LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics.

Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient.

Transitioning to GLP-1 RAs and SGLT2 Inhibitors as the First Choice for Managing Cardiometabolic Risk in Type 2 Diabetes.

PURPOSE OF REVIEW: This forward-looking review summarizes existing evidence from cardiovascular outcome trials on cardiometabolic risk-reduction in type 2 diabetes (T2DM) management, with attention to updating and personalizing recommendations from recent diabetes practice guidelines issued by cardiology societies. RECENT FINDINGS: T2DM management has shifted towards cardiometabolic outcome improvement rather than purely glycemic control. According to large clinical trials, sodium-glucose cotransporter-2 inhibitors showed robust results in reducing heart failure (HF) hospitalization and chronic kidney disease (CKD) progression, while glucagon-like peptide-1 receptor agonists demonstrated the largest effects on HbA1c reduction, weight loss, and atherosclerotic cardiovascular disease outcomes prevention, including stroke. Considering the distinct features of these new cardiometabolic agents, initial selection of therapy should be targeted to each individual patient, with consideration of combination therapy for the highest risk patients. Moreover, future studies should investigate the addition of obesity-predominant risk, in conjunction with coronary artery disease, stroke, CKD, and HF, as a new influential indicator for choosing the optimal cardiometabolic agent.

Vascular control of kidney epithelial transporters.

A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT1) receptors in the kidney, stimulating Na+ reabsorption. AT1 receptors in tubular epithelia control expression and stimulation of Na+ transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT1 receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na+ excretion in SMKO mice, we considered whether alterations in Na+ transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na+ transporters and associated proteins. Here, we show that levels of Na+-K+-2Cl- cotransporter isoform 2 (NKCC2) and Na+/H+ exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser71), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na+ channel. However, the increases in α- and γ-epithelial Na+ channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na+ excretion observed after cell-specific deletion of AT1 receptors from smooth muscle cells is associated with altered Na+ transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na+ transporters and contributing to the regulation of pressure natriuresis.NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise mechanism for how these medications control blood pressure is incompletely understood. Here, we show that mice lacking angiotensin receptors specifically in smooth muscle cells lead to alternation in tubular transporter amount and function. Thus, demonstrating the importance of vascular-tubular cross talk in the control of blood pressure.

Coronary artery calcium in 2023: Guidelines for LDL-C goals, non-statin therapies, and aspirin use.

Personalizing risk assessment and treatment decisions for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) rely on pooled cohort equations and increasingly coronary artery calcium (CAC) score. A growing body of evidence supports that elevated CAC scores correspond to progressively elevated ASCVD risk, and that scores of ≥100, ≥300, and ≥1000 denote risk that is equivalent to certain secondary prevention populations. This has led consensus guidelines to incorporate CAC score thresholds for guiding escalation of preventive therapy for lowering low-density lipoprotein cholesterol goals, initiation of non-statin lipid lowering medications, and use of low-dose daily aspirin. As data on CAC continues to grow, more decision pathways will incorporate CAC score cutoffs to guide management of blood pressure and cardiometabolic medications. CAC score is also being used to enrich clinical trial study populations for elevated ASCVD risk, and to screen for subclinical coronary atherosclerosis in patients who received chest imaging for other diagnostic purposes.

Online searches for hepatocellular carcinoma drugs mirror prescription trends across specialties and changes in guideline recommendations.

Background & aims: The treatment options for systemically progressed hepatocellular carcinoma (HCC) have significantly expanded in recent years. In this study, we aimed to evaluate the potential of Google searches as a reflection of prescription rates for HCC drugs in the United States (US). Methods: We conducted an in-depth analysis of US prescription data obtained from the IQVIA National Prescription Audit (NPA) and corresponding Google Trends data from January 2017 to December 2022. We focused on drugs used in the first line and second or later treatment lines for HCC, collecting data on their prescriptions and search rates. Search volumes were collected as aggregated search queries for both generic drugs and their respective brand names. Results: During the study period from Q1 2017 to Q4 2022, monthly prescriptions for drugs used in HCC treatment showed an 173% increase (from 1253 to 3422). Conversely online searches increased by 3.5% (from 173 to 179 per 10 million searches). Notably, strong correlations were observed between search interest and prescriptions for newer drugs, which indicates increasing usage, while older drugs with declining usage displayed limited correlation. Our findings suggest a growing role of non-physician professions in managing systemically progressed HCC within the US healthcare system, although oncologists remained primarily responsible for drug prescriptions. Conclusions: In conclusion, online search monitoring can offer the potential to reflect prescription trends specifically related to the treatment of HCC. This approach provides a swift and accessible means of evaluating the evolving landscape of HCC treatment.

Cardiovascular risk stratification among individuals with obesity: The Coronary Artery Calcium Consortium.

OBJECTIVE: The effectiveness of coronary artery calcification (CAC) for risk stratification in obesity, in which imaging is often limited because of a reduced signal to noise ratio, has not been well studied. METHODS: Data from 9334 participants (mean age: 53.3 ± 9.7 years; 67.9% men) with BMI ≥ 30 kg/m2 from the CAC Consortium, a retrospectively assembled cohort of individuals with no prior cardiovascular diseases (CVD), were used. The predictive value of CAC for all-cause and cause-specific mortality was evaluated using multivariable-adjusted Cox proportional hazards and competing-risks regression. RESULTS: Mean BMI was 34.5 (SD 4.4) kg/m2 (22.7% Class II and 10.8% Class III obesity), and 5461 (58.5%) had CAC. Compared with CAC = 0, those with CAC = 1-99, 100-299, and ≥300 Agatston units had higher rates (per 1000 person-years) of all-cause (1.97 vs. 3.5 vs. 5.2 vs. 11.3), CVD (0.4 vs. 1.1 vs. 1.5 vs. 4.2), and coronary heart disease (CHD) mortality (0.2 vs. 0.6 vs. 0.6 vs. 2.5), respectively, after mean follow-up of 10.8 ± 3.0 years. After adjusting for traditional cardiovascular risk factors, CAC ≥ 300 was associated with significantly higher risk of all-cause (hazard ratio [HR]: 2.05; 95% CI: 1.49-2.82), CVD (subdistribution HR: 3.48; 95% CI: 1.81-6.70), and CHD mortality (subdistribution HR: 5.44; 95% CI: 2.02-14.66), compared with CAC = 0. When restricting the sample to individuals with BMI ≥ 35 kg/m2 , CAC ≥ 300 remained significantly associated with the highest risk. CONCLUSIONS: Among individuals with obesity, including moderate-severe obesity, CAC strongly predicts all-cause, CVD, and CHD mortality and may serve as an effective cardiovascular risk stratification tool to prioritize the allocation of therapies for weight management.

Online searches for SGLT-2 inhibitors and GLP-1 receptor agonists correlate with prescription rates in the United States: An infodemiological study.

Several clinical trials have demonstrated that many SGLT-2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) can reduce the risk of cardiovascular events in patients with Type 2 diabetes and atherosclerotic cardiovascular disease. Recent reports indicate an underutilization of new cardiometabolic drugs, including SGLT2i and GLP-1 RA. We aimed to evaluate the use of online search volumes to reflect United States prescription rates. A repeated cross-sectional analysis of Google search volumes and corresponding data from the IQVIA National Prescription Audit (NPA) of pharmacy dispensing of newly prescribed drugs was performed. Monthly data for online searches and prescription between January 1, 2016 and December 31, 2021 were collected for selected SGLT2i and GLP-1 RA. Prescription data for drugs classes (SGLT2i and GLP-1 RA) and individual drugs were calculated as the total of queried data for branded drug names. Trends were analyzed for visual and quantitative correlation as well as predictive patterns. Overall, online searches increased by 157.6% (95% CI: 142.2-173.1%) and 295.2% (95% CI: 257.7-332.6%) for SGLT2i and GLP-1RA between 2016 and 2021. Prescription rates raised by 114.6% (95% CI: 110.8-118.4%) and 221.0% (95% CI: 212.1-229.9%) for SGLT2i and GLP-1RA for this period. Correlation coefficients (range 0.86-0.99) were strongest for drugs with growing number of prescriptions, for example dapagliflozin, empagliflozin, ertugliflozin, dulaglutide, and semaglutide. Online searches might represent an additional tool to monitor the utilization trends of cardiometabolic drugs. Associations were strongest for drugs with reported cardioprotective effect. Thus, trends in online searches complement conventionally acquired data to reflect and forecast prescription trends of cardiometabolic drugs.

National Trends in Use of Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists by Cardiologists and Other Specialties, 2015 to 2020.

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) mitigate cardiovascular risk in individuals with type 2 diabetes, but most eligible patients do not receive them. We characterized temporal trends in SGLT2i and GLP-1RA use by cardiologists compared with other groups of clinicians. Methods and Results We conducted a descriptive analysis of serial, cross-sectional data derived from IQVIA's National Prescription Audit, a comprehensive audit capturing ≈90% of US retail prescription dispensing and projected to population-level data, to estimate monthly SGLT2is and GLP-1RAs dispensed from January 2015 to December 2020, stratified by prescriber specialty and molecule. We also used the American Medical Association's Physician Masterfile to calculate average annual SGLT2is and GLP-1RAs dispensed per physician. Between January 2015 and December 2020, a total of 63.2 million SGLT2i and 63.4 million GLP-1RA prescriptions were dispensed in the United States. Monthly prescriptions from cardiologists increased 12-fold for SGLT2is (from 2228 to 25 815) and 4-fold for GLP-1RAs (from 1927 to 6981). Nonetheless, cardiologists represented only 1.5% of SGLT2i prescriptions and 0.4% of GLP-1RA prescriptions in 2020, while total use was predominated by primary care physicians/internists (57% of 2020 SGLT2is and 52% of GLP-1RAs). Endocrinologists led in terms of prescriptions dispensed per physician in 2020 (272 SGLT2is and 405 GLP-1RAs). Cardiologists, but not noncardiologists, increasingly used SGLT2is over GLP-1RAs, with accelerated uptake of empagliflozin and dapagliflozin coinciding with their landmark cardiovascular outcomes trials and subsequent US Food and Drug Administration label expansions. Conclusions While use of SGLT2is and GLP-1RAs by cardiologists in the United States increased substantially over a 6-year period, cardiologists still account for a very small proportion of all use, contributing to marked undertreatment of individuals with type 2 diabetes at high cardiovascular risk.