Aims: To compare the efficacy and safety of different hybrid closed loop (HCL) systems in people with diabetes through a network meta‐analysis.Methods: We searched MEDLINE, EMBASE, CENTRAL and PubMed for randomised clinical trials (RCTs) enrolling children, adolescents and/or adults with type 1 or type 2 diabetes, evaluating Minimed 670G, Minimed 780G, Control‐IQ, CamAPS Fx, DBLG‐1, DBLHU, and Omnipod 5 HCL systems against other types of insulin therapy, and reporting time in target range (TIR) as outcome.Results: A total of 28 RCTs, all enrolling people with type 1 diabetes, were included. HCL systems significantly increased TIR compared with subcutaneous insulin therapy without continuous glucose monitoring (SIT). Minimed 780G achieved the highest TIR ahead of Control IQ (mean difference (MD) 5.1%, 95% confidence interval (95% CI) [0.68; 9.52], low certainty), Minimed 670G (MD 7.48%, 95% CI [4.27; 10.7], moderate certainty), CamAPS Fx (MD 8.94%, 95% CI [4.35; 13.54], low certainty), and DBLG1 (MD 10.69%, 95% CI [5.73; 15.65], low certainty). All HCL systems decreased time below target range, with DBLG1 (MD −3.69%, 95% CI [−5.2; −2.19], high certainty), Minimed 670G (MD −2.9%, 95% CI [−3.77; −2.04], moderate certainty) and Minimed 780G (MD −2.79%, 95% CI [−3.94; −1.64], high certainty) exhibiting the largest reductions compared to SIT. The risk of severe hypoglycaemia and diabetic ketoacidosis was similar to other types of insulin therapy.Conclusions: We show a hierarchy of efficacy among the different HCL systems in people with type 1 diabetes, thus providing support to clinical decision‐making.Trial Registration: PROSPERO CRD42023453717

Cardiovascular outcome trials (CVOT) showed that treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA) is associated with significant cardiovascular benefits. However, CVOT are scarcely representative of everyday clinical practice, and real-world studies could provide clinicians with more relatable evidence. Here, literature was thoroughly searched to retrieve real-world studies investigating the cardiovascular and renal outcomes of GLP-1RA vs. other glucose-lowering drugs and carry out relevant meta-analyses thereof. Most real-world studies were conducted in populations at low cardiovascular and renal risk. Of note, real-world studies investigating cardio-renal outcomes of GLP-1RA suggested that initiation of GLP-1RA was associated with a greater benefit on composite cardiovascular outcomes, MACE (major adverse cardiovascular events), all-cause mortality, myocardial infarction, stroke, cardiovascular death, peripheral artery disease, and heart failure compared to other glucose-lowering drugs with the exception of sodium-glucose transporter-2 inhibitors (SGLT-2i). Initiation of SGLT-2i and GLP-1RA yielded similar effects on composite cardiovascular outcomes, MACE, stroke, and myocardial infarction. Conversely, GLP-1RA were less effective on heart failure prevention compared to SGLT-2i. Finally, the few real-world studies addressing renal outcomes suggested a significant benefit of GLP-1RA on estimated glomerular filtration rate (eGFR) reduction and hard renal outcomes vs. active comparators except SGLT-2i. Further real-world evidence is needed to clarify the role of GLP-1RA in cardio-renal protection among available glucose-lowering drugs.

Innovative GLP-1 receptor agonist (GLP-1RA)-based treatment strategies—such as tirzepatide, GLP-1RA plus basal insulin fixed-ratio combinations [FRC], GLP-1RA plus sodium glucose cotransporter-2 inhibitors [SGLT-2i] combinations, and high-dose GLP-1RA—have been listed among the most efficacious options for type 2 diabetes management. However, differences in their glucometabolic effects have not been assessed in dedicated head-to-head trials. In the absence of such trials, we aimed to provide a useful comparison among these treatment strategies to guide clinical practice. In this network meta-analysis, we searched PubMed, MEDLINE, and Web of Science (from database inception to June 24, 2023) for randomised controlled studies, published in English, that enrolled individuals with type 2 diabetes treated with tirzepatide, iGlarLixi, iDegLira, GLP-1RA plus SGLT-2i combination, or high-dose GLP-1RA (dulaglutide 3 mg and 4.5 mg, semaglutide 2 mg) compared with placebo or active comparators. Eligible studies reported change from baseline in HbA1c as an outcome, which was the primary outcome of this analysis. Secondary outcomes were changes in fasting and post-prandial glucose, bodyweight, LDL-cholesterol, blood pressure and risk of hypoglycaemia. We assessed risk of bias through the Cochrane Collaboration's tool (RoB2 tool), publication bias through visual inspection of funnel plots and Egger's test, and heterogeneity by comparing the magnitude of the common between-study variance (τ²) for each outcome with empirical distributions of heterogeneity variances. This network meta-analysis was registered in PROSPERO (CRD42022329878). 40 trials were included. Tirzepatide 15 mg ranked first in terms of HbA1c reduction compared to other GLP-1RA-based strategies, even those including insulin (vs. iDegLira MD −0.40%, 95% CI [−0.66; −0.14], low certainty; vs. iGlarLixi MD −0.48%, 95% CI [−0.75; −0.21], low certainty), without increasing the risk of hypoglycaemia (vs. iDegLira OR 0.35, 95% CI [0.16; 0.79], high certainty; vs. iGlarLixi OR 0.31, 95% CI [0.20; 0.48], high certainty). Tirzepatide 15 mg was also the most efficacious on weight lowering, even compared to high-dose GLP-1RA (eg, semaglutide 2 mg MD −6.56 kg, 95% CI [−7.38; −5.73], low certainty) and GLP-1RA plus SGLT-2i combination (MD −4.61 kg, 95% CI [−5.29; −3.93], low certainty). Risk of bias and publication bias were generally low throughout studies, while high levels of heterogeneity were detected for most outcomes. Aiming to support clinicians in tailoring treatment to patients’ needs, we suggest that a hierarchy among treatment strategies be devised considering the best options for type 2 diabetes. Tirzepatide, followed by GLP-1RA plus basal insulin FRC and GLP-1RA plus SGLT-2i combination, was associated with greater benefit on HbA1c than high-dose GLP-1RA. 10.13039/501100009703 Fondazione per la Ricerca Biomedica “Saverio e Isabella Cianciola” and Next Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8—Project Age-It: Ageing Well in an Ageing Society.

Purpose: Chronic kidney disease (CKD) is one of the most common complications of type 2 diabetes (T2D), and CKD-related disability and mortality are increasing despite the recent advances in diabetes management. The dual GIP/GLP-1 receptor agonist tirzepatide is among the furthest developed multi-agonists for diabetes care and has so far displayed promising nephroprotective effects. This review aims to summarize the evidence regarding the nephroprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) and tirzepatide and the putative mechanisms underlying the favorable renal profile of tirzepatide. Methods: A comprehensive literature search was performed from inception to July 31st 2023 to select research papers addressing the renal effects of GLP-1RA and tirzepatide. Results: The pathogenesis of CKD in patients with T2D likely involves many contributors besides hyperglycemia, such as hypertension, obesity, insulin resistance and glomerular atherosclerosis, exerting kidney damage through metabolic, fibrotic, inflammatory, and hemodynamic mechanisms. Tirzepatide displayed an unprecedented glucose and body weight lowering potential, presenting also with the ability to increase insulin sensitivity, reduce systolic blood pressure and inflammation and ameliorate dyslipidemia, particularly by reducing triglycerides levels. Conclusion: Tirzepatide is likely to counteract most of the pathogenetic factors contributing to CKD in T2D, potentially representing a step forward in incretin-based therapy towards nephroprotection. Further evidence is needed to understand its role in renal hemodynamics, fibrosis, cell damage and atherosclerosis, as well as to conclusively show reduction of hard renal outcomes.