The Role of Sodium-Glucose Co-Transporter-2 Inhibitors on Diuretic Resistance in Heart Failure.

Heart failure (HF) remains a major cause of morbidity and mortality worldwide. Recently, significant advances have been made in its treatment; however, diuretics remain the cornerstone in managing congestion in HF. Although diuretic resistance poses a significant challenge in the management of HF and is associated with poor outcomes, only limited alternative pharmaceutical options are available in clinical practice. The objective of this narrative review is to provide a comprehensive analysis of the current evidence on the effects of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on diuretic resistance in HF patients. The primary emphasis is placed on clinical data that assess the impact of SGLT-2 inhibitors on fluid balance, symptom improvement, and clinical outcomes and secondarily on safety profile and potential adverse effects associated with SGLT-2 inhibitor use in acute decompensated HF. The current evidence on the efficacy of SGLT-2 on diuretic resistance remains controversial. Findings from observational and randomized studies are quite heterogenous; however, they converge on the notion that although SGLT-2 inhibitors show promise for mitigating diuretic resistance in HF, their diuretic effect may not be potent enough to be widely used to relieve objective signs of congestion in patients with HF. Importantly, the introduction of SGLT-2 inhibitors in HF treatment appears to be generally well tolerated, with manageable adverse effects. Further research is needed to investigate the underlying mechanisms and the possible beneficial impact of SGLT-2 inhibitors on diuretic resistance in HF.

The Association between Coagulation and Atrial Fibrillation.

The existing literature highlights the presence of numerous coagulation factors and markers. Elevated levels of coagulation factors are associated with both existing and newly diagnosed cases of atrial fibrillation (AF). However, this article summarizes the role of coagulation in the pathogenesis of AF, which includes fibrinogen and fibrin, prothrombin, thrombomodulin, soluble urokinase plasminogen activator receptor, von Willebrand factor, P-selectin, D-dimer, plasminogen activator inhibitor-1, and platelet activation. Coagulation irregularities play a significant role in the pathogenesis of AF.

Interleukins: pathophysiological role in acute pancreatitis.

Acute pancreatitis (AP) is a common inflammatory state characterized by a clinical course that can lead to serious local and extrapancreatic organ malfunction and failure. Interleukins (ILs) are biologically active glycoproteins primarily produced by macrophages and lymphocytes. According to the literature, there are many ILs. However, this article represents a summary of the role of ILs in AP, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, and IL-20. The ways to modulate IL activity to reduce inflammation and improve outcomes in individuals with this condition are under investigation. Drugs that target specific ILs might be developed to mitigate the effects of AP.

The Effect of Sodium-Glucose Cotransporter Inhibitors on Renal Function as Adjunctive to Insulin in Adults with Type 1 Diabetes: An Updated Multilevel Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium-glucose cotransporter (SGLT) inhibitors on albuminuria levels and renal function in patients with type 1 diabetes mellitus (T1D). METHODS: The literature search was performed through Medline (via PubMed), Cochrane Library, and Scopus until November 11, 2023. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis. RESULTS: In total, 5221 participants with T1D among 11 RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB 2). SGLT inhibitors were associated with a significantly greater reduction in urine albumin-to-creatinine ratio (UACR) compared to controls (MD = - 23.13%; 95% CI = [- 33.69, - 12.57]; P < 0.001; level of evidence high). On the basis of subgroup analysis, this effect was consistent across all available SGLT inhibitors, irrespective of the dosage. Finally, a neutral class effect was observed on the estimated glomerular filtration rate (eGFR, MD = - 1.03 mL/min/1.73 m2; 95% CI = [- 2.26, 0.19]; P = 0.1; level of evidence moderate). Only empagliflozin was associated with a significant reduction in eGFR compared to placebo (MD = - 2.23 mL/min/1.73 m2; 95% CI = [- 3.62, - 0.84]; P = 0.002). CONCLUSION: Our findings suggest that adjunctive therapy with SGLT inhibitors results in a significant reduction in albuminuria, while their use is associated with a neutral effect on creatinine clearance, as a measure of renal function. Future renal outcome trials are needed to assess SGLT inhibitors' role in the pharmacological armamentarium against diabetic nephropathy in T1D.

Effect of sodium-glucose cotransporter-2 inhibitors on continuous glucose monitoring metrics, as adjunctive to insulin in adults with type 1 diabetes mellitus: a meta-analysis of randomized controlled trials.

AIMS: This meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on continuous glucose monitoring metrics as adjunctive to insulin in adults with type 1 diabetes mellitus (T1D). METHODS: A systematic literature search was conducted through Medline (via PubMed), Cochrane Library and Google Scholar until October 25, 2023. Dual-independent study selection, data extraction and quality assessment were conducted. Results were summarized with random effects meta-analysis. RESULTS: Eight RCTs were identified, involving a total of 2310 T1D patients. The use of SGLT2is on top of standard insulin therapy was associated with a significantly higher time in range (TIR) compared to placebo (mean difference (MD) 9.7 %; 95 % confidence interval (CI) [8.3, 1.11]; P < 0.001). The time above range was significantly lower in patients receiving SGLT2is (MD -8.71 %; 95 % CI [-11.62, -5.79]; P < 0.001), whereas no difference was observed regarding the time below range (TBR) (MD 0.34 %; 95 % CI [-0.17, 0.85]; P = 0.19). A significantly lower sensor-recorded mean daily glucose was noted in the group receiving SGLT2is (MD -16.55 mg/dL; 95 % CI [-19.82, -13.29]; P < 0.001). When considering the metrics of glucose variability, SGLT2is demonstrated a significant favorable effect on the mean amplitude of glucose excursions (MD -16.92 mg/dL; 95 % CI [-25.31, -8.13]; P < 0.001) and the mean standard deviation of weekly glucose levels (MD -7.67 mg/dL; 95 % CI [-11, -4.35]; P < 0.001). No significant effect was observed concerning the coefficient of variation (MD -1 %; 95 % CI [-2.39, 0.4]; P = 0.16). Regarding safety outcomes, SGLT2is were significantly linked to higher odds of diabetic ketoacidosis compared to insulin alone (OR 3.18; 95 % CI [1.79, 5.66]; P < 0.001), with no significant impact on severe hypoglycemia events (OR 1; 95 % CI [0.54, 1.85]; P = 0.1). CONCLUSION: Our findings suggest that in individuals with T1D, adjunct therapy with SGLT2is provides a significant benefit in terms of TIR and reduced glucose variability, without an increase in TBR.

Risk of subclinical atherosclerosis in primary Sjogren's syndrome: A systematic review and meta-analysis.

BACKGROUND: Currently, the guidelines for prevention and management of atherosclerosis in patients with Sjogren's syndrome (SS) do not differentiate from those concerning the general population. OBJECTIVES: The present systematic review aimed to summarize evidence from primary studies assessing the risk of subclinical atherosclerosis in patients with primary SS (pSS). METHODS AND RESULTS: Literature was searched until June 2023. Eligible records were randomized controlled trials and observational studies comparing subclinical atherosclerosis markers between pSS patients and healthy controls. DerSimonian-Laird random effects models were used to calculate overall effect estimates. Totally, 19 observational studies comprising 1625 participants were included. Compared to healthy controls, pSS patients had significantly higher values of carotid-femoral intima-media thickness (cfIMT) (MD= 0.07 mm; 95 % CI= [0.04, 0.11]; p <0.001) and were more frequently diagnosed with atherosclerotic plaques (OR= 1.9; 95 % CI= [1.32, 2.74]; p <0.001). Moreover, pSS patients showed a decreased flow and nitrate-mediated dilation (MD = -2.48 %; 95 % CI= [-4.57, -0.39]; p = 0.02, MD= -2.11 %; 95 % CI= [-3.22, -1.01]; p <0.001, respectively). Similar results were observed for the pulse-wave velocity (MD= 0.7 m/s; 95 % CI= [0.36, 1.05]; p <0.001) and the ankle-brachial index (OR= 5.78; 95 % CI= [2.23, 14.99]; p = 0.003). Based on meta-regression analyses, only the disease duration and erythrocyte sedimentation rate were positively and significantly associated with higher cfIMT values. CONCLUSION: Patients with pSS have an increased risk of subclinical atherosclerosis compared to healthy population and thus possibly require early and disease-specific intervention. Further research is warranted for more accurate cardiovascular risk management in SS.

Effect of tirzepatide on albuminuria levels and renal function in patients with type 2 diabetes mellitus: A systematic review and multilevel meta-analysis.

AIM: The present systematic review aimed to summarize the available evidence from published randomized controlled trials (RCTs) regarding the effect of tirzepatide on albuminuria levels and renal function in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Medline (via PubMed), Cochrane Library and Scopus were searched until 20 October 2023. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled with a three-level mixed-effects meta-analysis. RESULTS: In total, 9533 participants from eight RCTs were analysed. All RCTs had a low risk of bias, according to the Cochrane Collaboration tool (RoB2). Tirzepatide was associated with a significantly greater reduction in urine albumin-to-creatinine ratio compared with controls [mean difference (MD) -26.9%; 95% confidence interval (CI) (-34.76, -19.04); p < .001; level of evidence (LoE) moderate]. This effect remained significant in participants with baseline urine albumin-to-creatinine ratio ≥30 mg/g [MD -41.42%; 95% CI (-54.38, -28.45); p < .001; LoE moderate]. Based on subgroup analysis, the comparative effect of tirzepatide was significant against placebo and the insulin regimen, whereas no difference was observed compared with semaglutide. The beneficial effect of tirzepatide on albuminuria levels remained significant across all investigated doses (5, 10 and 15 mg), showing a dose-response relationship. A neutral effect was observed on the estimated glomerular filtration rate [MD 0.39 ml/min/1.73m2 ; 95% CI (-0.64, 1.42); p = .46; LoE moderate]. CONCLUSION: Our findings suggest that tirzepatide probably leads to a significant reduction in albuminuria across all administered doses, while its use is associated with a neutral effect on creatinine clearance as a measure of renal function.

Prognostic value of stress hyperglycemia ratio in patients with acute myocardial infarction: A systematic review with Bayesian and frequentist meta-analysis.

The present systematic review and meta-analysis aimed to investigate the prognostic value of stress hyperglycemia ratio (SHR) in patients with acute myocardial infarction (AMI). A total of 26 cohort studies, involving 87,974 patients, were analyzed. The frequentist meta-analysis showed that AMI patients with SHR in the upper quantile had a significantly higher hazard of major adverse cardiovascular and cerebrovascular events (MACCE, HR = 1.7; 95 % CI= [1.42, 2.03]; P < 0.001; I2 = 71 %; P <0.01), long-term (HR = 1.64; 95 % CI= [1.49, 1.8]; P < 0.001; I2 = 16 %; P = 0.29) and in-hospital all-cause mortality (OR = 3.87; 95 % CI= [2.98, 5.03]; P < 0.001; I2 = 54 %; P = 0.03) compared to those with lower SHR. Prespecified subgroup analyses revealed that these results were consistent irrespective of diabetes status (P = 0.32 and 0.73 for subgroup differences) and that SHR was a significant predictor of MACCE both in AMI with obstructive coronary arteries (HR = 1.57; 95 % CI= [1.34, 1.83]; P < 0.001; I2 = 66 %; P < 0.01) and MINOCA (HR = 2.57; 95 % CI= [1.86, 3.56]; P < 0.001; I2 = 0 %; P = 0.84). The Bayesian analyses with weakly prior assumptions yielded comparable results with the frequentist approach and provided strong evidence that higher SHR values were associated with significantly greater hazard of MACCE, short-term and long-term mortality. Further, prospective research is warranted to provide deeper insights into this newer index of stress hyperglycemia before its potential incorporation in clinical prediction scores.

Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials.

AIMS: The present systematic review aimed to synthesize available data from recently published randomized trials (RCTs) investigating the efficacy and safety of the novel, orally administered, small-molecule glucagon-like peptide 1 receptor agonists (GLP-1RAs) orforglipron and danuglipron for the treatment of type 2 diabetes mellitus (T2DM), obesity or both. METHODS: Literature search was performed through Medline (via PubMed), Cochrane Library and Scopus until August 16, 2023. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled with random effects meta-analysis. RESULTS: Totally, 1037 patients among seven RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB2). Novel GLP-1RAs led to significant reduction in HbA1c in patients with T2DM compared to controls (MD = -1.03 %; 95 % CI = [-1.29, -0.77]; P < 0.001). A significantly greater weight reduction was also noted both in patients with T2DM or obesity compared to controls (MD = -3.26 kg; 95 % CI = [-4.79, -1.72]; P < 0.001 and MD = -7.52 kg; 95 % CI = [-14.63, -0.41]; P = 0.038, respectively; P for subgroup differences = 0.25). Regarding safety, novel GLP-1RAs showed a neutral effect on the odds of severe hypoglycemia or serious adverse events (OR = 0.34; 95 % CI = [0.09, 1.31]; P = 0.11 and OR = 0.95; 95 % CI = [0.39, 2.34]; P = 0.91, respectively) and significantly higher odds of gastrointestinal, treatment-emergent adverse events (OR = 2.57; 95 % CI = [1.49, 4.42]; P < 0.001) and adverse events leading to discontinuation (OR = 2.89; 95 % CI = [1.22, 6.87]; P = 0.016). CONCLUSION: Preliminary evidence supports that orforglipron and danuglipron are efficient in glycemic control and weight reduction in T2DM, obesity or both. More longitudinal research is warranted in order to provide deeper insights into their efficacy, safety and tolerability before their potential incorporation in the pharmacological arsenal against T2DM or obesity.

Multimarker Approach as More Reliable Method Than Single Vitamin D in Relationship with Type 2 Diabetes Mellitus in Montenegrin Postmenopausal Women.

OBJECTIVE: Previous studies suggested that ethnic differences, sex and obesity could modify the relationship between 25-hydroxyvitamin D [25(OH)D], glycometabolic markers and/or type 2 diabetes mellitus (T2D). We aimed to examine the potential relationship between [25(OH)D] and T2D in postmenopausal women in Montenegro. In addition, we aimed to explore if a set of biomarkers, rather than [25(OH)D] as a single biomarker, could better explain its potential association with T2D. PATIENTS AND METHODS: A total of 116 postmenopausal, otherwise healthy women and 48 postmenopausal women with T2D were included. Univariable and multivariable binary logistic regression analysis, along with principal component analysis (PCA), were applied to test the associations between examined biomarkers/set of biomarkers with T2D. RESULTS: Women with T2D had lower serum [25(OH)D] levels than healthy controls (p = 0.024). No independent relationship between [25(OH)D] and T2D was found. PCA extracted three significant factors that were associated with T2D, i.e., age-glycometabolic-related factor (i.e., with positive loadings of age, glucose and insulin; OR = 11.321, p < 0.001), obesity-inflammation- related factor (i.e., with positive loadings of hsCRP and WC, and negative loading of [25(OH)D]; (OR = 2.079, p < 0.001)) and lipid-related factor (i.e., with positive loadings of TG and LDL-c, and negative loading of HDL-c; OR = 1.423, p = 0.044). CONCLUSIONS: The relationship between [25(OH)D] and T2D is modulated by central obesity (as measured by WC) and inflammation (as measured with hsCRP) in postmenopausal women. Their joint measurement, rather than [25(OH)D] itself, could provide better information for the risk assessment for T2D in postmenopausal women.

The new evidence on cardiorenal benefits of sodium-glucose cotransporter 2 inhibitors in type 1 diabetes: one step closer to their use in this setting?

Chronic kidney disease (CKD) affects 30-40% of persons with type 1 diabetes mellitus (T1DM), markedly increasing the risk of kidney failure and cardiovascular events. The excessive mortality observed in T1DM compared to the general population can be attributed to the presence of CKD, with cardiovascular disease as the leading cause of premature death. A recently published, robust real-world study investigated the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) adjunctive therapy on blood glucose levels, adverse events, and cardio-renal outcomes among individuals with T1DM. GLP-1 RA provided greater reduction in glycated hemoglobin in comparison to SGLT2i therapy, whereas the latter reduced the risk of CKD, heart failure, and hospitalization for any cause. However, the SGLT2i treated cohort had a higher risk of diabetic ketoacidosis (DKA). The study provides promising evidence that the protective cardiorenal effects of SGLT2i, previously confirmed in people with and without type 2 diabetes mellitus, might also be present in T1DM. However, the benefits and risks, especially the risk of DKA, should be further examined in dedicated large-scale randomized controlled trials.

Endometrial scratching during hysteroscopy in women undergoing in vitro fertilization: a systematic review and meta-analysis.

Objective: Endometrial scratching (ES) during hysteroscopy before embryotransfer (ET) remains doubtable on whether it benefits the reproductive outcomes. The optimal technique is not clear and repeated implantation failure as a challenging field in in vitro fertilization (IVF) seems to be the springboard for clinicians to test its effectiveness. Methods: Medline, PMC, ScienceDirect, Scopus, CENTRAL, Google Scholar were searched from their inception up to April 2023 for studies to evaluate the effectiveness of adding endometrial scratching during hysteroscopy before ET. Results: The initial search yielded 959 references, while 12 eligible studies were included in the analyses, involving 2,213 patients. We found that hysteroscopy and concurrent ES before ET resulted in a statistically significant improvement in clinical pregnancy rate (CPR) [RR = 1.50, (95% CI 1.30-1.74), p < 0.0001] and live birth rate (LBR) [RR = 1.67, (95% CI 1.30-2.15), p < 0.0001] with no statistically significant difference on miscarriage rate [RR = 0.80 (95% CI 0.52-1.22), p = 0.30]. Conclusion: Our meta-analysis suggests that hysteroscopy with concurrent ES may be offered in IVF before ET as a potentially improving manipulation. Future randomized trials comparing different patient groups would also provide more precise data on that issue, to clarify specific criteria in the selection of patients. Systematic Review Registration: PROSPERO (CRD42023414117).