UNASSIGNED: Efpeglenatide, a novel GLP-1 receptor agonist, has shown promise in improving glycemic control and inducing weight loss in individuals with type 2 diabetes (T2DM). This meta-analysis assessed its therapeutic potential and safety profile.
UNASSIGNED: A literature search was conducted on PubMed, SCOPUS, and Cochrane Central from inception until September 2023. We selected patients with T2DM and identified and compared those receiving efpeglenatide to placebo. Outcomes assessed included fasting plasma glucose (FPG), HbA1c, body weight, BMI, and cardiometabolic parameters. Data were analyzed using a random-effects model, with results presented as mean differences (MD) for continuous outcomes and risk ratios (RR) for safety analysis, along with their respective 95% confidence intervals. Quality assessment was conducted using the Cochrane risk of bias tool.
UNASSIGNED: We included 11 studies in our analysis. Efpeglenatide demonstrated significant reductions in FPG (MD = -1.53 mmol/L, 95% CI = [-2.86, -0.66], p < 0.01), HbA1c (MD = -0.84, 95% CI= [-1.08, -0.60], p < 0.01), body weight (MD = -2.24 kg, 95% CI = [-4.20, -2.00], p < 0.01), and BMI (MD = -1.61 kg/m2, 95% CI= [-2.12, -1.09], p < 0.01). However, efpeglenatide was associated with a moderate increase in the risk of gastrointestinal adverse events, nausea, diarrhea, and vomiting. There was a non-significant elevated risk of hypoglycemia.
UNASSIGNED: Efpeglenatide significantly improves glycemic outcomes and promotes weight loss in individuals with diabetes. However, it is associated with moderate adverse effects related to the gastrointestinal system. Thus, further trials are warranted to comprehensively assess its safety and efficacy to derive a robust conclusion.
UNASSIGNED:
UNASSIGNED: The online version contains supplementary material available at 10.1007/s40200-024-01409-3.

Atherosclerotic Cardiovascular Disease (ASCVD) is still one of the leading causes of death globally, with Coronary Artery Disease (CAD) being the most prevalent form of ASCVD. Patients with type 2 Diabetes Mellitus (DM) experience an increased risk for ASCVD during the disease course, with CAD being the most common cause of death among affected individuals, resulting in shorter life expectancy and increased morbidity among survivors. Recently, 2 novel classes of anti-diabetic drugs, namely Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors and Glucagon-Like Peptide-1 (GLP-1) receptor agonists, have shown impressive cardio-renal benefits for patients with type 2 DM, while they might decrease cardio-renal risk even in the absence of baseline DM. However, there is no evidence to date regarding their safety and efficacy in the setting of an acute coronary syndrome (ACS) event, regardless of concomitant DM. This study aims to provide a detailed, updated presentation of currently available clinical evidence concerning the potential role of SGLT-2 inhibitors and GLP-1 receptor agonists in the setting of an ACS, and to highlight whether those drug classes could be utilized as adjuncts to standard-of-care treatment in this specific patient population, along with a presentation of the potential short- and long-term cardiovascular benefits.

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically important weight loss effects in patients with type 2 diabetes. However, its effects on sustained weight loss in patients without diabetes remains unclear. Our objective was to examine the long-term efficacy and safety of semaglutide use for weight loss in patients with overweight/obesity and without diabetes. MEDLINE, EMBASE, and the Cochrane Libraries were systematically searched to identify randomized controlled trials that randomized participants with overweight/obesity and without diabetes to once-weekly 2.4 mg subcutaneous semaglutide versus placebo, with a follow-up of at least 68 weeks. The primary outcome was a change in relative body weight from baseline to the longest follow-up. Random-effects models with inverse variance weighting were used to estimate the weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs). A total of 4 randomized controlled trials (n = 3,087) were included. Of the 3 trials that provided body mass index by category (n = 2,783), 94.0% of the participants had a baseline body mass index ≥30 kg/m2. Compared with placebo, the use of semaglutide was associated with substantial decreases in long-term relative (WMD -12.1%, 95% CI -13.5 to -10.7) and absolute body weight (WMD -12.3 kg, 95% CI -13.6 to -11.0). At the longest follow-up, 33.4% of participants randomized to semaglutide achieved ≥20% weight loss compared with 2.2% with placebo (RR 15.08, 95% CI 9.31 to 24.43). The risk of gastrointestinal adverse events was higher in participants who took semaglutide than placebo (RR 1:47, 95% CI 1.28 to 1.68); however, the majority of these events were transient and mild-to-moderate in severity and did not require treatment discontinuation. In conclusion, semaglutide is efficacious for sustained weight loss in patients with overweight/obesity and without diabetes.

OBJECTIVE: We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus.
METHODS: We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA1c and body weight from baseline. Secondary outcomes were achievement of HbA1c target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework.
RESULTS: A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA1c (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia.
CONCLUSIONS: Our data show that s.c. tirzepatide had a more pronounced effect on HbA1c and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events.
BACKGROUND: PROSPERO registration no. CRD42022382594.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective medications for the treatment of type 2 diabetes and obesity. Pharmacological studies in rodents support an association between the use of GLP-1 RAs and the development of medullary thyroid cancer (MTC) resulting in a black box warning for these agents in patients at risk for this condition. Yet, the association between GLP-1 RAs and non-MTC remains controversial. Excessive worry about unproven thyroid cancer risk might lead to underutilizing GLP-1 RAs in patients who could otherwise experience substantial benefits. Unwarranted concerns about thyroid cancer could lead to unnecessary thyroid cancer screening and harms from overdiagnosis. Summary: The body of evidence assessing the association between GLP-1 RA use and thyroid cancer spans a wide range of methodologies, including basic and translational research investigating biological plausibility; randomized trials assessing clinical efficacy and providing the strongest evidence for causality; observational studies providing real-life outcome evaluation in larger populations but with limited evaluation of covariates or dependable outcome definitions; and pharmacovigilance studies that provide postmarketing assessments of a safety signal but do not address causality. There is biological plausibility supporting an association between GLP-1 RA and MTC in rodents, which is less clear for non-MTC in humans. Clinical evidence from randomized trials and associated meta-analysis suggest thyroid cancer as a rare event making effect estimates imprecise but without conclusive and consistent evidence of increase risk in those receiving GLP-1 RA. Observational studies at higher risk of bias also show low event rates for thyroid cancer, with effect estimates that are inconsistent among different studies. Pharmacovigilance studies consistently show a signal of increased reporting of thyroid cancer in patients treated with GLP-1 RA. Conclusions: Evidence from randomized controlled trials indicates occurrence of thyroid cancer is infrequent in individuals exposed to GLP-1 RA. Observational studies at higher risk of bias yield inconsistent results. Overall there is no conclusive evidence of elevated thyroid cancer risk. These findings can help clinicians when addressing patient\'s concerns about a potential yet unproven link between GLP-1 RA therapy and thyroid cancer.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), while developed as antihyperglycaemic medications for the treatment of type 2 diabetes, have proven to reduce major cardiovascular adverse events (MACEs) and hospitalization for heart failure (especially for SGLT2is) in dedicated cardiovascular outcome trials. The contribution of the glucose-lowering effect in the cardiovascular protection is uncertain and may differ between the two drug classes.
METHODS: This narrative review compares the relative effects of glycated hemoglobin (HbA1c) reduction on the cardiovascular protection provided by GLP-1RAs and SGLT2is in placebo-controlled cardiovascular outcome trials by using the results of either post-hoc mediation analyses or meta-regression studies.
RESULTS: Both mediation and meta-regression analyses suggest that the lower cardiovascular risk with GLP-1RAs partially but substantially tracks with their glucose-lowering effect, especially when considering the reduction in nonfatal strokes. In contrast, similar analyses fail to demonstrate any significant contribution of the glucose-lowering effect with SGLT2is, not only on MACEs but also on heart failure issues.
CONCLUSIONS: The contribution of improved glucose control in cardiovascular protection is limited, but is much greater for GLP-1RAs than for SGLT2is. Of note, such mediation or meta-regression analyses are exploratory and can only be viewed as hypothesis generating.

UNASSIGNED: Since 2005, the cardioprotective effects of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have garnered attention. The cardioprotective effect could be an added benefit to the use of GLP-1 RA. This systematic review and meta-analysis aimed at summarizing observational studies that recruited type 2 diabetes individuals with fewer cardiovascular (CV) events before enrolling in the research.
UNASSIGNED: Systematically, the databases were searched for observational studies reporting compound CV events and deaths in type 2 diabetics without having the risk of cardiovascular diseases (CVDs) compared to other glucose-lowering agents. A meta-analysis was carried out using random effects model to estimate the overall hazard ratio (HR) with a 95% confidence interval (CI). Five studies were found eligible for the systematic review including a total of 64,452 patients receiving either liraglutide (three studies) or exenatide (two studies).
UNASSIGNED: The pooled HR for major adverse cardiac event (MACE) and extended MACE was 0.72 (95% CI: 0.65 - 0.93, I2 = 68%) and 0.93 (95% CI: 0.89 - 0.98, I2 = 29%), respectively. The pooled HR for hospitalization due to heart failure (HHF) and occurrence of HF was 0.84 (95% CI: 0.77 - 0.91, I2 = 79%) and 0.83 (95% CI: 0.75 - 0.94, I2 = 95%), respectively. For stroke, GLP-1 RA was associated with a significant risk reduction of 0.86 (95% CI: 0.75 - 0.98, I2 = 81%). There was no significant myocardial infarction (MI) risk reduction with GLP-1 RA. As for all-cause mortality, the pooled HR for the occurrence of all-cause mortality was 0.82 (95% CI: 0.76 - 0.88, I2 = 0%). The pooled HR for the occurrence of CV death was 0.75 (95% CI: 0.65 - 0.85, I2 = 38%). GLP-1 RA therapy was associated with a significantly low risk of MACE, extended MACE, all-cause mortality, and CV mortality. Except for MACE, the heterogenicity among the studies was low.
UNASSIGNED: We conclude that GLP-1 RA is associated with a low risk of CV events composites and mortality. The findings support the cardioprotective effect of GLP-1 RA.

Glucagon-like peptide 1 (GLP-1) receptor agonists are widely used for glycemic control in patients with diabetes mellitus (DM) and are primarily indicated for type 2 diabetes mellitus (T2DM). GLP-1 receptor agonists have also been shown to have neuroprotective and antidepressant properties. Replicated evidence suggests that individuals with DM are significantly more likely to develop depression. Herein, we aim to investigate whether GLP-1 receptor agonists can be used prophylactically on patients with DM to lower the risk of incident depression. We conducted a systematic search for English-language articles published on the PubMed/MEDLINE, Scopus, Embase, APA, PsycInfo, Ovid and Google Scholar databases from inception to June 6, 2022. Four retrospective observational studies were identified that evaluated the neuroprotective effects of GLP-1 receptor agonists on incident depression in patients with DM. We found mixed results with regards to lowering the risk of incident depression, with two studies demonstrating a significant reduction in risk and two studies showing no such effect. A single study found that dulaglutide may lower susceptibility to depression. Our results were limited by high interstudy heterogeneity, paucity of literature, and lack of controlled trials. While we did not find evidence of GLP-1 receptor agonists significantly lowering risk of incident depression in patients with DM, promising neuroprotective data presented in two of the included papers, specifically on dulaglutide where information is scarce, provide the impetus for further investigation. Future research should focus on better elucidating the neuroprotective potential of different classes and doses of GLP-1 receptor agonists using controlled trials.

Glucagon-like peptide 1 (GLP-1) analogs regulate body weight and liver steatosis. Different body adipose tissue (AT) depots exhibit biological variability. Accordingly, GLP-1 analog effects on AT distribution are unclear.
To investigate GLP1-analog effects on adiposity distribution.
PubMed, Cochrane, and Scopus databases were screened for eligible randomized human trials. Pre-defined endpoints included visceral AT (VAT), subcutaneous AT (SAT), total AT (TAT), epicardial AT (EAT), liver AT (LAT), and waist-to-hip ratio (W:H). Search was conducted until May 17, 2022.
Data extraction and bias assessment were performed by two independent investigators. Treatment effects were estimated using random effects models. Analyses were performed on Review Manager v5.3.
Out of the 367 screened studies, 45 were included in the systematic review and 35 were used in the meta-analysis. GLP-1 analogs reduced VAT, SAT, TAT, LAT, and EAT, with non-significant effects on W:H. Overall bias risk was low.
GLP-1 analog treatment reduces TAT, affecting most studied AT depots, including the pathogenic VAT, EAT, and LAT. GLP-1 analogs may have significant roles in combating metabolic, obesity-associated diseases via reductions of key AT depot volumes.

Type 2 diabetes is associated with a higher risk of cardiac arrhythmias, especially in presence of cardiovascular disease and/or heart failure. Even if atrial fibrillation/flutter episodes are the most frequent and well-studied, ventricular arrhythmias (VA: tachycardia/fibrillation) are more severe and can lead to sudden cardiac arrest/death (SCA/SCD). The effects of glucose-lowering agents on the risk of VA/SCD remain poorly understood. Findings may be derived from experimental animal studies, randomised controlled trials/cardiovascular outcome trials and observational retrospective studies. A higher risk was attributed to hypoglycaemia when induced by insulin or even more critically by sulphonylureas. Insulin-secreting agents seem to be associated with a higher risk of cardiac arrhythmias compared with insulin sensitizers (metformin, thiazolidinediones), yet the risk linked to sulphonylureas remains controverted. Incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists) overall appear to be neutral regarding the risk of cardiac arrhythmias, despite some heterogeneous results. SGLT2 inhibitors appear to reduce the risk of SCA/SCD and possibly VA, yet only a non-significant trend was noticed in most reports. Overall, hazard ratios with SGLT2 inhibitors versus other therapies were lower for SCD (presumably of diverse causes) than for well demonstrated VA episodes. Underlying mechanisms remain uncertain and numerous pleiotropic effects may be involved. Prospective controlled trials and experimental studies specifically devoted to the effects of SGLT2 inhibitors on cardiac arrhythmias are needed to confirm their positive effects in diabetic patients and in individuals with heart failure irrespective of diabetes and, if possible, to carefully dissect the underlying protective mechanisms.