Accuracy of controlled attenuation parameter for liver steatosis in patients at risk for metabolic dysfunction-associated steatotic liver disease using magnetic resonance imaging: a systematic review and meta-analysis.

Background: The controlled attenuation parameter (CAP) enables the noninvasive assessment of liver steatosis. We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of CAP for identifying liver steatosis in patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD), using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the reference standard. Methods: We searched Medline, Embase, Cochrane Library and gray literature sources up to March 2024. We defined MASLD as MRI-PDFF ≥5%. We also assessed the accuracy of CAP for identifying patients with MRI-PDFF ≥10%. We calculated pooled sensitivity and specificity estimates using hierarchical random-effects models. We assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool, and the certainty in meta-analysis estimates using the Grading of Recommendations Assessment, Development and Evaluation framework. Results: We included 8 studies with 1116 participants. The prevalence of MASLD ranged from 65.2-93.9%. Pooled sensitivity and specificity of CAP for MRI-PDFF ≥5% were 0.84 (95% confidence interval [CI] 0.79-0.88) and 0.77 (95%CI 0.68-0.84), respectively, with an area under the receiver operating characteristic curve (AUROC) of 0.88. The pooled sensitivity and specificity for MRI-PDFF ≥10% were 0.83 (95%CI 0.80-0.87) and 0.72 (95%CI 0.59-0.82), with an AUROC of 0.85. The certainty in our estimates was low to very low because of the high risk of bias, inconsistency and imprecision. Conclusions: CAP has acceptable diagnostic accuracy for both MRI-PDFF ≥5% and MRI-PDFF ≥10%. Adequately powered and rigorously conducted diagnostic accuracy studies are warranted to establish the optimal CAP thresholds.

Semaglutide Concurrently Improves Vascular and Liver Indices in Patients With Type 2 Diabetes and Fatty Liver Disease.

Context: The cardiovascular benefits of semaglutide are established; however, its effects on surrogate vascular markers and liver function are not known. Objective: To investigate the effects of semaglutide on vascular, endothelial, and liver function in patients with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD). Methods: Overall, 75 consecutive subjects with T2DM and NAFLD were enrolled: 50 patients received semaglutide 1 mg (treatment group) and 25 patients received dipeptidyl peptidase 4 inhibitors (control group). All patients underwent a clinical, vascular, and hepatic examination with Fibroscan elastography at 4 and 12 months after inclusion in the study. Results: Treatment with semaglutide resulted in a reduction of Controlled Attenuation Parameter (CAP) score, E fibrosis score, NAFLD fibrosis score, Fibrosis-4 (FIB-4) score and perfused boundary region (PBR) at 4 and at 12 months (P < .05), contrary to controls. Patients treated with semaglutide showed a greater decrease of central systolic blood pressure (SBP) (-6% vs -4%, P = .048 and -11% vs -9%, P = .039), augmentation index (AIx) (-59% vs -52%, P = .041 and -70% vs -57%, P = .022), and pulse wave velocity (PWV) (-6% vs -3.5%, P = .019 and -12% vs -10%, P = .036) at 4 and at 12 months, respectively. In all patients, ΔPWV and ΔPBR were correlated with a corresponding reduction of CAP, E fibrosis, NAFLD fibrosis, and FIB-4 scores. Conclusion: Twelve-month treatment with semaglutide simultaneously improves arterial stiffness, endothelial function, and liver steatosis and fibrosis in patients with T2DM and NAFLD.

Metabolic Dysfunction-Associated Steatotic Liver Disease in People Living with HIV-Limitations on Antiretroviral Therapy Selection.

Chronic liver disease is one of the main causes of morbidity and mortality in people living with HIV (PLWH). The increasing life expectancy of PLWH, effective treatment for viral hepatitis, and Western dietary patterns as well as the adverse effects of antiretroviral therapy (ART) have rendered metabolic dysfunction-associated steatotic liver disease (MASLD) the most common chronic liver disease in PLWH. The risk factors for MASLD in PLWH include traditional MASLD risk factors and additional virus-specific factors, including the adverse effects of ART. The management of patients suffering from HIV and MASLD is often challenging. Apart from the conventional management of MASLD, there are also certain limitations concerning the use of ART in this patient population. In general, the appropriate combination of antiretroviral drugs should be chosen to achieve the triad of effective viral suppression, avoidance of mitochondrial dysfunction, and deterrence of worsening the patient's metabolic profile. In the current review, we discuss the epidemiology of MASLD in PLWH, the risk factors, and the disease pathogenesis, as well as the limitations in the use of ART in this patient population, while practical recommendations on how to overcome these limitations are also given.

Low dialysate sodium and 48-h ambulatory blood pressure in patients with intradialytic hypertension: a randomized crossover study.

BACKGROUND AND HYPOTHESIS: Intradialytic-hypertension (IDH) is associated with increased risk for cardiovascular events and mortality. Patients with IDH exhibit higher 48-h blood pressure (BP) levels than patients without this condition. Volume and sodium excess are considered a major factor contributing in the development of this phenomenon. This study evaluated the effect of low (137mEq/L) compared to standard (140mEq/L) dialysate sodium concentration on 48-h BP in patients with IDH. METHODS: In this randomized, single-blind, crossover study, 29 patients with IDH underwent 4 hemodialysis sessions with low (137mEq/L) followed by 4 sessions with standard (140mEq/L) dialysate sodium or vice-versa. Mean 48-h BP, pre-/post-dialysis and intradialytic BP, pre-dialysis weight, interdialytic weight gain (IDWG) and lung ultrasound B-lines were assessed. RESULTS: Mean 48-h SBP/DBP were significantly lower with low compared to standard dialysate sodium concentration (137.6±17.0/81.4±13.7mmHg with low vs 142.9±14.5/84.0±13.9mmHg with standard dialysate sodium, p=0.005/p=0.007 respectively); SBP/DBP levels were also significantly lower during the 44-h and different 24-h periods. Low dialysate sodium significantly reduced post-dialysis (SBP/DBP: 150.3±22.3/91.2±15.1mmHg with low vs 166.6±17.3/94.5±14.9mmHg with standard dialysate sodium, p<0.001/p=0.134 respectively) and intradialytic (141.4±18.0/85.0±13.4mmHg with low vs 147.5±13.6/88.1±12.5mmHg with standard dialysate sodium, p=0.034/p=0.013, respectively) BP compared with standard dialysate sodium. Pre-dialysis weight, IDWG and pre-dialysis B-lines were also significantly decreased with low dialysate sodium. CONCLUSIONS: Low dialysate sodium concentration significantly reduced 48-h ambulatory BP compared with standard dialysate sodium in patients with IDH. These findings support low dialysate sodium as a major non-pharmacologic approach for BP management in patients with IDH.Registered at ClinicalTrials.gov with study number NCT05430438.

Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

AIMS/HYPOTHESIS: We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. METHODS: We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA1c and body weight from baseline. Secondary outcomes were achievement of HbA1c target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. RESULTS: A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA1c (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. CONCLUSIONS/INTERPRETATION: Our data show that s.c. tirzepatide had a more pronounced effect on HbA1c and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. REGISTRATION: PROSPERO registration no. CRD42022382594.

Efficacy of pharmacologic interventions on magnetic resonance imaging biomarkers in patients with nonalcoholic fatty liver disease: systematic review and network meta-analysis.

BACKGROUND AND AIM: Several agents are under investigation for nonalcoholic fatty liver disease (NAFLD). We assessed the comparative efficacy of pharmacologic interventions for patients with NAFLD focusing on magnetic resonance imaging (MRI) biomarkers. METHODS: We searched Medline, Embase, and CENTRAL. We included randomized controlled trials of more than 12 weeks of intervention that recruited patients with biopsy-confirmed or MRI-confirmed NAFLD and assessed the efficacy of interventions on liver fat content (LFC) and fibrosis by means of MRI. We performed random-effects frequentist network meta-analyses and assessed confidence in our estimates using the CINeMA (Confidence in Network Meta-Analysis) approach. RESULTS: We included 47 trials (8583 patients). Versus placebo, thiazolidinediones were the most efficacious for the absolute change in LFC, followed by vitamin E, fibroblast growth factor (FGF) analogs, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with mean differences ranging from -7.46% (95% confidence interval [-11.0, -3.9]) to -4.36% (-7.2, -1.5). No differences between drug classes were evident. Patients receiving GLP-1 RAs or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs were more likely to achieve ≥30% relative reduction in LFC. Among agents, efruxifermin produced the largest reduction in LFC compared to placebo [-13.5% (-18.5, -8.5)], followed by pioglitazone, while being superior to most interventions. The effect of interventions on magnetic resonance elastography assessed fibrosis was small and insignificant. The confidence in our estimates was low to very low. CONCLUSIONS: Several drug classes may reduce LFC in patients with NAFLD without a significant effect on fibrosis; nevertheless, trial duration was small, and confidence in the effect estimates was low.

Noninvasive liver disease assessment to identify portal hypertension: Systematic and narrative reviews supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. HVPG, a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and availability, noninvasive liver disease assessments to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. APPROACH AND RESULTS: We conducted a systematic review of Ovid MEDLINE(R) Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database's inception to April 22, 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies, which compared noninvasive tests (blood and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥ 10 mm Hg) in patients with chronic liver disease. Outcomes included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. Nine studies with 2492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood-based tests, including aspartate-to-platelet ratio index (APRI) (56% sensitivity and 68% specificity) and FIB-4 (54% sensitivity and 73% specificity) had low accuracy measures. Imaging-based tests (transient elastography and shear wave elastography detection of liver stiffness measurement [LSM]) had better accuracy but also had substantial variation; at 15 kPa, TE sensitivity was 90%-96% and specificity was 48%-50%, while at 25 kPa, its sensitivity and specificity were 57%-85% and 82%-93%, respectively. The narrative review suggested that imaging-based tests are the best available noninvasive liver disease assessment to detect CSPH; CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. CONCLUSIONS: While imaging-based noninvasive liver disease assessment appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the systematic review. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

A Simple Guide to Randomized Controlled Trials.

Randomized controlled trials represent the cornerstone for the regulatory approval of drugs and evidence-based medicine and policy. Compared with observational studies random assignment of participants to each study arm guarantees an equal distribution of potential confounders thus achieving impartiality in the evaluation of between group differences and allowing for causal inferences to be drawn. These complex and costly medical experiments are tightly regulated and require substantial planning with great attention to several methodological aspects ranging from allocation concealment and blinding to sample size estimation, statistical analysis, and handling of protocol deviations. This brief guide offers useful insights into the design, conduct, and interpretation of clinical trial findings for beginners.

Reporting of adverse events of treatment interventions in multiple myeloma: an overview of systematic reviews.

The present study is an overview of systematic reviews focusing on adverse events of antimyeloma treatments. It provides a systematic description of adverse events as they are reported in the systematic reviews as well as a critical appraisal of included reviews. We conducted a comprehensive literature search in the most widely used electronic databases looking for systematic reviews that had an adverse event of an antimyeloma treatment intervention as primary outcome. Two independent reviewers conducted selection of included studies and data extraction on predesigned online forms and assessed study quality using AMSTAR 2. Overall corrected covered area (CCA) was calculated to examine the overlap of primary studies across systematic reviews. After screening eligible studies, 23 systematic reviews were included in this overview. Seven reviews with overall CCA of 14.7% examined cardiovascular adverse events of different drugs, including immunomodulatory drugs and proteasome inhibitors (mainly carfilzomib). Nine focused on infections, presenting with overall CCA of 5.8%, each one focused on a different drug or drug class. Three studied thromboembolism in patients treated either with lenalidomide, any immunomodulatory drug, or with daratumumab and had an overall CCA equal to 1.5%. Four more reviews focused on bortezomib-associated neurotoxicity, carfilzomib-associated renal toxicity, or second primary malignancies as an adverse event of lenalidomide or anti-CD38 monoclonal antibody treatment. The quality of included studies as judged by AMSTAR 2 was mostly critically low. Absence of a priori registered protocol and formal assessment of risk of bias of included primary studies were the most common shortcomings. Reporting of antimyeloma drug-associated toxicity is supported by multiple systematic reviews; nevertheless, methodological quality of existing reviews is mostly low.

Comparative efficacy of glucose-lowering drugs on liver steatosis as assessed by means of magnetic resonance imaging in patients with type 2 diabetes mellitus: systematic review and network meta-analysis.

PURPOSE: To assess the comparative efficacy of glucose-lowering drugs on liver steatosis as assessed by means of magnetic resonance imaging (MRI) in patients with T2D. METHODS: We searched several databases and grey literature sources. Eligible trials had at least 12 weeks of intervention, included patients with T2D, and assessed the efficacy of glucose-lowering drugs as monotherapies. The primary outcome of interest was absolute reduction in liver fat content (LFC), assessed by means of MRI. Secondary efficacy outcomes were reduction in visceral and subcutaneous adipose tissue. We performed random effects frequentist network meta-analyses to estimate mean differences (MDs) with 95% confidence intervals (CIs). We ranked treatments based on P-scores. RESULTS: We included 29 trials with 1906 patients. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (P-score 0.84) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (0.71) were the most efficacious in terms of liver fat content reduction. Among individual agents, empagliflozin was the most efficacious (0.86) and superior to pioglitazone (MD -5.7, 95% CI -11.2 to -0.3) (very low confidence). GLP-1 RAs had also the most favorable effects on visceral and subcutaneous adipose tissue. CONCLUSIONS: GLP-1 RAs and SGLT-2 inhibitors seem to be the most efficacious glucose-lowering drugs for liver steatosis in patients with T2D. Assessment of their efficacy on NAFLD in patients irrespective of presence of T2D is encouraged.

Management of type 2 diabetes in the new era.

PURPOSE: Management of type 2 diabetes is advancing beyond glycemic control and is increasingly based on cardiovascular risk stratification. This review summarizes recent advances in the field and identifies existing knowledge gaps and areas of ongoing research. METHODS: A bibliographic search was carried out in PubMed for recently published cardiorenal outcome trials, relevant guidelines, and studies on antidiabetic agents in the pipeline. RESULTS: Findings from cardiovascular outcome trials support the use of glucagon-like peptide 1 (GLP-1) receptor agonists or sodium-glucose cotransporter 2 (SGLT-2) inhibitors for patients with established cardiovascular disease or multiple risk factors, although it as yet remains uncertain whether the benefits are transferable to patients at lower absolute cardiovascular risk. Additionally, robust evidence suggests that SGLT-2 inhibitors improve clinical outcomes for people with concomitant heart failure or chronic kidney disease. Gut hormone multiagonists will likely represent another major addition to the therapeutic armamentarium for morbidly obese individuals with diabetes. Moreover, nonalcoholic fatty liver disease is a common comorbidity and several liver outcome trials are awaited with great interest. Use of insulin as first-line injectable therapy has been displaced by GLP-1 receptor agonists. Once-weekly formulations of basal insulins along with combinations with GLP-1 receptor agonists are also under development and could increase patient convenience. Technologies of glucose sensors are rapidly evolving and have the potential to reduce the burden of frequent blood glucose measurements, mainly for patients treated with intensified insulin regimens. CONCLUSION: Management of type 2 diabetes requires a holistic approach and recent breakthroughs are expected to improve the quality of care.

Plasma Lipids Profile in the Prediction of Non-Alcoholic Steatohepatitis in Adults: A Case-Control Study.

Patients with non-alcoholic steatohepatitis (NASH) show significantly faster progress in the stages of fibrosis compared to those with non-alcoholic fatty liver (NAFL) disease. The non-invasive diagnosis of NASH remains an unmet clinical need. Preliminary data have shown that sphingolipids, especially ceramides, fatty acids, and other lipid classes may be related to the presence of NASH and the histological activity of the disease. The aim of our study was to assess the association of certain plasma lipid classes, such as fatty acids, acylcarnitines, and ceramides, with the histopathological findings in patients with NASH. The study included three groups: patients with NASH (N = 12), NAFL (N = 10), and healthy [non non-alcoholic fatty liver disease (NAFLD)] controls (N = 15). Plasma samples were collected after 12 h of fasting, and targeted analyses for fatty acids, acylcarnitines, and ceramides were performed. Baseline clinical and demographic characteristics were collected. There was no significant difference in baseline characteristics across the three groups or between NAFL and NASH patients. Patients with NASH had increased levels of several fatty acids, including, among others, fatty acid (FA) 14:0, FA 15:0, FA 18:0, FA 18:3n3, as well as Cer(d18:1/16:0), compared to NAFL patients and healthy controls. No significant difference was found between NAFL patients and healthy controls. In conclusion, patients with NASH exhibited a distinctive plasma lipid profile that can differentiate them from NAFL patients and non-NAFLD populations. More data from larger cohorts are needed to validate these findings and examine possible implications for diagnostic and management strategies of the disease.

The Role of RASs /RVs in the Current Management of HCV.

The approval of combination therapies with direct-acting antiviral (DAA) regimens has led to significant progress in the field of hepatitis C virus (HCV) treatment. Although most patients treated with these agents achieve a virological cure, resistance to DAAs is a major issue. The rapid emergence of resistance-associated substitutions (RASs), in particular in the context of incomplete drug pressure, has an impact on sustained virological response (SVR) rates. Several RASs in NS3, NS5A and NS5B have been linked with reduced susceptibility to DAAs. RAS vary based on HCV characteristics and the different drug classes. DAA-resistant HCV variant haplotypes (RVs) are dominant in cases of virological failure. Viruses with resistance to NS3-4A protease inhibitors are only detected in the peripheral blood in a time frame ranging from weeks to months following completion of treatment, whereas NS5A inhibitor-resistant viruses may persist for years. Novel agents have been developed that demonstrate promising results in DAA-experienced patients. The recent approval of broad-spectrum drug combinations with a high genetic barrier to resistance and antiviral potency may overcome the problem of resistance.

Add-on interventions for the prevention of recurrent Clostridioides Difficile infection: A systematic review and network meta-analysis.

OBJECTIVES: We aimed to assess the comparative efficacy and safety of adjunctive interventions for the prevention of Clostridioides difficile recurrence. METHODS: We searched Medline, Embase, CENTRAL, and clinicaltrials.gov up to May 2021. We included randomized controlled trials comparing interventions added to antibiotic therapy for prevention of CDI recurrence, to placebo or each other. Efficacy outcomes were CDI and diarrhea recurrence. Safety outcomes included the incidence of any adverse event (AE), serious AEs, and discontinuation due to AEs. We performed random-effects network meta-analysis. We ranked interventions based on SUCRA (surface under the cumulative ranking curve) probabilities. We assessed confidence in estimates utilizing the CINeMA (Confidence in Network Meta-Analysis) framework. RESULTS: Fifteen trials (3909 patients) assessed 9 interventions. Oligofructose (OR 0.17; 95% CI, 0.07 to 0.46), NTCD-M3 (OR 0.29; 95% CI, 0.12 to 0.68), rifaximin (OR 0.47; 95% CI, 0.24 to 0.93), RBX2660 (OR 0.47; 95% CI, 0.22 to 0.99), the combination bezlotoxumab/actoxumab (OR 0.47; 95% CI, 0.37 to 0.60), and bezlotoxumab (OR, 0.53; 95% CI, 0.42 to 0.68) were associated with lower incidence of CDI recurrence than placebo (moderate confidence). Oligofructose was ranked highest, however data for oligofructose were derived solely from one small trial. Probiotics, actoxumab and SER-109 were not superior to placebo (low confidence). Probiotics were not well tolerated (low confidence) and actoxumab showed high rates of serious AEs (moderate confidence). CONCLUSION: Add-on treatment with oligofructose, NTCD-M3 spores, rifaximin, RBX2660, and bezlotoxumab likely reduces the risk of CDI. Evidence on probiotics and SER-109 are uncertain, thus adequately powered trials are warranted.

Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: A systematic review and network meta-analysis.

AIM: To compare the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library, and grey literature sources until 29 September 2020 for randomized controlled trials of at least 24 weeks' duration assessing the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. We performed frequentist network meta-analyses and calculated weighted mean differences and 95% confidence intervals combining trial arms of different approved doses of a given intervention into a single group. We evaluated the confidence in pooled estimates using the CINeMA (Confidence In Network Meta-Analysis) framework. RESULTS: In total, 424 trials (276 336 patients) assessing 21 antidiabetic medications from nine drug classes were included. Subcutaneous semaglutide was the most efficacious in reducing body weight followed by oral semaglutide, exenatide twice-daily, liraglutide, and the sodium-glucose co-transporter-2 (SGLT-2) inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. The same agents also conferred the greatest reductions in systolic blood pressure. Metformin had a modest effect in reducing body weight and systolic blood pressure. Diastolic blood pressure was reduced with the SGLT-2 inhibitors pioglitazone, exenatide twice-daily and semaglutide. In subgroup analyses of trials with over 52 weeks' duration, semaglutide and SGLT-2 inhibitors reduced both body weight and systolic blood pressure. CONCLUSIONS: Semaglutide and SGLT-2 inhibitors conferred reductions both in body weight and blood pressure that were sustainable for over 1 year of treatment. These agents may be preferable treatment options for patients with type 2 diabetes who are overweight/obese and/or hypertensive.

A Systematic Review Supporting the American Society for Dermatologic Surgery Guidelines on the Prevention and Treatment of Adverse Events of Injectable Fillers.

BACKGROUND: As the use of injectable skin fillers increase in popularity, an increase in the reported adverse events is expected. OBJECTIVE: This systematic review supports the development of American Society for Dermatologic Surgery practice guideline on the management of adverse events of skin fillers. METHODS AND MATERIALS: Several databases for studies on risk factors or treatments of injection-related visual compromise (IRVC), skin necrosis, inflammatory events, and nodules were searched. Meta-analysis was conducted when feasible. RESULTS: The review included 182 studies. However, IRVC was very rare (1-2/1,000,000 patients) but had poor prognosis with improvement in 19% of cases. Skin necrosis was more common (approximately 5/1,000) with better prognosis (up to 77% of cases showing improvement). Treatments of IRVC and skin necrosis primarily depend on hyaluronidase injections. Risk of skin necrosis, inflammatory events, and nodules may be lower with certain fillers, brands, injection techniques, and volume. Treatment of inflammatory events and nodules with antibiotics, corticosteroids, 5-FU, and hyaluronidase was associated with high response rate (75%-80%). Most of the studies were small and noncomparative, making the evidence certainty very low. CONCLUSION: Practitioners must have adequate knowledge of anatomy, elicit history of skin filler use, and establish preemptive protocols that prepare the clinical practice to manage complications.

Endoscopic management of refractory leaks and fistulas after bariatric surgery with long-term follow-up.

BACKGROUND: In selected cases of post-bariatric leaks and fistulas, endoscopy is an initial treatment modality. Management can be complex and require multiple endoscopic sessions with varying degrees of success. Our aim was to describe our tertiary care experience on endoscopy management of refractory post-bariatric leaks and fistulas. METHODS: Patients with post-bariatric leaks and/or fistulas who failed an initial endoscopic intervention were included. Endoscopic treatments were classified into four strategies: (1) closure management, (2) active drainage, (3) passive drainage, and (4) plugging. Clinical success and adverse events were assessed. RESULTS: A total of 25 patients (mean age = 45.3 ± 11.8 years and 56% female) were included. Clinical success was achieved in 20 patients (80%) with a mean of 3.0 ± 1.5 procedures and a median time to healing of 114.5 (53-210.3) days. Closure and plugging were the main successful strategies used for early and acute leaks/fistulas, while drainage was for late and chronic leaks/fistulas. Adverse events were observed in 13 patients (52%) with one serious adverse event. Patients with fistulas had a lower success rate (72.2% vs. 100%, P = 0.052). Of those with clinical failure (n = 5), four underwent reconstructive surgery, eventually led to success in 3 patients. The other one died of septic shock related to a complicated fistula. CONCLUSIONS: Complex multi-modality endoscopic management ultimately achieved clinical success in most cases of refractory leaks/fistulas post-bariatric with an acceptable safety profile. However, a close follow-up to detect the development of long-term failure is warranted. These patients should be referred to a specialized bariatric center with expertise in bariatric endoscopy and surgery.

Prospective Surveillance and Risk Reduction of Cancer Treatment-Related Lymphedema: Systematic Review and Meta-Analysis.

PROBLEM IDENTIFICATION: Secondary lymphedema is a chronic condition that may result from cancer-related treatments. Evidence is emerging on prospective surveillance and risk reduction. LITERATURE SEARCH: Databases were systematically searched through April 1, 2019, for comparative studies evaluating interventions aiming to prevent lymphedema in patients with cancer. DATA EVALUATION: A random-effects model was used to perform meta-analysis, when appropriate. SYNTHESIS: A total of 26 studies (4,095 patients) were included, with 23 providing data sufficient for meta-analysis. Surveillance programs increased the likelihood of detecting lymphedema. Physiotherapy, exercise programs, and delayed exercise reduced the incidence of lymphedema. IMPLICATIONS FOR RESEARCH: Future research should standardize (a) evidence-based interventions to reduce the development of lymphedema and increase the likelihood of early detection and (b) outcome measures to build a body of evidence that leads to practice change. SUPPLEMENTAL MATERIAL CAN BE FOUND AT&NBSP;HTTPS: //onf.ons.org/supplementary-material-systematic-review-cancer-treatment-related-lymphedema.

Targeted Therapy- and Chemotherapy-Associated Skin Toxicities: Systematic Review and Meta-Analysis.

PROBLEM IDENTIFICATION: Preventing and managing skin toxicities can minimize treatment disruptions and improve well-being. This systematic review aimed to evaluate the effectiveness of interventions for the prevention and management of cancer treatment-related skin toxicities. LITERATURE SEARCH: The authors systematically searched for comparative studies published before April 1, 2019. Study selection and appraisal were conducted by pairs of independent reviewers. DATA EVALUATION: The random-effects model was used to conduct meta-analysis when appropriate. SYNTHESIS: 39 studies (6,006 patients) were included; 16 of those provided data for meta-analysis. Prophylactic minocycline reduced the development of all-grade and grade 1 acneform rash in patients who received erlotinib. Prophylaxis with pyridoxine 400 mg in capecitabine-treated patients lowered the risk of grade 2 or 3 hand-foot syndrome. Several treatments for hand-foot skin reaction suggested benefit in heterogeneous studies. Scalp cooling significantly reduced the risk for severe hair loss or total alopecia associated with chemotherapy. IMPLICATIONS FOR RESEARCH: Certainty in the available evidence was limited for several interventions, suggesting the need for future research. SUPPLEMENTAL MATERIAL CAN BE FOUND AT&NBSP;HTTPS: //onf.ons.org/supplementary-material-targeted-therapy-and-chemotherapy-associated-skin-toxicity-systematic-review.

Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

BACKGROUND: Several pharmacologic options for type 2 diabetes are available. PURPOSE: To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes. DATA SOURCES: Several databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020. STUDY SELECTION: English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes. DATA EXTRACTION: Pairs of reviewers extracted data and appraised risk of bias. DATA SYNTHESIS: 453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A1c level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively. LIMITATION: Inconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk. CONCLUSION: In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes. PRIMARY FUNDING SOURCE: European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043).