Hepatic Events Prevention by Antihyperglycemic Therapies and Intervention Comparisons in Type 2 Diabetes: The HEPATIC-T2DM Network Meta-analysis.

<p dir="ltr"><b>Background: </b>Type 2 diabetes mellitus (T2DM) amplifies liver disease burden, yet the comparative hepatic effects of antidiabetic drugs remain poorly defined.</p><p dir="ltr"><b>Purpose: </b>To compare associations between antidiabetic drug classes and major adverse liver outcomes (MALOs) in adults with T2DM.</p><p dir="ltr"><b>Data Sources: </b>PubMed, EMBASE, and CENTRAL were searched from December 1946 through 23 August 2025.</p><p dir="ltr"><b>Study Selection: </b>Studies enrolling adults with T2DM that evaluated associations between antidiabetic drug classes in regards to MALOs were included.</p><p dir="ltr"><b>Data Extraction: </b>Data were extracted on study characteristics, drug exposures, and MALOs.</p><p dir="ltr"><b>Data Synthesis: </b>A 3-level Bayesian network meta-analysis with study- and database-level random effects was performed. Outcomes were reported as hazard ratios (HRs) and ranked using the surface under the cumulative ranking curve. Forty-six observational studies (n = 7,124,845) were included. Thiazolidinediones were least associated with hepatocellular carcinoma incidence, significantly lower than DPP-4 inhibitors (HR=0.50), GLP-1 receptor agonists (HR=0.72), insulin (HR=0.20), and sulfonylureas (HR=0.69). For decompensation (composite), GLP-1 receptor agonists (GLP-1RAs) were associated with the lowest hazard compared with all other classes (HRs 0.16–0.91, all significant). SGLT-2 inhibitors were least associated with cirrhosis (HR=0.66 vs DPP-4 inhibitors; HR=0.66 vs GLP-1RAs). GLP-1RAs were least associated with variceal bleeding and hepatic encephalopathy, whereas SGLT-2 inhibitors were least associated with liver-related mortality.</p><p dir="ltr"><b>Limitations: </b>All included studies were observational, precluding causal inference.</p><p dir="ltr"><b>Conclusions: </b>Liver-specific risk reduction is not uniform across antihyperglycaemic drug classes. Randomized trials are needed to determine whether these associations reflect true drug effects.</p>

<p dir="ltr"><b>Background: </b>Type 2 diabetes mellitus (T2DM) amplifies liver disease burden, yet the comparative hepatic effects of antidiabetic drugs remain poorly defined.</p><p dir="ltr"><b>Purpose: </b>To compare associations between antidiabetic drug classes and major adverse liver outcomes (MALOs) in adults with T2DM.</p><p dir="ltr"><b>Data Sources: </b>PubMed, EMBASE, and CENTRAL were searched from December 1946 through 23 August 2025.</p><p dir="ltr"><b>Study Selection: </b>Studies enrolling adults with T2DM that evaluated associations between antidiabetic drug classes in regards to MALOs were included.</p><p dir="ltr"><b>Data Extraction: </b>Data were extracted on study characteristics, drug exposures, and MALOs.</p><p dir="ltr"><b>Data Synthesis: </b>A 3-level Bayesian network meta-analysis with study- and database-level random effects was performed. Outcomes were reported as hazard ratios (HRs) and ranked using the surface under the cumulative ranking curve. Forty-six observational studies (n = 7,124,845) were included. Thiazolidinediones were least associated with hepatocellular carcinoma incidence, significantly lower than DPP-4 inhibitors (HR=0.50), GLP-1 receptor agonists (HR=0.72), insulin (HR=0.20), and sulfonylureas (HR=0.69). For decompensation (composite), GLP-1 receptor agonists (GLP-1RAs) were associated with the lowest hazard compared with all other classes (HRs 0.16–0.91, all significant). SGLT-2 inhibitors were least associated with cirrhosis (HR=0.66 vs DPP-4 inhibitors; HR=0.66 vs GLP-1RAs). GLP-1RAs were least associated with variceal bleeding and hepatic encephalopathy, whereas SGLT-2 inhibitors were least associated with liver-related mortality.</p><p dir="ltr"><b>Limitations: </b>All included studies were observational, precluding causal inference.</p><p dir="ltr"><b>Conclusions: </b>Liver-specific risk reduction is not uniform across antihyperglycaemic drug classes. Randomized trials are needed to determine whether these associations reflect true drug effects.</p>

To investigate the risk of hyperkalaemia in new users of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs. dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with type 2 diabetes mellitus (T2DM). Patients with T2DM who commenced treatment with an SGLT2 or a DPP-4 inhibitor between 2015 and 2019 were collected. A multivariable Cox proportional hazards analysis was applied to compare the risk of central laboratory-determined severe hyperkalaemia, hyperkalaemia, hypokalaemia (serum potassium ≥6.0, ≥5.5, and <3.5mmol/L, respectively), and initiation of a potassium binder in patients newly prescribed an SGLT2 or a DPP-4 inhibitor. A total of 28599 patients (mean age 60±11 years, 60.9% male) were included after 1:2 propensity score matching, of whom 10586 were new users of SGLT2 inhibitors and 18013 of DPP-4 inhibitors. During a 2-year follow-up, severe hyperkalaemia developed in 122 SGLT2 inhibitor users and 325 DPP-4 inhibitor users. Use of SGLT2 inhibitors was associated with a 29% reduction in incident severe hyperkalaemia [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.88] compared with DPP-4 inhibitors. Risk of hyperkalaemia (HR 0.81, 95% CI 0.71-0.92) and prescription of a potassium binder (HR 0.74, 95% CI 0.67-0.82) were likewise decreased with SGLT2 inhibitors compared with DPP-4 inhibitors. Occurrence of incident hypokalaemia was nonetheless similar between those prescribed an SGLT2 inhibitor and those prescribed a DPP-4 inhibitor (HR 0.90, 95% CI 0.81-1.01). Our study provides real-world evidence that compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with lower risk of hyperkalaemia and did not increase the incidence of hypokalaemia in patients with T2DM.

Type 2 diabetes mellitus (T2DM) is a recognized modifiable risk factor for HCC and liver-related mortality. The effects of newer antidiabetic agents-including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors-on hepatic outcomes remain uncertain. We aimed to evaluate whether these therapies reduce the risk of HCC and non-HCC liver-related events (LREs) in patients with T2DM. A systematic literature search was performed to identify studies reporting hepatic complications among patients with T2DM prescribed GLP-1 RAs, SGLT-2 inhibitors, or DPP-4 inhibitors. Comparisons were made against patients receiving various glucose-lowering therapies other than the drug of interest. Subgroup analyses were conducted in patients with chronic liver disease. Random-effects meta-analyses were used to estimate pooled hazard ratios (HRs). Of 2,228 records screened, 36 cohort studies comprising 5,363,858 patients were included. Compared with other glucose-lowering therapies, GLP-1 RAs were associated with significantly reduced risks of HCC (pooled HR 0.77, 95% CI [0.66-0.90]) and LREs (0.79 [0.65-0.95]). SGLT-2 inhibitors similarly conferred protection against HCC (0.76 [0.67-0.86]) and LREs (0.82 [0.73-0.92]). By contrast, DPP-4 inhibitors were not associated with hepatoprotection, showing neutral effects on HCC (1.12 [0.91-1.39]) and increased risk of LREs (1.24 [1.15-1.34]). In patients with chronic liver disease, GLP-1 RAs were uniquely associated with reduced hepatic decompensation (0.79 [0.71-0.88]). GLP-1 RAs and SGLT-2 inhibitors were associated with hepatoprotective effects compared with other glucose-lowering therapies in patients with T2DM, with GLP-1 RAs showing additional benefits in chronic liver disease. These findings provide evidence on the relationships between antidiabetic drug classes and liver-related outcomes in patients with T2DM and may inform clinical decision-making.

To the Editor: Incretin-based therapies for type 2 diabetes mellitus (T2DM) include incretin mimetics of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and incretin enhancers of dipeptidyl peptidase-4 (DPP-4) inhibitors.[1] With good hypoglycemic effects of incretin-based drugs that show no weight gain or hypoglycemia risk, these drugs are increasingly used in patients with T2DM. GLP-1 RAs are considered superior to DPP-4 inhibitors in controlling glycosylated hemoglobin, fasting blood glucose, and body weight.[2] However, the incidence of adverse events, such as adverse gastrointestinal reactions and dizziness caused by GLP-1 RAs, is higher than it is for DPP-4 inhibitors.[3] Unlike other anti-diabetic agents, safety concerns have been raised regarding the risk for gastrointestinal cancer associated with incretin-based treatments. Both a better understanding of their roles as second-line glucose-lowering treatments and a comprehensive assessment of their benefits and harms could inform the choice of treatment in clinical practice. Multicriteria decision analysis (MCDA), a general framework for constructing multicriteria decision models for benefit-risk assessment (BRA), has been widely used in health management and drug evaluation.[4,5] The stochastic multicriteria acceptability analysis (SMAA) model was developed from the traditional MCDA model to reduce the impact of the value preferences of decision-makers without requiring them to give subjective weight to decision-making indicators.[6,7] Previous studies have reviewed the multiple benefit and risk outcomes of GLP-1 RAs and DPP-4 inhibitors, but none have adopted the BRA evaluation model to synthesize multiple outcomes and obtain comprehensive comparison results. In this study, SMAA and network meta-analysis (NMA) were used to analyze the BRA of incretin-based treatments with other anti-diabetic agents to provide more comprehensive evidence for the clinical use of anti-diabetic agents in the treatment of T2DM. The risk/benefit outcomes were identified through reference to previous reviews, NMA, and drug information published by the Food and Drug Administration on incretin-based therapies. These included 26 outcomes, as shown in Figure 1 and Supplementary Table 1, https://links.lww.com/CM9/B446. Medline, Embase, ClinicalTrials.gov, and the Cochrane Library were searched from their inception to March 29, 2019. We used "Glucagon-Like Peptide-1 Receptors" and "Dipeptidyl-Peptidase IV Inhibitors" as keywords or MeSH terms, accompanied by EMTREE terms and relevant free words to search these databases.Figure 1: Value map of the BRA index of incretin-based therapies. Network plot presenting the trial data contributing evidence comparing incretin-based therapies for outcomes. (A) FPG, HbA1c, PPG, weight; (B) HDL, LDL, TC, TG; (C) DBP, heart rate, SBP; (D) Constipation, diarrhea, dyspepsia, gastroenteritis, nausea, vomiting; (E) All-cause death, hypertension, hypoglycemia, MACE, pancreatitis; (F) Arthralgia, cancers of digestive system, dizziness, headache. AGI: Alpha-glucosidase inhibitor; BRA: Benefit-risk assessment; DBP: Diastolic blood pressure; DPP-4: Dipeptidyl peptidase-4; FPG: Fasting plasma glucose; GLP-1 RAs: Glucagon-like peptide-1 receptor agonists; HbA1c: Glycosylated hemoglobin; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; MACE: Major adverse cardiovascular events; Met: Metformin; PPG: Postprandial plasma glucose; SBP: Systolic blood pressure; SGLT-2: Sodium-glucose co-transporter 2; SU: Sulfonylureas; TC: Total cholesterol; TG: Triglyceride; TZD: Thiazolidinediones.The inclusion criteria were as follows: (1) reports written in English; (2) randomized clinical trials (RCTs); (3) the subjects were T2DM; (4) the intervention measures were GLP-1 RAs or DPP-4 inhibitors; (5) metformin (Met), sulfonylureas (SU), thiazolidinediones (TZD), alpha-glucosidase inhibitor (AGI), sodium-glucose co-transporter 2 (SGLT-2) inhibitor, insulin, or placebo as control measures; (6) GLP-1 RAs and DPP-4 inhibitors as control drugs; and (7) relevant indicators appearing in the study are included in the literature. Exclusion criteria were as follows: (1) reports not written in English; (2) non-RCTs; (3) the subjects were not T2DM; (4) animal research and other basic research; (5) no GLP-1 RAs and DPP-4 inhibitors in the intervention; and (6) ongoing or unfinished experimental studies. Data were extracted, including trial information (author, title, publication year, sample size, trial duration, types of intervention, and control), population characteristics (diabetes duration, age, baseline level of glycosylated hemoglobin A1c (HbA1c), background treatment), types of intervention and control measures, benefit and risk indicators, and relevant results. Two investigators (FS and SBC) extracted data independently in duplicate. The quality of studies was assessed using the Cochrane risk of bias tool (generation of random sequence, allocation hidden, blind method of the research object, results blind method, data integrity, selective reporting, and funded by company randomization). The Bayesian method was used to analyze each risk/benefit outcome. The measure of each risk/benefit outcome indicator was expressed as mean difference or odds ratio and its 95% confidence interval. The first main result of SMAA was acceptability, that is the probability of the scheme ranking in the evaluation system. The second main result was the confidence factor (CF). This refers to the probability that the alternatives rank first when the central weight vector is selected. Based on SMAA, the results of inconsistent comparison pairs in the NMA results were replaced with the direct comparison of the results of the meta-analysis, and indicators that could be related to each other in the outcome indicators were removed for sensitivity to test the stability of the model results. Of the 26 related BRA outcomes [Figure 1 and Supplementary Table 1, https://links.lww.com/CM9/B446], 11 were benefit indicators, including glycosylated HbA1c, fasting plasma glucose, postprandial plasma glucose, weight, blood lipids, blood pressure, and heart rate. In all, 15 were risk indicators, including all-cause death, pancreatitis, constipation, diarrhea, dyspepsia, gastroenteritis, nausea, vomiting, arthralgia, hypertension, cancers of the digestive system, dizziness, headache, hypoglycemia, and major adverse cardiovascular events. A total of 589 RCTs involving 295,908 patients with T2DM were included. In all, 34 RCTs (16,023 patients with T2DM) on GLP-1 RAs and DPP-4 inhibitors were head-to-head comparisons. In other comparisons, comparators included metformin, SU, TZD, AGI, SGLT-2 inhibitors, insulin, and placebo. The overall quality of the literature is high, except for the high risk associated with the research object, the use of blind methods of outcome evaluation, and corporate sponsorship. We compared the effects of DPP-4 inhibitors and GLP-1 RAs on benefit and risk indicators, respectively. The effects of incretin and insulin, Met, SGLT-2 inhibitors, SU, TZD, and AGI on the benefit and risk indicators were also compared. The acceptability of GLP-1 RAs was better than that of DPP-4 inhibitors in 84.5% of cases. The CF for GLP-1 RAs being better than DPP-4 inhibitors was 99.5%. The acceptability of DPP-4 inhibitors was better than that of insulin in 93.1% of cases, and that of GLP-1 RAs were better than insulin in 90.6% of cases. The CF for DPP-4 inhibitors being better than insulin was 99.5%, and for GLP-1 RAs being better than insulin was 99.9%. The acceptability of Met was better than that of DPP-4 inhibitors in 61.5% of cases, and that of GLP-1 RAs were better than Met in 70.4% of cases. The CF for Met being better than DPP-4 inhibitors was 88.7%, and for GLP-1 RAs being better than Met was 92.2%. The acceptability of SGLT-2 inhibitors was better than that of DPP-4 inhibitors in 93.5% of cases, and that of SGLT-2 inhibitors was better than that of GLP-1 RAs in 76.0% of cases. The CF for SGLT-2 inhibitors being better than DPP-4 inhibitors was 99.7%, and for SGLT-2 inhibitors being better than GLP-1 RAs was 92.9%. The acceptability of DPP-4 inhibitors was better than that of SU in 80.4% of cases, and that of GLP-1 RAs was better than that of SU in 94.2% of cases. The CF for DPP-4 inhibitors being better than SU was 96.4%, and for GLP-1 RAs being better than SU was 99.9%. The acceptability of TZD was better than that of DPP-4 inhibitors in 58.6% of cases, and that of GLP-1 RAs was better than that of TZD in 69.8% of cases. The CF for TZD being better than DPP-4 inhibitors was 90.9%, and that for GLP-1 RAs being better than TZD was 97.1%. The acceptability of DPP-4 inhibitors was better than that of AGI in 72.1% of cases, and that of GLP-1 RAs was better than that of AGI in 89.4% of cases. The CF for DPP-4 inhibitors being better than AGI was 84.6%, and that for GLP-1 RAs being better than AGI was 98.9%. Based on SMAA, GLP-1 RAs were more likely to be superior to DPP-4 inhibitors in terms of BRA. The acceptability of GLP-1 RAs was better than those of insulin, SU, TZD, and AGI but lower than that of SGLT-2 inhibitors. The acceptability of DPP-4 inhibitors was higher than those of insulin and SU but lower than that of Met and SGLT-2 inhibitors. SMAA is a derivative model of MCDA, which is widely used in various industries. As it is presently used in the medical field, MCDA has eight steps: clarifying the decision-making environment, determining the evaluation index, collecting the specific data from each index, normalizing the data collected by each index, giving each index weight, calculating BRA values, conducting sensitivity analyses, and interpreting the results. Unlike the traditional MCDA model, SMAA reduces the impact of the value preferences of evaluators on decision-making and does not need decision-makers to give subjective weight to decision-making indicators. This study had many advantages. First, a total of 589 RCT studies involving 295,908 patients with T2DM were systematically searched and included in it. The sample size was large, and the bias risk for each study was evaluated. Second, 26 risk/benefit outcome indicators related to the treatment of T2DM with incretin were included, and the indicators were comprehensive and representative. Third, the SMAA model used in this study can reduce the subjectivity of decision-makers as they weight the indicators, at least to a certain extent. Further analysis regarding patient-level characteristics and their values and preferences are warranted (Supplementary Link: https://links.lww.com/CM9/B369). (Table 1) Table 1 - Results of SMAA analysis. Drug name Rank acceptability index (%) CF (%) GLP-1 RAs-DPP-4 inhibitors 84.5 99.5 DPP-4 inhibitors-insulin 93.1 99.5 GLP-1 RAs-insulin 90.6 99.9 Met-DPP-4 inhibitors 61.5 88.7 GLP-1 RAs-Met 70.4 92.2 SGLT-2 inhibitors-DPP-4 inhibitors 93.5 99.7 SGLT-2 inhibitors-GLP-1 RAs 76.0 92.9 DPP-4 inhibitors-SU 80.4 96.4 GLP-1 RAs-SU 94.2 99.9 TZD-DPP-4 inhibitors 58.6 90.9 GLP-1 RAs-TZD 69.8 97.1 DPP-4 inhibitors-AGI 72.1 84.6 GLP-1 RAs-AGI 89.4 98.9 AGI: Alpha-glucosidase inhibitor; CF: Confidence factor; DPP-4: Dipeptidyl peptidase-4; GLP-1 Ras: Glucagon-like peptide-1 receptor agonists; Met: Metformin; SGLT-2: Sodium-glucose co-transporter 2; SMAA: Stochastic multi-criteria acceptability analysis; SU: Sulfonylureas; TZD: Thiazolidinediones. Funding This work was supported by a grant from the National Natural Science Foundation of China (No. 72074011). Conflicts of interest None.

Effect of SGLT2 Inhibitors on Erythrocytosis and Arterial Thrombosis Risk in Patients with Type 2 Diabetes Mellitus: A Real-World Multi-Center Cohort Study across the United States

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023. RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest. Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done. A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE). Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons. In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU. American College of Physicians. (PROSPERO: CRD42022322129).

Finerenone and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), while the relative efficacy has not been determined. The databases of PubMed, Embase and Cochrane were searched for relevant cardiovascular or renal outcome trials of SGLT2i or finerenone. The end points were major adverse cardiovascular events (MACE), nonfatal stroke (NS), myocardial infarction (MI), hospitalization for heart failure (HHF), cardiovascular death (CVD), and renal composite outcome (RCO). Network meta-analysis was performed using Bayesian networks to obtain pooled hazard ratios (HR) and 95% confidence intervals (CI). The probability values for ranking active and placebo interventions were calculated using cumulative ranking curves. 1024 articles were searched, and only 9 studies were screened and included in this meta-analysis with 71793 randomized participants. Sotagliflozin (HR 0.72 95%CI 0.59-0.88, SUCAR=0.93) and canagliflozin (HR 0.80 95%CI 0.67-0.97, SUCAR=0.73) can significantly reduce the risk of MACE compared with placebo. Canagliflozin (HR 0.64 95%CI 0.48-0.86, SUCAR=0.73), sotagliflozin (HR 0.66 95%CI 0.50-0.87, SUCAR=0.69) and empagliflozin (HR 0.65 95%CI 0.43-0.98, SUCAR=0.68) can significantly reduce the risk of HHF compared with placebo. Empagliflozin (HR 0.62 95%CI 0.43-0.89, SUCAR=0.96) can significantly reduce the risk of CVD compared with placebo. Empagliflozin (HR 0.61 95%CI 0.39-0.96, SUCAR=0.74), canagliflozin (HR 0.66 95%CI 0.46-0.92, SUCAR=0.63), and dapagliflozin (HR 0.53 95%CI 0.32-0.85, SUCAR=0.88) can significantly reduce the risk of RCO compared with placebo. Finerenone has reduced the risk of MACE, MI, HHF, CVD and RCO to varying degrees, but they do not show significant difference from placebo and each SGLT2i. Both SGLT2i and finerenone could reduce the risk of MACE, HHF, MI, CVD, RCO. Finerenone has no obvious advantage than SGLT2i on the effects of cardiovascular and renal protective. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022375092.

Glucagon-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients With Cirrhosis and Diabetes

The Impact of Different Antidiabetic Drugs on Fracture Risk in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials With a Focus on SGLT2 Inhibitors

Background & AimsThe comparative effectiveness of antidiabetic therapies on hepatic outcomes in patients with type 2 diabetes mellitus (T2DM) is not well established.MethodsWe conducted a retrospective new-user cohort study emulating a target trial using electronic health records from the Mass General Brigham health system (USA) between January 2012 and June 2024. Adults with T2DM who newly initiated sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP4is), or sulfonylureas were included. Propensity scores were estimated using prespecified clinical and high-dimensional covariates, and overlap weighting was applied to achieve covariate balance.ResultsAmong 38,524 eligible patients, 12,344 initiated GLP-1RAs, 5,233 SGLT2is, 3,717 DPP4is, and 17,230 sulfonylureas. Over a median follow-up of 3.1 years, 1,743 hepatic decompensation events occurred. In the intention-to-treat analysis, GLP-1RAs (hazard ratio [HR] 0.58, 95% CI 0.38–0.88) and SGLT2is (HR 0.65, 95% CI 0.43–0.98) were associated with significantly lower risk compared with sulfonylureas. Pairwise analyses also showed reduced risk with GLP-1RAs (HR 0.59, 95% CI 0.39–0.89) and SGLT2is (HR 0.66, 95% CI 0.43–1.00) compared with DPP4is, with no significant difference between GLP-1RAs and SGLT2is. In the per-protocol analysis (1,151 events), GLP-1RAs (HR 0.43, 95% CI 0.22–0.82) remained strongly protective, while SGLT2is showed a trend toward reduced risk (HR 0.61, 95% CI 0.33–1.12). Sensitivity analyses excluding early events or using alternative weighting approaches produced consistent results.ConclusionIn patients with T2DM, initiation of GLP-1RAs or SGLT2is was associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and DPP4is. These findings support their preferential use in clinical practice.Impact and implicationsThis study provides robust real-world evidence on the comparative effectiveness of four major antidiabetic drug classes in reducing hepatic decompensation among patients with type 2 diabetes mellitus. Our findings suggest that glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors are associated with substantially lower risk of hepatic decompensation compared with sulfonylureas and dipeptidyl peptidase-4 inhibitors, supporting their preferential use in patients with coexisting diabetes and liver disease risk. These results are particularly relevant for clinicians managing patients with type 2 diabetes who may have unrecognized metabolic dysfunction-associated steatotic liver disease or other chronic liver diseases. In practice, these findings can help guide therapeutic decision-making by integrating liver-related outcomes into antidiabetic drug selection. However, future prospective studies are needed to validate these findings and clarify the mechanisms underlying the observed benefits.

To compare the impact of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase 4 (DPP-4) inhibitors on age-related macular degeneration (AMD) risk among patients with type 2 diabetes mellitus (T2DM). This multinational, retrospective cohort study used electronic medical records from healthcare institutions across 21 countries. Adults 50 years or older with T2DM who had a prior prescription of metformin and initiated SGLT2 or DPP-4 inhibitors from 2013 to 2023 were included. The SGLT2 and DPP-4 inhibitor groups were propensity score matched in a 1:1 ratio to balance baseline characteristics and were followed for up to 5 years to observe the occurrence of AMD. Statistical analysis was performed using the Cox proportional hazards model and Kaplan-Meier analysis. Our final analysis included 20,966 T2DM patients prescribed SGLT2 inhibitors and 20,966 prescribed DPP-4 inhibitors. Compared to the DPP-4 inhibitor group, the SGLT2 inhibitor group was associated with significantly lower risks of AMD (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.58-0.85) and dry AMD (HR, 0.61; 95% CI, 0.46-0.80) but not wet AMD (HR, 0.74; 95% CI, 0.48-1.16). SGLT2 inhibitors compared with DPP-4 inhibitors were linked to a reduced risk of AMD in the White population, patients prescribed empagliflozin or dapagliflozin, and individuals with glycated hemoglobin < 8.5%, estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2, hypertension, or dyslipidemia, regardless of body mass index level. In patients with T2DM, those prescribed SGLT2 inhibitors may experience lower risks of AMD and dry AMD compared to those prescribed DPP-4 inhibitors.

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients with psoriasis and comorbid type 2 diabetes: A population-based target trial emulation.

AimsInsulin therapy is a cornerstone in type 2 diabetes mellitus (T2DM) management, but its use is associated with several barriers, including hypoglycaemia, fear of injections and high costs. We compared the risk of insulin initiation and other treatment intensification between patients with T2DM newly treated with a sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) versus those newly treated with a dipeptidyl peptidase‐4 inhibitor (DPP4i).Materials and MethodsThis Japanese retrospective cohort study was conducted between 1 January 2015 and 31 March 2023 using the JMDC Claims Database. Patients with T2DM newly treated with an SGLT2i or a DPP4i were matched 1:1 using propensity score (n = 18 488 each). Incidence rates (IR) of insulin initiation, other antidiabetic drugs (OAD) and antihypertensive drugs added onto baseline treatment were calculated for each treatment group. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a Cox proportional hazards model.ResultsThe IR of insulin initiation was 0.95 and 2.12 per 1000 person‐years in the SGLT2i and DPP4i groups, respectively, with significantly lower risk in the SGLT2i group than in the DPP4i group (HR 0.46, 95% CI: 0.28–0.74, p = 0.001). The risks of OAD (HR 0.66, 95% CI: 0.64–0.69, p < 0.001) and antihypertensive drugs (HR 0.90, 95% CI: 0.85–0.95, p < 0.001) added onto baseline treatment were lower in the SGLT2i group than in the DPP4i group.ConclusionsThe risk of insulin initiation was lower in patients with T2DM newly treated with an SGLT2i than in those newly treated with a DPP4i. SGLT2i may reduce or delay the need for insulin therapy.