Glucagon-like Peptide-1 Receptor Agonists In Patients Research Articles

Glycaemic control and macrovascular and microvascular outcomes in type 2 diabetes: Systematic review and meta-analysis of cardiovascular outcome trials of novel glucose-lowering agents.

Using a systematic review and meta-analysis of placebo-controlled cardiovascular outcome trials (CVOTs) of newer glucose-lowering agents [sodium-glucose cotransporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is)] in type 2 diabetes (T2D), we aimed to determine the macrovascular and microvascular outcomes of these agents and clarify the relationships between glycated haemoglobin (HbA1c) reduction and risk of these outcomes. Randomized controlled trials were identified from MEDLINE, Embase and the Cochrane Library until September 2023. Study-specific hazard ratios with 95% confidence intervals (CIs) were pooled, and meta-regression was used to assess the relationships between outcomes and between trial arm HbA1c reductions. Twenty unique CVOTs (six SGLT-2is, nine GLP-1RAs, five DPP-4is), based on 169 513 participants with T2D, were eligible. Comparing SGLT-2is, GLP-1RAs and DPP-4is with placebo, the hazard ratios (95% CIs) for 3-point major adverse cardiovascular events were 0.88 (0.82-0.94), 0.85 (0.79-0.92) and 1.00 (0.94-1.06), respectively. SGLT-2is and GLP-1RAs consistently reduced the risk of several macrovascular and microvascular complications, particularly kidney events. DPP-4is showed no macrovascular benefits. There was potential evidence of an inverse linear relationship between HbA1c reduction and 3-point major adverse cardiovascular event risk (estimated risk per 1% reduction in HbA1c: 0.84, 95% CI 0.67-1.06; p = .14; R2 = 14.2%), which was driven by the component of non-fatal stroke (R2 = 100.0%; p = .094). There were non-significant inverse linear relationships between HbA1c reduction and the risk of several vascular outcomes. SGLT-2is and GLP-1RAs showed consistent risk reductions in macrovascular and microvascular outcomes. The vascular benefits of SGLT-2is and GLP-1RAs in patients with T2D extend beyond mere glycaemic control.

Exploration of the potential association between GLP-1 receptor agonists and suicidal or self-injurious behaviors: a pharmacovigilance study based on the FDA Adverse Event Reporting System database

BackgroundEstablishing whether there is a potential relationship between glucagon-like peptide 1 receptor agonists (GLP-1RAs) and suicidal or self-injurious behaviors (SSIBs) is crucial for public safety. This study investigated the potential association between GLP-1RAs and SSIBs by exploring the FDA Adverse Event Reporting System (FAERS) database.MethodsA disproportionality analysis was conducted using post-marketing data from the FAERS repository (2018 Q1 to 2022 Q4). SSIB cases associated with GLP-1RAs were identified and analyzed through disproportionality analysis using the information component. The parametric distribution with a goodness-of-fit test was employed to analyze the time-to-onset, and the Ω shrinkage was used to evaluate the potential effect of co-medication on the occurrence of SSIBs.ResultsIn total, 204 cases of SSIBs associated with GLP-1RAs, including semaglutide, liraglutide, dulaglutide, exenatide, and albiglutide, were identified in the FAERS database. Time-of-onset analysis revealed no consistent mechanism for the latency of SSIBs in patients receiving GLP-1RAs. The disproportionality analysis did not indicate an association between GLP-1RAs and SSIBs. Co-medication analysis revealed 81 cases with antidepressants, antipsychotics, and benzodiazepines, which may be proxies of mental health comorbidities.ConclusionsWe found no signal of disproportionate reporting of an association between GLP-1RA use and SSIBs. Clinicians need to maintain heightened vigilance on patients premedicated with neuropsychotropic drugs. This contributes to the greater acceptance of GLP-1RAs in patients with type 2 diabetes mellitus or obesity.Graphical

Efficacy and Safety of Glucagon-Like Peptide 1 Agonists in a Retrospective Study of Patients With Familial Partial Lipodystrophy.

Glucagon-like peptide 1 receptor agonists (GLP-1RA) are widely used for the management of diabetes mellitus (DM), but their efficacy in familial partial lipodystrophy (FPLD) is unknown. In this retrospective study, we evaluated the effect of GLP-1RA in patients with FPLD. We analyzed data, reported with SDs, from 14 patients with FPLD (aged 58 ± 12 years; 76.47% female) and 14 patients with type 2 DM (aged 58 ± 13 years; 71% female) before and 6 months after starting GLP-1RA. We observed reduction in weight (95 ± 23 to 91 ± 22 kg; P = 0.002), BMI (33 ± 6 to 31 ± 6 kg/m2; P = 0.001), HbA1c (8.2% ± 1.4% to 7.7% ± 1.4%; P = 0.02), and fasting glucose (186 ± 64 to 166 ± 53 mg/dL; P = 0.04) in patients with FPLD. The change in triglycerides after treatment was greater in the FPLD group compared with the DM group (P = 0.02). We noted acute pancreatitis in two case subjects with FPLD with longer therapy. Our study demonstrates the relative safety and effectiveness of GLP-1RA in patients with FPLD.

P-31 GLP1 receptor agonist in end-stage kidney disease: Are they safe and effective?

Abstract Introduction The novel antidiabetic therapies have been showing promising results in cardiovascular and renal protection besides diabetes treatment. GLP-1 receptor agonists (GLP-1RA) are well tolerated drugs with few side effects, but they are only approved for a glomerular filtration rate (GFR) higher than 15 mL/min. Anecdotal reports have been made of therapy with GLP-1RA in patients undergoing hemodialysis and intermittent hemodialysis with good results. Clinical Case A sixty-five-year-old male patient with stage 4 chronic kidney disease in the setting of hypertensive and diabetic nephropathy is accompanied at our Endocrinology Department due to non-insulin treated type 2 diabetes. His past-history was notable for atrial fibrillation, obstructive sleep apnea and chronic obstructive pulmonary disease. In what diabetes is concerned, he was under empagliflozin 10mg daily and dulaglutide 1.5mg weekly with excellent glycemic control. Despite optimized treatment and Nephrology follow-up, GFR continued to decay, standing currently at 11 mL/min, without any acute insult, acidosis or hyperkalemia. The patient is starting preparation for hemodialysis with construction of an arteriovenous fistula. At last appointment, despite the lower GFR he maintained an excellent glycemic control with HbA1c of 6% without hypoglycemia and remained clinically asymptomatic without nausea, vomiting, or abdominal pain. A pharmacokinetics study revealed a similar exposure to semaglutide independent of renal function (including severe renal impairment [10 patients] and end-stage kidney disease [10 patients]) with the drug being well tolerated in both subgroups without the need for dose adjustments. In our case, the patient maintained the weekly treatment, without reported and/or documented hypoglycemia and possible advantageous cardiovascular profile. In the future, GLP1RA may be a treatment option independently of the patient renal function.

The Impact of Glucagon-like Peptide 1 Receptor Agonists on Obstructive Sleep Apnoea: A Scoping Review.

Obstructive sleep apnoea (OSA) and associated hypopnoea syndromes are chronic conditions of sleep-disordered breathing with significant sequelae if poorly managed, including hypertension, cardiovascular disease, metabolic syndrome and increased mortality. Glucagon-like peptide 1 receptor agonists (GLP-1RA) have recently garnered significant interest as a potential therapeutic, attributed to their durable effects in weight loss and glycaemic control in metabolic syndromes, such as obesity and type 2 diabetes mellitus. This has led to significant investment into companies that produce these medications and divestment from traditional gold standard methods of OSA management such as continuous positive airway pressure machines. Despite these sentiments, the impacts of these medications on OSA outcomes are poorly characterised, with no high-quality evidence at this stage to support this hypothesis. This scoping review therefore aims to address the research question of whether GLP-1RAs lead to a direct improvement in OSA and associated hypopnoea syndromes. A scoping review was performed following a computer-assisted search of Medline, Embase and Cochrane Central databases. Papers that evaluated the use of GLP-1RA medications related to sleep-disordered breathing, OSA or other sleep-related apnoeic or hypopnoeic syndromes were included. Literature search and evaluation identified 9 articles that were eligible for inclusion. Of these, 1 was a study protocol, 1 was a case report, 1 was an abstract of a randomised controlled trial (RCT), 1 was a non-randomised clinical trial and the remaining 5 were randomised clinical trials of variable rigour. All studies evaluated the outcomes of GLP-1RAs in patients with diagnosed OSA or symptoms suggestive of this condition. This scoping review identified early evidence to suggest that GLP-1RAs may improve OSA as defined by reduction in apnoea-hypopnoea index (AHI). This evidence is however conflicting due to contradicting results demonstrated from other studies. Overall, these medications were tolerated well, with minor gastrointestinal side-effects reported in some cases. Of all included studies, the quality of evidence was low, with short lengths of follow-up to identify durable effects of these medications on OSA outcomes and identify adverse events. More rigorous, RCTs with sufficient length of follow-up are required before consideration of formalising these medications into OSA treatment guidelines, frameworks and policies are warranted.

Abstract 13450: Clinical Outcomes With GLP-1 Receptor Agonists in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, there remains uncertainty about the efficiency of GLP-1 RAs in patients with heart failure (HF). Methods: Randomized controlled trials (RCTs) that reported the effect of GLP-1 RAs on prognosis in patients with HF were identified by searching databases. Results: There were nine RCTs involving 8,920 patients with HF included. GLP-1 RAs significantly reduced the risk of MACE compared with placebo (HR [hazard ratio]: 0.87, 95% CI [confidence interval] 0.77-0.98) in patients with HF and T2DM. The benefit was not observed in all-cause death (HR: 0.99, 95% CI 0.84-1.15), hospitalization for HF (HR: 1.04, 95% CI 0.89-1.22), cardiovascular death (HR: 0.95, 95% CI 0.79-1.16), myocardial infarction (HR: 0.88, 95% CI 0.71-1.08), stroke (HR: 1.03, 95% CI 0.75-1.43) and death or hospitalization for HF (HR: 1.07, 95% CI 0.78-1.46). GLP-1 RAs did not improve the change in LVEF (MD [mean difference]: -0.86, p=0.12, LVEDV (MD: 3.54, p=0.11), LVESV (MD: 2.78, p=0.07) or NT-proBNP (MD: -140.36, p=0.08). However, GLP-1 RAs significantly increased the change in the 6-MWT (MD: 19.74, p=0.002). In the subgroup analyses, human GLP-1 RAs, but not nonhuman GLP-1 RAs, reduced the risk of MACE (p interaction=0.11). Grading of Recommendations Assessment, Development and Evaluation (GRADE) showed moderate certainty for MACE, all-cause death and hospitalization for HF. Trail Sequential Analysis (TSA) revealed that there may be a high possibility of false positive results for MACE. Conclusion: Compared with placebo, GLP-1 RAs may reduce the risk of MACE in patients with HF and T2DM, with a more significant efficiency of human GLP-1 RAs.

Renoprotective effects of combination treatment with sodium-glucose cotransporter inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus according to preceding medication

Aims Combination therapy with sodium-glucose cotransporter inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1Ras) is now of interest in clinical practice. The present study evaluated the effects of the preceding drug type on the renal outcome in clinical practice. Methods We retrospectively extracted type 2 diabetes mellitus patients who had received both SGLT2i and GLP1Ra treatment for at least 1 year. A total of 331 patients in the GLP1Ra-preceding group and 312 patients in the SGLT2i-preceding group were ultimately analyzed. Either progression of the albuminuria status and/or a ≥30% decrease in the eGFR was set as the primary renal composite outcome. The analysis using propensity score with inverse probability weighting was performed for the outcome. Results The incidences of the renal composite outcome in the SGLT2i- and GLP1Ra-preceding groups were 28% and 25%, respectively, with an odds ratio [95% confidence interval] of 1.14 [0.75, 1.73] ( p = .54). A logistic regression analysis showed that the mean arterial pressure (MAP) at baseline, the logarithmic value of the urine albumin-to-creatinine ratio at baseline, and the change in MAP were independent factors influencing the renal composite outcome. Conclusion With combination therapy of SGLT2i and GLP1Ra, the preceding drug did not affect the renal outcome.

FRI075 Single Center Retrospective Matched Cohort Study Of glp1ra-induced Weight Loss In Patients With Post-bariatric Weight Regain Vs Non-surgical Controls

Abstract Disclosure: A. Rivadeneira: None. M. Walker: None. R. Gallop: None. A. Amaro: Advisory Board Member; Self; Novo Nordisk. Research Investigator; Self; Eli Lilly & Company, Novo Nordisk. Background: Obesity prevalence worldwide is increasing. By 2030, almost one-fourth of US population will have severe obesity (BMI >35 mg/kg2). Bariatric surgery (BS) is an effective intervention for weight loss (WL) in patients with severe obesity; weight regain (WR) remains a concern. Over one-third of patients will regain more than 25% of total WL. GLP-1 receptor agonists (GLP1RA) have been effective for WL in patients with obesity. Effectiveness and safety of liraglutide and semaglutide in patients with WR after BS were observed in several retrospective studies. The difference in response to GLP1RA in patients with and without a history of bariatric surgery has not been assessed. Objectives: We aimed to retrospectively compare amount of WL and time to nadir in BMI matched individuals with history of WR following BS and without history of surgery treated with GLP1RA. Methods: Retrospective matched cohort study of the patients referred to Penn Metabolic Medicine (PMM) clinic for non-surgical weight management. We analyzed 63 patients with history of RYGB or VSG seen between 8/2015-8/2021 for WR and who received GLP1RA. BMI matched non-surgical (NS) cohort (N=60) treated with GLP1RA was built from the PMM patients of the same period for comparison. Results: Mean weight on presentation at PMM in surgical group (SG) was 273.1 lbs, (BMI 43.5 kg/m2), and in non-surgical one (NS) 264.9 lbs (BMI 43.3 kg/m2). Nadir weight after initiation of GLP1RA in SG 241.1 lbs and controls 244 lbs, with percentage WL of 11.8% in SG and 7.86% in NS controls (p-value 0.0081). Mean time to nadir weight after initiation of GLP1RA was 17.2 months for SG, and 9.2 months in NS controls (p-value <0.0001). Discussion: When treated with GLP1RA, patients with post-bariatric WR lost on average 12% of their weight and achieved nadir around 17 months. Weight matched NS controls lost less weight and entered a plateau phase faster, suggesting enhanced GLP1RA efficacy after bariatric surgery. Significant WL response to GLP1RA was similar in RYGB and VSG groups, supporting previously demonstrated GLP1RA efficacy for post-bariatric WR. Larger prospective trials are needed for confirmation. Reports suggest both RYGB and VSG increase postprandial GLP-1. Proposed WR mechanisms include hormonal changes, nutritional non-adherence, physical inactivity and maladaptive eating. Hormonal mechanisms include increase in ghrelin, decrease in GLP-1 and peptide YY, post-bariatric hypoglycemia and other pathways. Further studies are needed to elucidate the mechanism of enhanced GLP-1 RA efficacy in patients with WR after BS. The limitations of our study include a retrospective nature, modest sample size and the choice of GLP1RA limited to liraglutide, exenatide and semaglutide and guided by the subjects’ insurance plans. In the future, dual incretins will need to be studied in patients with WR after bariatric surgery. Presentation: Friday, June 16, 2023

Racial, ethnic and regional differences in the effect of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists on cardiovascular and renal outcomes: a systematic review and meta-analysis of cardiovascular outcome trials.

The cardiorenal protective effects of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) across racial and ethnic groups are not well defined. By conducting a systematic review and meta-analysis of all randomised, placebo-controlled, cardiovascular disease (CVD) outcomes trials (CVOTs), we aimed to compare racial/ethnic as well as regional patterns in the effects of SGLT2-Is and GLP1-RAs on cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). Trials were identified from MEDLINE, Embase, the Cochrane Library, and search of bibliographies to 7 July 2023. Setting North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa. North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa. people with type 2 diabetes enrolled in cardiovascular outcome trials of SGLT2-Is and GLP1-RAs. Outcomes were (i) major adverse cardiovascular events (MACE), (ii) composite CVD death/heart failure (HF) hospitalization; (iii) composite renal outcome; and (iv) their components. Study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled. In total, 14 unique CVOTs (7 comparing SGLT2-Is vs placebo and 7 comparing GLP1-RAs vs placebo) were eligible. The proportion of participants enrolled in the trials ranged from 66.6-93.2% for White populations, 1.2-21.6% for Asian populations, 2.4-8.3% for Black populations and 0.9-23.1% for Other populations. The HR (95% CI) for MACE comparing SGLT2-Is vs placebo was 0.92 (0.86-0.98), 0.69 (0.53-0.92) and 0.70 (0.54-0.91) for White, Asian and Hispanic/Latino populations, respectively. Comparing GLP1-RAs vs placebo, the corresponding HR (95% CI) was 0.88 (0.80-0.97), 0.76 (0.63-0.93) and 0.82 (0.70-0.95), respectively. SGLT2-Is reduced the risk of all other cardiorenal outcomes in White and Asian populations, except for HF hospitalizations in Asians. No effects were observed in Black populations except for a reduced risk of HF hospitalizations by SGLT2-I. SGLT1-Is reduced the risk of composite CVD death/HF hospitalization in North America and Europe, whereas GLP1-RAs reduced the risk of MACE in Europe. GRADE certainty of evidence ranged from moderate to high. There appears to be substantial racial/ethnic differences in the cardiorenal effects of SGLT2-Is and GLP1-RAs in patients with T2D, with consistent benefits observed among White and Asian populations and consistent lack of benefits in Black populations. Whether the differences are due to issues with under-representation of Black populations and low statistical power or racial/ethnic variations in the pharmacokinetics, pharmacodynamics and safety of SGLT2-Is and GLP1-RAs need further investigation.PROSPERO Registration: CRD42023401734.

Semaglutide versus GLP-1 agonists. Effectiveness, safety, and quality of life in patients with diabetes mellitus 2. The SEVERAL study

ObjectiveThe cardiovascular disease is the first cause of deaths in patients with diabetes mellitus 2. The objective is to evaluate and compare the weight loss in patients with diabetes treated with the different GLP-1 receptor agonists for the first time. Secondary endpoints are glycosylated hemoglobin reduction, changes in quality of life and physical activity and the safety of these drugs. MethodIt is a postauthorization, multicenter, non-randomized and prospective study. 360 Patients that will start treatment for the first time with GLP-1 receptor agonists will be recruited in 10 centers in the National Health System for a period of 6 months and 44 weeks of follow-up. The primary endpoint will be weight loss achieved with the different GLP-1 receptor agonists and the secondary endpoint will be glycosylated hemoglobin reduction, changes in the quality of life through the EuroQol-5D and changes physical activity through the SF-12 questionnaire, and also the safety of these drugs. The estimate recruitment period will be 6 months, from 1 December 2021 to 1 May 2022. The follow up will finish in December 2022. DiscussionThe SEVERAL study will try to provide information about weight loss efficacy, changes in quality of life, physical activity and safety of the GLP-1 receptor agonists in patients with diabetes that start treatment with these drugs in the real life. This study try to compare different GLP-1 receptor agonists in terms of effectiveness and safety for a better posterior election when these drugs are used in patients with diabetes mellitus 2 an d obesity.

313-OR: The Efficacy and Safety of Glucagon-Like-Peptide-1 Agonists in Patients with Familial Partial Lipodystrophy

Familial partial lipodystrophy (FPLD) syndromes are a rare group of conditions with abnormal fat distribution and deposition of fat in ectopic tissues such as liver and muscle, leading to challenging metabolic abnormalities. Glucagon-like peptide-1 receptor agonists (GLP1R-A) are used for management of other metabolic dysfunction, but their efficacy in FPLD syndromes is not known. In this retrospective EMR review, we evaluate the effect of GLP1R-A for DM management in patients with FPLD for whom there are no approved treatments in the US. We collected data from 17 patients with FPLD (age 58 ± 12; 76.47 % females) and 17 patients with type 2 DM (age 58 ± 13; 71% females) before and 6 months after starting GLP1R-A. Only cases where the sole change was the addition of GLP1R-A were included in the analyses. Reduction in weight (p=0.002), BMI (p=0.001), HbA1c (p=0.02), and fasting glucose (p=0.04) (Figure 1A-D) were observed in patients with FPLD. Only the change in triglycerides after six months of treatment was greater in patients with FPLD compared to patients with DM (p=0.02, 95%CI: 13.6 to 215.8) (Figure 1E). Overall, there were no differences in changes in other parameters, and no serious events were reported. However, we observed acute pancreatitis in two cases with FPLD with longer therapy. Our study demonstrates the relative safety and effectiveness of GLP1R-A in patients with FPLD for the first time. Disclosure S.K.Imam: None. M.C.Foss-freitas: None. R.Meral: None. E.A.Oral: Advisory Panel; Amryt Pharma Plc, Regeneron, Rejuvenate Bio, Third Rock Ventures, Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals, Regeneron, Other Relationship; Amryt Pharma Plc, Research Support; Amryt Pharma Plc, Novo Nordisk, Fractyl Health, Inc., Ionis Pharmaceuticals, Regeneron, GI Dynamics, Rejuvenate Bio. A.Dill gomes: None. F.Grissi: None.

1227-P: Cardiorenal Effectiveness of Empagliflozin vs. GLP-1 Receptor Agonists in Patients with Advanced Chronic Kidney Disease—Results from the EMPRISE Study

Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease, heart failure, and mortality. We reported the final year results of the EMPRISE study program in patients with type 2 diabetes (T2D) and advanced CKD. Using Medicare, Optum, and Marketscan data (2014-19), we identified 10,930 pairs of 1:1 propensity score-matched patients aged >18 years with T2D and CKD stage 3-4 who initiated empagliflozin (EMPA) or a glucagon-like peptide-1 receptor agonist (GLP-1RA). Primary outcomes were hospitalization for heart failure (HHF), a composite of myocardial infarction (MI) or stroke, and end-stage renal disease (ESRD). Secondary outcomes were MI, stroke, and all-cause mortality. We estimated hazard ratios (HR) and rate differences (RD), adjusting for 143 baseline covariates. Compared to GLP-1RA, EMPA was associated with a reduced risk of HHF [HR 0.68 (0.55-0.85); RD -9.44 (-14.78, -4.10)], and ESRD [HR 0.70 (0.56-0.87); RD -9.01 (-14.30, -3.72)], and a trend towards reduced risk for the composite outcome [HR 0.88 (0.72-1.07); RD -3.84 (-9.60, 1.93)]. Estimates for the secondary outcomes were: MI [HR 0.78 (0.61-1.00)], stroke [HR 1.16 (0.83-1.62)], and all-cause mortality [HR 1.08 (0.86-1.36)]. In patients with T2D and advanced CKD in routine care, we observed risk reductions for cardiorenal outcomes with EMPA vs. GLP-1RA. Disclosure P.T.Htoo: Employee; Johnson & Johnson. E.Patorno: Research Support; Boehringer Ingelheim Inc., National Institutes of Health, Patient-Centered Outcomes Research Institute, US Food and Drug Administration. H.Tesfaye: None. D.J.Wexler: Other Relationship; Novo Nordisk A/S. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis, Pfizer Inc. N.Schmedt: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. S.Schneeweiss: Consultant; Aetion, Inc., Research Support; UCB, Inc., Boehringer Ingelheim International GmbH, Stock/Shareholder; Aetion, Inc. J.M.Paik: None. Funding Boehringer Ingelheim (116283)

Increased Risk of Heart Failure Hospitalization With GLP-1 Receptor Agonists in Patients With Reduced Ejection Fraction: A Meta-Analysis of the EXSCEL and FIGHT Trials

Increased Risk of Heart Failure Hospitalization With GLP-1 Receptor Agonists in Patients With Reduced Ejection Fraction: A Meta-Analysis of the EXSCEL and FIGHT Trials

Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action.

Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders characterized by excess cardiovascular risk. Glucagon-like peptide1 (GLP1) receptor (GLP1R) agonists reduce body weight, glycaemia, blood pressure, postprandial lipaemia and inflammation - actions that could contribute to the reduction of cardiovascular events. Cardiovascular outcome trials (CVOTs) have demonstrated that GLP1R agonists reduce the rates of major adverse cardiovascular events in patients with T2DM. Separate phase III CVOTs of GLP1R agonists are currently being conducted in people living with heart failure with preserved ejection fraction and in those with obesity. Mechanistically, GLP1R is expressed at low levels in the heart and vasculature, raising the possibility that GLP1 might have both direct and indirect actions on the cardiovascular system. In this Review, we summarize the data from CVOTs of GLP1R agonists in patients with T2DM and describe the actions of GLP1R agonists on the heart and blood vessels. We also assess the potential mechanisms that contribute to the reduction in major adverse cardiovascular events in individuals treated with GLP1R agonists and highlight the emerging cardiovascular biology of novel GLP1-based multi-agonists currently in development. Understanding how GLP1R signalling protects the heart and blood vessels will optimize the therapeutic use and development of next-generation GLP1-based therapies with improved cardiovascular safety.

Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction

BackgroundNo study has compared the cardiovascular outcomes for sodium–glucose cotransporter-2 inhibitors (SGLT2i) head-to-head against other glucose-lowering therapies, including dipeptidyl peptidase 4 inhibitor (DDP4i) or glucagon-like peptide-1 receptor agonist (GLP-1RA)—which also have cardiovascular benefits—in patients with heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction.MethodsMedicare fee-for-service data (2013–2019) were used to create four pair-wise comparison cohorts of type 2 diabetes patients with: (1a) HFrEF initiating SGLT2i versus DPP4i; (1b) HFrEF initiating SGLT2i versus GLP-1RA; (2a) HFpEF initiating SGLT2i versus DPP4i; and (2b) HFpEF initiating SGLT2i versus GLP-1RA. The primary outcomes were (1) hospitalization for heart failure (HHF) and (2) myocardial infarction (MI) or stroke hospitalizations. Adjusted hazards ratios (HR) and 95% CIs were estimated using inverse probability of treatment weighting.ResultsAmong HFrEF patients, initiation of SGLT2i versus DPP4i (cohort 1a; n = 13,882) was associated with a lower risk of HHF (adjusted Hazard Ratio [HR (95% confidence interval)], 0.67 (0.63, 0.72) and MI or stroke (HR: 0.86 [0.75, 0.99]), and initiation of SGLT2i versus GLP-1RA (cohort 1b; n = 6951) was associated with lower risk of HHF (HR: 0.86 [0.79, 0.93]), but not MI or stroke (HR: 1.02 [0.85, 1.22]). Among HFpEF patients, initiation of SGLT2i versus DPP4i (cohort 2a; n = 17,493) was associated with lower risk of HHF (HR: 0.65 [0.61, 0.69]) but not MI or stroke (HR: 0.90 [0.79, 1.02]), and initiation of SGLT2i versus GLP-1RA (cohort 2b; n = 9053) was associated with lower risk of HHF (0.89 [0.83, 0.96]), but not MI or stroke (HR: 0.97 [0.83, 1.14]). Results were robust across range of secondary outcomes (e.g., all-cause mortality) and sensitivity analyses.ConclusionsBias from residual confounding cannot be ruled out. Use of SGLT2i was associated with reduced risk of HHF against DPP4i and GLP-1RA, reduced risk of MI or stroke against DPP4i within the HFrEF subgroup, and comparable risk of MI or stroke against GLP-1RA. Notably, the magnitude of cardiovascular benefit conferred by SGLT2i was similar among patients with HFrEF and HFpEF.

Glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes with and without chronic heart failure: A meta-analysis of randomized placebo-controlled outcome trials.

Glucagon-like peptide 1 receptor agonists (GLP1-RA) reduce atherosclerotic events in patients with type 2 diabetes (T2D) and a high cardiovascular risk. The effect of GLP1-RA to reduce heart failure (HF) has been inconsistent across T2D trials, and individual trials were underpowered to assess the effect of GLP1-RA according to HF history. In this meta-analysis we aim to assess the effect of GLP1-RA in patients with and without HF history in stable ambulatory patients with T2D. Random-effects meta-analysis of placebo-controlled trials. The hazard ratio (HR) and 95% confidence intervals (95% CI) were extracted from the treatment effect estimates of HF subgroup analyses reported in each individual study. The primary outcome was a composite of HF hospitalization or cardiovascular death. In total, 54 092 patients with T2D from seven randomized controlled trials were included, of whom 8460 (16%) had HF history. Compared with placebo, GLP1-RA did not reduce the composite of HF hospitalization or cardiovascular death in patients with HF history: HR 0.96, 95% CI: 0.84-1.08, but reduced this outcome in patients without HF history: HR 0.84, 95% CI: 0.76-0.92. GLP1-RA did not reduce all-cause death in patients with HF history: HR 0.98, 95% CI: 0.86-1.11, but reduced mortality in patients without HF history: HR 0.85, 95% CI: 0.79-0.92. GLP1-RA reduced atherosclerotic events regardless of HF history: HR 0.85, 95% CI: 0.75-0.97 with HF, and HR 0.88, 95% CI: 0.83-0.93 without HF. Treatment with GLP1-RA did not reduce HF hospitalizations and mortality in patients with concomitant T2D and HF, but may prevent new-onset HF and mortality in patients with T2D without HF. The reduction of atherosclerotic events with GLP1-RA was not influenced by HF history status.

Is the steady-state concentration, duration of action, or molecular weight of GLP-1RA associated with cardiovascular and renal outcomes in type 2 diabetes?

ImportanceDisparities were found in the cardiovascular and renal outcomes among different glucagon-like peptide 1 receptor agonist (GLP-1RA) subtypes. However, whether the characteristics of GLP-1RA itself are associated with these disparities remains unclear. ObjectiveTo assess the association between the steady-state concentration, duration of action, or molecular weight of GLP-1RA and the risks of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). Data SourcesPubMed, MEDLINE, EMBASE, Cochrane and Clinicaltrial.gov from inception to April 2022. Study SelectionRandomized controlled trials (RCTs) investigating GLP-1RAs in patients with T2D were included. Data Extraction And SynthesisLiterature screening and data extraction were performed independently by 2 researchers. The outcomes were computed as odds ratio (OR) and its 95% confidence interval (CI). Subgroup analyses were conducted according to steady-state concentration, duration of action and molecular weight of GLP-1RAs. Main Outcomes and MeasuresPrimary outcomes were major adverse cardiovascular events (MACE), composite renal outcome and all-cause mortality. ResultsIn all, 61 RCTs were included. When compared with non-GLP-1RA agents, GLP-1RAs with high steady-state concentration were associated with greater risk reduction in MACE (p for subgroup difference = 0.01) and the composite renal outcome (p for subgroup difference = 0.008) in patients with T2D. Greater risk reductions in MACE between GLP-1RA users versus non-GLP-RA users were observed in long acting stratum when compared with short acting stratum (p for subgroup difference = 0.04) in patients with T2D. The molecular weight of GLP-1RAs was not associated with the risk of cardiovascular and renal outcomes. Conclusions and RelevanceGLP-1RAs with high steady-state concentrations might be associated with greater risk reductions in cardiovascular and renal outcomes in patients with T2D. Long acting GLP-1RAs might outperform short acting ones in reducing the risk of cardiovascular outcomes. These findings provided new insights for guiding the clinical applications of GLP-1RAs in patients with T2D.

Effect of Glucagon-like Peptide-1 Receptor Agonists on Prognosis of Heart Failure and Cardiac Function: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Whether an antidiabetic drug, glucagon-like peptide-1 receptor agonist (GLP-1RA), could improve the prognosis of heart failure and cardiac function remains controversial. We conducted a systematic review and meta-analysis of randomized controlled trials to explore the influence of GLP-1RAs on heart failure in patients regardless of diabetes diagnosis. Literature in English from the PubMed, EMBASE, and Cochrane Library databases was searched from inception to July 2022. The study aim was to identify published, randomized, placebo-controlled trials testing GLP-1RAs in patients with or without diabetes. Outcomes were heart failure hospitalization, cardiac function, and structure measures. Twenty-two randomized controlled trials involving 61,412 patients are included in the meta-analysis. Overall, compared with the placebo group, GLP-1RA treatment could not significantly decrease heart failure hospitalization in patients with a history of heart failure (hazard ratio [HR], 1.07; 95% CI, 0.91 to 1.25; P=0.422). Six-minute walking test distances (WMD, 19.08 m; 95% CI, 4.81 to 33.36; P=0.01), E-wave (SMD, -0.40; 95% CI, -0.60 to -0.20; P < 0.001), early diastolic to late diastolic velocities ratio (WMD, -0.10; 95% CI, -0.18 to -0.02; P=0.01), mitral inflow E velocity to tissue Doppler e' ratio (WMD, -0.97; 95% CI, -1.54 to -0.41; P < 0.001), and E-wave deceleration time (WMD, -9.96 milliseconds; 95% CI, -18.52 to -1.41; P=0.02) increased significantly after administration of GLP-1RAs. However, GLP-1RAs do not significantly influence N-terminal pro-B-type natriuretic peptide levels (WMD, -20.02 pg/mL; 95% CI, -53.12 to 13.08; P=0.24), Minnesota Living with Heart Failure Questionnaire quality of life scores (WMD, -1.08; 95% CI, -3.99 to 1.84; P=0.47), or left ventricular ejection fractions (WMD, -0.37%; 95% CI, -1.19 to 0.46; P=0.38). GLP-1RAs did not reduce heart failure readmissions in patients with a history of heart failure and elevated N-terminal pro-B-type natriuretic peptide levels. Thus, the prognosis of heart failure was not improved, although GLP-1RAs did significantly improve left ventricular diastolic function in patients. PROSPERO identifier: CRD42021226231.

Comparison of Sodium-Glucose Cotransporter-2 Inhibitor and Glucagon-Like Peptide-1 Receptor Agonist Prescribing in Patients With Diabetes Mellitus With and Without Cardiovascular Disease

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in patients with type 2 diabetes mellitus (T2DM). We sought to describe trends in prescribing for SGLT2is and GLP1-RAs in diverse care settings, including (1) the outpatient clinics of a midwestern integrated health system and (2) small- and medium-sized community-based primary care practices and health centers in 3 midwestern states. We included adults with T2DM and ≥1 outpatient clinic visit. The outcomes of interest were annual active prescription rates for SGLT2is and GLP1-RAs (separately). In the integrated health system, 22,672 patients met the case definition of T2DM. From 2013 to 2019, the overall prescription rate for SGLT2is increased from 1% to 15% (absolute difference [AD] 14%, 95% confidence interval [CI] 13% to 15%, p <0.01). The GLP1-RA prescription rate was stable at 10% (AD 0%, 95% CI -1% to 1%, p=0.9). In community-based primary care practices, 43,340 patients met the case definition of T2DM. From 2013 to 2017, the SGLT2i prescription rate increased from 3% to 7% (AD4%, 95% CI 3% to 6%, p <0.01), whereas the GLP1-RA prescription rate was stable at 2% to 3% (AD1%, 95% CI -1 to 1%, p=0.40). In a fully adjusted regression model, non-Hispanic Black patients had lower odds of SGLT2i or GLP1-RA prescription (odds ratio 0.56, 95% CI 0.34 to 0.89, p=0.016). In conclusion, the increase in prescription rates was greater for SGLT2is than for GLP1-RAs in patients with T2DM in a large integrated medical center and community primary care practices. Overall, prescription rates for eligible patients were low, and racial disparities were observed.

PSUN188 Evaluating Response to GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus Managed at a Veterans Affairs Hospital

Abstract Type 2 diabetes mellitus (T2DM) is a leading cause of morbidity and mortality in people of all ages worldwide. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer an innovative and unique advancement in treatment for T2DM by not only benefiting blood glucose control but also potentially impacting other diabetes-related complications. However, clinical response to GLP-1 RA is not seen in all patient populations. Our goal was to determine the response rate of GLP-1 RA add-on therapy. We performed a retrospective study of veterans with T2DM initiated on any GLP-1 RA from January 1, 2015, to December 31, 2019, for a duration of at least 6 months to assess the response in terms of hemoglobin A1c (A1c), weight, and total daily insulin dose. Baseline characteristics of 332 patients were reviewed to evaluate response rate. Treatment response thresholds included an A1c reduction of at least 0.5%, weight loss of ≥ 3% of pretreatment body weight, and a ≥ 10% reduction in total daily insulin dose (TDD). We then classified veterans into those without a response, or with 1, 2, or all 3 responses based on data 6-12 months after initiating treatment. We considered it a complete response if all 3 categories were fulfilled. Semaglutide (n=141): 10.64% showed a response to A1c alone, 3.55% had weight reduction alone, and 2.84% had insulin reduction alone. 7.09% showed A1c and weight response, 24.82% had A1c and insulin response, and 13.48% had weight and insulin response. A complete response was seen in 33.33% of veterans. Liraglutide (n=131): 18.32% showed a response to A1c alone, 4.58% had weight reduction alone, and 11.45% had insulin reduction alone. 6.11% showed A1c and weight response, 19.08% had A1c and insulin response, and 8.40% had weight and insulin response. A complete response was seen in 25.19% of veterans. Dulaglutide (n=57): 22.81% showed a response to A1c alone, 3.51% had weight reduction alone, and 12.28% had insulin reduction alone. 8.77% showed A1c and weight response, 26.32% had A1c and insulin response, and 1.75% had weight and insulin response. A complete response was seen in 15.79% of veterans. In conclusion, semaglutide's most common response, in 33.33% of patients, was having a complete response, followed by a reduction in A1c and insulin reduction for 24.82% of patients, and then weight and insulin reduction for 13.48% of patients. Liraglutide's most common response, in 25.19% of patients, was having a complete response, followed by a reduction in A1c and insulin dose for 19.08% of patients, and then reduction in A1c alone for 18.32% of patients. Unlike the others, dulaglutide's most common response was not a complete response, but rather A1c and insulin reduction, for 26.32% patients. Dulaglutide also had 22.81% of patients respond with A1c alone. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.