Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.

To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. Systematic review and network meta-analysis. PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A1c and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A1c concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A1c and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. PROSPERO CRD42022342845.

Yao H ，Zhang A ，Li D ，Wu Y ，Wang CZ ，Wan JY ，Yuan CS ... -  《BMJ-British Medical Journal》

Comparative efficacy of incretin drugs on glycemic control, body weight, and blood pressure in adults with overweight or obesity and with/without type 2 diabetes: a systematic review and network meta-analysis.

The rapid development of multi-receptor drugs targeting glucagon-like peptide-1 receptor (GLP-1R) is driving significant advancements in the treatment of individuals with type 2 diabetes and obesity. This systematic review and network meta-analysis aims to compare the efficacy and safety of multi-receptor drugs in adults with overweight or obesity, with or without type 2 diabetes. A systematic search was conducted in PubMed, Cochrane, Web of Science, Embase, CNKI, and WanFang databases up to May 12, 2024. Randomized controlled trials (RCTs) with an intervention duration of at least 12 weeks were included. The population of interest consisted of individuals with overweight or obesity, with or without type 2 diabetes. Eligible studies compared multi-receptor drugs with placebo or other multi-receptor drugs. The primary outcomes were weight reduction, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), blood pressure changes, and adverse events. Risk of bias was assessed using the version 2 of the Cochrane risk-of-bias tool (ROB2), and a random-effects network meta-analysis was performed using the frequentist approach. Confidence in effect estimates was evaluated using the Confidence In Network Meta-Analysis (CINeMA) framework. A total of 24 trials, involving 9165 participants, were included. Retatrutide (mean difference (MD): -11.91 kg, 95% CI: -19.00 to -4.82, P-score: 0.80, p: 0.0003) and Tirzepatide (MD: -12.78 kg, 95% CI: -16.10 to -9.46, P-score: 0.89, p < 0.0001) exhibited superior efficacy in reducing body weight, with all other agents except Mazdutide (MD: -5.31 kg, 95% CI: -9.78 to -0.84, P-score: 0.37, p: 0.0189) achieving reductions of over 8 kg. In patients with type 2 diabetes, all agents reduced HbA1c by over 1%, with Tirzepatide (MD: -1.87%, 95% CI: -2.15 to -1.59, P-score: 0.87, p < 0.0001) and Mazdutide (MD: -1.89%, 95% CI: -2.43 to -1.35, P-score: 0.88, p < 0.0001) showing the greatest effects on glycemic control. For blood pressure management, Tirzepatide significantly reduced systolic blood pressure (MD: -6.69 mmHg, 95% CI: -7.62 to -5.75, P-score: 0.84, p < 0.0001) and diastolic blood pressure (MD: -3.73 mmHg, 95% CI: -4.75 to -2.71, P-score: 0.92, p < 0.0001), with nearly all agents lowering systolic blood pressure by more than 5 mmHg. Non-diabetic participants showed more pronounced improvements in both weight and blood pressure. Safety analysis revealed that Tirzepatide had a favorable safety profile and all agents showed no significant impact on serious adverse events compared to placebo. Multi-receptor drugs demonstrated substantial therapeutic potential in weight management, glycemic control, and blood pressure regulation in adults with overweight or obesity, with or without diabetes, with a generally favorable safety profile. https://www.crd.york.ac.uk/prospero/, identifier CRD42024554005.

Liu S ，Hu J ，Zhao C ，Liu H ，He C ... -  《Frontiers in Endocrinology》

Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. ClinicalTrials.gov NCT04109547. Novo Nordisk A/S.

Wang W ，Bain SC ，Bian F ，Chen R ，Gabery S ，Huang S ，Jensen TB ，Luo B ，Yuan G ，Ning G ，PIONEER 11 investigators ... -  《-》

Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes.

Approximately 40% of people with diabetes develop kidney failure and experience an accelerated risk of cardiovascular complications. Glucagon-like peptide 1 (GLP-1) receptor agonists are glucose-lowering agents that manage glucose and weight control. We assessed the benefits and harms of GLP-1 receptor agonists in people with chronic kidney disease (CKD) and diabetes. The Cochrane Kidney and Transplant Register of Studies was searched to 10 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. Randomised controlled studies were eligible if participants with diabetes and CKD were randomly allocated to a GLP-1 receptor agonist, placebo, standard care or a second glucose-lowering agent. CKD included all stages (from 1 to 5). Three authors independently extracted data and assessed the risk of bias using the risk of bias assessment tool 2. Pooled analyses using summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and/or hazard ratio (HR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. The primary outcomes included death (all-cause and cardiovascular), 3- and 4-point major adverse cardiovascular events (MACE), kidney failure, composite kidney outcome, and severe hypoglycaemia. The secondary outcomes included non-fatal or fatal myocardial infarction (MI) or stroke, non-fatal peripheral arterial events, heart failure, hospitalisation due to heart failure, estimated glomerular filtration rate or creatinine clearance, doubling of serum creatinine, urine albumin-to-creatinine ratio, albuminuria progression, vascular access outcomes, body weight, body mass index, fatigue, life participation, peritoneal dialysis infection, peritoneal dialysis failure, adverse events, serious adverse events, withdrawal due to adverse events, HbA1c, sudden death, acute MI, ischaemic stroke, and coronary revascularisation. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Forty-two studies involving 48,148 participants were included. All studies were conducted on people with type 2 diabetes, and no studies were carried out on children. The median study age was 66 years. The median study follow-up was 26 weeks. Six studies were conducted in people with CKD stages 1-2, 11 studies in people with CKD stages 3-5, one study in people on dialysis, and the remaining studies included people with both CKD stages 1-2 and 3-5. Risks of bias in the included studies for all the primary outcomes in studies that compared GLP-1 receptor agonists to placebo were low in most methodological domains, except one study that was assessed at high risk of bias due to missing outcome data for death (all-cause and cardiovascular). The overall risk of bias for all-cause and cardiovascular death in studies that reported the treatment effects of GLP-1 receptor agonists compared to standard care, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors were assessed as unclear or at high risk of bias due to deviations from intended interventions or missing data. For GLP-1 receptor agonists compared to insulin or another GLP-1 receptor agonist, the risk of bias for all-cause and cardiovascular death was low or unclear. Compared to placebo, GLP-1 receptor agonists probably reduced the risk of all-cause death (RR 0.85, 95% CI 0.74 to 0.98; I2 = 23%; 8 studies, 17,861 participants; moderate-certainty evidence), but may have little or no effect on cardiovascular death (RR 0.84, 95% CI 0.68 to 1.05; I2 = 42%; 7 studies, 17,801 participants; low-certainty evidence). Compared to placebo, GLP-1 receptor agonists probably decreased 3-point MACE (RR 0.84, 95% CI 0.73 to 0.98; I² = 65%; 4 studies, 19,825 participants; moderate-certainty evidence), and 4-point MACE compared to placebo (RR 0.77, 95% CI 0.67 to 0.89; 1 study, 2,158 participants; moderate-certainty evidence). Based on absolute risks of clinical outcomes, it is likely that GLP-1 receptor agonists prevent all-cause death in 52 people with CKD stages 1-2 and 116 in CKD stages 3-5, cardiovascular death in 34 people with CKD stages 1-2 and 71 in CKD stages 3-5, while 95 CKD stages 1-2 and 153 in CKD stages 3-5 might experience a major cardiovascular event for every 1000 people treated over 1 year. Compared to placebo, GLP-1 receptor agonists probably had little or no effect on kidney failure, defined as starting dialysis or kidney transplant (RR 0.86, 95% CI 0.66 to 1.13; I2 = 0%; 3 studies, 4,134 participants; moderate-certainty evidence), or on composite kidney outcomes (RR 0.89, 95% CI 0.78 to 1.02; I2 = 0%; 2 studies, 16,849 participants; moderate-certainty evidence). Compared to placebo, GLP-1 receptor agonists may have little or no effect on the risk of severe hypoglycaemia (RR 0.82, 95% CI 0.54 to 1.25; I2 = 44%; 4 studies, 6,292 participants; low-certainty evidence). The effects of GLP-1 receptor agonists compared to standard care or other hypoglycaemic agents were uncertain. No studies evaluated treatment on risks of fatigue, life participation, amputation or fracture. GLP-1 receptor agonists probably reduced all-cause death but may have little or no effect on cardiovascular death in people with CKD and diabetes. GLP-1 receptor agonists probably lower major cardiovascular events, probably have little or no effect on kidney failure and composite kidney outcomes, and may have little or no effect on the risk of severe hypoglycaemia in people with CKD and diabetes.

Natale P ，Green SC ，Tunnicliffe DJ ，Pellegrino G ，Toyama T ，Strippoli GF ... -  《Cochrane Database of Systematic Reviews》

Efficacy of Glucagon-like Peptide-1 Receptor Agonists in Overweight/Obese and/or T2DM Adolescents: A Meta-analysis Based on Randomized Controlled Trials.

The aim of this meta-analysis was to investigate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on blood glucose and weight in adolescents with overweight/obesity and/or type 2 diabetes mellitus (T2DM) aged <18 years. PubMed, Embase, Web of Science, and Cochrane Library were searched for all randomized controlled trials (RCTs) up to August 2023 comparing GLP-1RAs with placebo in overweight/obese and/or T2DM adolescents and extracted relevant data for meta-analysis. Fourteen RCTs were included in the meta-analysis with a total of 1,262 participants. Results revealed that the GLP-1RAs group had a more significant reduction in glycosylated hemoglobin A1c (HbA1c; risk difference (RD)=-0.34%, p<0.001) than the control group. However, there was no difference in fasting plasma glucose [fasting plasma glucose (FPG); RD=-2.07 mg/dL, p=0.065] between the two groups. Nonetheless, the experimental group that received exenatide showed no significant reduction in HbA1c (p=0.253) and FPG (p=0.611) between the two groups. The GLP-1RAs group had a more significant decline in body weight (RD=-4.28 kg, p=0.002) and body mass index (BMI) (RD=-1.63 kg/m2, p=0.002) compared to the control group. The experimental group was given liraglutide (RD=-2.31 kg, p=0.038) or exenatide (RD=-2.70 kg, p<0.001). Compared to the control group, the experimental group had a more significant drop in body weight than the control group. However, for the experimental group that received liraglutide, the BMI had a no significant reduction between the two groups (RD=-0.81 kg/m2, p=0.260). For the experimental group using exenatide, BMI declined more significantly in the intervention group than in the control group (RD=-1.14 kg/m2, p<0.001). This study showed that GLP-1RAs reduced HbA1c, FPG, and weight loss in overweight/obese and/or T2DM adolescents. Liraglutide was better than exenatide in terms of glucose reduction. Nevertheless, in terms of weight control, exenatide was more effective than liraglutide.

Dai M ，Dai S ，Gu L ，Xiang Z ，Xu A ，Lu S ，Yang Y ，Zhou C ... -  《-》