Glucagon-like Peptide-1 Receptor Agonist Therapy Research Articles

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.

402-P: Liraglutide Might Have Synergistic Renal Protection Effect with SGLT2 Inhibitors in Rapidly Progressive Diabetic Kidney Disease

Objective: SGLT2 inhibitor (SGLT2i) and GLP-1 receptor agonist (GLP-1RA) should be considered for patients with type 2 diabetes (T2D) with CKD. But very few data are available whether synergistic effects of both drugs exist. We assessed annual eGFR decline rate by adding SGLT2i in patients with T2D on GLP-1RA therapy. Methods: A total of 75 patients with T2D with CKD stage 3-4, treated by SGLT2i (empagliflozin 65%) were analyzed. The duration of diabetes at the time of recruitment were as follows: stage 3a (n=29); 11.9±5.4 yrs, stage 3b (n=28); 19.9±12.1 yrs, and stage 4 (n=18); 13.8±8.5 yrs. Macroalbuminuria existed in 49% (37/75). Average age was 70.3±12.2 yrs old. GLP-1RA (Liraglutide: n=36) was initially or additionally used in 41%, 64% and 44% respectively for glucose management, considering for ASCVD. Individual eGFR decline rate (slope) was calculated from the data for 46±20 months before using SGLT2i and 31±9 months after adding it. The effects on slopes by SGLT-2i, GLP-1RA combination therapies (GLP-1RA initiated at different timing) were compared with those without GLP-1RA therapy. Results: 1) i) Baseline on GLP-1RA initiation therapy -5.2±5.3 improved to -2.2±1.4 (P&amp;lt;0.05) after SGLT2i added. (n=11) ii) Slopes -5.0±3.5 improved to -1.2±4.5 (P&amp;lt;0.03) with simultaneous intensification by SGLT2i + GLP-1RA. (n=13) iii) Slopes -14.6±18.0 improved to -5.4±5.5 (P&amp;lt;0.05) by intensification by GLP-RA, then improved to -2.6±3.3 (P&amp;lt;0.05) with SGLT2i added. (n=14) In this rapidly declining group, macroalbuminuria highly existed in 71% (10/14), and nephrosis existed in 36% (5/14), but nephrosis all came into remission through this therapy. 2) SGLT2i monotherapy (n=37): Slopes -4.1±3.0 improved to -1.2±3.1 ml/min/1.73m2/year (P&amp;lt;0.001) after SGLT2i added. On this background, macroalbuminuria less existed (46%), and nephrosis existed none. Conclusion: Liraglutide might have synergistic renal protection effects with SGLT2i in rapidly progressive DKD. Disclosure K. Kashima: None. H. Shimizu: None. M. Yamada: None.

664-P: 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 (sema) may facilitate increased access to the benefits 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 overcome potential barriers to treatment persistence. The PIONEER 6 trial (NCT02692716; N=3183) examined the efficacy and safety of oral sema in patients (pts) with T2D either ≥50 years with established cardiovascular (CV) or kidney disease, or ≥60 years with CV risk factors. In total, 27% of pts stopped taking oral sema at least once during the trial due to an AE, but only 12% permanently discontinued due to an AE. We thus evaluated medication management strategies within PIONEER 6 to assess their role in supporting treatment continuation. Pts on oral sema underwent dose escalation starting at 3 mg, increasing to 7 mg after 4 weeks, and 14 mg after 8 weeks. Investigators were permitted to reduce the dose if AEs developed and to re-escalate the dose once symptoms had resolved or diminished. Pts were educated as needed to address GI tolerability issues throughout the trial. Pts who discontinued treatment because of an AE were encouraged to resume treatment once willing or once the AE had ceased. The time off oral sema was considered a treatment pause. If treatment pauses were &amp;gt;21 days, re-escalation from a lower dose was recommended to mitigate GI AEs. Discontinuation of oral sema (temporary and permanent) mostly occurred during the initial dose escalation period. In total, 23% of pts receiving oral sema had ≥1 treatment pause, the majority of whom (72%) had just one pause. The median duration of treatment pause was 21 (IQR 7-51) days. Importantly, 75% of pts restarted oral sema 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. Disclosure V. R. Aroda: Consultant; Self; Applied Therapeutics, Duke, Novo Nordisk, Pfizer Inc., Sanofi, Employee; Spouse/Partner; Janssen, Merck, Research Support; Self; Applied Therapeutics, Eli Lilly and Company, Fractyl, Medpace, Medpace, Novo Nordisk, Premier, Sanofi, Stock/Shareholder; Spouse/Partner; Janssen, Merck. R. Bauer: Employee; Self; Novo Nordisk A/S. A. L. Davies: Employee; Self; Novo Nordisk. E. B. Kreiner: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. P. J. Lin: Advisory Panel; Self; Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Canada Inc., Sanofi. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp &amp; Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. S. C. Bain: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Napp Pharmaceuticals, Novo Nordisk A/S, Sanofi, Consultant; Self; ADOCIA, Speaker’s Bureau; Self; Bayer AG, Medscape, WebMD LLC. Funding Novo Nordisk A/S

Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide1 Receptor Agonists.

Obesity is a chronic disease associated with many complications. Weight loss of 5–15% can improve many obesity-related complications. Despite the benefits of weight reduction, there are many challenges in losing weight and maintaining long-term weight loss. Pharmacotherapy can help people with obesity achieve and maintain their target weight loss, thereby reducing the risk of obesity-related complications. The prevalence of obesity in the USA has been increasing over the past few decades, and despite the availability of approved anti-obesity medications (AOMs), people with obesity may not be accessing or receiving treatment at levels consistent with the disease prevalence. Reasons for low levels of initiation and long-term use of AOMs may include reluctance of public health and medical organizations to recognize obesity as a disease, lack of reimbursement, provider inexperience, and misperceptions about the efficacy and safety of available treatments. This article aims to inform primary care providers about the mechanism of action of one class of AOMs, glucagon-like peptide 1 receptor agonists (GLP-1RAs), in weight loss and longer-term maintenance of weight loss, and the efficacy and safety of this treatment class. GLP-1RA therapy was initially developed to treat type 2 diabetes. Owing to their effectiveness in reducing body weight, once-daily subcutaneous administration of liraglutide 3.0 mg has been approved, and once-weekly subcutaneous administration of semaglutide 2.4 mg is being investigated in phase III trials, for obesity management. Considerations regarding adverse effects and contraindications for different drug classes are provided to help guide treatment decision-making when considering pharmacotherapy for weight management in patients with obesity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01710-0.

Short Term Glucagon‐Like Peptide‐1 Receptor Agonist Therapy Does Not Influence Hepatic De Novo Lipogenesis in Polycystic Ovary Syndrome

Background PCOS is common and associated with obesity and the metabolic syndrome. Adolescents with PCOS and obesity are more likely to have hepatic steatosis (HS) which portends worsening metabolic disease. Glucagon like peptide -1 receptor agonist (GLP1RA) therapy has been shown to reduce HS, but its influence on mechanisms such as decreasing of de novo lipogenesis (DNL) or free fatty acid (FFA) concentrations are unknown. Methods Adolescents with obesity and PCOS (N=22), half with HS, were enrolled. Participants underwent an overnight metabolic study followed by a morning oral sugar tolerance test (OSTT; 76-78 g glucose +25 g fructose), with half treated with an evening and morning dose of GLP1RA. Serum for fasting and post-OSTT hormones and metabolic markers was collected. DNL rates were measured fasting and during the OSTT using an overnight intravenous stable isotope 13C2 acetate infusion with measurements of incorporation of the tracer into VLDL-triglyceride palmitate. Hepatic fat was measured with MRI utilizing the Dixon method. Groups were compared via t-test or Mann-Whitney U. Metabolic curves between groups were compared via linear mixed effects models. Results TheGLP1RA (N=10, age 15.3 ± 2.2 years, BMI 34.9 ± 7.7 kg/m2, 50% HS) and control groups (N=12, age 16.0 ± 2.2, BMI 36.3 ± 5.7, 50% HS) were similar at baseline in terms of hormonal and metabolic measures, although the fasting serum TG were significantly higher in GLP1RA (126 [95,169] vs 87 [75,106] mg/dL). In GLP1RA, OSTT glucose curveswere significantly lower (p<0.001 overall), as were time points 20, 60, 75, 90, 105, 120, 135, 150, 180, and 210 minutes. Although the OSTT response curves between the groups were not different for FFA, insulin, glycerol or glucagon, fasting glucagon was lower, and insulin at 60 min and glycerol at 300 min were higher in GLP1RA. No significant group differences were found between measures of fractional DNL, although the GLP1RA group was non-significantly lower for every individual time point during fasting and post-OSTT. The absolute DNL level was similar between groups. Conclusions Two doses of GLP1RA treatment impacted fasting and OSTT glucose, insulin and glucagon responses. Glycerol and FFA concentrations did not change and there was a trend for lower fractional DNL. Further study after a longer duration of GLP1RA treatment is needed to determine if decreased DNL is associated with decreases in hepatic steatosis following GLP1RA therapy.

Evaluation of glucagon-like peptide-1 receptor expression in nondiabetic and diabetic atherosclerotic mice using PET tracer 68Ga-NODAGA-exendin-4.

Cardiovascular effects of glucagon-like peptide-1 receptor (GLP-1R) agonist therapies are potentially mediated by anti-inflammatory effects on atherosclerosis. Our study demonstrates that 68Ga-NODAGA-exendin-4, a radioligand specifically targeting GLP-1R, detects GLP-1R expression in inflamed atherosclerotic lesions in nondiabetic and diabetic hypercholesterolemic mice. Immunofluorescence staining suggests that GLP-1R is primarily localized in M2 macrophages in lesions. This study describes a new potential tool that may have translational relevance for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.

Impact of glucagon-like peptide-1 receptor agonists on adiponectin concentrations: A meta-analysis of randomized controlled trials.

Previous studies have reported an elevation in adiponectin concentrations using glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy; however, this possible pleiotropic effect is still uncertain. Thus, the objective of this meta-analysis of randomized controlled trials was to assess the impact of GLP-1 RA on adiponectin levels. This systematic review and meta-analysis included randomized controlled trials investigating the effect of GLP-1 RA on circulating adiponectin concentrations. Studies from PubMed, Web of Science, Scopus, and Google Scholar databases were included. A random-effects model and a sensitivity analysis using the leave 1-out method were conducted. A meta-analysis of 20 randomized controlled trials involving 1497 individuals demonstrated a significant increase in adiponectin levels after GLP-1 RA administration (weighted mean difference [WMD]: 0.59 μg/mL, 95% confidence interval [CI]: 0.10, 1.08, P= .02). Particularly, liraglutide had a significant effect on adiponectin (WMD: 0.55 μg/mL, 95% CI: 0.04, 1.06, P= .04), while exenatide did not affect these concentrations (WMD: 0.60 μg/mL, 95% CI: -0.23, 1.42, P= .16). GLP-1 RA treatment is associated with an increase in adiponectin levels.

Real-World Effectiveness of Once-Weekly Semaglutide From a US Commercially Insured and Medicare Advantage Population

PurposePatients managing type 2 diabetes mellitus (T2DM) often require combination therapy to meet their blood glucose control targets. With limited real-world evidence focused on the use of glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies, the objective of this study was to describe the association between semaglutide once weekly (OW) initiation and changes in hemoglobin A1c (A1c) levels. MethodsThis retrospective, descriptive cohort study used the HealthCore Integrated Research Environment (HIRE) to examine commercially insured and Medicare Advantage patients who had T2DM while taking semaglutide OW from December 1, 2017, to April 30, 2019. The first semaglutide OW prescription fill was defined as the study index date. Changes in mean A1c levels and A1c target attainment were evaluated among an intention-to-treat (ITT) population (overall group). Furthermore, a persistent population (PP) analysis on the same outcomes was performed that was limited to ITT patients who were observed to continue to use semaglutide OW at the time of the postindex A1c measurement. In addition, these outcomes were explored in patients stratified based on prior use of GLP-1RA therapy (experienced vs naive) and baseline A1c values >9% (75 mmol/mol). FindingsA total of 1888 patients were identified in the overall ITT group. The mean change in the overall ITT group between preindex and postindex A1c values was −0.9% percentage points (−9.8 mmol/mol) (mean preindex A1c, 8.2% [66.1 mmol/mol]) and −1.1 percentage points (−12.0 mmol/mol) (mean preindex A1c, 8.2% [66.1 mmol/mol]) in the PP subgroup (all P < 0.001). Among the subgroup of patients with a baseline A1c value >9% (75 mmol/mol), percentage point changes in A1c were −2.2 (−24.0 mmol/mol) and −2.4 (−26.2 mmol/mol) (all P < 0.001). When accounting for prior GLP-1RA use, the GLP-1RA–naive stratum had double the mean reduction in A1c compared with the GLP-1RA–experienced stratum (−1.2 [−13.1 mmol/mol] vs −0.6 [−6.6 mmol/mol] percentage points). ImplicationsSemaglutide OW is associated with clinically and statistically significant A1C reduction and increases in reaching A1 targets using real-world data, even in GLP-1RA–experienced patients, despite more frequent use of insulin or sodium glucose transport protein 2 inhibitors in this group. Target A1c attainment significantly increased overall and within all subgroups and strata, with approximately half of all patients attaining an A1c value <7% (53 mmol/mol) and three-quarters attaining an A1c value <8% (64 mmol/mol).

Glucagonostatic Potency of GLP-1 in Patients With Type 2 Diabetes, Patients With Type 1 Diabetes, and Healthy Control Subjects.

Hyperglucagonemia is a well-known contributor to diabetic hyperglycemia, and glucagon-like peptide 1 (GLP-1) suppresses glucagon secretion. Reduced inhibitory effects of glucose and GLP-1 on glucagon secretion may contribute to the hyperglucagonemia in diabetes and influence the success of GLP-1 receptor agonist therapy. We examined the dose-response relationship for GLP-1 on glucose-induced glucagon suppression in healthy individuals and patients with type 2 and type 1 diabetes. In randomized order, 10 healthy individuals with normal glucose tolerance, 10 patients with type 2 diabetes, and 9 C-peptide-negative patients with type 1 diabetes underwent 4 separate stepwise glucose clamps (five 30-min steps from fasting level to 15 mmol/L plasma glucose) during simultaneous intravenous infusions of saline or 0.2, 0.4, or 0.8 pmol GLP-1/kg/min. In healthy individuals and patients with type 2 diabetes, GLP-1 potentiated the glucagon-suppressive effect of intravenous glucose in a dose-dependent manner. In patients with type 1 diabetes, no significant changes in glucagon secretion were observed during the clamps whether with saline or GLP-1 infusions. In conclusion, the glucagonostatic potency of GLP-1 during a stepwise glucose clamp is preserved in patients with type 2 diabetes, whereas our patients with type 1 diabetes were insensitive to the glucagonostatic effects of both glucose and GLP-1.

Prescription Patterns of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists in Patients with Coronary Artery Disease.

To assess real-world data on the clinical implementation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in cardiovascular patients and to investigate barriers to prescribe these agents. Patients presenting with coronary artery disease (CAD) and type 2diabetes mellitus (T2DM) between 01/2014 and 04/2020 were included in the present analysis and followed prospectively. All first-time prescriptions of SGLT2i and GLP-1RA were identified. Among 1498 patients with CAD and T2DM, 17.6% of patients received an SGLT2i and 5.5% a GLP-1RA. The prescription of SGLT2i (+38.7%; p < 0.001) and GLP-1RA (+8%; p = 0.007) significantly increased during the observation period. Considering remuneration criteria for SGLT2i therapy, lowering the GFR cut-off to 30 ml/min/1.73 m2 would allow additional 26.6% of patients to qualify for an SGLT2i therapy. While SGLT2i therapy was inversely associated with CV mortality (adjusted hazard ratio of 0.18 [95% CI: 0.05-0.76]; p = 0.019), GLP-1RA therapy showed a trend for risk reduction. The present analysis revealed an infrequent prescription of SGLT2i and GLP-1RAs in patients with T2DM and CAD in clinical practice. Remuneration regulations that better reflect the inclusion criteria of the CV outcome trials would allow more patients at high risk to receive these CV protective drugs. Most importantly, while GLP-1RA therapy showed a trend for risk reduction of cardiovascular mortality, the use of SGLT2i had a strong inverse impact on cardiovascular mortality from a long-term perspective.

The effects of glucagon like peptide-1 (GLP-1) on cardiac remodeling: exploring the role of medication and physiological modulation after metabolic surgery.

Obesity and associated comorbidities reach epidemic proportions nowadays. Several treatment strategies exist, but bariatric surgery has the only longstanding effects. Since a few years, there is increasing interest in the effects of gastro-intestinal hormones, in particular Glucagon-Like Peptide-1 (GLP-1) on the remission of Type 2 Diabetes (T2DM) and its effects on cardiac cardiovascular morbidity, cardiac remodeling, and mortality. In the past years several high quality multicenter randomized controlled trials were developed to assess the effects of GLP-1 receptor agonist therapy on cardiovascular morbidity and mortality. Most of the trials were designed and powered as non-inferiority trials to demonstrate cardiovascular safety. Most of these trials show a reduction in cardiovascular morbidity in patients with T2DM. Some follow-up studies indicate potential beneficial effects of GLP-1 receptor agonists on cardiovascular function in patients with heart failure, however the results are contradictory, and we need long-term studies to make firm conclusions about the pleiotropic properties of incretin-based therapies. However, it seems that GLP-1 receptor agonists have different effects than the increased GLP-1 production after bariatric surgery on cardiovascular remodeling. One of the hypotheses is that the blood concentrations of GLP-1 receptor agonists are three times higher compared to GLP-1 increase after bariatric and metabolic surgery. The purpose of this narrative review is to summarize the effects of GLP-1 on cardiovascular morbidity, mortality and remodeling due to medication but also due to bariatric and metabolic surgery. The second objective is to explain the possible differences in effects of GLP-1 agonists and bariatric and metabolic surgery.

Peptidyl and Non-Peptidyl Oral Glucagon-Like Peptide-1 Receptor Agonists.

Glucagon-like peptide-1 (GLP-1) receptor agonists are efficacious glucose-lowering medications with salient benefits for body weight and cardiovascular events. This class of medications is now recommended as the top priority for patients with established cardiovascular disease or indicators of high risk. Until the advent of oral semaglutide, however, GLP-1 receptor agonists were available only in the form of subcutaneous injections. Aversion to needles, discomfort with self-injection, or skin problems at the injection site are commonly voiced problems in people with diabetes, and thus, attempts for non-invasive delivery strategies have continued. Herein, we review the evolution of GLP-1 therapy from its discovery and the development of currently approved drugs to the unprecedented endeavor to administer GLP-1 receptor agonists via the oral route. We focus on the pharmacokinetic and pharmacodynamic properties of the recently approved oral GLP-1 receptor agonist, oral semaglutide. Small molecule oral GLP-1 receptor agonists are currently in development, and we introduce how these chemicals have addressed the challenge posed by interactions with the large extracellular ligand binding domain of the GLP-1 receptor. We specifically discuss the structure and pharmacological properties of TT-OAD2, LY3502970, and PF-06882961, and envision an era where more patients could benefit from oral GLP-1 receptor agonist therapy.

Neutral effect of exenatide on serum testosterone in men with type 2 diabetes mellitus: A prospective cohort.

Endogenous testosterone increases with weight loss from diet, exercise, and bariatric surgery. However, little is known about testosterone levels after weight loss from medication. Uncover the effects of Glucagon-Like Peptide-1 receptor agonist (GLP-1 RA) therapy on serum testosterone. Prospective cohort study of men starting GLP-1 RA therapy for type 2 diabetes mellitus. 51 men lost 2.27kg (p=0.00162) and their HbA1c values improved by 0.7% (p=0.000503) after 6months of GLP-1 RA therapy. There was no significant change in testosterone for the group as a whole. However, in subgroup analyses, there was a significant difference in total testosterone change between men starting with baseline total testosterone <320ng/dL (238.5±56.5ng/dL to 272.2±82.3ng/dL) compared to higher values (438±98.2ng/dL to 412±141.2ng/dL) (p=0.0172);free testosterone increased if the baseline total testosterone was <320ng/dL (55.2±12.8pg/mL to 57.2±17.6pg/mL) and decreased if >320ng/dL (74.7±16.3pg/mL to 64.2±17.7pg/mL) (p=0.00807). Additionally, there were significant differences in testosterone change between men with HbA1c improvements ≥1% (351.6±123.9ng/dL to 394.4±136.5ng/dL) compared to men with HbA1c changes <1% (331.8±128.6ng/dL to 316.1±126.2ng/dL) (p=0.0413). GLP-1 RA therapy improves weight and HbA1c without adverse effects on testosterone. Those starting with lower testosterone values or attaining greater improvement in HbA1c may see additional benefits.

Sodium-glucose cotransporter-2 inhibitors and risk for genitourinary infections in older adults with type 2 diabetes.

Background and aims:Although landmark clinical trials have demonstrated an increased risk for genitourinary infection (GUI) after initiation of sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy that led to an FDA label warning, real world findings have been inconsistent and evidence specifically in older adults is lacking. The objective of the study was to examine the incidence of GUI in patients aged 65 years or older initiated on SGLT2i compared with glucagon-like peptide-1 receptor agonist (GLP1-RA) therapy at a large academic health system.Methods:A retrospective population-based cohort study was conducted using electronic health records of patients aged 65 years and older with a diagnosis of type 2 diabetes mellitus. Patients newly initiated on SGLT2i or GLP1-RA therapy with estimated glomerular filtration rate (eGFR) ⩾30 mL/min per 1.73 m² and active within the health system for at least 1 year prior to initiation were included. We compared the incidence of inpatient, emergency room, or outpatient diagnosis of GUI (bacterial and mycotic) within 6 months of SGLT2i or GLP1-RA initiation. A chi-square or Fisher’s exact test were used to analyze between-group differences for categorical variables, while a t-test was used for continuous variables. A Cox proportional hazards model was used to estimate the impact of confounding variables on the primary outcome.Results:One hundred and thirty-three patients were initiated on SGLT2i therapy and 341 patients newly initiated on GLP1-RA therapy. After adjusting for differences in age, A1c, body mass index, eGFR, race and sex, there was no statistically significant difference in GUI incidence within 6 months of SGLT2i versus GLP1-RA initiation (3.8% versus 6.5%, adjusted hazard ratio: 0.784, 95% confidence interval 0.260–2.367).Conclusion:We found no increased risk of composite GUI within 6 months of initiating SGLT2i compared with GLP1-RA therapy. These real-world data in older adults add to previous findings, which suggest no increased risk of urinary tract infection with SGLT2i initiation.Plain language summaryA class of antidiabetic medications and risk for genitourinary infections in older adults with type 2 diabetesOlder adults with type 2 diabetes often benefit from a class of antidiabetic medications known as sodium-glucose cotransporter-2 inhibitors (SGLT2is) which help to lower blood glucose, decrease risk for cardiovascular disease and prevent kidney disease progression. However, there is concern that these medications may increase risk for urinary tract infections and/or genital fungal infections in older adults based on clinical trial evidence. Our study evaluated the real-world occurrence of these safety events in patients aged 65 years or older who were newly started on these medications. We compared these patients with a group of patients newly started on an alternative class of antidiabetic agents which are not expected to increase risk for infections, known as glucagon-like peptide-1 receptor agonists (GLP1-RA). In our study, we included 133 patients who started an SGLT2i and 341 patients who started a GLP1-RA at a large teaching hospital. We evaluated the occurrence of infection up to 6 months after initiation of these mediations. We found no significant difference in infection rate between these two groups. We conclude in the study that the use of SGLT2i in older adults was not associated with increased risk for urinary tract infections or genital fungal infections when compared with GLP1-RA use.

Preference for Oral and Injectable GLP-1 RA Therapy Profiles in Japanese Patients with Type2 Diabetes: A Discrete Choice Experiment.

IntroductionGlucagon-like peptide 1 (GLP-1) receptor agonists (RAs) approved to date are administered by injection; therefore, patient perceptions of an oral GLP-1 RA are unknown. This discrete choice experiment explored preferences for (unbranded) oral and injectable GLP-1 RA profiles among Japanese patients with type 2 diabetes (T2D).MethodsAn online survey was designed using literature review and qualitative interview findings, and administered to Japanese patients with T2D and HbA1c ≥ 7.0% receiving oral antiglycaemic medication (with no experience of injectable antiglycaemic medication). Therapy profiles were created using Japanese head-to-head trial data for orally administered semaglutide (7 mg and 14 mg), injectable dulaglutide (0.75 mg), and injectable liraglutide (0.9 mg). Profiles were not labelled. Choice tasks tested preference between hypothetical profiles, preference between profiles with actual trial data, and willingness to initiate treatment. Relative importance of attributes was determined using conditional logit regression.ResultsA total of 500 respondents were analysed: mean age 61.2 years; 93.8% male; mean HbA1c 7.6%; 78.2% with HbA1c ≥ 7.0 to < 8%; 89% with HbA1c above personal target. Mean BMI was 25.4 kg/m2; 49% had obesity (≥ 25 kg/m2). The treatment attribute with greatest importance was mode and frequency of administration (49.1%), followed by nausea risk (30.8%), weight change (11.3%), and HbA1c change (8.8%). Oral semaglutide 7 and 14 mg-like profiles were both preferred: the 7 mg-like profile was preferred over dulaglutide (by 91.0% of respondents) and liraglutide (by 89.4%); the 14 mg-like profile was preferred over dulaglutide (by 88.2%) and liraglutide (by 94.4%). Willingness to initiate treatment was also higher for orally administered semaglutide-like profiles: 62.4% with 7 mg and 64.0% with 14 mg, versus 13.6% and 11.0% with injectable GLP-1 RA-like profiles. Subgroup results were generally consistent with the overall sample.ConclusionJapanese patients with T2D appear to prefer oral GLP-1 RA profiles over injectable GLP-1 RA profiles, and administration appears to be the most important factor in this decision. This highlights the unmet need for an effective and orally administered GLP-1 RA for the treatment of T2D in Japan.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-020-01561-1) contains supplementary material, which is available to authorized users.

Abstract 13807: Semaglutide Provides More Value for Money Than Dulaglutide or Liraglutide for Prevention of Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Established Cardiovascular Disease

Introduction: The Glucagon-Like Peptide-1 receptor agonists (GLP-1a) semaglutide, dulaglutide, and liraglutide reduce major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus ( T2DM) and established CVD. The American Diabetes Association currently recommends providing GLP-1a therapy to this patient population independently of glycaemic control. Despite proven clinical benefits, providing GLP-1a to all guideline eligible patients is a significant cost burden on healthcare systems. Therefore, it is imperative to compare the value for money of these agents. Hypothesis: The newly introduced GLP-1a Semaglutide may be cost-saving compared to dulaglutide and liraglutide for preventing MACE in patients with established CVD and T2DM. Methods: We calculated the cost needed to prevent one MACE, by multiplying the annualized number needed to treat to prevent one event, by the annual cost of the therapy. Efficacy estimates were extracted from published RCT data. We performed a sensitivity analysis to mitigate differences between trial populations and other uncertainties. Drug costs were based on published US prices. Results: The cost needed to prevent one MACE with semaglutide is $557,187 ($331,491-$2,194,483) compared to $1,179,360 ($732,888-$2,746,224) with liraglutide and $1,605,904 ($706,044-∞) for dulaglutide. Sensitivity analysis confirmed the advantage of semaglutide. Conclusions: Semaglutide prescribed for secondary prevention of MACE in patients with T2DM and established CVD seems to provide more value for money than dulaglutide and liraglutide for the same purpose.

&lt;p&gt;Real-World Adherence and Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists Therapy in Type 2 Diabetes Mellitus Patients in the United States&lt;/p&gt;

AimTo assess adherence and discontinuation of injectable glucagon-like peptide-1 receptor agonists (GLP-1 RA) at 12 and 24 months among adult type 2 diabetes mellitus (T2DM) patients in the United States initiating GLP-1 RA using the administrative claims-based database, Optum Clinformatics® Data Mart 7.1.MethodsA retrospective study was conducted from 01/2009 to 12/2017. Patients were required to be continuously enrolled for 12 months prior to their first GLP-1 RA prescription. Proportion of days covered (PDC) from prescription claims ≥0.80 defined adherence. Discontinuation was defined as a ≥90-day gap from the last date of GLP-1 RA supply to the first date of subsequent prescription claim.ResultsA total of 4791 T2DM patients had ≥1 and 3907 had ≥2 GLP-1 RA prescription claims. 50.9% and 47.4% of patients were adherent at 12 and 24 months, respectively. Adherence was significantly higher among patients on weekly vs daily doses (p<0.001). Median time to discontinuation was 13 months. The discontinuation rate was 47.7% and 70.1% at 12 and 24 months, respectively, with differences at 24 months for age and dosing frequency (p<0.001 for both).ConclusionOver half of T2DM patients initiating GLP-1 RA were non-adherent and the majority (70.1%) discontinued therapy by 24 months. Reasons for non-adherence and discontinuation merit further research.