.0]). ConclusionsIn a largely primary-prevention population of people undergoing routine care, no differences were observed in MACE risk among initiators of SGLT2i and GLP1-RA. However, compared with GLP1RA, the use of SGLT2i was associated with an increased risk of ischemic stroke that was small in absolute magnitude.

Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist.

Background/Objectives:Hypothalamic obesity (HO) frequently occurs following suprasellar tumors from a combination of decreased energy expenditure and increased energy intake. Glucagon-like peptide-1 receptor agonist (GLP1RA) therapy is associated with increased satiety and energy expenditure. We hypothesized GLP1RA therapy in patients with HO would cause both lower energy intake and increased energy expenditure.Subjects/Methods:Forty-two patients aged 10–26 years (median 16 years) with HO with suprasellar tumors were randomized to GLP1RA (exenatide extended release once-weekly, ExQW, n=23) or placebo (n=19). Thirty seven (81%) patients completed the 36-week double-blind placebo-controlled trial. Total energy expenditure (TEE) was measured with doubly labeled water, physical activity was assessed with actigraphy, and intake was estimated with ad libitum buffet meal. Results are presented as adjusted mean between-group difference.Results:As compared with treatment with placebo, treatment with ExQW was associated with decreased energy intake during a buffet meal (−1 800 kJ (−430 kcal), 95% CI −3 184 to −418 kJ, p= 0.02). There were no significant differences in physical activity between groups. ExQW (vs. placebo) treatment was associated with a decrease in TEE (−695 kJ/day (−166 kcal/day), 95% CI −1 130 to −264 kJ/day, p< 0.01, adjusted for baseline TEE). The treatment effect was still significant after further adjustment for change in body composition (−372 kJ/day (−89 kcal/day), 95% CI −699 to −42 kJ/day, p= 0.04) or change in leptin (−695 kJ/day (−166 kcal/day), 95% CI −1 130 to −264 kJ/day, p< 0.01). This decrease in TEE occurred despite an increase in lean mass and fat mass (1.7 vs. 1.3 kg lean mass, p= 0.88 and 1.5 vs. 4.6 kg fat mass, p= 0.04, ExQW vs. placebo).Conclusions:Treatment with a GLP1RA was associated with a decrease in food intake but also a decrease in TEE that was disproportionate to change in body composition.

The Enhanced Cardiac Outcome of Conjugated SGLT2 Inhibitors and GLP-1RA Therapy in Diabetic Patients.

Cardiovascular disease secondary to diabetes continues to threaten the survivability of many people all over the world. We assess the most recent findings of synergistic effects of combined glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in lowering cardiac complications in the diabetic population. We describe drug therapies' mechanism of action, postulated cardioprotective process, the additive value of conjugated therapy, and analyze recently reported study and its limitation. SGLT2 inhibitors and GLP-1RAs have gained popularity due to their ability to reduce major adverse cardiovascular events in diabetic patients. There is emerging evidence of the additional cardiovascular benefit from the combined application of SGLT2 inhibitors and GLP-1RAs therapy demonstrated by a recent real-world cohort study. Reducing cardiac mortality in patients with diabetes by administering dual antihyperglycemic therapies (GLP-1Rs and SGLT2 inhibitors) might play a key role in the future treatment of the diabetic population.

The effect of GLP-1 receptor agonists in pre-clinical rodent models of Parkinson’s disease: A systematic review and meta-analysis

BackgroundParkinson’s Disease (PD) is a progressive neurodegenerative condition associated with significant morbidity. Currently, there are limited pharmacological options and none of the therapies available are disease-modifying. This systematic review and meta-analysis considers a novel drug class through the research question – in pre-clinical rodent models of PD, is GLP-1 receptor agonist therapy neuroprotective when compared to vehicle controls? MethodsA literature search was conducted to locate relevant pre-clinical studies. Two separate outcomes were considered. The primary outcome was indicators of dopaminergic neurotransmission. The secondary outcome was indicators of motor symptoms. Untreated PD models were compared to PD-models treated with GLP-1 receptor agonists. The final meta-analysis was conducted using the Cochrane RevMan software and represented continuous data using the inverse variance statistical method and random effects analysis model. The final study statistic was represented as an SMD value with a p-value < 0.05 considered statistically significant. Study heterogeneity and publication bias was assessed using I2 values and funnel plots respectively. ResultsEleven studies fit the inclusion criteria and were included in the final analysis. For the primary outcome (n = 128), there was a statistically significant relative improvement of dopaminergic neurotransmission (SMD 1.71, 95% CI = 0.74–2.68, p = 0.0005, I2 = 76%). For the secondary outcome (n = 280), there was a statistically significant improvement in motor outcomes (SMD 2.11, 95% CI = 1.14–3.09, p < 0.0001, I2 = 89%). ConclusionsGLP-1 receptor agonist therapy is neuroprotective in pre-clinical models of PD. This study provides the clinical foundation and research support for the design of rigorous clinical trials to further investigate these results in human PD populations.

Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial.

Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes. Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor-by-treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term. The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58-0.94] and 0.70 [0.37-1.30], respectively), expanded MACEs (0.77 [0.62-0.96] and 0.87 [0.51-1.48]), renal composite (0.70 [0.59-0.83] and 0.52 [0.33-0.83]), and MACEs or death (0.74 [0.59-0.93] and 0.65 [0.36-1.19]) did not differ by baseline SGLT2 inhibitor use (P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use. The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496298.

Incorporating Treatment Pauses, Dosing Flexibility and Education to Support GLP-1RA Therapy Persistence

As the first oral GLP-1 receptor agonist (GLP-1RA), oral semaglutide may increase accessibility of GLP-1RA therapy in broader care settings. Understanding the management of GLP-1RA therapy when intolerability occurs, including gastrointestinal (GI) adverse events (AEs), is important to maintain treatment persistence. The PIONEER 6 trial (NCT02692716; N=3183) examined the efficacy and safety of oral semaglutide in patients with type 2 diabetes either ≥50 years with established cardiovascular/kidney disease or ≥60 years with cardiovascular risk factors. While 27% of patients temporarily discontinued semaglutide on ≥1 occasion during the trial, 12% permanently discontinued due to AE(s). We evaluated medication management strategies within PIONEER 6 to assess their role in supporting treatment continuation. Patients taking semaglutide underwent dose escalation (initiation, 3 mg; 4 weeks, 7 mg; 8 weeks, 14 mg). Investigators could reduce the dose if AEs developed and re-escalate once symptoms resolved/diminished. Patients were educated to address GI AEs throughout the trial. Patients who discontinued treatment because of AEs were encouraged to resume treatment once the AE had ceased. If patients discontinued semaglutide for >21 days, re-escalation from a lower dose was recommended to mitigate GI AEs. Discontinuation mostly occurred during the initial dose escalation period. In total, 23% of patients receiving semaglutide had ≥1 treatment pause, of which, 72% had one pause. Median duration of treatment pause was 21 days. Importantly, 75% of patients restarted semaglutide after the first AE-related treatment discontinuation. These data highlight the role of treatment pauses, flexibility and education in mitigating potential AEs to support treatment persistence on GLP-1RAs.

The association between GLP-1 receptor agonist and diabetic ketoacidosis in the FDA adverse event reporting system

Background and aimsIn 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom (UK) and food and drug administration (FDA) of the United States of America (US) suggested that the relationship between glucagon-like peptide-1 receptor agonists (GLP-1RA) and diabetic ketoacidosis (DKA) deserved attention. This study is aiming to assess the association between GLP-1RA and DKA/ketosis in the FDA Adverse Event Reporting System (FAERS) database. Methods and resultsUsing FAERS database, we firstly extract the number of DKA reports from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019 and calculate proportional reporting ratios (PRRs). We then mined each FAERS file from 2004 Q1 to 2020 Q4 and obtained detailed information on DKA reports. From the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019, there are 1382 DKA cases (1491 ketosis cases) associated with GLP-1RA in the FAERS database. There was a slight disproportionate reporting of DKA associated with overall GLP-1RA (PRR 1.49, 95%CI 1.24–1.79, p < 0.001) after excluding the impact of SGLT2i, T1D and insulin. Any disproportionality disappeared after selecting the GLP-1RA combined with insulin for comparison. ConclusionsWhen GLP-1RA not combined with insulin, the disproportionality of DKA reports associated with GLP-1RA was observed. Our analysis mined the FAERS database to provide evidence and highlight the potential association between DKA adverse events and GLP-1RA therapy that clinicians tend to overlook.

Gastrointestinal Tolerability of Once-Weekly Dulaglutide 3.0 mg and 4.5 mg: A Post Hoc Analysis of the Incidence and Prevalence of Nausea, Vomiting, and Diarrhea in AWARD-11.

BackgroundGastrointestinal (GI) events are the most frequent treatment-emergent adverse events (TEAEs) reported for glucagon-like peptide-1 receptor agonist therapies. This post hoc analysis of the AWARD-11 phase 3 trial assessed the GI tolerability of dulaglutide at once-weekly doses of 1.5, 3.0, and 4.5 mg.MethodsThe AWARD-11 trial randomized patients to once-weekly dulaglutide 1.5 mg (n = 612), 3.0 mg (n = 616), or 4.5 mg (n = 614) for 52 weeks. Patients started on dulaglutide 0.75 mg for 4 weeks before escalating stepwise every 4 weeks until the final randomized dose was reached. This study analyzes the onsets, incidences, prevalences, and severities of nausea, vomiting, and diarrhea events reported through 52 weeks.ResultsThe highest incidences of nausea (≤ 8%), vomiting (≤ 2%), and diarrhea (≤ 4%) were primarily observed soon after the initiation of dulaglutide treatment at 0.75 mg. Incidence then declined throughout the remainder of the study, even with dose escalation to 1.5, 3.0, and 4.5 mg. Most of these GI TEAEs were mild to moderate in severity, with severe nausea, vomiting, or diarrhea events occurring in ≤ 0.6% of patients. Treatment discontinuation due to nausea was low across treatment groups (≤ 1.5%).ConclusionsThe tolerability profiles of dulaglutide 3.0 mg and 4.5 mg were consistent with that of the 1.5-mg dose. Patients experiencing GI events were most likely to do so within 2 weeks of treatment initiation, and few patients experienced a new GI event after escalating to the 3.0-mg or 4.5-mg dose. Severe events were infrequent, and when they did occur, no relationship with dose at time of event was observed. Supplementary file1 (MP4 33880 kb) Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01140-9.

Understanding the place for GLP-1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection.

Since the first glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) was approved in 2005 (exenatide twice daily) for type 2 diabetes (T2D), the class has developed with newer compounds having more pronounced effects on glycaemic control and body weight. Also, administration regimes have become more convenient with once weekly injections, and recently an oral administration has become available. Large-scale randomized controlled cardiovascular (CV) outcome trials (CVOTs) have shown that GLP-1RA therapy can reduce the risk of CV disease (CVD) in high-risk individuals with T2D. In addition, GLP-1RAs may have renal benefits driven by new-onset macroalbuminuria, although no effect on hard renal endpoints has been found. Subsequently, the place for GLP-1RA therapy has changed over recent years, with most societies endorsing GLP-1RA therapy in patients with established or high risk of CVD independently of glycaemia. Initiation of GLP-1RA therapy can be complex due to differences in efficacy, side effects and safety profiles as well as administration forms within the class. Implementing guideline recommendations into ideal patient selection may be challenging both in specialty and non-specialty settings. To ensure adequate and proactive use of modern glucose-lowering medications in the treatment of T2D, it is essential to recognize patients with high risk or documented CVD. The present review provides an overview of the efficacy and benefits of the currently available GLP-1RA compounds. Furthermore, we review the results from recent large-scale CVOTs in a clinical context and suggest improving the implementation of GLP-1RA therapy across specialties to improve overall patient selection.

Cardiovascular morbidity and mortality in patients with type 2 diabetes using novel antidiabetic medicines as add-on therapy: an observational real-world study

ObjectiveTo evaluate the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy on cardiovascular (CV) morbidity and...

Circulating microRNAs Signature for Predicting Response to GLP1-RA Therapy in Type 2 Diabetic Patients: A Pilot Study

Type 2 diabetes (T2D) represents one of the major health issues of this century. Despite the availability of an increasing number of anti-hyperglycemic drugs, a significant proportion of patients are inadequately controlled, thus highlighting the need for novel biomarkers to guide treatment selection. MicroRNAs (miRNAs) are small non-coding RNAs, proposed as useful diagnostic/prognostic markers. The aim of our study was to identify a miRNA signature occurring in responders to glucagon-like peptide 1 receptor agonists (GLP1-RA) therapy. We investigated the expression profile of eight T2D-associated circulating miRNAs in 26 prospectively evaluated diabetic patients in whom GLP1-RA was added to metformin. As expected, GLP1-RA treatment induced significant reductions of HbA1c and body weight, both after 6 and 12 months of therapy. Of note, baseline expression levels of the selected miRNAs revealed two distinct patient clusters: “high expressing” and “low expressing”. Interestingly, a significantly higher percentage of patients in the high expression group reached the glycemic target after 12 months of treatment. Our findings suggest that the evaluation of miRNA expression could be used to predict the likelihood of an early treatment response to GLP1-RA and to select patients in whom to start such treatment, paving the way to a personalized medicine approach.

Second-Line Therapy for Type 2 Diabetes Management: The Treatment/Benefit Paradox of Cardiovascular and Kidney Comorbidities.

To examine whether glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are preferentially initiated among patients with cardiovascular disease, heart failure (HF), or nephropathy, where these drug classes have established benefit, compared with dipeptidyl peptidase 4 inhibitors (DPP-4i), for which corresponding benefits have not been demonstrated. We retrospectively analyzed claims of adults with type 2 diabetes included in OptumLabs Data Warehouse, a deidentified database of commercially insured and Medicare Advantage beneficiaries, who first started GLP-1RA, SGLT2i, or DPP-4i therapy between 2016 and 2019. Using multinomial logistic regression, we examined the relative risk ratios (RRR) of starting GLP-1RA and SGLT2i compared with DPP-4i for those with a history of myocardial infarction (MI), cerebrovascular disease, HF, and nephropathy after adjusting for demographic and other clinical factors. We identified 75,395 patients who started GLP-1RA, 58,234 who started SGLT2i, and 91,884 who started DPP-4i. Patients with prior MI, cerebrovascular disease, or nephropathy were less likely to start GLP-1RA rather than DPP-4i compared with patients without these conditions (RRR 0.83 [95% CI 0.78-0.88] for MI, RRR 0.77 [0.74-0.81] for cerebrovascular disease, and RRR 0.87 [0.84-0.91] for nephropathy). Patients with HF or nephropathy were less likely to start SGLT2i (RRR 0.83 [0.80-0.87] for HF and RRR 0.57 [0.55-0.60] for nephropathy). Both medication classes were less likely to be started by non-White and older patients. Patients with cardiovascular disease, HF, and nephropathy, for whom evidence suggests a greater likelihood of benefiting from GLP-1RA and/or SGLT2i therapy, were less likely to start these drugs. Addressing this treatment/benefit paradox, which was most pronounced in non-White and older patients, may help reduce the morbidity associated with these conditions.

The therapeutic effects of glucagon-like peptide-1 receptor agonists and metformin on polycystic ovary syndrome: A protocol for systematic review and meta-analysis.

Background:Obesity and insulin resistance (IR) are common in polycystic ovary syndrome (PCOS), which contribute to reproductive and metabolic abnormalities. Metformin increases insulin sensitivity, but it is associated with unsatisfied benefits of weight loss. Recent studies have reported that glucagon-like peptide 1 (GLP-1) receptor agonists improve IR and reduce weight in women with PCOS. We conducted a systematic review and meta-analysis to compare the effects between GLP-1 receptor agonists and metformin, and between GLP-1 receptor agonist-metformin combination and GLP-1 receptor agonists in overweight/obese women with PCOS on anthropometric, metabolic, reproductive outcomes.Methods:Databases including PubMed, EMBASE, Web of Science, and Cochrane Library were selected to search for randomized controlled trials (RCTs) published in English up to March 2020. Eligible studies were identified according to the inclusion criteria. The primary outcomes included menstrual frequency, body mass index (BMI), total testosterone, and the homeostatic model assessment of insulin resistance. GRADE criteria were implemented to assess the quality of evidence for primary outcomes.Results:Seven RCTs were selected for analysis, comprising 464 overweight/obese women with PCOS. In the low-quality evidence, a meta-analysis demonstrated that GLP-1 receptor agonists showed better effects relative to metformin on the reduction of body mass index (mean difference − 1.72; 95% confidence interval −2.46 to −0.99, P < .001) and homeostatic model assessment of insulin resistance (standard mean difference −0.37; 95% confidence interval − 0.60,− 0.15, P = .001). Moreover, the combination therapy exhibited similar effects on primary outcomes relative to GLP-1 receptor agonist alone. GLP-1 receptor agonists were also found to be associated with lower abdominal girth compared to metformin. A meta-analysis of gastrointestinal discomfort showed no significant difference between GLP-1 receptor agonist and metformin therapies, and between the combination therapy and GLP-1 receptor agonist alone.Conclusions:GLP-1 receptor agonists appear to be more beneficial for weight loss and IR improvement compared to metformin for overweight/obese women with PCOS. However, the combination treatment displays comparable effects with GLP-1 receptor agonist alone. The incidence of gastrointestinal discomforts was similar in different groups. However, the quality of the body of evidence is “low.” Further prospective RCTs and cost-effectiveness analyses are also warranted to guide GLP-1 receptor agonists to treat women with PCOS.