Influence of early use of sodium-glucose transport protein 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on the legacy effect of hyperglycemia.

A phenomenon known as legacy effect was observed that poor glycemic control at early stage of patients with newly-diagnosed type 2 diabetes (T2D) increases the risk of subsequent cardiovascular diseases (CVD). Early use of some novel anti-hyperglycemic agents, such as sodium-glucose transport protein 2 inhibitors (SGLT-2i), may attenuate this effect, but the evidence is limited. Two retrospective cohorts of newly diagnosed T2D patients from 2010-2023 were assembled using the Yinzhou Regional Health Care Database (YRHCD) with different definitions of the early exposure period - the 1-year exposure cohort and 2-year exposure cohort, which were comprised of subjects who had HbA1c measurement data within 1 year and 2 years after their T2D diagnosis, respectively. Using Cox proportional hazards models, we examined the association between high HbA1c level (HbA1c>7%) during the early exposure period and the risk of subsequent CVD. This analysis was performed in the overall cohort and three subpopulations with different treatments during the early exposure period, including patients initiating SGLT-2i or glucagon-like peptide-1 receptor agonists (GLP-1RA), patients using dipeptidyl peptidase-4 inhibitors (DPP-4i), and patients without using SGLT-2i, GLP-1RA, and DPP-4i. Besides, subgroup analyses were performed by stratifying patients into age <55 and ≥55 years. A total of 21,477 and 22,493 patients with newly diagnosed T2D were included in the two final cohorts. Compared with patients with mean HbA1c ≤ 7% during the early exposure period, those with HbA1c>7% had higher risks of incident CVD, with a HR of 1.165 (95%CI, 1.056-1.285) and 1.143 (95%CI, 1.044-1.252) in 1-year and 2-year exposure period cohort. Compared to non-users, in patients initiating SGLT-2i/GLP-1RA within 1 or 2 years after T2D diagnosis, higher HbA1c level at baseline was not associated with CVD in both two cohorts. In subgroup analyses, results were generally consistent with the main analysis. Poor glycemic control in the early stage of T2D increased later CVD risk in Chinese adults with newly diagnosed T2D. Compared to non-users, this association was smaller and non-significant in patients receiving SGLT-2i/GLP-1RA during the early stage of T2D, indicating early use of these drugs may have the potential to mitigate legacy effects of hyperglycemia.

Deng S ，Zhao H ，Chai S ，Sun Y ，Shen P ，Lin H ，Zhan S ... -  《Frontiers in Endocrinology》

Sex Differences in Cardiovascular Effectiveness of Newer Glucose-Lowering Drugs Added to Metformin in Type 2 Diabetes Mellitus.

Raparelli V ，Elharram M ，Moura CS ，Abrahamowicz M ，Bernatsky S ，Behlouli H ，Pilote L ... -  《Journal of the American Heart Association》

Sodium-glucose co-transporter-2 inhibitors and the risk of venous thromboembolism: A nationwide population-based study and meta-analysis.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have off-target effects on haemoconcentration and anti-inflammation. The impact of SGLT-2i on the risk of venous thromboembolism (VTE) in patients with diabetes mellitus (DM) remains unclear. This study aimed to evaluate the risk of newly diagnosed VTE in patients with DM using SGLT-2i in comparison to dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA). In this nationwide retrospective cohort study, we used data from Taiwan's National Health Insurance Research Database. Patients with diabetes aged 20 years or older who received SGLT-2i, DPP-4i, or GLP-1RA between 1 May 2016, and 31 December 2020, were included. The risks of VTE in SGLT-2i users were compared with those of DPP-4i and GLP-1RA users. A Cox regression model with stabilised inverse probability of treatment weighting was used to calculate hazard ratio (HR) for VTE risk. Additionally, a meta-analysis of relevant articles published before 23 May 2023, was conducted. Data from 136,530 SGLT-2i, 598,280 DPP-4i, and 5760 GLP-1RA users were analysed. SGLT-2i use was associated with a lower risk of VTE than DPP-4i (HR, 0.70; 95% CI, 0.59-0.84; p < 0·001), but not with GLP-1RA (HR, 1.39; 95% CI, 0.32-5.94; p = 0.66). Our meta-analysis further supported these findings (SGLT-2i vs. DPP-4i: HR, 0.71; 95% CI, 0.62-0.82; p < 0·001; SGLT-2i vs. GLP-1RA: HR, 0.91; 95% CI, 0.73-1.15; p = 0.43), suggesting the robustness of our retrospective analysis. In patients with DM, SGLT-2i was associated with a lower risk of VTE compared to DPP-4i, but not GLP-1RA.

Tsai HR ，Lin YJ ，Yeh JI ，Huang YC ，Liu PP ，Peng CC ，Hsu JY ，Lee YC ，Loh CH ，Lin SM ，Huang HK ... -  《-》

Glucagon-like-peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes in diabetes in relation to achieved glycemic control. A Danish nationwide study.

Zareini B ，Sørensen KK ，Pedersen-Bjergaard U ，Loldrup Fosbøl E ，Køber L ，Torp-Pedersen C ... -  《-》

Comparison of GLP-1 Receptor Agonists, SGLT-2 Inhibitors, and DPP-4 Inhibitors as an Add-On Drug to Insulin Combined With Oral Hypoglycemic Drugs: Umbrella Review.

Background: The objective was to evaluate the efficacy of the combination of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sodium-glucose cotransporter 2 inhibitor (SGLT-2i) in the treatment of Type 2 diabetes with poor efficacy of basic insulin and metformin/sulfonylurea by umbrella review. Materials and Methods: Forming the data of publication of each database through 13 September 2022, PubMed, EMBASE, and Cochrane Library were surveyed. Results: A total of seven meta-analyses were included in the umbrella review. The combination of GLP-1 RA (WMD -3.41 [-5.61, -1.21], p = 0.002), SGLT-2i (WMD -5.34 [-9.56, -1.13], p = 0.013), and DPP-4i (WMD -5.56 [-7.39, -3.73], p ≤ 0.001) can significantly reduce HbA1c levels, respectively. The combination of GLP-1 RA (WMD -1.55 [-2.92, -0.18], p = 0.027), SGLT-2i (WMD -2.96 [-6.68, 0.77], p = 0.12), and DPP-4i (WMD -2.05 [-2.82, -1.28], p ≤ 0.001) can significantly reduce fasting plasma glucose (FPG) levels, respectively. The combination of GLP-1 RA (WMD -3.24 [-5.14, -1.34], p < 0.001) can significantly reduce body weight of Type 2 diabetes mellitus (T2DM). The dose of basic insulin in diabetes patients after combined use of GLP-1 RA (WMD -2.74 [-4.26, -1.22], p ≤ 0.001) was significantly reduced. The combination use of GLP-1 RAs (OR 1.28 [1.05, 1.56], p = 0.017) increases the risk of hypoglycemia. Conclusions: The combination of GLP-1 RAs, DPP-4i, and SGLT-2i can effectively lower HbA1c and FPG in T2DM patients who have poor therapeutic effects on basic insulin combined with metformin/sulfonylureas, respectively. Compared to placebo, GLP-1 RAs can significantly reduce body weight and basic insulin dosage, while DPP-4i and SGLT-2i have a lower risk of hypoglycemia. Trial Registration: CRD42023410345.

Chai S ，Niu Y ，Liu F ，Wu S ，Yang Z ，Sun F ... -  《-》