Incretin-based therapies for the management of cardiometabolic disease in the clinic: Past, present, and future.

Among newer classes of drugs for type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are incretin-based agents that lower both blood sugar levels and promote weight loss. They do so by activating pancreatic GLP-1 receptors (GLP-1R) to promote glucose-dependent insulin release and inhibit glucagon secretion. They also act on receptors in the brain and gastrointestinal tract to suppress appetite, slow gastric emptying, and delay glucose absorption. Phase 3 clinical trials have shown that GLP-1 RAs improve cardiovascular outcomes in the setting of T2DM or overweight/obesity in people who have, or are at high risk of having atherosclerotic cardiovascular disease. This is largely driven by reductions in ischemic events, although emerging evidence also supports benefits in other cardiovascular conditions, such as heart failure with preserved ejection fraction. The success of GLP-1 RAs has also seen the evolution of other incretin therapies. Tirzepatide has emerged as a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA, with more striking effects on glycemic control and weight reduction than those achieved by isolated GLP-1R agonism alone. This consists of lowering glycated hemoglobin levels by more than 2% and weight loss exceeding 15% from baseline. Here, we review the pharmacological properties of GLP-1 RAs and tirzepatide and discuss their clinical effectiveness for T2DM and overweight/obesity, including their ability to reduce adverse cardiovascular outcomes. We also delve into the mechanistic basis for these cardioprotective effects and consider the next steps in implementing existing and future incretin-based therapies for the broader management of cardiometabolic disease.

TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis.

Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This study sought to determine whether these effects could be translated in vivo and to determine the molecular mechanisms involved. CRISPR/Cas9-generated Trim2-/- mice that underwent a periarterial collar model of inflammation-induced angiogenesis exhibited significantly less adventitial macrophage infiltration relative to wildtype (WT) littermates, concomitant with decreased mRNA expression of macrophage marker Cd68 and reduced adventitial proliferating neovessels. Mechanistically, TRIM2 knockdown in endothelial cells in vitro attenuated inflammation-driven induction of critical angiogenic mediators, including nuclear HIF-1α, and curbed the phosphorylation of downstream effector eNOS. Conversely, in a hindlimb ischemia model of hypoxia-mediated angiogenesis, there were no differences in blood flow reperfusion to the ischemic hindlimbs of Trim2-/- and WT mice despite a decrease in proliferating neovessels and arterioles. TRIM2 knockdown in vitro attenuated hypoxia-driven induction of nuclear HIF-1α but had no further downstream effects on other angiogenic proteins. Our study has implications for understanding the role of TRIM2 in the regulation of angiogenesis in both pathophysiological contexts.

2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The increasing rates of obesity and type 2 diabetes mellitus may lead to increased prevalence of nonalcoholic fatty liver disease (NAFLD). We aimed to determine the current and recent trends on the global and regional prevalence of NAFLD. METHODS: Systematic search from inception to March 26, 2020 was performed without language restrictions. Two authors independently performed screening and data extraction. We performed meta-regression to determine trends in NAFLD prevalence. RESULTS: We identified 17,244 articles from literature search and included 245 eligible studies involving 5,399,254 individuals. The pooled global prevalence of NAFLD was 29.8% (95% confidence interval [CI], 28.6%-31.1%); of these, 82.5% of included articles used ultrasound to diagnose NAFLD, with prevalence of 30.6% (95% CI, 29.2%-32.0%). South America (3 studies, 5716 individuals) and North America (4 studies, 18,236 individuals) had the highest NAFLD prevalence at 35.7% (95% CI, 34.0%-37.5%) and 35.3% (95% CI, 25.4%-45.9%), respectively. From 1991 to 2019, trend analysis showed NAFLD increased from 21.9% to 37.3% (yearly increase of 0.7%, P < .0001), with South America showing the most rapid change of 2.7% per year, followed by Europe at 1.1%. CONCLUSIONS: Despite regional variation, the global prevalence of NAFLD is increasing overall. Policy makers must work toward reversing the current trends by increasing awareness of NAFLD and promoting healthy lifestyle environments.

Treatment and Renal Outcomes Up to 96 Weeks After Tenofovir Alafenamide Switch From Tenofovir Disoproxil Fumarate in Routine Practice.

BACKGROUND AND AIMS: Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population. APPROACH AND RESULTS: We analyzed 834 patients with CHB previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA < 20 IU/mL), biochemical (alanine aminotransferase [ALT] < 35/25 U/L for male/female), and complete (viral+biochemical) responses, as well as estimated glomerular filtration rate (eGFR; milliliters per minute per 1.73 square meters) up to 96 weeks after switch. Viral suppression (P < 0.001) and ALT normalization (P = 0.003) rates increased significantly after switch, with a trend for increasing complete response (Ptrend = 0.004), while the eGFR trend (Ptrend  > 0.44) or mean eGFR (P > 0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR < 90 (chronic kidney disease [CKD] stage ≥2), mean eGFR decreased significantly while on TDF (P = 0.029) but not after TAF switch (P = 0.90). By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1. CONCLUSIONS: Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.

Poor adherence to hepatocellular carcinoma surveillance: A systematic review and meta-analysis of a complex issue.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance is associated with improved outcomes and long-term survival. Our goal is to evaluate adherence rates to HCC surveillance. METHODS: We performed a systematic search of the PubMed and Scopus databases and abstract search of relevant studies from recent major liver meetings. All searches and data extraction were performed independently by two authors. Analysis was via random-effects models and multivariate meta-regression. RESULTS: A total of 22 studies (n = 19 511) met inclusion criteria (original non-interventional studies with defined cirrhosis or chronic hepatitis B or chronic hepatitis C with advanced fibrosis populations, and surveillance tests and intervals). Overall adherence rate was 52% (95% CI 38%-66%). Adherence was significantly higher in cirrhotic patients compared to chronic hepatitis B and other high-risk patients, in European compared to North American studies, in less than 12-month compared to yearly surveillance intervals, and in prospective compared to retrospective studies (71%, 95% CI 64%-78% vs 39%, 95% CI 26%-51%, P < .001). The between-study heterogeneity of all above analyses was significant (P < .001). Only the study design (retrospective vs prospective cohort) had statistical significance in a multivariate meta-regression model (P < .05) and could account for some of the differences above. CONCLUSIONS: Overall adherence rate to HCC surveillance was suboptimal at 52% with no significant differences by liver disease aetiology or study location in multivariate meta-regression analysis. Further research and educational efforts are needed to improve the current rate of HCC surveillance.

Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs.

Owing to their potent glucose-lowering efficacy and substantial weight loss effects, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now considered part of the frontline therapeutic options to treat both type 2 diabetes mellitus and nondiabetic overweight/obesity. Stemming from successful demonstration of their cardiometabolic modulation and reduction of major adverse cardiovascular events in clinical outcome trials, GLP-1 RAs have since been validated as agents with compelling cardiovascular protective properties. Studies spanning from the bench to preclinical and large-scale randomised controlled trials have consistently corroborated the cardiovascular benefits of this pharmacological class. Most notably, there is converging evidence that they exert favourable effects on atherosclerotic ischaemic endpoints, with preclinical data indicating that they may do so by directly modifying the burden and composition of atherosclerotic plaques. This narrative review examines the underlying pharmacology and clinical evidence behind the cardiovascular benefits of GLP-1 RAs, with particular focus on atherosclerotic cardiovascular disease. It also delves into the mechanisms that underpin their putative plaque-modifying actions, addresses existing knowledge gaps and therapeutic challenges and looks to future developments in the field, including the use of combination incretin agents for diabetes and weight loss management.

Differences in liver and mortality outcomes of non-alcoholic fatty liver disease by race and ethnicity: A longitudinal real-world study.

BACKGROUND/AIMS: Understanding of nonalcoholic fatty liver disease (NAFLD) continues to expand, but the relationship between race and ethnicity and NAFLD outside the use of cross-sectional data is lacking. Using longitudinal data, we investigated the role of race and ethnicity in adverse outcomes in NAFLD patients. METHODS: Patients with NAFLD confirmed by imaging via manual chart review from any clinics at Stanford University Medical Center (1995-2021) were included. Primary study outcomes were incidence of liver events and mortality (overall and non-liver related). RESULTS: The study included 9,340 NAFLD patients: White (44.1%), Black (2.29%), Hispanic (27.9%), and Asian (25.7%) patients. For liver events, the cumulative 5-year incidence was highest among White (19.1%) patients, lowest among Black (7.9%) patients, and similar among Asian and Hispanic patients (~15%). The 5-year and 10-year cumulative overall mortality was highest for Black patients (9.2% and 15.0%, respectively, vs. 2.5-3.5% and 4.3-7.3% in other groups) as well as for non-liver mortality. On multivariable regression analysis, compared to White patients, only Asian group was associated with lower liver-related outcomes (aHR: 0.83, P=0.027), while Black patients were at more than two times higher risk of both non-liver related (aHR: 2.35, P=0.010) and overall mortality (aHR: 2.13, P=0.022) as well as Hispanic patients (overall mortality: aHR: 1.44, P=0.022). CONCLUSION: Compared to White patients, Black patients with NAFLD were at the highest risk for overall and non-liver-related mortality, followed by Hispanic patients with Asian patients at the lowest risk for all adverse outcomes. Culturally sensitive and appropriate programs may be needed for more successful interventions.

Differential Mortality Outcomes in Real-world Patients with Lean, Nonobese, and Obese Nonalcoholic Fatty Liver Disease.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is commonly associated with obesity but can develop in normal-weight people (lean NAFLD). We compared outcomes in lean, overweight, and obese NAFLD. Methods: This retrospective chart review included patients at Stanford University Medical Center with NAFLD confirmed by imaging between March 1995 and December 2021. Lean, overweight, and obese patients had body mass index of <25.0, >25.0 and <29.9, and ≥30.0 kg/m2 for non-Asian and >23.0 and ≥27.5 for overweight and obese Asian patients. Results: A total of 9061 lean (10.2%), overweight (31.7%), and obese (58.1%) patients were included. Lean patients were 5 years older than obese patients (53±17.4 vs. 48.7±15.1 years), more were female (59.6% vs. 55.2%), white (49.1% vs. 46.5%), had NASH (29.2% vs. 22.5%), cirrhosis (25.3% vs.19.2%), or nonliver cancer (25.3% vs. 18.3%). Fewer had diabetes (21.7% vs. 35.8%) or metabolic comorbidities (all p<0.0001). Lean NAFLD patients had liver-related mortality similar to other groups but higher overall (p=0.01) and nonliver-related (p=0.02) mortality. After multivariable model adjustment for covariates, differences between lean and obese NAFLD in liver-related, nonliver-related, and overall mortality (adjusted hazard ratios of 1.34, 1.00, and 1.32; p=0.66, 0.99, and 0.20, respectively) were not significant. Conclusions: Lean NAFLD had fewer metabolic comorbidities but similar adverse or worse outcomes, suggesting that it is not benign. Healthcare providers should provide the same level of care and intervention as for overweight and obese NAFLD.

Only one-third of hepatocellular carcinoma cases are diagnosed via screening or surveillance: a systematic review and meta-analysis.

BACKGROUND/OBJECTS: Early hepatocellular carcinoma diagnosis is associated with better long-term survival. Studies of at-risk patients who are monitored in routine practice have reported an overall adherence rate to hepatocellular carcinoma screening/surveillance of approximately 60% and suboptimal diagnostic efficacy of the current screening/surveillance tools. However, it is unclear how many hepatocellular carcinoma patients were actually diagnosed via screening/surveillance given these obstacles. Therefore, via a systematic review of PubMed and Scopus databases from 2000 to 2019, we aimed to identify the proportion of patients with hepatocellular carcinoma diagnosed via screening/surveillance in routine practice. METHODS: We included original research articles of studies of patients already diagnosed with hepatocellular carcinoma that reported the proportion of hepatocellular carcinoma diagnosed via screening/surveillance. RESULTS: The study included 60 studies and 50 554 hepatocellular carcinoma cases. The pooled proportion of hepatocellular carcinoma diagnosed by screening/surveillance was 37% (95% confidence interval: 31%-44%) and differed by geographic region (North America/Asia/Europe/Oceania/Africa/South America, 31%/42%/41%/30%/29%/47%, P = 0.017, respectively) and by surveillance interval (<12 months 39% vs. 12 months 19%, P < 0.01) but not by disease etiology, cirrhosis status, clinical setting, practice setting, hepatocellular carcinoma diagnosis period, or surveillance method. CONCLUSION: Globally, hepatocellular carcinoma was diagnosed via screening/surveillance in less than half of the patients (37%) regardless of healthcare setting or liver disease etiology and without improvement over time despite several recent guideline updates. Research is needed to understand the barriers to screening/surveillance to include medical as well as social and cultural influences.

Pulmonary embolectomy: should it be offered earlier rather than later?

Deep venous thrombosis and pulmonary embolism are associated with approximately 250,000 hospitalizations each year. Nearly seventy percent of patients who die of a pulmonary embolism do so within the first hour after onset of symptoms, so prompt and appropriate treatment is needed. Pulmonary embolectomy is a viable alternative for massive and submassive pulmonary embolism. We report 3 cases of successful pulmonary embolectomy.

Screening and management of viral hepatitis and hepatocellular carcinoma in Mongolia: results from a survey of Mongolian physicians from all major provinces of Mongolia.

BACKGROUND: According to Globocan, Mongolia has the highest worldwide hepatocellular carcinoma (HCC) incidence (78.1/100 000, 3.5× higher than China). AIMS AND METHODS: We conducted an anonymous survey of physicians from major provinces who attended an educational liver symposium, analysing their demography, practice, knowledge, perceptions and proposed solutions. Multivariate logistic regression was used to estimate OR relating demography and practice factors with higher provider knowledge and improvement. RESULTS: Of the 121 attendees, 44-95 (36-79%) responded to each question. Most were female (87%), young (79% age <50), subspecialists (81%), university-affiliated (74%), and practised in urban areas (61%). The mean pretest and post-test scores per physician were 60.4±20.4 and 65.6±21.3, with no observed significant predictors for baseline knowledge or improvement. Most (>80%) noted that <50% of patients who need hepatitis or HCC screening receive it. The main perceived barriers to screening were inability to pay for tests, lack of guidelines and poor patient awareness. Hepatitis treatment rates were low; 83% treated hepatitis C virus in <10 patients in the past year, and 86% treated hepatitis B virus in <10 patients/month. Treatment barriers were multifactorial, with cost as a principal barrier. Proposed solutions were universal screening policies (46%), removal of financial barriers (28%) and provider education (20%). CONCLUSIONS: Physicians from major regions of Mongolia noted low screening for viral hepatitis, even lower treatment rates, financial barriers and the need for increased educational efforts. We advocate broad-based medical education tailored to local needs and based on needs assessment and outcome measurements.