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.

FibroScan-AST score for diagnosing fibrotic MASH: A systematic review and meta-analysis of diagnostic test accuracy studies.

BACKGROUND AND AIM: Following the approval of the first agent for the management of metabolic dysfunction-associated steatohepatitis (MASH), identification of patients with fibrotic MASH (MASH with NAS ≥ 4 and fibrosis stage ≥ 2) is crucial. We assessed the performance of FibroScan-aspartate aminotransferase (AST) score (FAST) for ruling in/out fibrotic MASH. METHODS: We searched Medline, Cochrane Library, Web of Science, Scopus, and gray literature sources up to January 11, 2024. Studies were eligible if they assessed the accuracy of FAST score for the detection of fibrotic MASH using biopsy as the reference standard at previously reported thresholds (FAST ≥ 0.67 for ruling-in and ≤ 0.35 for ruling-out fibrotic MASH). We calculated pooled sensitivity and specificity estimates for FAST thresholds alongside 95% confidence intervals following bivariate random- effects models. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: We included 16 studies with 8838 participants. A FAST score ≥ 0.67 yielded a pooled specificity of 0.87 (0.82-0.90) while a FAST score ≤ 0.35 yielded a summary sensitivity of 0.88 (0.83-0.91). At a prevalence of 30%, the positive predictive value for ruling-in fibrotic MASH was 60% while the negative predictive value for ruling-out the target condition was 91%. AST levels, cirrhosis prevalence, and number of pathologists reviewing biopsies were sources of heterogeneity among studies. The certainty of evidence was low to very low. CONCLUSIONS: FAST score can be used as a triage test for ruling out fibrotic MASH. Nevertheless, its low positive predictive value necessitates sequential testing for ruling-in fibrotic MASH.

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.

Socioeconomic aspects of incretin-based therapy.

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have demonstrated cardiovascular benefits in people with type 2 diabetes. However, socioeconomic disparities in their uptake may constrain the collective advantages offered by these medications to the broader population. In this review we examine the socioeconomic disparities in the utilisation of incretin-based therapies and discuss strategies to address these inequalities. Based on real-world evidence, the uptake of GLP-1 RAs is reduced in people who live in socioeconomically disadvantaged areas, have low income and education level, or belong to racial/ethnic minorities, even though these individuals have a greater burden of type 2 diabetes and cardiovascular disease. Contributing factors include suboptimal health insurance coverage, limited accessibility to incretin-based therapies, financial constraints, low health literacy and physician-patient barriers such as provider bias. Advocating for a reduction in the price of GLP-1 RAs is a pivotal initial step to enhance their affordability among lower socioeconomic groups and improve their value-for-money from a societal perspective. By implementing cost-effective strategies, healthcare systems can amplify the societal benefits of incretin-based therapies, alongside measures that include maximising treatment benefits in specific subpopulations while minimising harms in vulnerable individuals, increasing accessibility, enhancing health literacy and overcoming physician-patient barriers. A collaborative approach between governments, pharmaceutical companies, healthcare providers and people with diabetes is necessary for the effective implementation of these strategies to enhance the overall societal benefits of incretin-based therapies.

Peripheral nailfold capillary microscopic abnormalities in rheumatoid arthritis are associated with arterial stiffness: Results from a cross-sectional study.

Vascular injury eventually resulting in the establishment of cardiovascular disease is a serious complication in rheumatoid arthritis (RA). Nailfold videocapillaroscopy (NVC) is a non-invasive imaging modality that enables the quantitative and qualitative assessment of the peripheral microvasculature. Nevertheless, capillaroscopic patterns remain inadequately defined in RA, especially regarding their clinical significance as potential markers of systemic vascular impairment. Consecutive RA patients underwent NVC using a standardized protocol, to assess the following parameters: capillary density, avascular areas, capillary dimensions, microhemorrhages, subpapillary venous plexus, and presence of ramified, bushy, crossed and tortuous capillaries. Carotid-femoral pulse wave velocity (PWV) and pulse pressure were measured as well-acknowledged markers of large artery stiffening. The vast majority of our cohort (n = 44) presented a combination of non-specific and abnormal capillaroscopic parameters. Capillary ramification was associated with both PWV and pulse pressure, even after adjustment for cardiovascular risk factors and systemic inflammation. Our study highlights the high prevalence of a wide range of capillaroscopic deviations from the normal patterns in RA. Furthermore, it provides for the first time evidence of an association between structural disorders of the microcirculation and markers of macrovascular dysfunction, suggesting that NVC might have a role as an index of generalised vascular impairment in RA.

Effects of sodium-glucose co-transporter-2 inhibitors by background cardiovascular medications: A systematic review and meta-analysis.

AIM: To explore whether the beneficial cardiovascular (CV) effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease. METHODS: We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs). RESULTS: We included 12 trials comprising 83 804 patients. SGLT-2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), b-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b-blocker plus MRA, or an ARNI plus b-blocker plus MRA (HRs ranged from 0.61 to 0.83; P > .1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all-cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate. CONCLUSIONS: The benefit of SGLT-2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified.

Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing approval. Individual trials have assessed the clinical profile of tirzepatide vs different comparators. We conducted a systematic review and meta-analysis to assess the efficacy and safety of tirzepatide for type 2 diabetes. METHODS: We searched PubMed, Embase, Cochrane and ClinicalTrials.gov up until 27 October 2021 for randomised controlled trials with a duration of at least 12 weeks that compared once-weekly tirzepatide 5, 10 or 15 mg with placebo or other glucose-lowering drugs in adults with type 2 diabetes irrespective of their background glucose-lowering treatment. The primary outcome was change in HbA1c from baseline. Secondary efficacy outcomes included change in body weight, proportion of individuals reaching the HbA1c target of <53 mmol/mol (<7.0%), ≤48 mmol/mol (≤6.5%) or <39 mmol/mol (<5.7%), and proportion of individuals with body weight loss of at least 5%, 10% or 15%. Safety outcomes included hypoglycaemia, gastrointestinal adverse events, treatment discontinuation due to adverse events, serious adverse events, and mortality. We used version 2 of the Cochrane risk-of-bias tool for randomised trials to assess risk of bias for the primary outcome. RESULTS: Seven trials (6609 participants) were included. A dose-dependent superiority in lowering HbA1c was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from -17.71 mmol/mol (-1.62%) to -22.35 mmol/mol (-2.06%) vs placebo, -3.22 mmol/mol (-0.29%) to -10.06 mmol/mol (-0.92%) vs GLP-1 RAs, and -7.66 mmol/mol (-0.70%) to -12.02 mmol/mol (-1.09%) vs basal insulin regimens. Tirzepatide was more efficacious in reducing body weight; reductions vs GLP-1 RAs ranged from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg. Incidence of hypoglycaemia with tirzepatide was similar vs placebo and lower vs basal insulin. Nausea was more frequent with tirzepatide vs placebo, especially with tirzepatide 15 mg (OR 5.60 [95% CI 3.12, 10.06]), associated with higher incidence of vomiting (OR 5.50 [95% CI 2.40, 12.59]) and diarrhoea (OR 3.31 [95% CI 1.40, 7.85]). Odds of gastrointestinal events were similar between tirzepatide and GLP-1 RAs, except for diarrhoea with tirzepatide 10 mg (OR 1.51 [95% CI 1.07, 2.15]). Tirzepatide 15 mg led to higher discontinuation rate of study medication due to adverse events regardless of comparator, while all tirzepatide doses were safe in terms of serious adverse events and mortality. CONCLUSIONS/INTERPRETATION: A dose-dependent superiority on glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with increased incidence of gastrointestinal adverse events. Study limitations include presence of statistical heterogeneity in the meta-analyses for change in HbA1c and body weight, assessment of risk of bias solely for the primary outcome, and generalisation of findings mainly to individuals who are overweight or obese and already on metformin-based background therapy. PROSPERO registration no. CRD42021283449.

Sotagliflozin for patients with type 2 diabetes: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of sotagliflozin in patients with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library, and grey literature sources up to August 2021 for randomized controlled trials (RCTs) that compared sotagliflozin with placebo or other antidiabetic agents in patients with type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed three secondary efficacy and 15 safety outcomes. We synthesized data using weighted mean differences (WMDs) and odds ratios (ORs), along with 95% confidence intervals (CIs). RESULTS: We included 11 RCTs comprising 16 411 subjects in the meta-analysis. Compared with placebo, sotagliflozin reduced HbA1c (WMD -0.42%, 95% CI -0.56 to -0.29), body weight (WMD -1.33 kg, 95% CI -1.57 to -1.09), and systolic blood pressure (WMD -2.44 mmHg, 95% CI -2.81 to -2.07). No difference was evident against other active comparators. Sotagliflozin reduced myocardial infarction (OR 0.72, 95% CI 0.54 to 0.97) and heart failure (OR 0.68, 95% CI 0.58 to 0.79) compared with placebo, and had a neutral effect on all-cause mortality, cardiovascular mortality, and stroke. Treatment with sotagliflozin was safe regarding the incidence of serious adverse events, hypoglycaemia, and diabetic ketoacidosis. Nevertheless, it was associated with an increased incidence of diarrhoea, genital infections, and volume depletion events. CONCLUSIONS: Sotagliflozin reduces blood glucose, body weight, and systolic blood pressure, and demonstrates a beneficial effect on heart failure and myocardial infarction. Its overall safety profile is comparable with other sodium-glucose co-transporter-2 inhibitors.

KDIGO made 12 recommendations for managing diabetes with CKD.

SOURCE CITATION: Navaneethan SD, Zoungas S, Caramori ML, et al. Diabetes management in chronic kidney disease: synopsis of the 2020 KDIGO Clinical Practice Guideline. Ann Intern Med. 2020. [Epub ahead of print]. 33166222.

Ultra-rapid-acting insulins for adults with diabetes: A systematic review and meta-analysis.

We performed a systematic review and meta-analysis of randomized controlled trials to assess the efficacy and safety of the novel, ultra-rapid-acting insulins aspart and lispro in adults with type 1 or type 2 diabetes. Our primary outcome was change in HbA1c from baseline. We additionally assessed eight efficacy and six safety endpoints. We calculated weighted mean differences (WMD) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, alongside 95% confidence intervals (CIs). We additionally assessed statistical heterogeneity among studies with the I2 statistic, considering values greater than 60% as indicative of substantial heterogeneity. Nine studies comprising 5931 patients were included in the systematic review; eight active-controlled studies could be synthesized in terms of a meta-analysis. Treatment with ultra-rapid-acting insulins had a similar effect on change in HbA1c compared with rapid-acting insulins (WMD -0.02%, 95% CI -0.08 to 0.05, I2  = 61% for patients with type 1 diabetes and -0.02%, 95% CI -0.09 to 0.04, I2  = 19% for patients with type 2 diabetes). Similarly, no difference was evident in terms of change in fasting plasma glucose, self-measured plasma glucose, body weight, basal or bolus insulin dose, incidence of serious adverse events and hypoglycaemia. Compared with rapid-acting insulins, ultra-rapid-acting insulins reduced 1- and 2-hour postprandial glucose (PPG) increment based on a liquid meal test, both in patients with type 1 and type 2 diabetes (WMD -0.94 mmol/L, 95% CI -1.17 to -0.72, I2  = 0% and -0.56 mmol/L, 95% CI -0.79 to -0.32, I2  = 0%, respectively, for change in 1-hour PPG increment). In conclusion, ultra-rapid-acting insulins were as efficacious and safe as rapid-acting insulins, showing a favourable effect solely on PPG control.

Comparative efficacy and safety of glucose-lowering drugs as adjunctive therapy for adults with type 1 diabetes: A systematic review and network meta-analysis.

AIM: To assess the efficacy and safety of glucose-lowering drugs used as an adjunct to insulin therapy in adults with type 1 diabetes. METHODS: We searched Medline, Embase and the Cochrane Central Register of Controlled Trials up to 24 January 2020 for randomized controlled trials. Our primary outcome was change in HbA1c. We additionally assessed eight efficacy and six safety secondary endpoints. We performed random effects frequentist network meta-analysis to estimate mean differences (MDs) and odds ratios (ORs), alongside 95% confidence intervals (CIs). We assessed risk of bias and evaluated confidence in the evidence for the primary outcome. RESULTS: We included 58 trials comprising 13 216 participants. Overall, sodium-glucose co-transporter (SGLT) inhibitors, liraglutide, glibenclamide, acarbose and metformin reduced HbA1c compared with placebo (MDs ranging from -0.46% [95% CI -0.64% to -0.29%] for empagliflozin to -0.20% [-0.35% to -0.06%] for metformin). SGLT inhibitors, exenatide daily, liraglutide and metformin reduced body weight and total daily insulin dose, while liraglutide and SGLT inhibitors reduced blood pressure. Diabetic ketoacidosis and genital infections were more frequent with SGLT inhibitors, while exenatide, liraglutide, pramlintide and metformin increased the incidence of nausea. No drug increased the incidence of severe hypoglycaemia. Confidence in evidence was mainly moderate to very low. CONCLUSIONS: Specific drugs may improve glycaemic control and reduce body weight, blood pressure and total daily insulin dose in patients with type 1 diabetes. However, low quality of evidence and an increased risk of diabetic ketoacidosis, genital infections or gastrointestinal adverse events should be taken into consideration by healthcare providers and patients. Future long-term trials are needed to clarify their benefit-to-risk profile and elucidate their role in clinical practice.

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.

Some glucose-lowering drugs reduce risk for major adverse cardiac events.

SOURCE CITATION: Zhu J, Yu X, Zheng Y, et al. Association of glucose-lowering medications with cardiovascular outcomes: an umbrella review and evidence map. Lancet Diabetes Endocrinol. 2020;8:192-205. 32006518.

In type 2 diabetes, SGLT2 inhibitors were linked to diabetic ketoacidosis vs. DPP-4 inhibitors.

SOURCE CITATION: Douros A, Lix LM, Fralick M, et al. Sodium-glucose cotransporter-2 inhibitors and the risk for diabetic ketoacidosis: a multicenter cohort study. Ann Intern Med. 2020;173:417-25. 32716707.

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).

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.

Patients' and Clinicians' Preferences on Outcomes and Medication Attributes for Type 2 Diabetes: a Mixed-Methods Study.

BACKGROUND: Patients' views on the relative importance of treatment outcomes and medication attributes for type 2 diabetes may differ from clinicians' perceptions. OBJECTIVE: To assess which treatment outcomes and medication attributes are considered important by patients and clinicians for therapeutic decisions in type 2 diabetes. DESIGN: Exploratory, sequential, mixed-methods design comprising a qualitative (focus groups) and a quantitative (survey) phase. PARTICIPANTS: Patients in the focus groups (n = 33) and the survey study (n = 656) were recruited from 4 and 9 diabetes clinics across Greece, respectively. Clinicians in the survey study (n = 363) were identified from Greek registries for healthcare professionals. MEASUREMENTS: We conducted 6 focus groups to obtain patients' views regarding the impact of type 2 diabetes on their lives. Identified themes informed the development of a survey, which aimed to assess which outcomes and medication attributes are considered most important by patients and clinicians. We calculated odds ratios to compare patients' and clinicians' responses. RESULTS: The focus groups identified 6 main themes and 15 subthemes. In the survey study, patients were more likely than clinicians to rate prevention of amputation (odds ratio, 9.32; 95% CI, 6.51 to 13.35), diabetic eye disease (6.16; 4.63 to 8.21), sexual dysfunction, and stroke as important, while clinicians were more likely than patients to choose risk for hypoglycemia, and reduction of all-cause mortality, HbA1c, and body weight. Compared with clinicians, patients were less concerned about drug cost (0.16; 0.11 to 0.23), but more concerned about route of administration and need for less frequent glucose self-monitoring. CONCLUSIONS: Patients and clinicians differ in the perception of the relative importance of treatment outcomes and drug characteristics. Individual patient preferences should be explored and implemented in the therapeutic decision-making for type 2 diabetes.

Oral semaglutide for type 2 diabetes: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of oral semaglutide, a novel glucagon-like peptide-1 receptor agonist, for patients with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library and grey literature sources up to July 1, 2019 for randomized controlled trials (RCTs) comparing oral semaglutide with placebo or other antidiabetic agents. The primary outcome was change from baseline in HbA1c. Secondary outcomes included change from baseline in body weight and blood pressure, cardiovascular endpoints, severe hypoglycaemia, gastrointestinal adverse events and diabetic retinopathy. We synthesized results using weighted mean differences (WMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, along with 95% confidence intervals (CIs). RESULTS: We included 11 RCTs with 9890 patients in the systematic review. Compared with placebo, oral semaglutide reduced HbA1c and body weight (WMD -0.89%, 95% CI -1.07 to -0.71 and - 2.99 kg, 95% CI -3.69 to -2.30, respectively). Oral semaglutide was also superior to other active comparators (including liraglutide, empagliflozin and sitaglipitin) in terms of lowering HbA1c (WMD -0.35%, 95% CI -0.43 to -0.26) and reduction of body weight (WMD -1.48 kg, 95% CI -2.28 to -0.67), and had a favourable effect on systolic blood pressure. Compared with placebo, oral semaglutide reduced all-cause mortality (OR 0.58, 95% CI 0.37 to 0.92) and cardiovascular mortality (OR 0.55, 95% CI 0.31 to 0.98), and had a neutral effect on myocardial infarction, stroke, severe hypoglycaemia and diabetic retinopathy. However, treatment with oral semaglutide increased the incidence of nausea, vomiting and diarrhea, while events of acute pancreatitis were rare. CONCLUSIONS: Oral semaglutide can effectively and safely reduce blood glucose, body weight and systolic blood pressure. Nevertheless, it is associated with increased incidence of gastrointestinal adverse events. Further research is needed to clarify its long-term safety and comparative effectiveness against other antidiabetic agents.

Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of combination therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and a sodium-glucose co-transporter-2 inhibitor (SGLT2i) in patients with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library and grey literature sources up to 2 December 2019 for randomized controlled trials in adults with type 2 diabetes assessing the combination of GLP-1RA and SGLT2i, either as co-initiation therapy or as add-on to each other, against placebo or an active comparator. The primary outcome was change in HbA1c . Secondary outcomes included change in body weight, blood pressure and estimated glomerular filtration rate, and incidence of severe hypoglycaemia, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke and hospitalization for heart failure. We pooled data using random effects meta-analyses. RESULTS: Seven trials (1913 patients) were eligible. Compared with GLP-1RA, GLP-1RA/SGLT2i combination therapy was associated with a greater reduction in HbA1c (weighted mean difference -0.61%, 95% CI -1.09% to -0.14%, four studies), body weight (-2.59 kg, -3.68 to -1.51 kg, three studies) and systolic blood pressure (-4.13 mmHg, -7.28 to -0.99 mmHg, four studies). Compared with SGLT2i, GLP-1RA/SGLT2i combination therapy reduced HbA1c (-0.85%, -1.19% to -0.52%, six studies) and systolic blood pressure (-2.66 mmHg, -5.26 to -0.06 mmHg, six studies), but not body weight (-1.46 kg, -2.94 to 0.03 kg, five studies). After excluding data for one trial that had a considerably longer duration than the remaining studies, body weight was also reduced versus SGLT2i (-1.79 kg, -2.99 to -0.59 kg, five studies). Combination therapy did not increase the incidence of severe hypoglycaemia. Data for mortality and cardiovascular outcomes were scarce. CONCLUSIONS: GLP-1RA/SGLT2i combination therapy seems to reduce HbA1c , body weight and systolic blood pressure without increasing the risk of severe hypoglycaemia compared with either GLP-1RA or SGLT2i. No conclusions can be made regarding long-term effectiveness or the effect on cardiovascular outcomes.

Performance of Baveno VI and Expanded Baveno VI Criteria for Excluding High-Risk Varices in Patients With Chronic Liver Diseases: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: We aimed to assess the accuracy of Baveno VI criteria for identification of high-risk varices (HRVs) and varices of any size in patients with compensated advanced chronic liver disease (cACLD). METHODS: We performed a systematic search of publications through December 2018 for studies that assessed the accuracy of Baveno VI criteria for screening for varices in patients with cACLD. We used hierarchical models to synthesize evidence. We also conducted a post hoc analysis to assess the accuracy of Εxpanded Baveno VI criteria. We appraised the confidence in estimates using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: We identified 30 studies (8469 participants). Pooled values of Baveno VI criteria for HRVs (26 studies) were a sensitivity of 0.97 (95% CI, 0.95-0.98) and a specificity of 0.32 (95% CI, 0.26-0.39). Pooled sensitivity of Εxpanded Baveno VI criteria for HRVs (12 studies) was 0.90 (95% CI, 0.85-0.93) and specificity was 0.51 (95% CI, 0.45-0.57). In 1000 patients with cACLD, with a prevalence of HRVs of 20%, Baveno VI criteria would prevent endoscopy in 262 patients, but 6 patients with HRVs would be missed. Instead, use of the Εxpanded Baveno VI criteria would result in 428 patients avoiding endoscopy, but 20 patients with HRVs would be missed. The credibility of our findings is moderate or low, mainly owing to the retrospective design of most studies. CONCLUSIONS: Baveno VI criteria have high diagnostic accuracy as a triage test for screening for HRVs in patients with cACLD. Expanded Baveno VI criteria could reduce the proportion of unnecessary endoscopies further, nevertheless with a higher rate of missed HRVs.