Insulin glargine 100units/ml / Lixisenatide 33micrograms/ml solution for injection 3ml pre-filled disposable devices

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) affects up to 30% of the global population, yet effective pharmacological treatments remain limited. This systematic review and meta-analysis evaluated the efficacy of GLP-1 receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists in managing MAFLD. METHODS: We systematically searched PubMed/MEDLINE, Cochrane CENTRAL, Web of Science, and Scopus, through July 2025. Randomised controlled trials (RCTs) assessing GLP-1 receptor agonists or dual GLP-1/GIP GIP receptor Agonists in managing MAFLD patients were included. Primary outcomes included liver fat content, liver enzymes, and glycemic parameters. Meta-analyses were performed with subgroup analyses by receptor target, treatment duration, control type, and age. In addition, implementing a formal GRADE evaluation framework. RESULTS: Twenty-six trials involving 3,453 participants were included. GLP-1 receptor agonists significantly reduced liver fat content (MD: -3.37%, 95% CI: -4.98 to -1.76, p < 0.001), ALT levels (SMD: -0.47, 95% CI: -0.73 to -0.22, p < 0.001), and AST levels (SMD: -0.29, 95% CI: -0.53 to -0.05, p < 0.05). Significant improvements were observed in HbA1c (SMD: -0.67, 95% CI: -0.99 to -0.34, p < 0.001), fasting glucose (MD: -0.60 mmol/L, 95% CI: -0.92 to -0.27, p < 0.001), HOMA-IR (SMD: -0.34, 95% CI: -0.66 to -0.02, p < 0.05), and total cholesterol (MD: -0.23 mmol/L, 95% CI: -0.30 to -0.15, p < 0.001). Liver stiffness showed no significant improvement (MD: -0.12 kPa, 95% CI: -0.75 to 0.50, p = 0.70). Dual GLP-1/GIP agonists demonstrated superior efficacy compared to mono GLP-1 agonists for reducing liver fat (MD: -7.15, 95% CI: -10.23 to -4.07, p < 0.001 versus MD: -2.44, 95% CI: -4.18 to -0.71, p < 0.01), representing a 2.9-fold greater effect. Long-term treatment (lasting over 48 weeks) demonstrated enhanced benefits across all outcomes. Overall, changes in body weight were not significant (MD: -1.51 kg, 95% CI: -4.07 to 1.06, p = 0.25). CONCLUSIONS: This meta-analysis provides evidence for the effectiveness of GLP-1 receptor agonists in managing MAFLD, with dual GLP-1/GIP agonists demonstrating superior hepatic benefits. Long-term therapy (lasting more than 48 weeks) is necessary for optimal outcomes. These findings support clinical implementation, particularly for patients with concurrent diabetes or obesity, positioning dual agonists as promising advancements in treatment.

Abstract licence: CC BY-NC-ND

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used therapies for cardiovascular risk reduction in type 2 diabetes (T2D). With the emergence of the SURPASS-CVOT trial, tirzepatide (a dual GIP/GLP-1 receptor agonist) has entered the therapeutic landscape; however, its comparative effect on cardiovascular outcomes compared to placebo and individual GLP-1RAs remains undefined.MethodsWe conducted a systematic review and frequentist network meta-analysis (NMA) of RCTs enrolling adults with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular (CV) risk. Eligible RCTs evaluated tirzepatide or GLP-1RAs and reported major adverse cardiovascular events (MACE), CV mortality, all-cause mortality, non-fatal myocardial infarction (MI) or non-fatal stroke. A class-level NMA was conducted to estimate the incremental benefit of tirzepatide and GLP-1RAs over placebo, and an agent-level NMA was conducted to explore differences between tirzepatide and individual GLP-1RA agents. Subgroup analyses, including established cardiovascular disease populations, and leave-one-out sensitivity analyses were performed.ResultsEleven trials met inclusion criteria (10 GLP-1RA trials and 1 tirzepatide trial [SURPASS-CVOT]). In the class-level analysis, tirzepatide significantly reduced MACE (HR 0.79, 95% CI 0.69-0.91), CV mortality (HR 0.77, 95% CI 0.66-0.90), all-cause mortality (HR 0.74, 95% CI 0.65-0.83), non-fatal MI (HR 0.77, 95% CI 0.61-0.97), and non-fatal stroke (HR 0.79, 95% CI 0.64-0.97) compared to placebo. Formal statistical comparisons between tirzepatide and the GLP-1RA class could not be performed within the constraints of the NMA; however, point estimates across outcomes numerically favored tirzepatide compared with placebo. In the agent-level analysis, tirzepatide reduced MACE compared to placebo (HR 0.81, 95% CI 0.70-0.94) and lixisenatide (HR 0.79, 95% CI 0.65-0.97). Subgroup and sensitivity analyses did not substantially change point estimates.ConclusionAmong adults with T2D and established ASCVD or high CV risk, class-level analysis demonstrated that tirzepatide significantly reduced the risk of cardiovascular events compared to placebo; at the agent-level, tirzepatide demonstrated comparable efficacy to individual GLP-1RAs. These findings suggest that tirzepatide provides cardiovascular benefit at least comparable to established GLP-1RAs, supporting its emerging role in cardiovascular risk reduction in T2D.

Abstract licence: CC BY

BackgroundObesity plays a pivotal and modifiable role in the development and progression of type 2 diabetes mellitus (T2DM). Clinicians increasingly use lower doses of liraglutide (1.2 mg and 1.8 mg) to achieve clinically meaningful weight loss while maintaining effective glycemic control in people with T2DM and obesity. In this meta-analysis, we compared the efficacy and safety of liraglutide 1.2 mg and 1.8 mg in this population.MethodsWe systematically searched PubMed, the Cochrane Central Register of Controlled Trials, LENS, ClinicalTrials.gov, and the Virtual Health Library (VHL) for randomized controlled trials published in English up to 30 September 2024. We included trials with 24-52 weeks of treatment that evaluated liraglutide at doses of 1.2 mg or 1.8 mg against placebo or glucose-lowering therapies (GLTs). Comparators included insulin, sulfonylureas, dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), other glucagon-like peptide-1 receptor agonists (GLP-1RAs), and oral antidiabetic drugs (OADs). We assessed changes in body weight and HbA1c as efficacy outcomes and evaluated the occurrence of nausea and vomiting as safety outcomes. Two reviewers independently extracted data and assessed study quality using PRISMA guidelines and the Cochrane Risk of Bias 2 tool.ResultsWe included 25 RCTs comprising 10,593 participants. Liraglutide 1.2 mg (8 studies, 3,455 participants) produced a mean weight reduction of -1.24 kg versus GLTs, -0.75 kg versus placebo, and -2.46 kg versus OADs. Liraglutide 1.8 mg (22 studies, 8,259 participants) achieved significantly greater weight loss of -2.30 kg versus GLTs, -1.93 kg versus placebo, and -2.81 kg versus OADs. When compared with oral semaglutide, exenatide, dulaglutide, lixisenatide, and albiglutide, liraglutide showed comparable efficacy. For glycemic control, liraglutide 1.2 mg reduced HbA1c by -0.24% versus OADs, while liraglutide 1.8 mg reduced HbA1c by -0.26% versus GLTs. Liraglutide 1.2 mg showed a numerically lower incidence of nausea and similar rates of vomiting compared with other GLP-1RAs.ConclusionLiraglutide 1.2 mg and 1.8 mg doses improve weight and glycemic outcomes with a favourable safety profile, supporting its role as an effective therapeutic option for comprehensive management of T2DM with comorbid obesity.

Abstract licence: CC BY-NC

Limited head-to-head studies compare established glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP-4is), and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) to insulin in the management of uncontrolled type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis evaluated the efficacy and safety of traditional GLP-1 RAs, DPP-4is, and SGLT-2is compared with insulin. Comprehensive searches were conducted in the Cochrane Database, PubMed, MEDLINE, ClinicalTrials.gov, and EMBASE for publications from January 2010 to June 2022, with an additional search extended through June 2025 to capture newly published studies. Randomized controlled trials (RCTs) comparing insulin with established GLP-1 RAs, DPP-4is, or SGLT-2is were included. Thirteen trials involving 5,807 participants were identified. Nine trials compared GLP-1 RAs to insulin, four compared DPP-4is to insulin, and one examined SGLT-2i combined with DPP-4i versus insulin. Compared with insulin, traditional non-insulin agents were associated with greater reductions in hemoglobin A1c (HbA1c) (mean difference (MD) = -0.27, 95% confidence interval (CI) -0.5 to -0.03), body weight (MD = -3.27, 95% CI -4.16 to -2.38), and systolic blood pressure (MD = -3.55, 95% CI -4.92 to -2.17). Insulin use carried a higher relative risk of hypoglycemia (risk ratio (RR) = 2.24, 95% CI 1.88-2.67). Subgroup analyses showed that GLP-1 RAs were superior to insulin in reducing HbA1c and hypoglycemic events, whereas DPP-4is achieved similar glycemic control with improved safety profiles. These findings suggest that established GLP-1 RAs, DPP-4is, and SGLT-2is offer superior or comparable efficacy with better safety than insulin in insulin-naïve patients with uncontrolled T2DM.

Abstract licence: CC BY