The effect of sodium-glucose co-transporter-2 (SGLT2) inhibitors on blood interleukin-6 concentration: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The low-grade chronic inflammation in diabetes plays an important role in development of cardiovascular and renal complications. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recognized as protective agents for cardio-renal complications. Interleukin-6 (IL-6) is positively associated with the pathophysiology of metabolic-related pathologies. The aim of this meta-analysis is to investigate the effect of SGLT2 inhibitors on blood IL-6 concentration in randomized controlled trials (RCTs). METHODS: Embase, PubMed, and Scopus were systematically searched up to 1st of November 2023. The eligible studies were RCTs with adult population that had provided blood IL-6 for both control and intervention groups. Cochrane risk-of-bias tool were for study quality assessment. Data were analyzed using random effect model via Stata statistical software. RESULTS: Eighteen studies with a total of 5311 patients were included. Of which 3222 and 2052 patients were in intervention and control arm, respectively. Of the total population, 49.7% were men. The study durations ranged from 8 to 52 weeks. The pooled analysis showed a significant association between the use of SGLT2 inhibitors and lower IL-6 levels (standardized mean difference (SMD) = -1.04, Confidence Interval (CI): -1.48; -0.60, I2 = 96.93%). Dapagliflozin was observed to have a higher IL-6-lowering effect (SMD = -1.30, CI: -1.89; -0.71, I2 = 92.52) than empagliflozin or canagliflozin. Sub-group analysis of control groups (SMD = -0.58 (-1.01, -0.15) and -1.35 (-2.00, -0.70 for the placebo and active control sub-groups, respectively) and duration of interventions (SMD = -0.78 (-1.28, -0.28) and -1.20 (-1.86, -0.55) for study duration of ≤ 12 and > 12 weeks, respectively) did not change the results. Meta-regression analysis showed a significant correlation between the level of HbA1c and IL-6-lowering efficacy of SGLT2 inhibitors. CONCLUSION: IL-6 levels are significantly reduced with the use of SGLT2 inhibitors with HbA1c as the only marker influencing such reductions, and dapagliflozin had the highest potency. The anti-inflammatory effect of SGLT2 inhibitors supports their broader use to address diabetic complications related to inflammatory responses.

The effect of dietary approaches to stop hypertension and ketogenic diets intervention on serum uric acid concentration: a systematic review and meta-analysis of randomized controlled trials.

Hyperuricemia as a risk factor for metabolic diseases is proved to be profoundly modified by dietary approaches. This systematic review and meta-analysis of randomized control trials (RCT) was conducted to investigate the effect of two nutritional interventions; dietary approaches to stop hypertension (DASH) diet and ketogenic diet (KD) on serum uric acid (UA) concentrations. Our systematic search was for RCTs in which KD or DASH diet were assigned to adults for at least 2 weeks or more. Until March 2023 in Embase, Web of Science, PubMed, and Scopus databases, 10 eligible RCTs that intervened with DASH diet (n = 4) or KD (n = 6) and had provided laboratory data on serum UA were found. Summary effect was calculated by random-effects model. Results from the meta-analysis of the 4 DASH diet RCTs with a total of 590 participants revealed significant decrease in serum UA after at least 4 weeks of interventions (mean difference (MD) = ‒0.25; 95% CI ‒0.4 to ‒0.1 mg/dL; p < 0.01; I2 = 0%). The pooled meta-analysis of the 6 included RCTs of KD reporting data of 267 participants showed no significant changes in serum UA (MD = 0.26; 95% CI ‒0.47 to 0.98 mg/dL, I2 = 95.32%). However, a non-significant reduction of UA in the subgroup analysis of very low-calorie KD (VLCKD) studies (MD = ‒0.04; 95% CI ‒0.29 to 0.22, I2 = 0%) was obtained. DASH diet has an ameliorating effect on serum UA and may be recommended for hyperuricemia states such as gout. In addition, we have shown that serum UA level following KD remained unchanged. Although, in view of the heterogeneity across the studies, further investigations are needed to determine the effect of KD and VLKD on serum UA concentrations.

Postmortem Histopathologic Findings and SARS-CoV-2 Detection in Autopsy Kidneys of Patients With COVID-19: A Systematic Review and Meta-Analysis.

OBJECTIVES: This systematic review and meta-analysis aimed to investigate the prevalence of postmortem kidney histopathologic features of patients with coronavirus disease 2019 (COVID-19) in addition to the rate of renal tropism in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We searched Web of Science, PubMed, Embase, and Scopus up to September 2022 to identify eligible studies. A random-effects model was used to estimate the pooled prevalence. Cochran Q test and Higgins I2 were used to assess evidence of heterogeneity. RESULTS: In total, 39 studies were included in the systematic review. The meta-analysis included 35 studies consisting of a total of 954 patients, with an average age of 67.1 years. The pooled prevalence of acute tubular injury (ATI)-related changes was the predominant finding (85% [95% confidence interval, 71%-95%]), followed by arteriosclerosis (80%), vascular congestion (66%), and glomerulosclerosis (40%). Endotheliitis (7%), fibrin microthrombi (12%), focal segmental glomerulosclerosis (1%), and calcium crystal deposits (1%) were seen in a smaller number of autopsies. The overall average rate of virus detection was 47.79% in the pooled data of 21 studies (272 samples). CONCLUSIONS: The main finding-ATI-correlated to clinical COVID-19-associated acute kidney injury. The presence of SARS-CoV-2 in kidney samples in addition to vascular lesions in kidneys can be linked to direct kidney invasion by the virus.

The effect of EMPAgliflozin on markers of inflammation in patients with concomitant type 2 diabetes mellitus and Coronary ARtery Disease: the EMPA-CARD randomized controlled trial.

Systemic inflammation and oxidative burden in patients with type 2 diabetes mellitus (T2DM) causes deleterious cardiovascular outcomes. We sought to investigate the clinical antioxidative and anti-inflammatory effects of empagliflozin. Platelet function, oxidant and antioxidant biomarkers and pro-inflammatory agents at baseline and at 26 weeks were measured. A total of 95 patients (41.05% male, mean age 62.85 ± 7.91 years, mean HbA1c 7.89 ± 0.96%) with concomitant T2DM and coronary artery disease (CAD) were randomized (1:1) to receive empagliflozin (10 mg/daily) or placebo. Patients treated with empagliflozin had lower levels of interleukin 6 (IL-6) (adjusted difference (adiff): - 1.06 pg/mL, 95% CI - 1.80; - 0.32, P = 0.006), interleukin 1ß (IL-1ß) and high-sensitive C-reactive protein (Hs-CRP) (adiff: - 4.58 pg/mL and - 2.86 mg/L; P = 0.32 and 0.003, respectively) compared to placebo. There were elevations in super oxidase dismutase (SOD) activity, glutathione (GSHr), and total antioxidant capacity (TAC) with empagliflozin (adiff: 3.7 U/mL, 0.57 muM, and 124.08 mmol/L, 95% CI 1.36; 6.05, 0.19; 0.95, and 47.98; 200.18, P = 0.002, 0.004, and 0.002, respectively). While reactive oxygen species (ROS) improved significantly (adiff: - 342.51, 95% CI - 474.23; - 210.79, P < 0.001), the changes in catalase activity (CAT), malondialdehyde (MDA), or protein carbonyl groups (PCG) were not significant. Moreover, the P-selectin antigen expression on platelet surface was significantly reduced (adiff: - 8.81, 95% CI - 14.87; - 2.75, P = 0.005). Markers of glycemic status (fasting blood glucose, HbA1c, and HOMA-IR (homeostatic model assessment for insulin resistance) significantly improved (P < 0.001). Among patients with T2DM and CAD, 6-month treatment with empagliflozin can mitigate inflammation, platelet activity and oxidative stress and is associated with clinical cardiovascular benefits.Trial Registration Iranian Registry of Clinical Trials. www.IRCT.ir , Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.

Study rationale and design of a study of EMPAgliflozin's effects in patients with type 2 diabetes mellitus and Coronary ARtery disease: the EMPA-CARD randomized controlled trial.

BACKGROUND: Recent trials have revealed that sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are effective against hyperglycemia and also reduce micro- and macro-vascular complications in patients with type 2 diabetes mellitus (T2DM). Most of the beneficial cardiovascular effects have been investigated in patients with heart failure and coronary artery disease (CAD). Yet, few human studies have been conducted to investigate the molecular mechanisms underlying these clinically beneficial effects in patients with CAD. Accordingly, the EMPA-CARD trial was designed to focus on the molecular effects of empagliflozin in patients with T2DM and CAD. METHODS: In this multicenter, triple-blind randomized controlled trial, patients with documented known T2DM and CAD will be recruited. They will be randomized on a 1:1 ratio and assigned into two groups of empagliflozin 10 mg/daily and placebo. The primary endpoint is the effect of empagliflozin on changes of plasma interleukin 6 (IL-6) after 26 weeks of treatment. The secondary endpoints will consist of changes in other inflammatory biomarkers (Interleukin 1-beta and high-sensitive C-reactive protein), markers of oxidative stress, platelet function, and glycemic status. DISCUSSION: The EMPA-CARD trial mainly tests the hypothesis that SGLT2 inhibition by empagliflozin may improve inflammatory status measured as reduction in inflammatory biomarkers in patients with T2DM and CAD. The results will provide information about the underlying mechanisms of SGLT2 inhibition that mediate the beneficial effects of this medication on clinical outcomes. TRIAL REGISTRATION: Iranian Registry of Clinical Trials. www.IRCT.ir , Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.