Use Of Glucagon-like Peptide-1 Receptor Agonists Research Articles

Incorporating SGLT2i and GLP-1RA for Cardiovascular and Kidney Disease Risk Reduction: Call for Action to the Cardiology Community

Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.

Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes.

OBJECTIVETo determine the respective associations of premorbid glucagon-like peptide-1 receptor agonist (GLP1-RA) and sodium–glucose cotransporter 2 inhibitor (SGLT2i) use, compared with premorbid dipeptidyl peptidase 4 inhibitor (DPP4i) use, with severity of outcomes in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.RESEARCH DESIGN AND METHODSWe analyzed observational data from SARS-CoV-2–positive adults in the National COVID Cohort Collaborative (N3C), a multicenter, longitudinal U.S. cohort (January 2018–February 2021), with a prescription for GLP1-RA, SGLT2i, or DPP4i within 24 months of positive SARS-CoV-2 PCR test. The primary outcome was 60-day mortality, measured from positive SARS-CoV-2 test date. Secondary outcomes were total mortality during the observation period and emergency room visits, hospitalization, and mechanical ventilation within 14 days. Associations were quantified with odds ratios (ORs) estimated with targeted maximum likelihood estimation using a super learner approach, accounting for baseline characteristics.RESULTSThe study included 12,446 individuals (53.4% female, 62.5% White, mean ± SD age 58.6 ± 13.1 years). The 60-day mortality was 3.11% (387 of 12,446), with 2.06% (138 of 6,692) for GLP1-RA use, 2.32% (85 of 3,665) for SGLT2i use, and 5.67% (199 of 3,511) for DPP4i use. Both GLP1-RA and SGLT2i use were associated with lower 60-day mortality compared with DPP4i use (OR 0.54 [95% CI 0.37–0.80] and 0.66 [0.50–0.86], respectively). Use of both medications was also associated with decreased total mortality, emergency room visits, and hospitalizations.CONCLUSIONSAmong SARS-CoV-2–positive adults, premorbid GLP1-RA and SGLT2i use, compared with DPP4i use, was associated with lower odds of mortality and other adverse outcomes, although DPP4i users were older and generally sicker.

Major adverse cardiovascular and limb events in patients with diabetes treated with GLP-1 receptor agonists vs DPP-4 inhibitors.

The safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) in major cardiovascular adverse events were previously examined in cardiovascular outcome trials. However, the effects of these drugs on adverse limb outcomes were poorly examined. This study aimed to determine the real-world outcomes of patients with diabetes mellitus receiving GLP1RAs as compared with those receiving DPP4is in terms of major adverse cardiovascular and limb events. A retrospective cohort study was conducted with data collected by the Taiwan National Health Insurance database between 1 May 2011 and 31 December 2017. Patients who were treated for type 2 diabetes with a GLP1RA or DDP4i during this period (n = 1,080,993), were identified. The primary outcome was a composite of major adverse limb events, defined as peripheral artery disease (PAD), critical limb ischaemia, percutaneous transluminal angioplasty or peripheral bypass for PAD, and amputation. The secondary cardiovascular outcome was the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke. Propensity-score matching (PSM) at a 1:3 ratio between GLP1RA and DPP4i groups was done to minimise possible selection bias. A total of 948,342 individuals treated between 1 May 2011 and 31 December 2017, were identified, with 4460 in the GLP1RA group and 13,380 in the DPP4i group after PSM. The incidence of primary composite outcome events was significantly lower in those treated with GLP1RAs compared with those treated with DPP4is (2.59 vs 4.22 events per 1000 person-years; subdistribution HR [SHR] 0.63 [95% CI 0.41, 0.96]), primarily due to lower rates of amputation (1.29 events per 1000 person-years for GLP1RAs vs 2.4 events per 1000 person-years for DPP4is; SHR 0.55 [95% CI 0.30, 0.99]). Treatment with GLP1RAs was also associated with significantly lower risks of secondary composite outcome events (11.02 vs 17.95 events per 1000 person-years; HR 0.62 [95% CI 0.51, 0.76]). Moreover, the observed beneficial effects of GLP1RAs on reducing composite adverse limb outcomes were particularly noticeable in the non-cardiovascular patients and statin users (p for interaction <0.05). In individuals with diabetes, the use of GLP1RAs was associated with significantly lower risks of major adverse limb events when compared with the use of DPP4is. The reduction in risk was driven largely by reduced rate of amputations. Moreover, treatment with GLP1RAs was also associated with lower risks of cardiovascular death, non-fatal stroke, non-fatal myocardial infarction and death from any cause. However, some unexplored confounding factors may exist in this observation study and future large-scale randomised controlled trials are needed.

Clinical Perspectives on the Use of Subcutaneous and Oral Formulations of Semaglutide.

Early and effective glycemic control can prevent or delay the complications associated with type 2 diabetes (T2D). The benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly recognized and they now feature prominently in international T2D treatment recommendations and guidelines across the disease continuum. However, despite providing effective glycemic control, weight loss, and a low risk of hypoglycemia, GLP-1RAs are currently underutilized in clinical practice. The long-acting GLP-1RA, semaglutide, is available for once-weekly injection and in a new once-daily oral formulation. Semaglutide is an advantageous choice for the treatment of T2D since it has greater efficacy in reducing glycated hemoglobin and body weight compared with other GLP-1RAs, has demonstrated benefits in reducing major adverse cardiovascular events, and has a favorable profile in special populations (e.g., patients with hepatic impairment or renal impairment). The oral formulation represents a useful option to help improve acceptance and adherence compared with injectable formulations for patients with a preference for oral therapy, and may lead to earlier and broader use of GLP-1RAs in the T2D treatment trajectory. Oral semaglutide should be taken on an empty stomach, which may influence the choice of formulation. As with most GLP-1RAs, initial dose escalation of semaglutide is required for both formulations to mitigate gastrointestinal adverse events. There are also specific dose instructions to follow with oral semaglutide to ensure sufficient gastric absorption. The evidence base surrounding the clinical use of semaglutide is being further expanded with trials investigating effects on diabetic retinopathy, cardiovascular outcomes, and on the common T2D comorbidities of obesity, chronic kidney disease, and non-alcoholic steatohepatitis. These will provide further information about whether the benefits of semaglutide extend to these other indications.

Diabetes and COVID-19: A Tale of 2 Pandemics.

Diabetes and COVID-19: A Tale of 2 Pandemics.

Risk of diabetic macular oedema with sodium-glucose cotransporter-2 inhibitors in type 2 diabetes patients: A multi-institutional cohort study in Taiwan.

To investigate the risk of diabetic macular oedema (DMO) associated with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM). We conducted a retrospective cohort study by analysing a large multi-institutional electronic medical records database in Taiwan. We included adult patients with T2DM without DMO newly receiving either SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1RAs) during the period 2016 to 2018. We used propensity scores with inverse probability of treatment weighting to generate comparable groups. The study outcome was incident DMO, determined by clinical diagnosis during outpatient visits or admissions. We followed patients from the index date to either DMO occurrence, last clinical visit, patient death, or December 31, 2020. We performed Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of DMO. We included 9986 new users of SGLT2 inhibitors (mean [SD] age 59.6 (12.1) years, median [interquartile range {IQR}] glycated haemoglobin [HbA1c] 70 (61-81)mmol/mol, estimated glomerular filtration rate [eGFR] 89.1 [71.4-108.7] mL/min/1.73 m2 and urine albumin-creatinine ratio [UACR] 26.1 [9.7-117.6] mg/g) and 1067 new users of GLP-1RAs (mean [SD] age 58.4(41.5) years, median [IQR] HbA1c 73 [64-84] mmol/mol, eGFR 91.6 [68.6-114.0] mL/min/1.73 m2 and UACR 37.6 [11.1-153.2] mg/g) with similar baseline characteristics. Lower DMO risks were observed among patients newly receiving SGLT2 inhibitors (7.9/1000 person-years), compared to those receiving GLP-1RAs (10.7/1000 person-years) with an HR of 0.75 (95% CI 0.64-0.88). Our findings suggest use of SGLT2 inhibitors was associated with lower risk of DMO in T2DM patients in clinical practice, compared to use of GLP-1RAs. Future studies are necessary to confirm this observation.

Use of glucagon-like peptide-1 receptor agonists for pediatric patients with obesity and diabetes: The providers' perspectives.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been widely used in adults with Type 2 diabetes (T2D) and obesity. We sought to evaluate the experience of pediatric endocrinology providers with GLP-1RA and factors that guide them on whether and how to prescribe these medications. We surveyed the members of the Pediatric Endocrine Society regarding the use of GLP-1RA in their practice. The respondents (n= 102) were predominantly from academic centers (84%) and 75%reported using GLP-1RA in pediatric patients, mostly to treat T2D and obesity. Patient tolerance for the medication was reported to be the driving factor determining the duration of treatment. Gastrointestinal side effects were observed more commonly than local reactions or elevation of pancreatic enzymes. Lack of clinical experience was reported to be a major barrier for prescribing GLP-1RA, particularly among those with more than 5 years of clinical experience. Finally, liraglutide was used more often (93%) than other GLP-1RA. The use of GLP-1RA has increased in pediatric patients. Recent Food and Drug Administration approval of liraglutide for pediatric obesity will likely further increase its prescription rate. Providers should be vigilant about side effects and adjust the doses of GLP-1RA accordingly. More efforts should be made by professional societies to educate pediatric endocrinology providers about the proper use of GLP-1RA and enhance their confidence in prescribing these medications.

220-OR: Comparing Cardiovascular Benefits between GLP-1RA and SGLT2i as an Add-On to Metformin among U.S. Adults with Type 2 Diabetes (T2D)

Head-to-head comparison of clinical benefits between glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) are scarce. In this study, we aimed to compare real world cardiovascular benefits associated with the use of GLP-1RA vs. SGLT2i as add-on therapies to metformin among US adults with T2D. Methods: This study used data from the IBM® MarketScan® Commercial Claims Databases (2012-2018). We identified metformin users, age ≥ 18 and with T2D, who initiated GLP-1RA or SGLT2i between Mar 29th and Dec 31st, 2013. Patients were followed until the primary endpoint, end of the study period (Dec 31st 2018), study drug discontinuation or initiation of the other study drug, or disenrollment from the health plan (whichever occurred first). The primary endpoint was a major cardiovascular composite (MCC), including acute myocardial infarction (MI), hospitalization for congestive heart failure (CHF), and stroke. The secondary endpoints included individual components of MCC. We constructed Cox proportional hazard regression models to compare the risks of cardiovascular endpoints between GLP-1RA and SGLT2i users, controlling for demographics, clinical characteristics, and the Diabetes Complication Severity Index. Results: We identified 11,911 adults with T2D who initiated a GLP-1RA or SGLT2i as an add-on therapy to metformin. No difference in the risk of MCC or any secondary endpoints was observed between GLP-1RA users and SGLT2i users who did not have established cardiovascular disease. However, significantly lower risks of MCC (HR:0.67, 95% CI: 0.47-0.97) and CHF (HR:0.47, 95% CI:0.28-0.79) was observed among SGLT2i users compared with GLP-1RA users, among individuals with established cardiovascular complications. Conclusions: Results suggest a greater cardioprotective benefit from SGLT2i compared to GLP-1RA when used for secondary prevention among adults with T2D. Disclosure C. E. Deremer: Research Support; Self; Pfizer Inc., Speaker’s Bureau; Spouse/Partner; Pharmacy Times, Stock/Shareholder; Self; Portola Pharmaceuticals, Inc. J. Guo: None. S. M. Vouri: None. M. J. Haller: Board Member; Self; SAB Biotherapeutics, Inc., Consultant; Self; MannKind Corporation, Other Relationship; Self; Janssen Pharmaceuticals, Inc., Sanofi. W. T. Donahoo: None. A. G. Winterstein: Research Support; Self; Merck Sharp &amp; Dohme Corp. H. Shao: Research Support; Self; Sanofi.

489-P: Facilitating Collaboration through TeleECHO Education in Diabetes

Project ECHO is a collaborative model of medical education that engages clinicians in a continuous learning system via real-time, interactive videoconferencing. During TeleECHO sessions, expert specialist teams at an academic ‘hub’ are linked with care teams in local communities throughout the world. Each session is case-based, with learners and faculty presenting their patient experiences in a HIPAA compliant manner, promoting collaboration and competence building. As an official ECHO hub, MLG recently completed a large-scale, TeleECHO series on treating to guidelines and managing cardiovascular and renal risk in patients with T2DM, consisting of 47 sessions that reached 1976 healthcare professionals. With the ongoing COVID-19 pandemic, these sessions provided a unique way to facilitate a case-based dialogue among community-based practitioners and a national expert, sharing best practices that to apply to the care of individual patients. MLG recorded each session and used the most informative cases to create an enduring activity that is available for one year online. To further support the translation of education into practice and encourage HCP-patient dialogue, MLG also provided learners access to an online Personalized Poster Portal. Learners could choose a variety of images and design a poster that was shipped to their practice setting. There have been 613 poster orders thus far. The outcomes that MLG has collected regarding this unique program and its point-of-care tools indicate how CME can lead to not only improved knowledge but can also translate to practice behavior. While learners demonstrated significant gains across learning objectives, baseline knowledge of the latest data on the use of GLP-1 receptor agonists and SGLT2inhibitors to reduce cardiovascular events demonstrated a need for such education. MLG proposes to partner with Project ECHO to share these results via a poster at the ADA Scientific Sessions. Disclosure R. Allen: None. L. K. Welch: None.

Insulin Withdrawal in Diabetic Kidney Disease: What Are We Waiting for?

The prevalence of type 2 diabetes mellitus worldwide stands at nearly 9.3% and it is estimated that 20–40% of these patients will develop diabetic kidney disease (DKD). DKD is the leading cause of chronic kidney disease (CKD), and these patients often present high morbidity and mortality rates, particularly in those patients with poorly controlled risk factors. Furthermore, many are overweight or obese, due primarily to insulin compensation resulting from insulin resistance. In the last decade, treatment with sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have been shown to be beneficial in renal and cardiovascular targets; however, in patients with CKD, the previous guidelines recommended the use of drugs such as repaglinide or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), plus insulin therapy. However, new guidelines have paved the way for new treatments, such as SGLT2i or GLP1-RA in patients with CKD. Currently, the new evidence supports the use of GLP1-RA in patients with an estimated glomerular filtration rate (eGFR) of up to 15 mL/min/1.73 m2 and an SGLT2i should be started with an eGFR > 60 mL/min/1.73 m2. Regarding those patients in advanced stages of CKD, the usual approach is to switch to insulin. Thus, the add-on of GLP1-RA and/or SGLT2i to insulin therapy can reduce the dose of insulin, or even allow for its withdrawal, as well as achieve a good glycaemic control with no weight gain and reduced risk of hypoglycaemia, with the added advantage of cardiorenal benefits.

Safety and Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Children and Adolescents with Obesity: A Meta-Analysis

To determine the weight, body mass index (BMI), cardiometabolic, and gastrointestinal effects of glucagon-like peptide-1 (GLP-1) receptor agonists in children with obesity. Web of Science, PubMed/MEDLINE, and Scopus databases from 01/01/1994-01/01/2021 for randomized control trials examining the weight, BMI, cardiometabolic, or gastrointestinal effects of GLP-1 receptor agonists in children and adolescents with obesity. Data were extracted by 2 independent surveyors and a random effects model was applied to meta-analyze generic inverse variance outcomes. Primary outcomes were related to weight and cardiometabolic profile, and secondary outcomes of interest were gastrointestinal-related treatment-emergent adverse events. Nine studies involving 574 participants were identified, of which 3 involved exenatide and 6 involved liraglutide. GLP-1 receptor agonists use caused a modest reduction in body weight (mean difference [MD] -1.50 [-2.50,-0.50] kg, I2 64%), BMI (MD -1.24 [-1.71,-0.77] kg/m2, I2 0%), and BMI z score (MD -0.14 [-0.23,-0.06], I2 43%). Glycemic control was improved in children with proven insulin resistance (glycated hemoglobin A1c MD -1.05 [-1.93,-0.18] %, I2 76%). Although no lipid profile improvements were noted, a modest decrease in systolic blood pressure was detected (MD -2.30 [-4.11,-0.49] mm Hg; I2 0%). Finally, analysis of gastrointestinal-related treatment-emergent adverse events revealed an increased risk of nausea (risk ratio 2.11 [1.44, 3.09]; I2 0%), without significant increases in other gastrointestinal symptoms. This meta-analysis indicates that GLP-1 receptor agonists are safe and effective in modestly reducing weight, BMI, glycated hemoglobin A1c, and systolic blood pressure in children and adolescents with obesity in a clinical setting, albeit with increased rates of nausea. CRD42020195869.

Glucagon-like peptide-1 receptor agonists improve biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomised controlled trials.

To conduct a meta-analysis and systematic review to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on clinical biomarkers of inflammation and oxidative stress in patients with type 2 diabetes. Medline, Embase and the Cochrane Library were searched for randomised controlled trials (RCTs) that examined changes with GLP-1RAs in a priori selected biomarkers of inflammation: C-reactive protein (CRP), adiponectin, tumour necrosis factor-alpha (TNFα), plasminogen activator inhibitor-1, interleukin-6, leptin; and of oxidative stress: malondialdehyde (MDA); 8-iso-prostaglandin F2α; and 8-hydroxy-2'-deoxyguanosine (8-OHdG). We included 40 eligible RCTs (n=6749) with a median follow-up of 6months, a mean participant age of 53.1 years, 56.3% females, glycated haemoglobin (HbA1c) 55.6 mmol/mol, body mass index 28.8kg/m2 and diabetes duration 7.46 years. Analysis of GLP-1RAs versus standard diabetes therapies or placebo revealed significant reductions in CRP, TNFα and MDA, and significant increases in adiponectin for (mean difference -0.54 mg/L [-0.75, -0.34]; standard mean difference [SMD] -0.39 [-0.62, -0.15]; SMD -0.84 [-1.61, -0.06] and SMD 0.30 [0.12, 0.49], respectively [95% confidence intervals]). Systolic blood pressure decreased significantly and was significantly and strongly correlated with a reduction in CRP. Homeostatic model assessment of insulin resistance was also significantly correlated with a reduction in CRP, but HbA1c was not. There is strong evidence supporting clinically relevant anti-inflammatory and antioxidant effects of GLP-1RAs. This may be used to guide future targeted clinical use of GLP-1RAs and the development of medications seeking to target the cardioprotective properties of GLP-1RAs.

Ambulatory noninsulin treatment of type 2 diabetes mellitus in the United States, 2015 to 2019.

To examine trends in the noninsulin drug treatment of type 2 diabetes, including first- and second-line therapies on top of metformin, from 2015 to 2019. We conducted a descriptive analysis of cross-sectional data using the IQVIA National Disease and Therapeutic Index, a nationally representative audit of ambulatory physician practices in the United States. We focused on the use of noninsulin pharmacological treatments for type 2 diabetes among individuals aged 35 years and older between January 1, 2015 and December 31, 2019. The main outcome was type 2 diabetes visits where a prescription drug was used ("treatment visit"). Ambulatory diabetes visits decreased from 30.1 million treatment visits in 2015 to 29.5million treatment visits in 2019. Among treatment visits where a single drug was prescribed, the use of metformin declined from 57.0% of monotherapy in 2015 to 46.0% of monotherapy in 2019, while during the same period the share of monotherapy accounted for by glucagon-like peptide-1 (GLP-1) receptor agonists increased from 4.3% to 8.5% and the share accounted for by sodium-glucose cotransporter-2 (SGLT2) inhibitors increased from 7.3% to 19.5%. Among treatment visits where metformin plus another drug was prescribed, the share of second-line therapy accounted for by dipeptidyl peptidase-4 (DPP-4) inhibitors decreased from 21.9% of treatment visits in 2015 to 20.8% of treatment visits in 2019; sulphonylurea use declined from 45.2% to 32.7%, use of SGLT2 inhibitors increased from 14.5% to 21.2% and use of GLP-1 receptor agonists increased from 9.8% to 18.2%. Significant changes in the landscape of ambulatory care for diabetes have taken place during the past 6 years, including moderate declines in metformin monotherapy, moderate declines in second-line sulphonylurea use, and large increases in SGLT2 use. These changes underscore the dynamic nature of drug utilization for diabetes in the United States, and reflect the effects of emerging evidence, evolving clinical guidelines and evolving regulatory and payment policies.

Is there a role for glucagon-like peptide-1 receptor agonists in the treatment of male infertility?

Glucagon‐like peptide‐1 receptor agonists (GLP1‐RAs) are novel anti‐hyperglycemic drugs efficacious on glucose control, weight loss, and cardiovascular prevention. These drugs may also be effective in modulating testicular function. In fact, they increase serum testosterone levels in diabetic and/or obese patients with functional hypogonadism on a dysmetabolic basis. Although part of this effect can be ascribed to weight loss, some evidence suggests that there is a direct effect at the testicular level. Indeed, human Leydig, Sertoli, and germ cells express GLP1 receptors. GLP1‐RAs improve sperm metabolism, motility, and insulin secretion in vitro. Likewise, GLP1‐RAs exert positive effects on the metabolism of human Sertoli cells in vitro. Finally, GLP1 is secreted by mouse Leydig cells and this suggests the presence of a paracrine mechanism by which these cells could support the metabolism of Sertoli cells. Therefore, the widespread use of GLP1‐RAs in clinical practice may reveal an important role in the management of male infertility in obese and/or diabetic patients given the negative impact of these diseases on testicular steroidogenesis and spermatogenesis. This should suggest the design of randomized controlled studies aimed at evaluating the effects of these drugs on testicular function.

A Possible Advantage of Glucagon-Like Peptide 1 Receptor Agonist in Kidney Transplant Recipients With Type 2 Diabetes

Diabetic kidney disease (DKD), a devastating complication of diabetes, is one of the leading causes of end stage kidney disease (ESKD). Kidney transplantation provides superior outcomes for ESKD patients with type 2 diabetes, giving opportunities to be free from dialysis, but needs lifetime immunosuppressive medications to avoid graft kidney rejection. Post-transplant hyperglycemia, however, remains to be unsolved, because immunosuppressive agents, including glucocorticoids and calcineurin inhibitors, may result in impaired insulin secretion and sensitivity. Safe and promising anti-diabetic strategy is long-awaited among kidney transplant recipients (KTRs) with type 2 diabetes. Enormous evidence has accumulated that Glucagon-like peptide 1 (GLP-1) receptor agonists have potential to maintain kidney function as well as improve glucose tolerance in patients with DKD. The present study was designed to elucidate the association between GLP-1 receptor agonist use and better graft kidney function in KTRs with type 2 diabetes. Among KTRs with type 2 diabetes between 2012 and 2019, 73 with GLP-1 receptor agonist use and 73 without GLP-1 receptor use were identified in our center. After propensity matching, 50 KTRs were newly initiated with GLP-1 receptor agonist use or other antidiabetic medications. Baseline characteristics were well-balanced in the 2 groups. KTRs with GLP-1 receptor agonist use had greater kidney function 12 months after initiation of GLP-1 receptor agonists, compared to their counterpart KTRs without GLP-1 receptor agonists, according to estimated glomerular filtration ratio (p=0.01). Interestingly, transient decrease of body mass index was observed in KTRs with GLP-1 receptor agonist use during the 12 months. All GLP-1 receptor agonist-initiated KTRs were followed up through December 31, 2019. In conclusion, GLP-1 receptor agonist treatment was associated with better graft kidney function in KTRs with type 2 diabetes. Pharmacological GLP-1 receptor activation showed favorable tolerability and may alleviate graft kidney damage in KTRs with type 2 diabetes.

CONTEMPORARY NATIONAL PATTERNS OF ELIGIBILITY AND UTILIZATION OF NOVEL CARDIOPROTECTIVE ANTI-HYPERGLYCEMIC AGENTS IN TYPE 2 DIABETES

Background Sodium glucose transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively lowered cardiovascular risk in large clinical trials for patients with type 2 diabetes at high risk for these complications, and have recommended by guidelines. To evaluate the contemporary landscape in which these recommendations would be implemented, we examined the use of these medications according to clinical guideline practice. Methods and Results In the National Health and Nutrition Examination Survey for 2017-2018, we defined compelling indications for SGLT-2 inhibitors by the presence of atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (CKD), and for GLP-1RAs by the presence of established or high risk ASCVD, based on large clinical trials that have been incorporated in guideline recommendations of the American College of Cardiology (ACC) and American Diabetes Association (ADA). We then evaluated utilization of these medications among patients with physician-diagnosed type 2 diabetes. All analyses incorporated complex survey design to produce nationally representative estimates. A total 1104 of 9254 sampled individuals had type 2 diabetes, representing 10.6% (95% CI 9.7-11.6) of the US population or 33.2 million adults nationally. Of these, 52.6% (47.7-57.5) had an indication for SGLT-2 inhibitors, 32.8% (28.8-37.2) for GLP-1RAs, and 26.6% (22.2-31.7) for both medications. During 2017-2018, 4.5% (2.4-8.2) were treated with SGLT-2 inhibitors and 1.5% (0.7-3.2) with GLP-1RAs. ASCVD, heart failure, or CKD were not independently associated with SGLT-2 inhibitor or GLP-1RA use in patients with diabetes. Conclusions Despite a large number of patients being eligible for guideline recommended cardiorenal protective therapies, there are substantial gaps in the use of SGLT-2 inhibitors and GLP-1RAs, limiting their public health benefits.

Is it Time to Expand Glucagon-like Peptide-1 Receptor Agonist Use for Weight Loss in Patients Without Diabetes?

The obesity and type 2 diabetes mellitus epidemics demonstrate thatsimply emphasizing a healthy lifestyle is insufficient. While weight loss medications have historically been considered "cosmetic", glucagon-like peptide-1 receptor agonists (GLP1-RAs) also reduce cardiovascular risk in patients with type 2 diabetes. Therefore, we assessed whether GLP1-RAs warrant use in patients who are overweight (body mass index 27.0-29.9 kg/m2) without weight-related comorbidity. We reviewed trials of available GLP1-RAs with a natural GLP1 backbone given their trend toward cardiovascular benefit and excluded trials requiring concurrent antidiabetic agents associated with weight gain. We assessed 20 phase III trials of GLP1-RAs studied in cardiovascular outcome trials. The GLP1-RAs consistently produced weight loss. Hypoglycemia risk with GLP1-RAs was generally low without other precipitating factors, whereas gastrointestinal adverse effects were common. Dulaglutide 1.5 mg weekly did not produce sufficient weight loss to support its use specifically for weight loss, while data supporting dulaglutide 3.0 or 4.5 mg weekly were limited to a single trial. Weight loss was sufficient with liraglutide 1.8 mg daily in one trial and was consistently sufficient with liraglutide 3.0 mg daily. Oral and injectable semaglutide at both doses consistently produced weight loss, though demonstrated a potential increased risk for retinopathy. Overall, we suggest five GLP1-RAs can be used in the treatment of overweight (body mass index 27.0-29.9 kg/m2 without weight-related comorbidity) with shared decision making to address each medications' key limitation: liraglutide 1.8 mg daily (less demonstrated weight loss), liraglutide 3.0 mg daily (no cardiovascular outcome trial at this dose), and oral and injectable semaglutide at both doses (uncertain retinopathy risk and pending cardiovascular outcome trial of high-dose semaglutide). Use should be limited to patients who fail, refuse, or cannot access lifestyle interventions for weight loss, and should be accompanied by standard restrictions on and monitoring of weight loss medications. We expect additional and earlier use of weight loss therapies to help clinicians curb the obesity and type 2 diabetes epidemics.

Use of GLP1RAs and occurrence of respiratory disorders: A meta-analysis of large randomized trials of GLP1RAs.

No large sample studies have been designed to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP1RAs) in the primary and secondary prevention of respiratory disorders. We aimed at evaluating the relationship between use of GLP1RAs and occurrence of 12 kinds of respiratory disorders. Large randomized placebo-controlled trials of GLP1RAs were included. We conducted meta-analysis using random effects model and measured heterogeneity using I2 . Treatment effect was presented as risk ratio (RR) and 95% confidence interval (CI). Seven trials including 55922 participants were included in meta-analysis. The occurrence rates of various respiratory disorders were low, with the minimum of 0.02% (pulmonary fibrosis) and the maximum of 2.31% (pneumonia). Although not reaching statistical significance, GLP1RAs versus placebo showed the reduced trends in the risks of nine kinds of respiratory disorders including pneumonia (RR 0.89, 95% CI 0.78-1.01), squamous cell carcinoma of lung (SCCL; RR 0.55, 95% CI 0.25-1.21), asthma (RR 0.82, 95% CI 0.51-1.32), and chronic obstructive pulmonary disease (COPD; RR 0.89, 95% CI 0.73-1.10), but the increased trend in interstitial lung disease (ILD; RR 1.89, 95% CI 0.87-4.08). GLP1RAs had neutral effects on two other respiratory disorders. Heterogeneity in any meta-analysis was absent or low. GLP1RAs show the reduced trends in the risks of nine kinds of respiratory disorders (eg, pneumonia, SCCL, asthma, and COPD), but the increased trend in the risk of ILD. However, these findings need to be validated by further studies due to the low incidence rates of all the respiratory disorders.

Glucagon-like peptide-1 receptor agonists in patients treated with antipsychotics

IntroductionGlucagon-like peptide-1 (GLP-1) is an endogenous peptide that stimulates insulin secretion and decreases glucagon secretion. The use of GLP-1 receptor agonists (GLP-1RA) showed efficacy reducing the weight and glucose levels in patients with and without type 2 diabetes. This effect was also associated with a decreased risk of major cardiovascular events.ObjectivesOur aim is to review the role of GLP-1RA in psychiatric patients at cardio-metabolic risk due to antipsychotics treatment.Methods We reviewed articles published in PubMed using the keywords: “GLP-1” “glucagon like peptide” “antipsychotics” and “psychiatry”.ResultsThe number need to treat (NNT) to achieve clinical meaningful weight loss was 3.8. GLP-1RA treatment was also associated with greater reductions in body mass index, fasting glucose, HbA1c and visceral fat. This effect is true for antipsychotic treatment in general and for those on clozapine and olanzapine in particular. Overall, the GLP-1RA are well tolerated with nausea being the most common related adverse effect. Other variables such as age, sex, psychosis severity, nausea or any adverse drug reaction did not affect the weight loss.ConclusionsStudies showed a promising role in the management of antipsychotics induced weight gain, particularly in clozapine and olanzapine treated patients. Although these promising results, the route of administration, with a daily or weekly subcutaneous injection, and the GLP-1RA associated financial costs, can be viewed as important factors which can limit the wide use of this type of treatment in psychiatric patients.DisclosureNo significant relationships.

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).