We aimed to determine whether sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and incretin-based agents combination therapy produces more benefits than SGLT2is alone in patients with type 2 diabetes mellitus (T2DM). PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing SGLT2is plus Dipeptidyl-Peptidase 4 inhibitors (SGLT2is/DPP4is) or glucagon like peptide-1 receptor agonists (SGLT2is/GLP-1RAs) against SGLT2is as monotherapy or add-on to metformin in T2DMs. A total of 13 studies with 7350 participants were included. Combination with GLP-1RAs exhibited more HbA1c reduction (WMD: −0.8; 95% CI, −1.14 to −0.45%), weight loss (−1.46; 95% CI, −2.38 to −0.54 kg), and systolic blood pressure (SBP) reduction (−2.88; 95% CI, −4.52 to −1.25 mmHg) versus SGLT2is alone but increased the gastrointestinal disorder risk (RR: 1.68; 95% CI, 1.14-2.47). Combination with DPP4is exhibited an extra effect on HbA1c reduction (−0.47; 95% CI, −0.58 to −0.37%), a neutral effect on weight (0.19; 95% CI, −0.11 to 0.48 kg) and SBP (−0.01; 95% CI, −0.85 to 0.63 mmHg), and ameliorated the genital infections risk (0.73; 95% CI, 0.54-0.97) versus SGLT2is. Meta-regression indicated the hypoglycemic efficacy of SGLT2is/DPP4is is higher in Asians than in other ethnics, and the differences in BMI across ethnic groups may mediate this effect. SGLT2is and incretin-based agents combination therapy is efficacious and safe versus SGLT2is alone in T2DMs. Particularly, combination with GLP-1RAs shows additional benefits to glycemic, weight, and SBP control to a larger extent than DPP4is, while combination with DPP4is ameliorates the risk for genital infection seen with SGLT2is.We highlight the need for individualized treatment related to the selection of this novel combination therapy. KEYWORDSincretin-based agents, meta-analysis, SGLT2 inhibitors, type 2 diabetes

Uric acid (UA) is the final product of purine metabolism in the human body, and impaired purine metabolism can increase the uric acid in serum, finally resulting in hyperuricemia (HUA). Current evidences suggest that urates might have antioxidant properties under certain circumstances, but most evidences suggest that urates promote inflammation. Hyperuricemia leads to the formation of urate crystals, which might be recognized as a red flag by the immune system. Such a response stimulates macrophage activation, leads to the activation of NOD-like receptor protein 3 (NLRP3) inflammasome vesicles, and ultimately the production and liberation of interleukin-1b (IL-1b) and interleukin-18 (IL-18), which can mediate inflammation, apoptosis and necroinflammation and cause an inflammatory cascade response. The kidney is one of the most commonly affected organs in HUA, which promotes the development of chronic kidney disease (CKD) by damaging endothelial cells, activating the renin-angiotensin system (RAS), and promoting inflammatory responses. Pharmacological interventions and lifestyle modifications are the primary means for controlling gout and lowering UA. The febuxostat is safe for CKD patients in the UA lowering therapy. Although dialysis can reduce UA levels, the application of drug is also necessary for dialysis patients. This article reviews the synthesis and metabolism of UA, etiology of HUA, the relationship between HUA and kidney disease, the treatment of gout and gouty nephropathy (GN).

Aims:We undertook a systematic review and meta-analysis to assess the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2is) concerning kidney outcomes in patients with type 2 diabetes mellitus (T2DM), with or without prevalent kidney disease.Materials and Methods: PubMed, Web of science, Embase and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) to assess the efficacy and safety of treatment with SGLT2is versus placebo in patients with T2DM. The weighted mean difference (WMD) and its 95% confidence interval (CI) were applied for continuous variables, and the risk ratio (RR) and corresponding 95% CI were used for dichotomous outcomes. Patients were categorized according to whether the baseline mean estimated glomerular filtration rate (eGFR) was less or was more than 60 mL/min/1.73 m 2 .Results: A total of 25 eligible studies with 43 721 participants were included. There was an initial and small decrease in eGFR during the early treatment period (WMD, −4.63; 95% CI, −6.08 to −3.19 mL/min/1.73 m 2 ), which was noted at 1-6 weeks and gradually narrowed over time, with a decline in protection from eGFR in the long term (WMD, 3.82; 95% CI, 2.80-4.85 mL/min/1.73 m 2 ).SGLT2is significantly delayed albuminuria progression (RR, 0.71; 95% CI, 0.66-0.76), promoted albuminuria regression (RR,1.71; 95% CI, 1.54-1.90), improved the composite of ≥40% decrease in eGFR, in the need for renal-replacement and in death from renal causes (RR, 0.57; 95% CI, 0.49-0.66), and reduced all-cause mortality (RR, 0.84; 95% CI, 0.75-0.94). At the same time, they significantly increased the risk of genital infection (RR, 3.43; 95% CI, 2.87-4.10) vs placebo in patients with T2DM. Meta-regression analyses showed that eGFR-preservation effects were not significantly associated with basic patient characteristics (age, BMI, HbA1c, eGFR level), but were influenced by drug administration (treatment duration, type, dosage of SGLT2is). Subgroup analyses showed that the relative effects on renal outcomes of SGLT2is vs placebo were similar across eGFR subgroups (P heterogeneity >0.05).Conclusions: SGLT2is slowed eGFR decline, lowered albuminuria progression, improved adverse renal endpoints and reduced all-cause mortality, but increased risk of genital infections vs placebo in patients with T2DM. The indication of consistent renal benefits across categories of baseline eGFR levels may allow additional individuals to benefit from SGLT2is therapy.

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Background Diabetic nephropathy (DN) is a critical and the most common microvascular complication and its pathogenesis is still faintly understood. Thus, this study was performed to examine the long non-coding RNA ZNFX1 Antisense Gene Protein 1 (lncRNA ZFAS1) biological function and mechanism of regulation in DN. Method Human glomerular mesangial cells (HGMC) were induced with high glucose (HG, 25 mM) to establish HG-induced cell viability, pro-inflammation observed in DN. After, target miRNA and mRNA were predicted through Lncbase and Targetscan. Subsequently, the expression of ZFAS1, miR-588, and ROCK1 in DN clinical samples and cell-model was examined through qRT-PCR and western blot analysis. We upheld the targeted interaction between miR-588 and ZFAS1 or ROCK1 through a dual-luciferase reporter assay. The proliferation of the cell was also examined through CCK-8 assay, while the level of HG-induced oxidative stress was established by measuring reactive oxygen species (ROS) level, and also the activities of antioxidant enzymes in the cell. Lastly, the level of accumulated extracellular matrix (ECM) protein-fibronectin and collagen type IV, and inflammatory cytokines produced by the cell was analyzed through western blot analysis and ELISA. Results ZFAS1 was significantly upregulated in the DN blood samples and HG-induced HGMC. Prediction result revealed that the ZFAS1 endogenously targets the miR-588 seed sequence while miR-588 plays a role in post-transcriptional regulation of ROCK1 mRNA. Moreover, we found that miR-588 expression was significantly downregulated in DN blood samples and negatively correlates with ZFAS1 expression. Further results show that silencing ZFAS1 had a protective effect on HG-induced proliferation, oxidative stress, fibrosis, and inflammation in HGMC while miR-588 inhibition and ROCK1 overexpression reversed this effect. Conclusions Altogether, our data suggest that ZFAS1 regulates the proliferation, oxidative stress, fibrosis, and inflammation of high glucose-induced diabetic nephropathy through the miR-588/ROCK1 axis.