CVD Prevention in Asia- A Status Update and Future Directions

Lee HY, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans that discussed on cardiovascular disease prevention in Asia. According to Zhao D, et al., JACC Asia 2021 paper, cardiovascular disease is the leading cause of death in Asia in 2019 with 35% of total death while 39% of CVD deaths and premature death. From 1990 to 2019, CVD deaths increased 5.6 million to 10.8 million. Crude mortality rates increased both in men and women and age-standardized CVD mortality is decreasing. The proportion of premature CVD deaths was substantially lower in high-income Asian countries. In total CVD deaths among Asian regions, IHD and stroke deaths have high proportion.

Obesity, aging, and high salt intake are the triple threat to cardiovascular disease control in Asia. As per the East-West center 2002 study, there will be significant growth of the elderly population > 75 years old in Asia till 2050. From 2000-2020, obesity showed increased prevalence in Asian countries, and the obesity rate in elderly is increasing. In Wild S, et al., 2004 study, India will have the highest prevalence of diabetes by 2030 with 151% increase in patients. Lancet’s 2019 study showed that an age-standardized proportion of deaths are attributable to individual dietary risks with excessive intake of high sodium in the Asian population. SBP change with age is directly proportional according to their habitual daily salt intake. In the Korean HT population, the same distribution of renin activity status was observed as white westerners. In the Asian region, high sodium intake has a direct association with an increased risk of stroke. Also, Perkvoic V, et al. study showed the linear relationship between SBP and stroke risk is markedly more pronounced in Asian patients than in Caucasian patients. Elderly patients have a high risk of hypertension among chronic conditions. As per the 2021 study, hypertension and diabetes have a high prevalence as comorbidities in HF patients.

CVD mortality rate is continuously increasing in Asia. CVD mortality in Asia showed marked geographic differences due to the combined effects of age and other determinants including SES. Whereas IHD is the main dominant type for CVD deaths in Central, Western, and Southern Asia, stroke is much more common than IHD in Eastern and South-eastern Asia. Social aging, obesity, and high salt intake become triple threats of CVD control in Asia, forming a vicious cycle.

Implementation Strategies to Improve Global Heart Failure Care: HFrEF Polypills

Agarwal A, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans. The high-quality evidence stated that guideline-directed medical therapy (GDMT) substantially reduces morbidity and mortality of patients. 1 in 4 patients with HFrEF are discharged on GDMT. The lack of GDMT is associated with higher mortality at 5 years (p<0.001). A systemic review from 14 RCTs exhibited no consistent effect on GDMT at hospital discharge. From these trials, there is no trials from low- and middle-income countries.

Qualitative research is done in Kerala with 21 semi-structured in-depth interviews. Among 1400 patients hospitalized with HF, a locally contextualized quality improvement intervention increased GDMT at discharge from 28% in the control period to 41% in the intervention period. Additional implementation strategies are needed to improve care for HFrEF patients. HFrEF polypills work as a pragmatic implementation strategy. A pilot randomized trial investigated the HFrEF polypill implementation strategy in India. 40 patients were randomized in 1:1 proportion. Polypill intervention was done stepwise. In step 1 half dose, step 2 full dose, and step 3 double dose of drugs was given. In a multicentre, type I hybrid, randomized clinical trial, 900 patients were equally randomized. The primary outcome of the study was a composite rate of CVD mortality and HF hospitalizations at 12 months.

Future directions of HFrEF polypill formative research can be done through the 4 stages

• Implementation – Implementation in other settings within and beyond India
• Evaluation – Evaluating additional multi-level implementation strategies
• Evolution – Incorporating new medications into future-generation HFrEF polypills
• Extension – Extending the polypill-based implementation strategy to other under-treated conditions

Long-term goals as global cardiovascular physician should include generating new evidence as a global cardiovascular clinical trialist to improve cardiovascular care in low and middle-income countries and bring lessons back to the US, using implementation science methods to contextualize, scale, and increase the impact of interventions across global settings, developing expertise in regulatory science to lead large scale trials and translate findings to global health policy to impact clinical practice and public health and mentoring trainees and early career scientists to advance the field of global CV health research, including global CV trials.

Anticoagulation Strategies in Non-critically Ill Hospitalized Covid-19 Patients: Principal Outcomes of The Freedom Covid Anticoagulation Trial

Fuster V, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans. Mononuclear cell activation, endothelial cell inflammation, and vascular damage are the hallmarks of COVID-19, which cause diffuse in situ pulmonary micro thrombosis in addition to arterial and venous thrombosis. The standard of care in hospitalised COVID-19 patients is prophylactic dose anticoagulation. It is unknown if full-dose oral anticoagulation with a direct-acting anticoagulant or a heparin-based regimen can further enhance clinical results without causing more bleeding.

An international investigator-sponsored trial in which 3600 hospitalized patients with confirmed COVID-19 not requiring ICU-level treatment were randomized 1:1:1 to prophylactic-dose SQ Enoxaparin (40 mg qd; 30 mg qd for CrCI <30 ml/min); full-dose SQ Enoxaparin (1 mg/kg bid; 1 mg/kg qd for CrCI <30mL/min), or oral Apixaban (5 mg bid; 2.5 mg bid for high-bleeding risk). The primary endpoints assessed were; 30-day composite rate of all-cause mortality, requirement for ICU level of care, systemic thromboembolism, or ischemic stroke, and the primary safety endpoint assessed was the in-hospital rate of BARC types 3 or 5 bleeding.

Out of a total of 3434 non-critically ill hospitalized COVID-19 patients, 1149 patients were randomized to prophylactic-dose Enoxaparin, 1150 patients to full-dose Enoxaparin or 1135 patients to Apixaban. The mean age was 52.5 ± 15.9 years; 59.8% were male, 19.6% had diabetes, 16.6% were current or past smokers, and 8.4% had chronic lung disease. Corticosteroids and Remdesivir were both used pre-admission in 21.6% and 9.5%, respectively. 89.8% of CT scans and 81.5% of chest x-rays taken at admission were abnormal. Follow-up is complete through 30 days and is ongoing through 90 days.

This is the largest randomised trial to date evaluating outcomes with various anticoagulant regimes in patients hospitalised with COVID-19 who are non-critically ill.

The STELLAR Phase III Trial: A Study of Sotatercept in Combination with Background Therapy for The Treatment of Pulmonary Arterial Hypertension

Hoeper M, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans. A progressive condition known as pulmonary arterial hypertension (PAH) causes proliferative remodeling of the pulmonary arteries and elevations in pulmonary vascular resistance (PVR). Sotatercept binds to select TGF-β superfamily ligands and rebalances anti-proliferative (BMPR-II-mediated) and pro-proliferative (ActRIIA-mediated) signaling, potentially reversing pulmonary vascular remodeling.

In the PULSAR Phase II trial, Sotatercept dramatically and sustainably decreased PVR throughout the course of 18 months of treatment. STELLAR is the pivotal Phase III trial of Sotatercept in adult participants (pts) with PAH. In the multicenter, double-blind STELLAR trial, PAH patients were randomized1:1 to receive Sotatercept or a placebo subcutaneously every three weeks along with background PAH medication. The beginning dose of Sotatercept was 0.3 mg/kg, and the goal dose was 0.7 mg/kg. The primary endpoint assessed was the change from baseline at week 24 in 6MWD and a total of 9 secondary endpoints ((improvement of WHO FC or maintenance of WHO FC II; ≥30% decrease in NT-proBNP or <300 ng/L; and ≥30 m improvement in 6MWD); improvements in PVR, NT-proBNP, and WHO FC; time to clinical worsening or death; achievement of low French Risk score; and improvement in PAH-SYMPACT® domain scores (Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts).

A total of 323 patients have enrolled in the study and the study met its primary endpoint (change from baseline at week 24 in 6MWD) and 8 of the 9 secondary endpoints and the overall safety profiles were consistent with other studies.

Sotatercept provided broad therapeutic benefit across a range of effectiveness endpoints and significantly increased exercise capacity as measured by the 6MWD. Our findings demonstrate the clinical efficacy of Sotatercept as a novel mechanistic PAH treatment when used in conjunction with current PAH medications.

A Novel Breakthrough in Wrist-Worn Transdermal Troponin-I-Sensor Assessment for Acute Myocardial Infarction

Evaluation of patients with possible acute myocardial infarction (AMI) is one of the most common presentations in the emergency room, yet the diagnostic steps are time-consuming and expensive.

Sengupta S, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans, that evaluated a wrist-worn transdermal infra-red spectrophotometric sensor (ISS) for the bloodless estimation of elevated Troponin I (Trop-I) in a multi-center prospective cohort study of AMI patients.

 239 AMI patients from five sites were enrolled. The final diagnosis was adjudicated using ECG, Trop-I, echocardiography (regional wall motion abnormality), or a coronary angiogram (detecting a culprit lesion). A transdermal ISS- the Sderived machine-learning model was trained using data from three sites and externally validated with biochemical and clinical data from two sites.

The ISS model predicted elevated Trop-I with the area under the receiver operator characteristics of 0.89 (95% confidence interval [CI], 0.71-0.99; sensitivity, 0.89; specificity, 0.97) and 0.92 (95% CI, 0.78-0.99; sensitivity, 0.91; specificity, 0.90), for internal and external validation cohorts, respectively. In addition, a prediction of elevated Trop-I was associated with regional wall motion abnormalities (Odds Ratio [OR], 8.3; CI, 2.6-26.2; P=0.0003) and significant coronary stenosis (OR, 5.8; CI:1.4-23.3; P=0.01).

The use of a transdermal-ISS for bloodless estimation of Trop-I may substantially improve early diagnosis and risk stratification of AMI patients.

“Just The Two of Us” HFrEF and HF Sans rEF

Lewsey S, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans. HFrEF is defined as LVEF < 35%, < 40%, and HFpEF is defined as LVEF >40 % or ≥ 40% in CHARM,EMPEROR, DELIVER, SPIRIT-HF trials. The existence of an ‘evidence gap’ for the patients with mid-range LVEF occurred due to the historical development of HF trials rather than due to a strong pathophysiological basis for a third entity in HF.  The ESC said a grey area exists between HFrEF and HFpEF. These patients have an LVEF that ranges from 40 to 49%, hence the term HFmrEF. EF is a continuous variable, HFmrEF is not distinct, and any cutoff used to categorize is arbitrary. HFmrEF is a clinical overlap and not clinically distinct. A retrospective analysis from HF RCTs that have included LVEF between 40-45% suggests benefit from similar therapies to those with LVEF ≤ 40%.

Recommendations for patients with (Stage C) mildly reduced (41-49%) LVEF:

• An ACE-I, ARB, beta-blocker, MRA, and Sacubitril/ Valsartan may be considered for patients with HFmrEFto reduce the risk of hospitalization and death.

HFmrEF originated to stimulate inquiry into a systematically understudied group of patients and not a strong pathophysiologic basis for the third entity of HF. HFmrEF physiologically behaves as HFrEF, eccentric LV remodeling, decreased contractility, and the rightward shift of the end-diastolic pressure relation. Intraobserver variability ~8-21% and interobserver variability 6-13% in LVEF measurement, measurement bias, and misclassifications for a category of LVEF of 8% (41-49%). LVEF is dynamic and as such the HFmrEF population is not comprised of the same trajectories of EF, which matter more than static EF.

HFmrEF  is not clinically or biomarker distinct, this population is difficult to capture. HFmrEF may be subject to undertreatment from already pervasive clinical inertia and barriers to GDMT implementation.

Usefulness Of H2FPEF Score for Predicting New Atrial Fibrillation

H2FPEF score consists of six factors: heavy, hypertension, atrial fibrillation (AF), pulmonary hypertension, elder, and high filling pressure. These factors are known to be associated with left ventricular diastolic dysfunction.

Suwa Y, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans that evaluated whether the H2FPEF score could predict new AF development in patients without clinically significant cardiac disease.

Among patients referred for clinically-indicated echocardiogram in 2007-2008, those with EF>=50% and no clinical HF or cardiac structural abnormalities were consecutively included and followed up to September 2022. Patients who had a history of AF were excluded. Cox proportional hazards modeling was used to assess predictors of new AF development.

Of a total number of 961 patients (61±15year-old, 48%men), 39 (4.1%) developed new AF during a mean follow-up of 80±66 months. In a Cox-proportional hazard modeling, H2FPEF score was an independent predictor of AF development (per1, HR=1.51, 95%CI=1.05-2.16). The Kaplan-Meier estimates of cumulative event-free survival by H2FPEF status (<2 vs. >2) are shown (Figure).

H2FPEF score can predict new AF development in patients without clinically significant cardiac disease.

Mitral and Tricuspid TEE: Guideline-Based Screening for SHD

Hahn R, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans which talks about the new field – interventional cardiography. These are based on new guidelines that are published last year. These new guidelines are approved by a group of experts. We have multiple probe manipulation (Advance/Withdraw, rotate (CW/CCW), Ante- and Retro-Flexion, Right and left Flexion, and Mechanical Rotation), and advanced 2D and 3D imaging techniques (Simultaneous Multiplane, Real Time 30, 30 MPR, Full Volume 30, Zoom 30, and Color 30) that can be used to adequately characterize the valves. However, a few imaging techniques such as deep esophageal or shallow transgastric imaging were added to the new guidelines.

The techniques allow one to see 2D and 3D images. Functional imaging is also needed for the quantification of disease severity. The commissural view is one of the major imaging views. This allows us to sweep from lateral to medial and vice versa, and helps to understand the severity and location of valve malformation and mitral valve regurgitation. In addition, it is necessary to perform quantification.

Utilizing a protocol as a starting point for imaging in all procedures and all patients enables standardization of image acquisition, reduction in variability in the quality of imaging and reporting, and ultimately better patient care.

The transgastric view becomes an essential view for procedures and therefore should be attempted in all pre-procedural proceedings. The transgastric use is essential because apparently, not all regurgitation takes place in A2 P2 scallops. This is a 2D view where one can see all the tricuspid valves. Papillary muscles and chordae can be identified. With the use of the Deep Transgastric Level view, one can mimic a 5-chamber view as well as 3 chamber view.

One of the other essentials for structural imaging is anatomy. The ACCC/AHA guidelines are very clear that one should consider Transcatheter aortic valve repair (TAVR) if the anatomy is suitable.

The Carpentier classification divides mitral valve regurgitation into three types based on leaflet motion: Type I: normal leaflet motion (Leaflet perforation), Type II: excessive leaflet motion (Mitral valve prolapse/Flail), and Type III: restricted leaflet motion (Mitral Annular Ca/RHD). Finding the intended gripping zone(s) by locating the TR on colour Doppler and imaging the leaflets during systole and diastole to determine length and gaps are the screening’s objectives.

Imaging protocols should be tailored to be comprehensive but focused on the abnormal structure identified and/or transcatheter intervention under consideration.

Training Guidelines for Interventional Echo: Competencies Defined

Sayan E, presented a session at the American College of Cardiology (ACC) on 6^th March 2023, at New Orleans which talks about transcatheter therapies. Transcatheter therapies for heart disease have advanced significantly over a decade and interventional echocardiography (IE) has an integral role in a plethora of heart interventions such as in all four heart valves including transcatheter mitral valve replacement, transcatheter tricuspid valve-in-valve (ViV), electrophysiology assessment Heart valves and interventions, LAO ablation, TAVR, etc. Imaging techniques have also evolved in parallel, such as Live 30 MPR (used in every single intervention), 4D intra-cardiac echo (emerging technology), and Live T fusion (adjunct to complex interventions).

The term “interventional echocardiographer (IE)” was first coined in 2009 by Dr. Martin Lyons. IE is an integral part of the multidisciplinary cardiac team with specialized functions in the overall path of care. The imager must also have specific knowledge and technical skills in all aspects of structural heart disease. However, skills are mostly acquired on a hands-on basis through on-the-job training and proctoring.

The ability to give interventionalists with imaging advice for transcatheter procedures comprehend how echocardiography can assist avoid or diagnose procedural problems, be fluent with 3D imaging, and have frequent exposure to these procedures are all requirements for this profession. In a retrospective cohort study, it was seen that after mitral valve surgery or interventions, the adjusted RR of mortality was 61% lower for patients in the dedicated heart team compared to no heart team, and 29% lower compared to a general heart team (without an imaging cardiologist).

According to the CMS National Coverage Determination TEER (2021), the concept of the Heart Team embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. The heart team should include a cardiac surgeon, interventional cardiologist, echocardiographer, and HF cardiologist (for FMR).

Fellows who have completed an ACGME-accredited 3-year general cardiology or 1-year CT anesthesiology fellowship or are practicing cardiologists or cardiothoracic anesthesiologists with specialization in TEE and have significant work experience can access Level III-SHD training.

Interventional echocardiography is a novel imaging specialization that is rapidly growing. Formalizing training, meanwhile, presents both possibilities and drawbacks. To make sure that interventional echocardiographers have the skills essential to handle this challenging duty, training criteria are required.

Functional Evaluation After Structural Intervention: TTE Pearls

Betz J, presented a session at the American College of Cardiology on 6^th March 2023 which talks about Transcatheter aortic valve replacement (TAVR). TAVR is a minimally invasive heart procedure to replace a thickened aortic valve that cannot fully open (aortic valve stenosis). TAVR can help restore blood flow and reduce the signs and symptoms of aortic valve stenosis. However, there are several complications associated with TAVR such as paravalvular regurgitation (4-6%), mitral regurgitation (rare), annular rupture (1%), coronary obstruction (<1%), valve embolization (rare), RV perforation (Pacemaker-related). The forming mechanism for paravalvular AR after TAVR is calcification or shallow, deep, or undersized implantation of the valve. Post-TAVR is one of the most common procedures performed in the cath lab.

By looking at short-axis aortic levels where the circumferential extent of aortic regurgitation can be broadly identified through the imaging planes, one can identify valvular and paravalvular regurgitation. This can help determine the severity of pulmonary vascular resistance (PVR) also. Further to being useful in the short-axis view, a circumferential extent, sweeping over the detected numerous jets is also crucial.

It is crucial to have a CW Doppler for the pressure half-time once doctors have determined there is no leak at the short-axis level (PHT). A low PHT may signal severe regurgitation. Another symptom that there could be severe regurgitation is color imaging of the descending thoracic aorta if professionals notice diastolic flow reversal. The LVOT must not close in order for the aortic valve to calcify.

The LVOT Diameter is measured immediately proximal to the inflow aspect of the stent (From the leading edge to the following edge). In order to stay clear of the pre-valve acceleration area, the PW sample volume is placed close to the valve.

One of the many topics we must address is spectral doppler, which is quite significant. Doppler’s alignment is one of the most important factors; when aligned correctly, it provides accurate value. Angle correction feature usage in aortic continuous wave doppler is not recommended (avoided). Instead, it is suggested to test every window that is offered and record all attempts in other windows. According to one study, up to 25% of individuals’ aortic stenosis severity is incorrectly calcified as a result of disregarding the non-apical window.

The zoom/open view of the LVOT is the secret to success in this case. It was suggested to ensure correct volume placement to optimize gain, to use all available windows for CW and non-imaging probes, and to sweep through the valve to seek for PVL.

Cardiovascular 2022 Heart Failure Guidelines… What is Needed in 2023 and Beyond to Ensure Equitable Care for All Patients?

Yancy CW, presented a session at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans, that evaluated 2022 HF guidelines in comparison to recent 2023 guidelines. There are four pillars are present for the treatment of HFrEF are:

1. At risk of HF (Stage A)
2. Pre-HF (Stage B)
3. Treatment of HFrEF Stage C
4. Treatment of HFrEF Stage D

In Stage A, blood pressure should be controlled in accordance with GDMT for hypertension to prevent symptomatic HF in patients with hypertension. In patients with type 2 diabetes and either established CVD or at high cardiovascular risk, SGLT2i should be used to prevent hospitalizations for HF. In Stage B, in patients with LVEF ≤40%, ACEi should be used to prevent symptomatic HF and reduce mortality. In patients with a recent or remote history of MI or ACS, statins should be used to prevent symptomatic HF and adverse cardiovascular events. New treatment strategies in HF, including sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi) are added in stage C. In patients with advanced (stage D) HF refractory to GDMT and device therapy who are eligible for and awaiting MCS or cardiac transplantation, continuous intravenous inotropic support is reasonable as “bridge therapy”.

In patients with HFpEF, SGLT2i, MRAs, ARB, ARNi may be considered particularly among patients with LVEF. In patients with HFimpEF after treatment, GDMT should be continued to prevent relapse of HF and LV dysfunction, even in patients who may become asymptomatic.

The 4 pillars of medical ethics are:

1. The pillar of beneficence
2. The pillar of non-maleficence
3. The pillar of autonomy
4. The pillar of justice

The pillar of beneficence is about promoting the good for others. In medicines mean acting in a way that helps your patients. Non-maleficence refers to not causing harm to your patients. The pillar of autonomy refers to patient’s right to make their own healthcare decisions known as self-determination. The principle of justice refers to fairness with medicine and equal distribution of resources.

Four pillars of therapy plus the four pillars of ethics are the path to health equity in heart failure.

Determining Cost and Value in Heart Failure Therapy

Allen LA, presented a session at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans. Heart failure is typically chronic and associated with multimorbidity, where multiple new treatments in recent years have been shown to improve survival but also add significant burdens and cost for patients. Understanding the totality of patient (and family caregiver) costs is related to management is critical to delivering patient-centered, high value care that maximizes health outcomes and patient experience.

The most important word or concept in medicine is value. As per 2011 survey data, US healthcare spending growth is uniquely high with increasing national health expenditures by 81.8% while healthcare outcome i.e., life expectancy is uniquely low. This shows that US healthcare has low value.

Financial toxicity is defined as problems a patient has related to the cost of medical care. In medical expenditure panel survey 2014-2018, for those with HF, 33% patients reported financial hardship due to medical bills and 13% patients were not able to pay bills at all. In Markov model that stimulated monthly outcomes based on results from the EMPEROR-Preserved and DELIVER trials, adding SGLT2i to standard therapy is projected to cost $141200 per quality adjusted life year gained. An SGLT2i would not be cost effective if there is no mortality benefit.

OOP cost is tricky to get and convey and it depends on health insurance product of which there are thousands and pre-authorization. Also, other drug expenses that push patients into different copay categories during the year.

Efforts to communicate and address healthcare costs are emerging, including tailored, real-time, integrated estimates of out-of-pocket costs. Given the significant costs to patients associated with stacking of evidence-based therapies, improving equitable access to care will require improved data on the relative value of treatments as well as changes in healthcare policy and financing.

Rapid Simultaneous Initiation of HFrEF Quad Therapy is the Best Approach to Ensure Optimization of Medical Management

Vardeny O, presented a session at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans. Comprehensive guideline directed medical therapy (GDMT) extends lives and reduces hospitalizations as compared to conventional therapy. In 55-year-old patient, ARNI+βB+MRA+SGLT2i are estimated to extend event free survival by 8.3 years vs. ACEI+ βB alone. In patients with HFrEF, Quadruple GDMT i.e, ARNI, beta-blockers, MRA and SGLT2i are recommended. In patients with symptomatic HFrEF, SGLT2i are recommended to HHF and CV mortality, irrespective of presence of T2DM.

Benefits of certain GDMT accrue early and delaying initiation exposes patients to potentially avoidable risk. Packer et al., 2014 paper showed the early benefit of Sacubitril/Valsartan over Enalapril. In JAMA 2021 study, Dapagliflozin showed clinical benefit with significant reduction in risk of primary efficacy outcome of HHF and CV death or worsening HF by 4 weeks. In DELIVER trial, Dapagliflozin showed significantly lower primary endpoint as compared to placebo. Each therapy has a treatment effect independent prior initiation (or dose) of other therapies, and may enable use of other GDMT. In PARADIGM-HF study, Sacubitril/Valsartan showed similar benefit irrespective of beta-blocker use or dose. Also, Sacubitril/Valsartan showed lower CV death in patients treated with MRA. Sacubitril/Valsartan did not lead to discontinuation of GDMT and may facilitate sustained use of MRAs due to stabilization of kidney function and potassium compared with enalapril. Empagliflozin was associated with a 22% reduced risk of MRA discontinuation post randomization as compared to placebo. Severe hyperkalemia was less common in the Empagliflozin group.

GDMT and HFrEF consists of 4 medication classes, with evidence to support early clinical benefit after initiation. No biologic rationale is suggested for waiting to add therapies until full dose achieved of prior therapy. Earlier use of ARNI and SGLT2i may enable sustained use of MRA. More research is needed on optimal strategies for rapid simultaneous initiation of quadruple GDMT.

Step by Step Initiation of HFrEF Quad Therapy is the Best Approach to Ensure Optimization of Medical Management

Aguilar D, presented a session at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans. As per Biegus, et al., 2022 study, in treatment of patients with HFrEF, today’s challenge is that too many people with HFrEF remain untreated and experience treatment delays with medications that extend survival and prevent worsening HF. There is clear need to improve initiation, titration and adherence of GDMT for all patients living with HF. 2022 AHA/ACC/HFSA guidelines for management of HF recommended that simultaneous initiation or sequencing and order of GDMT are usually individualized according to patient’s symptoms, vital signs, functional status and dose not necessarily need to be done according to the sequence of trial publications and should not be delayed. 

HFrEF trials were performed sequentially and on background of optimal HF therapy predominantly in ambulatory patients. Acute HF trials added an individual therapy after hemodynamic stability and most patients on background therapy. HF guidelines leave open the question of how to initiate and sequence therapies. A personalized approach is suggested based on patient profiling/characteristics and potential adverse effects of the HF medication. Sequential therapy allows for personalization and shared decision making with the patient (right drug in right patient at the right time). Allen A, et al., 2022 study stated that GDMT should be initiated and intensified in a sequence that priorities meds with the greatest expected benefit and drawing on areas where the patient has ample reserves.

An evidence gap exists for how best to initiate and sequence HFrEF quad therapy. Sequential initiation allows for personalization based on patient characteristics, medication factors and allows for shared decision making. Nonetheless, underutilization and delayed treatment with lifesaving HFrEF pharmacotherapies must be improved. It is critical to identify improvement strategies i.e., GDMT titration clinics, HER interventions, telehealth, multidisciplinary HF management programs, electronically administered patient awareness tools.

Controversies at the Intersection of Structural Heart Disease and Cardiac Electrophysiology Management of Atrial Fibrillation After PFO Closure

Patent Foramen Ovale (PFO) is present in 25% of adults. Its prevalence is higher with cryptogenic CVA. If the stroke is due to a paradoxical embolism, it is likely to carry a significant risk of recurrence.

Baykaner T, presented a session held at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans that discussed the management of Atrial Fibrillation after PFO closure.

The early RCTs between 2012-13 failed to meet the primary efficacy point but the later RCTs in 2017-18 like RESPECT, REDUCE, CLOSE, DEFENSE-PFO trials showed a benefit of PFO closure versus best medical therapy to prevent recurrent CVA in patients ≤60 years.

The SCAI guidelines for the Management of Patent Foramen Ovale:

The onset of AF after the closure of PFO was noted in earlier studies. PFO closure in patients with CVA attributable to PFO and paradoxical emboli, to avoid the use of OACs. The concurrent presence of AF would render the transcatheter PFO closure redundant, as patients would have an ongoing indication for OAC. Monitoring extensively (i.e., ILR) for AF in patients with cryptogenic CVA and PFO can detect AF in >10% of the patients who otherwise would have undergone PFO closure.

There is a potential procedure-related higher incidence of AF after PFO closure mostly reported in the first 4-6 weeks, which may subside long-term, and may not necessitate life-long OAC.

New Onset LBBB with Normal EF After TAVR

Left bundle branch block (LBBB) is a common complication contributing to approximately 20-25%. Majority will resolve after POD1.

Kiani S, presented a session held at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans, and discussed the associated risk of LBBB after TAVR and ancillary risk factors for HAVB/CHB.

Approximately 15%-31% are associated with HAVB/CHB, the majority are asymptomatic and are also associated with new PPM. The risk of Sudden Cardiac Death (SCD) is up to 3.2%. The risk factors for the persistence of LBBB are absolute QRS width and implant depth. The risk factors for HAVB were wider QRS and chronic kidney disease. Risk stratification was conducted. 708 patients having TAVR out of that 180 (25%) have LBBB after TAVR. The utility of EP study showed HV ≥ 70ms and 44% sensitivity. The QRS was >150 or PR was > 240. The ambulatory rhythm monitoring showed a rate of AVB in 10%-25% and a rate of SCD in 1%-1.3%. It is still unclear who is truly low risk.

Patients at highest risk show:

• QRS > 150
• Abnormal HV
• Low implant death
• Worsening condition on EKG

It is unclear who is at low risk. Local factors should be considered while evaluating.

Transvenous Leads Should Be Extracted Before Percutaneous Tricuspid Valve Replacement -Con Jailing is Safer Than Extraction

The most common mechanism leading to pacemaker-induced tricuspid regurgitation was restricted leaflet mobility, followed by adherent leaflet to the leads, leaflet perforation, scarring of leaflets, and chondral entrapment. The pacemaker-induced tricuspid regurgitation was found to be protective compared to pacemaker-associated TR with improved survival (hazard ratio [HR 0.76;95% confidence interval [CI], 0.68-0.98)

Hahn R, presented a session held at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans that discussed whether transvenous leads should be extracted before percutaneous tricuspid valve replacement -con and the benefits and risks of jailing over-extraction

The approach to removing leads prior to TV surgery varied with individual surgeons. The repair was attempted when the valve was not extensively damaged. The B. Pfannmueller et al. study suggested that patients with pre-existing PPL, who require TV surgery for significant TR without evidence of PPL-induced TR, can undergo TV repair without removal of the PPL. In tricuspid regurgitation following TLE a clinically significant increase in TR was noted in 5.6% patients (n=124), removal of ≥ 2 leads and powered sheath-assisted extraction were significantly associated with an increase in TR score. The Park SJ et al study reported a significant acute TRI in 11.5%. The European Lead Extracted Controlled (ELECTRa) study showed a higher risk of major complications or death in TR patients, with TLE. The Anderson TL et al study showed that TTVR in the setting of trans-TV pacemaker leads without lead extraction or re-replacement can be performed safely with a low risk for complications, offering an alternative to surgical TV replacement. The risk of CIED-related infection in jailing is estimated to be 4.7 per 1000 person-years.

The benefits of jailing were avoidance of TLE complications and extraction was noted as avoidance of complications of jailing. The complications associated with jailing were endocarditis, CIED dysfunction, and TTVR complication. The complications associated with extraction were venous injury, tricuspid valve injury, cardiac avulsion, and death.

A Randomized Trial of A Personalized Clinical Decision Support Intervention to Improve Statin Prescribing in Patients with Atherosclerotic Cardiovascular Disease (PCDS Statin)

High-intensity statin (HIS) use remains low in patients with atherosclerotic cardiovascular disease (ASCVD) despite guideline recommendations. Reasons include therapeutic inertia (TI) and statin-associated side effects (SASE). Do personalized reminders targeting TI or SASE improve HIS use in ASCVD patients?

Virani S.S, presented a session held at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans evaluated whether personalized reminders improve HIST use.

In a randomized clinical trial in the Department of Veterans Affairs, an intervention was developed by constructing machine learning algorithms that use structured and unstructured data via natural language processing (NLP) to identify SASEs and by performing qualitative interviews to determine patient and clinician perspectives on SASEs and clinician information needs. The intervention included centrally processed reminders individualized to each patient and sent to primary care clinicians 2-7 days before the patient visit. Information included the date and type of ASCVD diagnosis, statin, and dose, date of last statin fill, date and type of any SASE, and guideline resources on HIS definition and SASE management. Usual care included access to the patient dashboard with statin guideline compliance assessments. After guideline education, 27 primary care clinics were randomized: 14 to the intervention (117 clinicians, 18,427 ASCVD patients) and 13 to usual care (128 clinicians, 18,215 ASCVD patients). Outcomes include a pre-post change in HIS (primary) and statin (secondary) use between intervention and usual-care sites.

Baseline HIS/statin use at intervention and usual-care sites was 52.6%/81% and 55.6%/82.2%, respectively. In the intervention arm, the algorithm identified SASEs in 23% of patients; individualized reminders on 5156 patients have been delivered to date. The trial began in August 2021 and will end in November 2022.

Centrally controlled reminders allowed rapid upscaling of the intervention to several sites. The study results informed how informatics-driven interventions can improve evidence-based care delivery in large healthcare system.

Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations for Heart Failure (BETTER CARE-HF): A Pragmatic, Cluster-randomized Trial Comparing Two Ambulatory Clinical Decision Support Tools

Approximately 68,000 preventable deaths occur every year due to shortfalls in prescribing of proven therapies for heart failure with reduced ejection fraction (HFrEF), particularly mineralocorticoid receptor antagonists (MRA). Electronic clinical decision support (CDS) is a low-cost, scalable approach with the potential to improve prescribing, but optimal CDS format and timing in the ambulatory cardiology setting are unknown. Using an established CDS framework, semi-structured interviews, and pilot testing two targeted CDS tools were developed that notify cardiologists of patients in their care who were eligible for MRA therapy: 1) a best practice alert (BPA) that notifies cardiologists during individual visits, and 2) a monthly in-basket message that allows for review of multiple patients between visits

Mukhopadhyay A, presented the BETTER CARE-HF Trial at the session held at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans that evaluated the effectiveness of an electronic alert vs. message vs. usual care to improve prescribing of HF therapy.

BETTER CARE-HF is a three-arm, pragmatic, cluster-randomized trial comparing the effectiveness of the alert vs. message vs. usual care on the primary outcome of MRA prescribing. Key secondary outcomes include time to prescription and provider engagement with CDS (e.g. actions taken). The adults included were with EF≤40%, outpatient cardiology visits, and no active MRA prescription. The patients with systolic blood pressure (SBP)5.1 mmol/L, any potassium ≥5.5 mmol/L, most recent glomerular filtration rate (GFR) ≤30 mL/min/1.73m2, or documented MRA intolerance were excluded. Patients were cluster randomized by cardiologists across a large health system (>50 practices, 180 cardiologists [60 per arm]).

Overall, 1,859 patients were randomized, of whom 70.8% were male, 68.7% White, 81.4% non-Hispanic, and 84.9% English speaking. The median age was 73. The average EF was 33%, with average potassium of 4.3 mmol/L, GFR 68 mL/min/1.73m2, and SBP 123 mmHg. Primary and secondary outcomes will be presented.

BETTER CARE-HF is the first study to directly compare the effectiveness of an alert vs. message to improve prescribing. Our findings can be rapidly disseminated with the potential to improve morbidity and mortality for patients with HFrEF, and can also inform the development of future CDS interventions for other diseases.

Atrial Pacing for Heart Failure with Preserved Ejection Fraction: A Randomized Clinical Trial

Reduced heart rate (HR) during exercise is common in patients with heart failure with preserved ejection fraction (HFpEF) and associated with reduced aerobic capacity, but it remains unknown if restoring exertional HR through pacing would be beneficial.

Barry A, presented a session held at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans and reported the implantation of a cardiac pacemaker to increase exercise HR is not effective to improve submaximal or peak exercise capacity or functional status in patients with HFpEF and chronotropic incompetence.

Single-Center, Double-Blinded, Randomized, Cross-Over Trial testing the effects of rate-adaptive atrial pacing on the primary endpoint of Oxygen Consumption (VO2) at anaerobic threshold (VO2,AT) and secondary endpoints of peak VO2, ventilatory efficiency (VE/VCO2 slope), patient-reported health status by the Kansas City Cardiomyopathy Overall Summary Score (KCCQ-OSS), and N-Terminal Pro-B-Type Natriuretic peptide levels in patients with HFpEF and chronotropic incompetence.

A total of 32 patients were recruited and 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no-pacing first for 4 weeks, followed by 4-week washout period, and then cross-over for an additional 4 weeks. In the absence of pacing, peak VO2 and VO2 at anaerobic threshold (VO2,AT) were both correlated with peak exercise HR (r=0.46-0.51, both p0.27 for all). Atrial pacing was associated with a decrease in O2 pulse (p=0.002), which may have mitigated any gains in exercise performance

The present study provides strong evidence that implantation of pacemakers to increase exercise heart rate is ineffective to improve functional status in patients with HFpEF and chronotropic incompetence. These results challenge our current understanding of chronotropic incompetence in HFpEF, and suggest that a lower-than-expected peak HR is a consequence of premature exercise cessation rather than a cause of exercise limitation.

Translating Polygenic Risk for Coronary Artery Disease into Clinically Actionable Information Using Causal A.I.

A polygenic score (PGS) measures a person’s inherited risk for coronary artery disease (CAD), but it is unclear how this information can be used to inform clinical care.

Ference BA, presented a session held at the American College of Cardiology (ACC) on 5^th March 2023, at New Orleans that determined how much each person must lower their LDL, SBP, or both to overcome their inherited polygenic risk for CAD using Causal AI.

The PGS consisting of 4,051,820 variants was used to estimate the lifetime risk of major coronary events (MCE: fatal or non-fatal-MI; or coronary revascularization) among participants in each decile of the PGS. Then a causal AI algorithm was used that integrates information from Mendelian randomization studies and randomized trials to estimate the reduction in LDL or SBP needed to reduce risk among participants in each decile of PGS to the same level as participants with average PGS. These estimates were validated by comparing the observed event curves in each group.

Among 445,774 participants (54.1% women) followed to a median age of 70.9 years, 31,524 participants experienced a first MCE during 17,054,722 person-years of follow-up. For the vast majority of participants, the polygenic risk for CAD was overcome with small lifetime reductions in LDL and SBP (FIGURE). However, the amount of LDL or SBP lowering needed to overcome polygenic risk increases the later LDL or SBP lowering is initiated.

Causal AI can translate a PGS for CAD into clinically useful information by quantifying how much each person must lower their LDL or SBP to overcome their inherited polygenic risk for CAD.

Bempedoic Acid and Cardiovascular Outcomes in Statin Intolerant Patients at High Cardiovascular Risk

Nissen SE, presented the CLEAR Outcomes Trial at the session held at the American College of Cardiology (ACC) on 4^th March 2023, at New Orleans, that evaluated whether Bempedoic acid, an ATP citrate lyase inhibitor lower the risk of major adverse cardiovascular events in statin-intolerant patients.

The CLEAR OUTCOMES trial was a randomized, placebo-controlled, double-blind trial. It enrolled 13970 patients with LDL C ≥ 100 mg/dL. Patients and providers were required to document in writing that the patient was unable to tolerate two or more statins or alternatively, a single statin if unwilling or advised not to take a second statin. The patient and provider were required to provide written confirmation that the patient was aware of the benefits of statins to reduce the risk of CV events, including death. Bempedoic acid, 180 mg daily, or matching placebo was administered to patients. The primary endpoint was a composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization with 1620 events and ≥2 years follow-up required for completion. The first key secondary endpoint was time to the first occurrence of the composite of cardiovascular death, nonfatal stroke, or nonfatal MI with 810 events required.

The incidence of a primary end-point event was significantly lower with Bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; p = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; p = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; p = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; p = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.

Bempedoic acid was well tolerated in a mixed population of primary and secondary prevention patients unable to take statins. It lowered LDL C by 21.7% and hsCRP by 22.2% with small increases in the incidence of gout and cholelithiasis. The primary end point, 4 component MACE was reduced 13%, 3 component MACE 15%, myocardial infarction 23% and coronary revascularization 19%.

The CLEAR Outcomes trial provides a sound rationale for use of Bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.

TRILUMINATE Pivotal: A Landmark Randomized Clinical Trial of Transcatheter Tricuspid Valve Edge-to-Edge Repair for Tricuspid Regurgitation

Severe tricuspid regurgitation is a debilitating condition that is associated with substantial morbidity and often with poor quality of life. Decreasing tricuspid regurgitation may reduce symptoms and improve clinical outcomes in patients with this disease.

Sorajja P, presented the TRILUMINATE Pivotal study results at the session held at the American College of Cardiology (ACC) on 4^th March 2023, at New Orleans that evaluated the safety and effectiveness transcatheter tricuspid repair with the TriClip device in the symptomatic patients with severe tricuspid regurgitation who are intermediate or greater estimated risk for mortality with tricuspid valve surgery.

The Prospective, randomized, controlled, multi-center trial was the first trial to test the superiority of TriClip therapy in addition to medical therapy (Device group) over medical therapy alone. 450+ subjects were enrolled.  The primary endpoint was a composite of mortality or tricuspid valve surgery, heart failure hospitalizations, and quality of life improvement ≥15 points assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), evaluated at 12 months in a hierarchical fashion using the Finkelstein-Schoenfeld methodology. The secondary endpoint was assessed hierarchically in the following order: 1) Freedom from major adverse events (MAE) after procedure attempt (femoral vein puncture) at 30 days (Device group only) 2) Change in KCCQ at 12 months (superiority of Device vs. Control) 3) TR Reduction to moderate or less at 30-day post-procedure (superiority of Device vs. Control) 4) Change in 6MWD at 12 months (superiority of Device vs. Control).

TR was reduced by TriClip therapy to moderate or less in 87%, vs. only 4.8% for the control group, and reduction was sustained to 1- year follow-up. The primary endpoint was met (p=0.02) demonstrating device superiority, driven mainly by significant improvement in QOL. The degree of TR reduction was related to the degree of improvement in QOL. The 30-day MAE rate was only 1.7%, and death and pacemaker implant each occurred in 0.6%. Survival free of mortality and TV surgery was high at 1 year in both groups (~90%).

The TriClip device was highly effective in reducing TR and led to significant improvements in quality of life in one year. With the excellent benefit-to-risk profile of the TriClip system, a historically untreated population will have a treatment option to improve their quality of life.

Statins To Prevent the Cardiotoxicity from Anthracyclines: The STOP-CA Trial

Anthracyclines are a key component of several cancer regimens. The administration of anthracyclines is associated with a reduction in left ventricular ejection fraction (LVEF) leading to clinical heart failure. The retrospective data support the hypothesis that statins may reduce the cardiotoxicity of anthracyclines.

Neilan TG, presented a session at the American College of Cardiology (ACC) on 4^th March 2023, at New Orleans, that discussed the results of STOP-CA study which evaluated the effect of Atorvastatin, compared to placebo, on the occurrence of cardiac dysfunction among patients with lymphoma being treated with anthracyclines.

The STOP-CA study is a multicenter, randomized, double-blind, placebo-controlled trial. 300 patients with either lymphoma (Hodgkin’s or Non-Hodgkin’s) was scheduled to receive anthracycline-based chemotherapy. Patients were randomly assigned in a 1:1 ratio to receive Atorvastatin (40 mg) or placebo starting prior to anthracyclines and continued for 1 year. The primary endpoint was the proportion of patients in each group with a ≥10% reduction in the LVEF to less than 55% within the first year of therapy. A secondary endpoint was the absolute LVEF in each group at follow-up, adjusted for the baseline LVEF.

At baseline, among the entire cohort, the LVEF was 63±4.6%. In total, 286 participants (95%) completed the trial. At 12 months, among the entire cohort, the LVEF was 59±5.9%. At 12 months, among the entire cohort, 46 participants (15%) had a decline in the LVEF of ≥ 10% from prior to chemotherapy to a final value of < 55%. Adherence with study drug was documented in > 90%. The incidence of the primary endpoint at 12 months was 9% in the atorvastatin group and 22% in the placebo group (p=0.002). The incidence of this secondary endpoint was 13% in the atorvastatin group and 29% in the placebo group (p=0.001).

For the participants with lymphoma who were treated with anthracyclines, the prophylactic use of Atorvastatin over 12 months was associated with a lower rate of cardiac systolic dysfunction.

Impact of Heart Failure Management Using Thoracic Fluid Monitoring from A Novel Wearable Sensor: Results of The Benefits of Microcor (μCor) in Ambulatory Decompensated Heart Failure (BMAD) Trial

Despite advances in medical and device therapy, heart failure (HF) remains a disease characterized by frequent hospitalization.

Boehmer J, presented a session at the American College of Cardiology (ACC) on 4^th March 2023, at New Orleans, that discussed the efficacy analysis with the use of thoracic fluid index (TFI) monitoring using a novel radiofrequency-based sensor in the BMAD trial.

The BMAD trial enrolled subjects from clinical sites in the US and Europe over 45 months. All subjects were asked to wear the μCor system for 90 days and were assigned by site into a control group with investigators were blinded to TFI and a treatment group using TFI to guide HF therapy. The endpoints of the study were investigator engagement of μCor system data in the context of HF management in the treatment subjects with an objective to evaluate HF emergency visits (ER) and hospitalizations or death, reported here by Kaplan-Meier analysis as time to first event.

 A total of 522 subjects were enrolled with 502 receiving the device and included in this intent to treat analysis. Subjects are characterized as 55% HFpEF, 42% female, age 68 ± 13 years, 53% non-ischemic. There were 42 treatment subjects with a HF event compared to 63 control subjects representing a 36% reduction in HF events (HR = 0.64; p=0.02).

HF management using TFI results in a 36% reduction in HF ER visits and hospitalizations or death.

My Way or the Highway: Surgical and Cath Controversies in Congenital Heart Disease

Muniz J and Gearhart A, presented a session at the American College of Cardiology (ACC) on 4^th March 2023, at New Orleans that discussed two cases. Fontan physiology can have long-term effects such as fontan pathway disruption, collateral shuts, arrhythmias, pleural effusion, hepatic fibrosis or malignancy, renal insufficiency, stroke, thrombophilia, thyroid disease, etc and the factors impacting biventricular repair are dextocardia/mesocaria, coronary artery anomalies, atrioventricular valve hyperplasia and/or significant straddle, etc.

Although a biventricular approach may seem preferable, it is an inappropriate candidate which is associated with significant mortality as well as pulmonary hypertension, valvar dysfunction, and LV systolic and diastolic dysfunction and the treatment options are limited for these co-morbidities. History of endocardial fibroelastosis and smaller LV stroke volume/BSA are independent factors associated with adverse outcomes among patients with borderline hypoplastic left heart undergoing biventricular conversion.

Borderline heart is a heterogeneous mix of unbalanced AVC, coarctation and VSD, complex transposition of great arteries, upstairs downstairs ventricles, and double inlet ventricle. The modified paradigm of borderline heart consists of single ventricle palliation and primary biventricular repair. Single ventricle palliation can either move towards or Fontan or staged ventricular recruitment.

Surgical approach is the mainstay therapy for sinus venous ASD and bicaval canulation and cardiac arrest can be managed by pump repair. In the Warden procedure, pulmonary veins enter high in SVC and SVC entry into RA baffled across sinus venous defect and SVC reimplanted into RA appendage. The best management strategy for sinus venous ASD should be applicable to entire cohort, widely available, easily executed, low morbidity/mortality with minimally invasive approach and excellent long-term profile. Sinus venous defects can be closed by catheter by planning, assessing morphology, selection of appropriate stents and balloons, and technique details to deliver these in correct positions.

In conclusion, one bad decision can impact transplant eligibility and can result in end-organ dysfunction and increased potential for sensitization. An individualised approach is most prudent.

Effect of Remogliflozin on Biomarkers Compared to Empagliflozin Inpatients of Type 2 Diabetes Mellitus with Chronic Heart Failure

SGLT2 inhibitors reduce heart failure hospitalisation and N-terminal pro-brain natriuretic peptide (NTproBNP) levels in HF.

Sengupta S, presented a session at the American College of Cardiology (ACC) on 4^th March 2023, at New Orleans, that evaluated the effect of Remogliflozin in patients of T2DM with CHF as compared to Empagliflozin using NT-proBNP as index of therapeutic effects.

In this multicentric, prospective study, 71 patients of DM with CHF (EF<40%) with NTproBNP>600pg/ml were included. 38 patients were in Remogliflozin (R) group and 33 in Empagliflozin (E) group. Baseline demographic, glycaemic, cardiac and renal parameters were comparable between 2 groups (p>0.05).

Mean NT-proBNP level improved from baseline to 3 months in both groups (R group: 2781±2695 to 1451±1183 pg/ml, p=0.0007); (E group: 2672±2181 to1602±1436 pg/ml, p=0.004) respectively, but no significant difference was seen between two groups (p= 0.64, Figure 1). Mean HbA1c was 7.87±1 at baseline and improved to 7.58±1.3 at 3 months in R-group; 7.78±0.1 at baseline and improved to 7.44±1.2 at 3 months in E-group. The mean eGFR was 75.6±27.4 at baseline and 81.7±28.4 at 3 months in R-group; 78.1±21.3 at baseline and 71.7±22.9 at 3 months in E-group. Systolic BP reduced from 127±21 mmHg at baseline to 123±14 mmHg at 3 months in R group (p<0.05). No adverse events occur in either group.

Remogliflozin improved glycaemic parameters and NTproBNP as an index of therapeutic effects in T2DM patients with CHF. Remogliflozin was well tolerated and non-inferior to Empagliflozin in T2DM patients with CHF.

Navigating the Post Pandemic Staffing Crisis: The Way Forward for Cath Labs

Welt F, presented a session at the American College of Cardiology (ACC) on 4^th March 2023, at New Orleans. Health care employment fell by 17,500 jobs in September, with losses in hospitals (-8100 jobs) and nursing residential care settings (-37,000 jobs) outweighing gains in ambulatory care settings (-28,200 jobs). Revisions through July were modest, adjusting total health care jobs up by 7,000. Compare to the Feb 2020 pre-pandemic peak, employment in ambulatory care settings has almost completely returned, at about 5000 fewer jobs (-0.1%), while hospitals employ 93,000 fewer jobs (-1.8%). Overall healthcare employment in 5,24,000 jobs (3.2%) below the February 2020 pre-pandemic peak. Total employment remains about 5 million jobs, or 3.3%, below pre-pandemic levels. The unemployment rate fell to 4.8%.

The possible reasons for the crisis are:

• Enduring attempts to control the public health crisis
• Fiscal visibility of small and large healthcare systems that can be related to temporary closure of outpatient clinics, limitation of elective cases. There were large downstream effects on new staffing hires, budgets and retention
• Personal decisions of individuals leaving the healthcare sectors with early retirement or job/career transitions. The factors of health or family or childcare were also considered

The layered strategies can be applied for the society, state and federal layer, administrative layer and individual clinician layer such as improve awareness and advocacy initiatives to address the crisis, commit to re-evaluate rewards philosophy, implementing innovative training pathways to provide more health care workers i.e., RN, RT, echo techs etc. make workforce health and well-being a priority, resiliency, emotional support and recovery. The staff should be leveraged. Flexibility/care model redesigns should be introduced. The academic partnerships should be strengthened to build the pipelines and re-instill hope and focus on path forward.

Clinical Trial Recruitment: Challenges and Solutions in the COVID Era

Davidson LJ, presented a session at the American College of Cardiology (ACC) on 4th March 2023, at New Orleans that discussed the challenges to clinical enrolment and their solutions in COVID times. The challenges we faced to clinical trial enrollment on a good day are:

• Identifying objects
• Inclusion of diverse patient populations
• Follow up
• Meeting pre-specified recruitment numbers
• Interpreting data and drawing conclusions

These leads to inadequate power, inability to reach primary endpoints, cofounding variables, biased samples and inability to generalize results and need for protocol modifications. In fact recent survey shows that 47% of valve disease patients DO NOT get information on clinical trials that may might be eligible for. 63.7% of patients stated that they received their information about clinical trials form somewhere other than a doctor, surgeon or their hospital. It can be say that we may missing the opportunities to recruit the patients into trials. COVOD-19 exacerbated already existing inequalities in clinical trial participation.

The lesson learned from the pandemic with clinical trial recruitment are

• Virtual visits are feasible and patients are willing to adopt to this
• Research protocol should have prospective contingency planning
• Consider opt-out strategies

The important considerations for clinical trial enrollment should be implemented are referral base and relationships should be build. Leverage your website to recruit patients directly, highlight the educational programmes and social media, direct referral Apps for physicians can be given to use.

Clinical trial recruitment presents many challenges, which are only exacerbated during a pandemic. Novel methods of interacting with patients i.e., virtual visits, addressing unique concerns of patients during pandemic, follow up and data analysis are imperative. The key to method is maintaining a strong referral basis and diversifying the methods by which you are accessible for referrals.

Time to Get Green – Managing Cath Lab Utilization and Waste

Ahmed B, presented a session at the American College of Cardiology (ACC) on 4th March 2023, at New Orleans which explore the Cath lab and waste management. Why we need a greener Cath lab practice is

• To reduce wasteful practices and optimize utilization
• For the cost savings
• To make better climate change
• Its stronger impact on healthcare system

Climate change is considered to be the biggest threat to human civilization in the 21^st century and environmental pollution is a cardiac risk factor to people. Global healthcare system is the 5^th largest contributor to global GHG emissions. US healthcare system is leading the charge-US healthcare output is greater than the output of all sectors in the UK. US healthcare system is responsible for 10% of US GHG emissions. The Cath lab sustainability team should be establish with nurses, Techs, Cath Lab manager, students, trainees, Physicians. The Cath lab sustainability plan can be outlined by assessing the existing process and identifying ways to limit landfill waste. Systemic changes should be made across the spectrum of utilization. The ways to reduce, reuse and recycle products should be identified and periodic re-assessment of output is necessary.

Life cycle assessments and other industrial ecology procedures and tools, such as circular economy, can be used to furthermore evaluate healthcare services at multiple levels, incorporating: global supply chain, national healthcare systems, whole hospital/health systems, clinical pathways and procedures, in- dividual drugs, medical devices, and basic materials. A healthcare-specific industrial ecology framework that merges top-down (macro scale) and bottom-up (micro scale) approaches is required, to review clinical activities, and to enhance the general use of research that pursue to guide execution attempts and track health- care environmental performance development.

From Heresy to Necessity: Same Day Discharge for TAVR – How We Do It

Cohen MG, presented a session at the American College of Cardiology (ACC) on 4th March 2023, at New Orleans. The key points to be considered for the same day discharge (SDD) of patients are:

• Patient and environmental factors
• Procedural factors
• Complications

JAHA 2022 paper stated the insights from the nationwide readmission database of SDD patients after transcatheter aortic valve replacement (TAVR) from 2015 to 2019. Total 158, 591 patients were included in the study in which only 9.6% patients had SDD and 41.5% patients were non-SDD while 57.9% patients were ScD/TDD (second‐ or third‐day discharge). The SDD patients showed higher rate of readmissions as compared to non-SDD patients (p=0.30). The next day discharge (NDD) and ScD/TDD patients also had high rate of readmissions than non-SDD patients (p=0.01, p=0.66 resp.)

In wood D, et al. JACC 2019 paper, the Vancouver 3M clinical pathway is implemented for NDD patients in which 1400 patients were screened, 411 patients were enrolled at 13 centers. 80% of patients were discharge on next day. 5.7% patients had PPM implantation and 0.24% patients required late heart block PPM. The 3M-TAVR Economic study showed similar clinical outcomes between 3M TAVR and S3i Registry. Also, 3M-TAVR approach showed lower 30-day costs as compared to S3i. Programme implementation involves the steps of a QI process i.e., pathway development, evaluation and modification. SDD decisions are based on individualized team discussions at patient bedside.

SDD patients are highly selected because of lower risk, uncomplicated TF procedures, high THV implantation technique and without conduction abnormalities. Majority of patients in published series treated with SE THV. Economic considerations will reduce hospital costs and improve hospital margins. However, it may lead to lower payment by Medicare.

ISHKEMIA-CKD EXTEND – Clinical Outcomes at 5 years of Follow-up

• Largest treatment strategy trial of SIHD and advanced CKD.
• At 5 years, in ISHKEMIA-CKD patients, high rates of death (~39%) and CV death (~28%) were observed.
• An initial invasive and conservative strategy resulted in similar survival at a median of 5 years follow-up.

15-Month results of the MASTER DAPT trial

• APT intensity (DAPT vs SAPT or SAPT vs no APT) was also influenced by perceived ischemic risk or prior ischemic events, but not by bleeding risk or prior bleeding events.
• Majority of patients in the prior standard continued DAPT beyond 12 months despite the absence of prior ischemic events.
• NACE and MACCE remained similar and MCB was low at 15 months suggesting no ischemic or fatal events and at least persistent bleeding with abbreviated compared to the standard treatment after Ultimaster stent implantation in unselected HBR patients.

PARADISE-MI Trial – Win ratio analysis

• The PARADISE-MI trial demonstrated that Sacubitril/Valsartan was superior than Ramipril in high-risk survivors of MI.
• Win ratio analysis can be a useful adjunct to the conventional time-to-first event analysis for trials with composite outcomes, where the ranking of the clinical importance of the different types of events is considered relevant.
• This analysis can inform the design of future CV trials in population.

PANTHER – P2Y12 inhibitor versus aspirin monotherapy in patients with coronary artery disease

• P2Y12 inhibitor monotherapy was associated with lower risks of CVD, MI, and resulting in a reduced risk of net adverse clinical events.
• The incidence of major bleeding was similar, but GI bleeding and haemorrhagic stroke were lower with P2Y12 inhibitor monotherapy.
• Long-term P2Y12 inhibitor monotherapy is better than long-term aspirin monotherapy for secondary prevention in patients with CAD.

FOURIER-OLE primary results

• Long-term use of Evolocumab with a median follow-up of more than 7 years appears to be safe and well-tolerated.
• Early initiation of Evolocumab is beneficial for CVD and CVD mortality over several years.
• FOURIER-OLE study results argue for early initiation of marked and sustained LDL-C reduction for maximum clinical effect.

FIDELITY: Causes of mortality

• Finerenone not only reduced the risk of all-cause and CV mortality but also reduced the risk of sudden cardiac death.
• The effect of Finerenone on mortality outcomes was more pronounced in patients with higher baseline eGFR.
• Finerenone improves prognosis even in well-managed patients.

Management concepts of plaque erosion

• Plaque erosion was found in 25-40% of ACS.
• In vivo diagnosis of plaque erosion became possible.
• Conservative management with prolonged anti-platelet therapy be an option for patients with ACS caused by erosion.

Plaque erosion and its role in acute coronary syndrome

• Plaque erosion is more frequent in NSTEMI than STEMI.
• Potential differences in plaque erosion and plaque rupture in terms of gender and age groups, triggers, and plaque composition.
• Better prognosis than ACS associated with plaque rupture.

Blood pressure treatment targets: what do the guidelines say?

• The updated NICE guideline continues to recommend a treatment range and target BP of 140/90 mmHg, in contrast to the following treatment targets recommended by the ESC/ESH.
• Individualized studies after considering age, frailty, co-morbidity, baseline BP and tolerance of BP lowering drugs reveal that the optimal BP target is not the same for every patient.
• Efforts to reduce CV risk in hypertensive patients should make full use of various BP measures, in routine care or through self-monitoring, in conjunction with treatment regimens to achieve high TITREs.

How to achieve blood pressure targets in clinical practice?

• Inadequate preparation, incorrect BP measurement (home or office), lack of adherence to medical visits, lifestyle changes, and medications are some of the factors that make achieving and maintaining BP goals in the real world difficult.
• The optimum antihypertensive strategy should be based on an individual’s CV risk profile, as well as BP levels and drug tolerance.
• A healthy lifestyle (low salt consumption, moderate to vigorous aerobic activity, or the DASH diet) may prevent or delay the onset of hypertension and lower CV risk. It also improves the effectiveness of antihypertensive medication.

SGLT2 inhibitors in HFpEF – Light at the end of the tunnel

• SGLT2i was first intended to treat diabetes, but studies have shown that it is also useful in the prevention and treatment of HF.
• In individuals with HFpEF or HFmrEF, dapagliflozin treatment decreases the risk of the primary composite outcome of CV death or worsening HF.
• The EMPEROR-Preserved study showed that empagliflozin outperforms placebo in improving HF outcomes in patients with symptomatic stable HFpEF on good baseline GDMT, regardless of diabetes status.

SGLT2 inhibitors across the spectrum of heart failure

• ACEi/ARBs, Neprilysin inhibitors, BBs, MRAs, and SGLT2i are the “living five” or “fantastic/fab four” live-saving therapies for HFrEF.
• According to the DELIVER trial, dapagliflozin reduced the combined risk of worsening HF or CV death in patients with HFmrEF or HFpEF.
• The SOLOIST-WHF study concluded that the primary end goal of the total number of CV fatalities, hospitalizations, and urgent visits for HF was considerably lower with the SGLT2 and SGLT1 inhibitor sotagliflozin compared with placebo in patients with diabetes who had worsening HF.

Practical considerations for treating HF with mildly reduced and preserved EF

• In the absence of AF or valve disease, LA enlargement reflects chronically elevated LV filling pressure.
• The ASIAN-HF registry showed that very young HFpEF patients had a 3-fold higher mortality and twice the hypertrophy than the control group.
• In Paragon-HF, mortality rates were comparable across all regions, despite regional variations in patient characteristics and HF hospitalization rates. Similarly, subsequent analysis of I-Preserve and Charm-P tests showed no change in mortality across regions.

Implementing best practices across the spectrum of heart failure

• To avoid morbidity, patients with HFpEF and HTN should be administered titrated drugs to achieve their BP targets, in accordance with recognized clinical practice recommendations.
• SGLT2i is an ideal cardio-renal-metabolic therapy for HF, as one pill/day significantly improves survival, prevents hospitalization, and improves QoL and functional status.
• According to one study, in a 55-year-old patient with HFrEF, comprehensive therapy (with ARNI+BB+MRA+SGLT2i) provided an overall 6.3 additional years compared to conventional therapy (ACE/ARB+BB).

COVID-PACT – Antithrombotic therapy in critically Ill COVID-19 patients

• To lower the risk of VTE in critically ill patients who do not have COVID-19, thromboprophylaxis is recommended.
• According to current guidelines, SDPAC should be used instead of FDAC in severely sick COVID-19 patients.
• In order to reduce thrombotic problems in a subset of critically sick COVID-19 patients, FDAC should be taken into consideration while balancing the risk of thrombosis and hemorrhage.

ACT Outpatient Trial: Colchicine and Aspirin in community patients with COVID-19

• The year 2021 saw an estimated 3.8 billion people infected with COVID-19 and nearly 18 million deaths.
• Antiplatelet medication may benefit patients with severe COVID-19 through a variety of mechanisms, including inhibition of platelet aggregation and reduction of platelet-derived inflammation.
• Colchicine, high-dose aspirin, and rivaroxaban are being studied as possible COVID-19 modulators in individuals who have not improved with standard therapy.

ACT Inpatient Trial: Colchicine and Rivaroxaban plus Aspirin in patients hospitalized with COVID-19

• One out of every five patients in the ward with COVID-19 died in the ACT inpatient trial (high mortality rate).
• Colchicine did not give a mortality advantage in the ACT study, regardless of whether the patient is on MV or has previously been vaccinated, or if the patient has long or short duration of symptoms.
• A meta-analysis of intensified anticoagulation in inpatients showed a clear 40% decrease in VTE, although this reduction does not give advantage in terms of mortality reduction.

Cardiovascular disease prevention in 2033

• Cardiovascular disease prevention can be done by targeting modifiable causes of disease.
• Use of AI /digital platform for personalized health promotion or guiding health management through predict, prescribe and prevent may work better.
• Personalizing diet and lifestyle GUIDANCE by conducting digital ‘personalized’ n-of-1 trials on the platform to ‘learn’ the best way in which each person can minimize the exposure to the cause of disease.

How will we approach coronary artery disease in 2033?

• Multi-slice spiral computed tomography will be the new sole diagnostic tool for bypass grafting, FASTTRACK CABG trial without using conventional invasive cine angiography.
• The use of Hologram will be prevalent and the use of blended therapy will be normal in PCI.
• Aspirin will be replaced by monotherapy of a specific anti-platelet.

Management of Valvular Heart Disease in 2033

• The screening of VHD will be done by Artificial Intelligence/ Machine learning (ECGs) in the future.
• Bioprosthetic valve platforms will be introduced: Edwards Resilia tissue valve, Anteris DurAVR and Foldax TRIA polymer valve.
• TAVR will be the dominant technology for AVR and most AS anatomic scenarios.

Screening, prevention, and treatment of AF: what we will be doing in 2033?

• For individualized risk prediction for AF, new algorithms will be utilized.
• AF will be screened via contact-free optical screening or a smart wearable.
• In 2033, new medications will prevent strokes, and ablation technology will manage the rate and rhythm of AF.

Management of Heart Failure in 2033: My predictions

• Patients will manage their own volume status with a patient self-management approach directed by a physician and congestion will be measured by AI or smart wearables.
• Extracellular vesicles will be used as a biomarker in understanding the pathophysiology and in therapy.
• Focus will be on, why women are more prone to HFpEF than men to understand HFpEF and how to prevent it.

Digital cardiology & Artificial Intelligence- Where will it take us in 2033?

• AI will increase convenience for patients and staff.
• The AI won’t replace doctors but will help them.
• Lot of companies have FDA- cleared machine learning products for cardiology.

Implementing ESC 2021 Guideline-recommended HF care: where do we stand now?

• Initiate standard therapies as soon as possible and titrate every 2-4 weeks to target or maximallyntolerated dose over 3-6 months
• The ESC/HFA society recommends personlized approach for treatment of heart failure.
• Real-world data suggest better outcomes with simultaneous vs sequential prescription of Ivabradine and Sacubitril/Valsartan in patients with HFrEF.

Individualized approach in HF management: What more can we do?

• A personlized approach, adjusting guideline-directed medical therapy to patient profile, may allow to achieve a better and more comprehensive therapy for each individual patient than the more traditional, forced titration of each drug class before initiating treatment with the next.
• As per the 2021 ESC consensus on HF patient profiling for tailoring medical therapy, achieing better and more comprehensive therapy for each indivual patient is a must.
• Ivabradine can be added in patients who have low BP and elevated HR and are currently taking SGLT2i, MRA, diuretics, BB.

INVICTUS – Rivaroxaban versus VKA for rheumatic atrial fibrillation

• Rheumatic heart disease (RHD) affects more than 40 million people worldwide, primarily young people and people living in low-middle income countries, and about 20% of symptomatic RHD patients also suffer from AF (or elevated stroke risk).
• An anticoagulant that does not require monitoring would be of great benefit to RHD-AF patients.
• According to the INVICTUS trial, in RHD-AF patients, VKA reduced ischemic stroke and mortality without increasing the risk of major bleeding. This trial also showed a reduction in mortality with VKA.

PACIFIC-AMI – Efficacy and safety of factor XIa inhibitor asundexian on top of dual antiplatelet therapy after acute myocardial infarction

• Patients with AF are known to be at an increased risk of stroke due to their tendency to develop atrial thrombi.
• After acute myocardial infarction, antiplatelet therapy with aspirin and a P2Y12 inhibitor (DAPT) is considered the standard of care.
• According to the Pacific-AMI study, asundexion (an oral factor XIa inhibitor) was well tolerated in the Phase 1 trial and its 50 mg daily dosage resulted in almost complete (>90%) suppression of factor XIa activity.

GLP-1 RAs: more than just glucose-lowering agents

• Globally, approximately 10% of cardiologists, endocrinologists, or HCPs are using GLP-1 RA for the management of diabetes.
• GLP-1RAs target both fasting and postprandial glycemia, in general by increasing insulin and decreasing glucagon levels.
• In patients with T2D at high cardiovascular risk, studies (such as LEADER, SUSTAIN-6, Harmony Outcomes, REWIND, or AMPLITUDE-O) have revealed that GLP-1-RA significantly reduces 3-P MACE (composite of CV death, nonfatal MI, or nonfatal stroke) compared to placebo.

The Evolution of T2D and CV Guidelines

• In accordance with AHA/ASA 2021, in patients with established ASCVD, including stroke, GLP-1-RA should be added to metformin regardless of baseline HbA1c.
• Lifestyle modification, glucose targeting, BP control, dyslipidemia management (LDL-C), antiplatelet therapy, weight control, and anti-inflammatory therapy are considered multifactorial approaches to T2D management.
• Interventions for glucose management (pre-diabetes and diabetes) will reduce the risk of neurocognitive and discrete stroke events.

Real-world evidence: a bridge between trials and clinical practice

• The ESC guidelines on management of AF recommend structured characterization and a better care (ABC) approach.
• NOACs are generally recommended as first line therapy (Class I, Level A).
• Real-world evidence builds on data from RCTs to demonstrate the safety and effectiveness profile of NOACs in the real world.

Practical considerations for the use of GLP-1-RAs in the clinic

• Although GLP-1-RAs have shown cardiovascular benefits in people with T2D at high risk of CV events, they are not frequently used by cardiologists.
• GLP-1-RAs have a more pronounced effect on ASCVD than SGLT2i. Whereas, SGLT2i shows a more pronounced effect on HHF and CKD than GLP-1-RAs.
• GLP-1-RAs do not increase the risk of hypoglycemia when combined with other glucose-lowering therapies (e.g. metformin, SGLT2i, and thiazolidinediones).

GLORIA-AF: New Phase III data from this innovative registry program

• Dabigatran showed significant relative risk reduction of major bleeding by 39% and all-cause death by 22% vs VKA.
• Dabigatran was associated with a 41% lower relative risk of major bleeding vs rivaroxaban.
• There were similar risks of clinical outcomes with dabigatran vs apixaban.

What do real-world analyses tell us about NOACs?

• In a large, real-world FDA/MCS analysis, each NOAC was associated with reduced risk of thromboembolic stroke vs warfarin.
• As per GARFIELD-AF study, NOACs were associated with significantly lower rates of major bleeding and all-cause death vs VKA.
• As per GARFIELD-AF registry, dabigatran was the only NOAC with significant reduction in major bleeding and all-cause mortality vs VKA.

Great debate: Hypertension during exercise should be treated

• Hypertension during exercise is common and may contribute to the overall burden of pressure-related and residual CV risk.
• Exercise BP:
  • Cannot be used to diagnose hypertension.
  • Does not reflect vascular pathology or pre-hypertension.
  • Is not associated with reduced exercise capacity.
• One should not be concerned about an increase in blood pressure during exercise; rather, blood pressure should be under control before commencing the exercises.

How to treat a patient with heart failure and LVEF> 40%

• Heart failure with preserved ejection fraction (HFpEF) is often under-diagnosed in clinical practice and poses a threat.
• Empagliflozin is the first drug to reduce CV death or first hospitlization for heart failure (HHF) in HFpEF patients.
• Effect of Empagliflozin on CV death and first HHF is consistent across multiple patient subgroups with HFpEF.
• In HFpEF patients Empagliflozin protects the kidney by slowing the decline of renal function.

TAVI: Gaps in evidence and expanding indications

• Biomarker screening/inclusion criteria is an important tool to identify patients with less severe aortic stenosis (AS) with evidence of left venticular damage.
• The expanding indications for transcatheter aortic valve implantation (TAVI) are asymptomatic severe AS and “at risk” moderate AS.
• The future is upstream AS treatment which consists of improved biomarkers, access to care, pre-emptive aortic valve repair.

Minimalist TAVR and rapid discharge protocols: The future standards of care

• Minimalist transcatheter aortic valve replacement is a safe, predictable, and well-planned procedure with tailored resources.
• It lacks GA, Swan Ganz, Arterial Line, and Foley.
• If the team agrees on same-day discharge for post-TAVR patients, it occurs before 7 PM, and out-patient visits on post-TAVR days 1 and 2.

Valve-in-valve TAVI for bioprosthetic valve failure

• As per 2020 ACC/AHA guidelines, SAVR is indicated for patients aged < 65 years, SAVR or TAVI for age 65-80 years and TAVI for age > 80 years.
• For patients with longer life-expectancy, consider life-time management before first re-valving.
• Choose a bioprosthetic valve with good durability and possibility for safe valve-in-valve when it fails.

Hypertension guidelines: the experts’ perspective

• For adults with hypertension requiring pharmacological treatment, WHO 2021 recommends combination therapy, preferably with SPC as an initial treatment.
• Latest evidence guideline recommends SPCs as a first line treatment.
• SPCs promote adherence, simplify the treatment strategy, improve medication persistence, and improve blood pressure management.

Which SPC for this patient with diabetes and chronic kidney disease?

• Renin angiotensin blockers are more effective at reducing albuminuria than other antihypertensive agents.
• Renin angiotensin blockers are recommended as part of treatment strategy in HTN patients in the presence of microalbuminuria or proteinuria.
• Blood pressure target for CKD patients recommended by international guidelines is <140/90 mmHg.

In search of atrial fibrillation in stroke patients: How to find it and handle it

• The diagnosis of AF on post-stroke monitoring requires documentation by an ECG of sufficient quality to allow confirmation by a health professional with expertise in ECG rhythm interpretation.
• In adult patients with ischemic stroke or TIA of undetermined origin, it is recommended that the longer duration of cardiac rhythm monitoring of more than 48 h and if feasible with implantable loop recorder to increase the detection of subclinical AF.
• In adult patients with ischemic stroke or TIA of undetermined origin, it is suggested to use of additional outpatient monitoring compared with in-hospital cardiac rhythm monitoring to increase the detection of AF.

Are ACE inhibitors still the cornerstone of cardiovascular protection?

• Perindopril improves life/death cycle of the endothelium and works well when combined with either Ca²⁺ antagonists, diuretics and/or statins.
• Prescribing ARBs for hypertension deprives patients from the benefit of ACEi on the coronary artery.
• In RCTs, ACEi exert a better coronary artery protection than ARBs.
• Perindopril reduces death and improves life of endothelium leads to prevention of ACS.
• In post AMI patients, perindopril decreases endothelial apoptosis.

Can we individualize treatment of hypertensive patients with single-pill combination therapies?

• Recent guidelines suggests to start with two drugs and ideally as a SPC.
• Single pill combination is more effective and provides rapid BP control than monotherapy and two free drugs.
• Single pill combination enhances adherence, improves CV protection and is more cost-effective.
• In PROGRESS trial, Perindopril and/or Indapamide showed 28% risk reduction of recurrent stroke.

Optimal medical treatment of chronic coronary syndromes (CCS)- from the old model to a new combination approach

• More tailored pharmacological treatment before considering percutaneous coronary intervention is required.
• The stepwise approach for CCS should be abandoned for a rationale combination of hemodynamic and metabolic agents alogn with reconsideration of preventive strategies.
• Triemtazidine can be used for symptom control in CCS as an early combination therapy with BB and CCB.

What should be the optimal quadri-therapy in clinical practice?

• A substantial proportion of patients (possibly 10-20%) need 4 drugs for BP control, i.e., to reach target.
• Beta-blockers are effective on BP reduction and have favourable effects on variety of clinical conditions that may co-exist with hypertension.
• A novel quadruple SPC with Perindopril/Indapamide/Amlodipine/Bisoprolol will offer a novel attractive asset of BP control.

Changing paradigms in LDL-C reduction

• Combination treatments should be prioritized over monotherapy.
• There is a need to enhance the number of accessible LDL receptors.
• Bemepodoic acid is beneficial at lowering LDL-C levels.

LDL-C: New insights into its role as casual risk factor and target for therapy

• An annual dosage of siRNA vaccine presents a viable method for lowering LDL, reducing cardiovascular events, and decreasing the progression of atherosclerosis.
• Starting at age 55, twice-yearly siRNA treatment reduces LDL by 52%.
• Injectables ensures compliance.

Targeting the PCSK9 pathway: Where do novel therapies fit in?

• Inclisiran-the first-in-class siRNA is EU and FDA approved for LDL lowering in two doses per year.
• Gene editing therapy inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis by RNA interference.
• Blocking PCSK9 synthesis reduces LDL levels and is one of the most sought after novel approaches investigated by pharmaceutical firms.

Addressing the unmet needs in LDL-C lowering- What can we expect?

• According to evidence, the combination of ezetimibe, bempedoic acid, and inclisiran is more effective in reducing LDL-C levels.
• At their maximum dose, statins have several drawbacks.
• Novel agents, such as the CETP inhibitor Obicetrapib, as well as oral PCSK9 modulators, have showed encouraging outcomes

2022 ESC Guidelines on ventricular arrhythmias and sudden cardiac death

• Genetic testing and genetic should be undertaken in patients with clinical suspicion or clinical diagnosis of catecholaminergic polymorphic ventricular tachycardia.
• It is advised that public access defibrillation be made available in areas where cardiac arrest is more prone to occur.
• Promoting community training in basic life support is advised to boost bystander CPR and AED use.

2022 ESC Guidelines on cardio-oncology

• Features 272 new guidelines for the definition, diagnosis, treatment, and prevention of cancer therapy-related CV toxicities, as well as the management of CV induced directly or indirectly by cancer.
• Echocardiography is suggested as the first-line modality for assessing heart function in cancer patients, with csrdiovascular magnetic resonance being evaluated when echocardiography is unavailable or undiagnostic.
• Cancer and CV symptom burden, cancer prognosis, cancer therapies needing alternative solutions, drug-drug interactions, and patient preferences should all be considered when making treatment decisions.

2022 ESC Guidelines on pulmonary hypertension

• It is suggested for all individuals with suspected pulmonary hypertension to get transthoracic echocardiography guidance for right heart imaging (TTE).
• Right heart catheterization is recommended to confirm the diagnosis of pulmonary hypertension (particularly PAH or CTEPH) and to support treatment options.
• Initial combination treatment with PDE5i and an endothelin receptor antagonist is advised in individuals with IPAH/HPAH/DPAH who are at low or intermediate risk of mortality.

2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery

• Patients with CVD, CV risk factors (including age >65 years), or symptoms indicative of CVD should utilize hs-cTN or hs-CTN I before immediate or high risk NCS, as well as at 24 and 48 hours thereafter.
• Individuals with CVD, CV risk factors (including age >65 years), or symptoms indicative of CVD should have BNP or NT-proBNP measured before intermediate and high risk NCS.
• It is not advisable to start beta-blockers before non-cardiac surgery on a regular basis.

Results of the treatment in the morning versus evening (TIME) study

• TIME study is pragmatic, decentralised, large study comparing the effects of evening vs. morning dosage on CV outcomes.
• Allocating antihypertensive medicine to the evening dose did not enhance the primary endpoint.
• Patients can be instructed that they can take their antihypertensive medicine in the morning or evening because the timing has no effect on cardiovascular outcomes.

SECURE – Secondary prevention of cardiovascular disease in elderly

• A polypill therapy regimen comprising aspirin, atorvastatin, and ramipril resulted in fewer recurrent cardiovascular events after myocardial infarction, likely due to greater adherence.
• The polypill method is safe to use, with no differences in adverse events between groups.
• Using a cardiovascular polypill as a substitution approach might be an important component of the global strategy to improve secondary prevention.

PERSPECTIVE –Efficacy and safety of sacubitril/valsartan compared to valsartan on cognitive function in patients with CHF and HFpEF trial

• Sacubitril/valsartan did not affect cognitive function assessed during a comprehensive battery of tests in an adequately powered, blinded, 3-year randomised trial
• Beta-amyloid deposition in the brain was less in patients treated with Sacubitril/valsartan compared to valsartan.
• There was no evidence of an increased risk of cognitive impairment by neprilysin inhibition related to beta-amyloid accumulation in the brains of individuals with HFmrEF/HFpEF.

Interventional solutions for heart failure

• The FDA has approved an innovative treatment for heart failure called Baroreceptor Stimulation, which relieves symptoms of HFrEF.
• Baroflex Activation Therapy (BAT) reduces sympathetic activity while improving parasympathetic activity.
• In BEAT HF trial, the BAT improved the quality of life and NT-pro-BNP considerably.

Myosin inhibitors in hypertrophic obstructive cardiomyopathy

• Mavacamten is the first in class for inhibiting cardiac myosin and lowering profibrotic gene expression.
• Mavacamten is authorized by the FDA in the United States under the REMS program; nevertheless, medication interactions must be avoided.
• The REDHOOD study revealed that Aficatem is a next-generation agent that reduces hypercontractility

The beginning of the end for NOACs? The extra mile

• NOACs are an effective therapy option for stroke in individuals with NVAF, diabetes, and compromised renal function.
• NOACs are recommended for the treatment of cancer associated thrombosis by clinical recommendations like as ISTH, ASCO, ESC, NCCN, and ITAC.
• When compared to LMWH, patients taking a NOAC have greater effectiveness and a comparable overall major bleeding risk.

Personalized Pharmacotherapy for Patients with T2D

Blonde L, talked about pharmacotherapy of T2DM patients in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 14^th May, 2022. According to AACE 2020 and ADA 2022 guidelines, if patients have established or high risk for ASCVD, HF and/or CKD, then independent of glycemic control, targets and/or treatment [including metformin use] a GLP1-RA or SGLT2i with proven efficacy/benefit for the individual patient’s condition[s] is recommended as part of the glucose lowering regimen and comprehensive cardiovascular risk reduction. In SGLT2i CVOTs, EMPA-REG OUTCOME and CANVAS trials showed higher CV event rates as compared to DECLARE-TIMI 58, VERTIS CV. Also, SGLT2i showed non-significant results in non-fatal stroke in these 2 trials. GLP-1RA CVOTs showed that SUSTAIN-6 and REWIND trials had 39% and 24% RRR resp. in non-fatal stroke. In the IRIS (Insulin Resistance Intervention after Stroke Trial), Individuals with insulin resistance but no diabetes, recent history of ischemic stroke or TIA randomized to receive pioglitazone or placebo. Primary outcome of fatal or nonfatal stroke or MI occurred in 9% of those receiving pioglitazone vs. 11.8% of placebo group (p=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%) resp. (p<0.001). Pioglitazone associated with lower risk of stroke or MI and of diabetes but higher risks of weight gain, edema, and fracture. Low doses of pioglitazone <45 mg/d showed much of benefit with reduction in stroke , MI and new onset diabetes with less AEs other than fractures as compared to full dose. Empagliflozin, dapagliflozin have proven benefit  canagliflozin has proven benefit [in those with diabetic  nephropathy with albuminuria]. Empagliflozin and dapagliflozin HF benefits extend to those without T2D and for empagliflozin not limited to HFrEF. VERIFY trial showed that initial metformin and vildagliptin combination slowed decline of glycemic control as compared to metformin alone or vildagliptin added after to metformin. Several major trials i.e DAPA-HF, EMPUSE, EMPEROR-Reduced, EMPEROR-Preserved showed excellent reduction in CV events.

Clinicians could enter a patient’s characteristics and see from analysis of large numbers of similar patient, how they were treated and what their outcomes were. Pharmacogenetics is a study of genetic causes of individual variations in drug response. Pharmacogenomics has simultaneous impact of multiple mutations in the genome that may determine patient’s response to drug therapy. Ultimately merger of pharmacogenetics, pharmacogenomics, clinical data, and artificial intelligence using machine learning and derived algorithms may allow prediction of adverse outcome risks and treatments that can diminish them.

Successful Co-Management between Endocrinology and Primary Care – Diabetes

Wang CCL, presented a session on diabetes management at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 14^th May, 2022. 4-Stage Progression Spectrum of Diabetes is 1) Insulin resistance 2) Prediabetes 3) T2DM 4) Vascular complications. T2D is a progressive disease in which intensification of management is needed over time. Diabetic kidney disease (DKD) may shorten life expectancy by 16 Years as compared to healthy individuals. Life span loss (16 years) with early DKD is much worse than with early CKD (6 years) or diabetes (10 years). Albuminuria can occur long before eGFR declines in DKD. Based on KDIGO 2011 guidelines, increase in urine albumin-to-creatinine ratio (UACR) and eGFR is directly associated to increase in risk of all-cause mortality. As per Lancet study, ACR is an independent and better predictor of CV mortality than eGFR across the full range of kidney function. ACR ≥10 mg/g was significantly associated with increased CV mortality, but eGFR was not until. According to ADA 2022 and AACE 2020 guidelines, GLP-1 RAs can be used in place of metformin, if metformin is contraindicated or adverse events  interfere or as part of initial combination therapy with  metformin if A1C is 1.5%-2.0% above  recommended levels or after metformin to avoid weight gain or hypoglycaemia. GLP1-RA and SGLT2i are preferred choice to minimize weight gain or promote weight loss. GLP1RA, SGLT2i, DPP-4i, TZD can be used to minimize hypoglycaemia. In people with T2D and ASCVD, GLP1-RA has proven CVD benefit and SGLT2 inhibitor can be used if eGFR is adequate. SGLT2 reduced HF and/or CKD progression if eGFR is adequate and GLP-1 RA is used if SGLT2i is contraindicated, not tolerated, or eGFR not adequate in T2D patients with HF and CKD. As per Lancet 2019, renal function decline was slowed with SGLT2 by 33% to 66% which showed improved renal outcomes in CVOTs. Major diabetes complications increase with age. Older patients had higher rates of eGFR and albuminuria. Severe hypoglycemia is associated with a higher risk of mortality. Also, hypoglycaemia increases the rate of thrombosis in T2D patients.

Diabetes treatment can now be individualized with we can now treat diabetes, not just chase blood sugar. Diabetes medications have glycemic benefit, but many also have cardiovascular and renal benefits. Hypoglycemia should be discussed at every visit: ask questions and review glucose data. New glucagon formulations make treatment easier, faster, and safer. Choose medications with lower hypoglycemia risks. A1C alone is insufficient for detecting hypoglycaemia. A1C is the OLD standard. CGM is the NEW standard.

Pharmacotherapy for Weight Management: Present and Future

Lofton H, presented a session on pharmacotherapy for weight management at American Association of Clinical Endocrinology (AACE) Annual Meeting on 14^th May, 2022. NIH Consensus Statement on Pharmacotherapy for Weight Management includes:

• Adjunct to a comprehensive weight-loss programme that includes nutritional counselling and physical activity
• BMI of 30 kg/m²
• BMI of 27 kg/m² with concomitant obesity-related risk factors or diseases

Newer agents introduced for weight management includes phentermine/topiramate, buproprion/Naltrexone XR, Liraglutide, Cellulose/Citric acid, and Semaglutide. The potential side-effects of phentermine/topiramate include paresthesia, dizziness, dysgeusia, insomnia, constipation, dry mouth and laboratory abnormalities may include metabolic acidosis, elevated creatinine, and lowering of glucose levels. The potential adverse events of buproprion/Naltrexone XR include nausea, constipation, headache, vomiting, dizziness, insomnia, and dry mouth.

Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist and the potential side-effects of Liraglutide are nausea, diarrhoea, constipation, vomiting, headache, etc. Semaglutide causes a significant reduction in body weight as compared to placebo over a period of 68 weeks and was able to achieve ≥20% of weight loss in comparison to placebo. 

To conclude, there are medications in pipeline such as Tirzepatide which has a GLP/GIP mechanism with patient experiences such as delayed gastric emptying, greater satiety, and increased energy expenditure. The administration is subcutaneous weekly and weight loss of 7-9.6Kg in T2DM. Another molecule is Cagrilintide which is a amylin analogue and has weekly subcutaneous administration.

Successful Co-Management between Endocrinology and Primary Care – Thyroid

Pearce E, presented a session on thyroid management at American Association of Clinical Endocrinology (AACE) Annual Meeting on 14^th May, 2022. Common thyroid problems are Hypothyroidism, Hyperthyroidism (thyrotoxicosis), and Nodular thyroid disease. The ways to detect these thyroid problems are hormonal levels, testing of antibodies, and radiology and pathology. 

Causes of Hypothyroidism are autoimmune thyroiditis (Hashimoto’s – most common), Previous thyroid surgery and/or therapy, iodine deficiency, and drug-induced. The treatment of choice in Hypothyroidism is levothyroxine (LT4). Use of LT3/LT4 combinations is not supported by evidence and T3-containing therapies should never be used during pregnancy. As soon as the pregnancy is announced, hypothyroid women should be advised to increase their LT4 dose by 25-30% which can be done by increasing their dose by 2 tablets weekly.

The medical management of hyperthyroidism includes MMI as a first-line agent (except in early pregnancy) and optimal treatment is for a period of 12-18 months. Thyroiditis is an Inflammatory destruction of thyroid follicular cells which has subacute and painless/post-partum phases. In the thyrotoxic phase of painless sporadic and postpartum thyroiditis, beta-blockers are recommended in the symptomatic treatment. In the symptomatic, hypothyroid Phase, treat with L-T4 for 6 months; then withdraw to determine whether thyroid function has normalized. Patients with thyroid nodules should be monitored closely and biopsy/re-biopsy need to be reconsidered if tumor grows > 50% in volume and > 20% increase in at least two nodule dimensions with minimal increase of 2 mm

In conclusion, there is no evidence to support LT3/LT4 combination therapy and Methimazole is preferred antithyroid medication over PTU and treatment is not required in all elderly patients with abnormal TSH.

Medical Management of Obesity Post-Bariatric Surgery Anti-Obesity Medications

Soleymani T, talked about obesity management after bariatric surgery in session at American Association of Clinical Endocrinology (AACE) Annual Meeting on 14^th May, 2022. The main objectives are to identify Weight Regain & Insufficient Weight Loss in post-bariatric population, understand the role of anti-obesity drugs in the post-bariatric surgery, and identify the factors contributing to the selection of anti-obesity medications. Insufficient weight loss is defined as <50% excess weight loss at 18 months and there is no standard definition of weight regain.

The prevalence of weight regain post-LAGB, post-LSG, Post-RYGB are 38%, 27.8%, 3.9% respectively. The prevalence of insufficient weight loss post-LSG is 32-40% and post RYGB, AGB, and LSG combined is 20%. The underlying causes of WR and IW are hormonal, nutritional factors, physical inactivity, behavioural and anatomical factors, and genetics.

The prevention and management strategies include a multidisciplinary approach that consists of obesity Medicine Specialist, metabolic and bariatric surgeon, Dietitian, Behaviorist, Exercise trainer. The treatment options include bariatric surgery revision, endoscopic procedure, and anti-obesity medications. In a study of 319 patients with WR or IR, Topiramate demonstrated a statistically significant response for weight loss and were twice as likely to lose 10% of weight. In post-bariatric surgery weight management, when AOM was started at weight loss plateau, from pre-surgery to their new nadir weight, participants shed a higher percentage (41.2%) of their total body weight. When AOM initiated after weight regain, patients lost lesser percentage (−27.1%) of total body weight from pre-surgery to their new nadir weight

To conclude, weight regain after bariatric surgery is not uncommon and AOM are used for WR and IR. The best time to initiate AOM appears to be at postsurgical nadir weight OR when weight plateau is reached and post-operative bariatric patients treated with two or more anti-obesity medications have shown greater weight loss.

Use of SGLT2 Inhibitors in the Inpatient Setting

Gianchandani R, presented a session on SGLT2 inhibitors use in inpatient setting at American Association of Clinical Endocrinology (AACE) Annual Meeting on 14^th May, 2022. Mr. T is a 60-year-old patient was diagnosed with non-ischemic heart failure with a decreased ejection fraction three months ago. Shortness of breath and exhaustion led to my first hospitalisation. T2DM for 5 years, successfully controlled with metformin and a healthy lifestyle (A1c- 6.8%). During admission, metformin was held. Prior to this hospitalisation, HF is titrating diuretics, ACEIs, and other cardiac medicines and cardiology team wants to start SGLT2 inhibitor while inpatient.

SGLT2 inhibitors works by reducing MACE events, heart failure and DKD. As per ADA algorithm of T2DM treatment based on co-morbidities, SGLT2i have proven benefits in the HF population.

As per DAPA-HF and EMPA-Reg, after SGLT2 Inhibitor initiation, effects were rapidly apparent within 4 weeks and sustained benefit was observed for 24 months. As per EMPA-Reg trial, Empagliflozin caused improvement in NYHA functional class at 28 days and sustained effect was observed for 52 weeks. As per SOLOIST Trial, Sotagliflozin was administered during or immediately after discharge (>50%). Hospitalizations and urgent visits for HF and CV fatalities have decreased. Patients with acute HF randomization within 3 days of hospitalization, had both new and chronic HF patients in trial, and had few patients with HFrEF and HFpEF. As per DARE-19 trial, 88% recovery was achieved with dapagliflozin as compared to 85% with placebo.

To conclude, starting SGLT2 inhibitors provides synergy with ongoing HF medications and maximises time of clinical benefit. It decreases hyperkalemia risk and time to benefit is reduced.

The Efficacy and Risks of SGLT2 Inhibitors

Rasouli N, presented a session on efficacy and risks of SGLT2is at American Association of Clinical Endocrinology (AACE) Annual Meeting on 14^th May, 2022. The efficacy of SGLT2 inhibitors focuses on glucose lowering effects, cardioprotective effects, renal protection effects post MI and atrial fibrillation. Dapagliflozin and ertugliflozin were noninferior to empagliflozin and canagliflozin in reducing the composite outcome of MACE by 14%. People with T2D and established ASCVD benefit more from the cardioprotective benefits and the cardio-protective effects are not dose-dependent.

The heart failure quadruple therapy includes ARNI, beta-blockers, MRA, and SGLT2i. In individuals with T2D, all SGLT2 inhibitors reduce the incidence of HF hospitalisation and CV death. In people with HFrEF, dapagliflozin and empagliflozin lower the risk of HF hospitalisation and CV death regardless of T2D diagnosis. In persons with HFpEF, independent of T2D diagnosis, empagliflozin lowers the risk of HF hospitalisation and CV death.

One thing to keep in mind is that all SGLT2 inhibitors carry a ketoacidosis warning and the DKA occurred at an incidence of 0.6 to 2.2 occurrences per 1000 person-years in participants randomised to an SGLT2 inhibitor. The high-risk population includes ketogenic diets, history of alcohol abuse, history of severe gastroparesis and recurrent vomiting, patients who abruptly stop their insulin, hospitalized for major surgical procedures or acute serious medical illnesses. Ketone monitoring should be employed in high-risk population. Dapagliflozin and empagliflozin have not been associated with an increased risk of lower limb amputation

To conclude, SGLT2i have modest glucose-lowering effects and recommended as the first line therapy in T2D patients with HF. SGLT2i is part of quadruple therapy for HFrEF independent of the dx of DM.

Diabetic Muscle Infarction: An Uncommon Diabetic Complication with a Lack of Standardized Treatment

Suarez C, presented a session on diabetic muscle infarction at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 14^th May, 2022.  Diabetic muscle infarction (DMI) is a rare but deadly condition that has been linked to poorly managed diabetes. An African American man with end-stage renal failure presented with an unusual case of diabetic muscular infarction (ESRD) is presented. The difficulties in diagnosing and treating this uncommon illness are discussed.

A 42-year-old African-American man with uncontrolled type 2 diabetes and ESRD went to the hospital with acute new-onset right lower limb discomfort and swelling. The anterior medial thigh of the right lower leg was indurated, sensitive, and swollen, with pitting oedema and warmth to touch over the whole length of the thigh but sparing the inguinal and perineal regions, as well as the knee. The diagnosis of DMI was reached on clinical grounds, based on the patient’s history of poorly controlled diabetes, as well as the patient’s presentation and MRI findings. Low-dose aspirin, acetaminophen, and tighter glycemic control were given to the patient.

Following up with the patient, it was discovered that his thigh pain had improved, but the right thigh swelling had persisted for about 2-3 months. NSAIDs were avoided due to his ESRD with residual function. DMI is a rare diabetes complication that was first recorded in 1965. It’s most common in people who have advanced, poorly managed diabetes, with a mean HgA1C of 9.34% at the time of diagnosis. Although this ailment is usually self-limiting, NSAID treatment has demonstrated to have a faster healing time than bed rest alone, PT, or surgery. In individuals with renal illness, NSAID use may be restricted, thus pharmaceutical options should be investigated.

Diabetic myonecrosis, also known as muscular infarction, is a rare but serious illness that doctors must be aware of, given the rising frequency of diabetes mellitus. Due to its broad differential, it can present with a variety of clinical symptoms and can be difficult to identify. A clinical diagnosis can be made and validated with suggestive MRI results.

Triglycerides as a Factor in Residual ASCVD Risk

Brinton EA, talked about high TG and ASCVDin a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 13^th May 2022. In PROVE IT-TIMI 22 trial, TG ≥150 mg/dL predicts higher CHD risk despite LDL-C<70 mg/dL on statin therapy. 50-80% of  CVD still  occurs despite  statin monothearpy;  much of that  residual relates to high triglycerides (HTG). In MIRACL clinical trial, even normal to mildly-elevated TG associates with increased CVD Risk by 25-50%. AHA stated that a meal that contained up to 15 g of fat  was associated with  minimal (20%) increases in peak postprandial TG levels,  whereas high-fat meals (ex. 50 g),  including those served in  popular fast-food restaurants, increased TG levels by at least 50% beyond fasting levels. Since TG-lowering medicines lower TG levels by only 20%-50%, the noise in non-fasting TG is minimal. According to IMPROVE-IT and FOURIER 2021 studies, Apo B predicts MI risk better than TG or Non-HDL-C. REDUCE-IT study showed that pure EPA plus statins significantly decreases the risk of CVD. In TG-Lowering Omega-3 CV Outcome Trials, low-dose EPA+DHA Mix (as diet-Supplement or therapy) showed no decrease in CVD. EPA increases heme oxygenase-1 expression, potentially increasing anti-oxidant/cytoprotective effects and  preserves vascular endothelial function post il-6 exposure compared to DHA or AA. Proteomic analyses show that EPA downregulates pro-inflammatory proteinsand upregulates anti-inflammatory proteins but DHA does the opposite (like the pro-inflammatory IL-6 control). Pure EPA (IPE) is better than EPA + DHA Mix. Fibrates appeared to decrease CVD in patients with DM2/HTG/Low HDL-C but PROMINENT was negative. It seems appropriate to conclude from PROMINENT that fenofibrate is NOT useful for ASCVD prevention in HTG/Low HDLC patients. IPE is the only proven agent to decrease ASCVD in HTG/Low HDLC.

HTG patients have increased ASCVD risk by many mechanisms. Total TG, Non-HDLC (& apo B, if available) were used to assess the CV risk.  Advanced lipid measurements are controversial; Apo B is very good but required extra test/money. Others (sd LDL, direct RLPC, VLDLP+IDLP, LDLP, etc.) can be inferred from TG & Non-HDLC and are likely not worth it, yet. To treat patients with HTG to lower ASCVD risk, always encourage diet and lifestyle first, manage diabetes (w/ pio, SGLT2i, GLP1-RA), obesity, high blood pressure. Statins are 1st-line in essentially all patients. If the TG is still >~135 mg/dL fasting (or >150 non-fasting), add IPE, if at all possible, Rx “DAW/brand only, generic IPE not indicated to decrease ASCVD or for TG <500.

Ethnic Diversity for Cardiovascular Disease Risks in South Asia

Hoang TD, presented the cardiovascular data of South Asians in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 13^th May 2022. The objective of the session was to review cardiovascular data available for South Asians and discuss treatment strategy for South Asian patients. South Asia (SA) is most densely populated regions on the planet and showed higher hospitalization and mortality rates from ASCVD compared with NHWs and other racial/ethnic minority groups. Indian men showed higher mortality than women CTA showed increase percentage stenosis and involvement of multiple vessels.  Also, younger asians showed higher prevalence of DM and dyslipidemia compared with NHWs. SA more likely to have multivessel disease requiring CABG. Outcomes after PCI are generally similar in SA and NHWs. Some studies evaluating CV events and mortality after isolated CABG showed consistently poorer outcomes for SA. Statin is the mainstay therapy for hypercholesterolemia in South Asians. The suggested LDL-C goal is <100 mg/dL for high risk patients and < 70 mg/dL for very high risk. The LAI recommends an LDL-C goal < 50 mg/dL in all patients in secondary prevention or very high risk primary prevention but proposes an optional goal ≤30 mg/dL in extreme-risk patients (eg, coronary artery disease + familial hypercholesterolemia).

Rosuvastatin and Atorvastatin are well tolerated and effective in this population. Ezetimibe lowers plasma LDL-C by inhibiting the activity of NPC1L1 protein, resulting in reduced intestinal cholesterol absorption. IMPROVE-IT study exhibited that adding ezetimibe to simvastatin leads to 24% more LDL-C reduction. AIM-HIGH and HPS-2 THRIVE studies showed no incremental clinical benefit with Niacin. No South Asian studies have been conducted on the effects of niacin on CV outcomes. Statins primarily target LDL-C. Fibrates preferentially increase HDL-C, lower TG, and increase size of LDL-C particles particularly beneficial for South Asians.

In South Asians of US, evidence to date confirms the higher burden of CVD. It is recommended to use the QRISK3 calculator in clinical decisions to reduce CVD risk as early as childhood years and encourage healthy lifestyle in SA. Early recognition and treatment of CV risk factors is necessary to mitigate the CVD burden in SA. Imaging techniques (CAC) are significant for accurate risk stratification. Community strategies should be applied such as educate, promote health literacy and provide culturally competent health care.

Glycemic Monitoring and Use of Glucose Lowering Agents in Advanced CKD

Galindo RJ, presented a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 13^th May 2022. The session covered the current status of end stage kidney disease (ESKD) in diabetes mellitus (DM) patients, glycemic monitoring i.e. HbA1c, Glycated Albumin, Fructosamine, or CGM (goals) in advanced CKD, role of glucose lowering agents; orals, non-Insulin agents, Insulin, AIDs for advanced CKD. Insulin and glucose metabolism in CKD is altered and leads to increased risk of both hyperglycemia. hypoglycemia. According to KDIGO 2020, accuracy and precision of HbA1c measurement declines with advanced CKD (G4-G5), particularly among patients treated by dialysis in which HbA1c measurements have low reliability.

A glucose management indicator (GMI) derived from CGM data can be used to index glycemia for individuals in whom HbA1c is not concordant with directly measured blood glucose (BG) levels or clinical symptoms. Daily glycemic monitoring with CGM or SMBG may help to prevent hypoglycemia and improve glycemic control when antihyperglycemic therapies associated with risk of hypoglycemia are used. An individualized HbA1c target is recommended ranging from <6.5% to <8.0% in patients with diabetes and CKD not treated with dialysis. Linagliptin (no renal adjustment) (+/- basal insulin) or Sitagliptin is recommended for mild hyperglycemia. Repaglinide (short acting, ~4-5 hrs) or short-acting insulin can be given for meal related hyperglycemia. GLP1 agonists with proven CKD benefits are Dulaglutide, Semaglutide weekly and Liraglutide daily. As per AWARD study, Dulaglutide showed eGFR decline ≥40% or reduction in ESRD vs Insulin glargine.  Insulin therapy is not shown to prevent progression of DKD. Starting with lower doses (0.25 units total daily dose), combine basal insulin with non-insulin agents, mixed insulin (70/30% or 75/25%) or BASAL – BOLUS should be the last option.

There is critical need for better glycemic monitoring in advanced CKD (1-2 finger sticks per day do not provide the full picture). CGM (eGMI) may overcome the limitation of HbA1c in this population and provide a more detailed assessment of glycemic excursion. Avoid over-insulization (higher risk of hypo and hyper crises). More studies and information is required on newer drugs DPP4 inhibitor, GLP1 agonist and devices in ESKD.

 A Blind Spot: Weight Bias and Health Disparities in Obesity Care

Kahan S, presented a session on weight bias in health care at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 13^th May 2022. Weight Bias is making (negative) assumptions or judgments (consciously or unconsciously) based on the appearance ofexcess weight. Persons with obesity are societally considered acceptable targets of stigma. As BMI increases patients receive less respect. 7 A’s” to address weight bias in healthcare are: 

• Appreciate the complexity of obesity
• Awareness of implicit assumptions and beliefs
• Attention to what’s in our control
• Appreciate that shaming doesn’t motivate
• Support patients’ Autonomy
• Address consequences of stigma
• Advocate and Educate

Implicit anti-fat bias 2001 study stated that Implicit Association Test (IAT) indicated that more items were correctly classified when fat people was paired with negative attributes than with positive attribute. In attention to weight bias following points should be implemented:

• Provide wide-based, higher weight capacity chairs or consider specialized bariatric chairs, when possible
• Offer large (or thigh-sized) blood pressure cuffs and neutral waiting room literature
• Offer extra-large gowns and educate your staff about obesity and weight bias

Respondents who perceived judgment were significantly more likely to attempt weight loss. Among patients whose primary care providers (PCP) discussed weight loss, 20% achieved ≥10% weight loss if they did not perceive judgment by their PCP as compared to 14% who perceived judgment.

A RCT showed that a psychological intervention for weight bias internalization (WBI) produced short term reductions in weight self stigma in person with obesity. People should be advocated and educated about the complexity of obesity. Be an advocate in your practice hospital, community, and with your peers, advocate to policymakers and challenge weight bias in the public.

Weight bias refers to a wide range of discriminatory and harmful attitudes toward people deemed to be overweight. It can include beliefs such as  that heavier people are usually unhealthy,  having excess weight is easy to modify and is usually a person’s fault. Healthcare professionals are biased against people deemed as having overweight or obesity.  It is also important to note that people with obesity can be healthy. Regardless of their weight or health practices, all people need access to quality, compassionate healthcare professionals who will not guilt, shame, or judge them.

Diagnosis and Investigation of Diabetes Insipidus

Kahric NJ, presented in nephrogenic diabetes insipidus in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 13^th May 2022. Water is the largest component of our body and since the major determinant of body water is AVP-regulated water excretion by the kidneys, therefore AVP is the most important hormone in the body. The types of diabetes insipidus are

1. Central Diabetes Insipidus
2. Hereditary Nephrogenic Diabetes Insipidus
3. Acquired Nephrogenic Diabetes Insipidus
4. Primary Polydipsia
5. Gestational diabetes insipidus
6. Osmoreceptor dysfunction

Central (neurogenic, pituitary, or neurohypophyseal) DI is characterized by decreased secretion of arginine vasopressin (AVP). Its prevalence is rare i.e. <1:25,000. Tumors associated with central DI are craniopharyngioma, germinoma (pinealoma), meningioma, lymphoma, metastatic (lung, breast). Mutations in the AVP gene is associated with hereditary central DI (autosomal dominant). Nephrogenic Diabetes Insipidus is even less common than neurogenic DI and it is clinically evident from birth. Mutations in the AVP V2 receptor gene is associated with hereditary nephrogenic DI. Primary polydipsia is most common cause of polyuria in Western countries. Dipsogenic polydipsia reset thirst threshold (mass lesions, granulomatous disease, idiopathic, aging) and psychogenic polydipsia increased fluid intake for reasons other than true thirst. The treatment of diabetes insipidus includes: Water, Antidiuretic agents (CDI) – AVP, desmopressin (DDAVP), chlorpropamide, carbamazepine and antiduresis enhancing agents (NDI) – Diuretics (thiazides, amiloride) and Indomethacin.

The general goals of treatment of all forms of DI are correction of any pre-existing water deficits and reduction of ongoing excessive urine losses. In adults, 50% of the deficit should be corrected in the first 24 h and the remainder over the next 24-48 hrs above the estimated urine output plus insensible looses. In children, correction of hypernatremia should not exceed 12 mmol/L/24h to minimize the risk of brain edema. The volumes replaced must include not only the calculated deficit, but also ongoing insensible and urine water losses; antidiuretic therapy is usually necessary to do this in DI.

Diabetes Technologies in 2022

Sadhu A, presented a session on automated algorithm in diabetes management at American Association of Clinical Endocrinology (AACE) Annual Meeting on 13^th May, 2022. Machine Learning Algorithms in Automated Insulin Delivery (AID): Proportional Integral and Derivative (PID) – Used in various industries since 1940’s (automotive, manufacturing). Algorithm has three terms (Proportional, integral and derivative). It is a single input (CGM), single output (Insulin dose) systems. It has simpler dynamics, low computational burden. However, it uses only the current difference between measured (CGM) and desired blood glucose. Many additional modules added to predict blood glucose trends and to accommodate constraints. Constraints usually restrict the insulin dose computed by the algorithm and it is difficult to personalize the controller parameters.

AID Algorithms: Model Predictive Control (MPC) is based on advanced concepts in systems and control engineering. It has a higher computational burden caused by real-time optimization. It relies on availability of mathematical models describing glucose-insulin dynamic.

AID Machine Learning Algorithms: Fuzzy Logic- has a high cost of maintenance and revision of the rule base. As the numbers of rules are increased, conflict resolution algorithms are needed. Medical and programming expertise is needed for personalizing the system.

Three-quarters of HCPs selected cost and coverage for diabetes drugs as a barrier to improved outcomes. Similarly, cost and coverage for diabetes devices was also cited as a barrier by most HCPs, however, Endocrinologists are more likely to select this as a barrier than PCPs. Poor patient engagement/adherence with recommendations was also selected as a barrier by most HCPs. Over 40% of HCPs selected disparities in knowledge, confidence, and access to digital health resources as a barrier.

Adrenal Imaging Strategies – Which and When?

Blake M, presented a session at American Association of Clinical Endocrinology (AACE) Annual Meeting on 13^th May, 2022. Inaugural AAES Guidelines for Adrenalectomy published in JAMA Surgery 2022, includes experts in endocrinology, pathology, radiology & surgery and consists of evidence-based & consensus recommendations for surgery of adrenal disease. Also, routine follow-up of a non-functional adrenal nodule with benign imaging characteristics and non-contrast CT HU.

European Society of Endocrinology 2016, recommend establishing if adrenal mass is benign or malignant at the time of detection. If NCCT is consistent with a benign mass (HU≤10) homogeneous & 4cm, no further imaging is required.

If mass is indeterminate on NCCT & negative hormonal work-up, 3 options acknowledging patient’s clinical context: immediate additional imaging with another modality, interval imaging in 6–12months (non-contrast CT or MRI), or surgery without further delay. Imaging can help characterize many adrenal lesions including most incidentalomas. CT and MRI are the main imaging modalities.

Medical societies have some different strategy guidelines particularly regarding follow-up imaging for adrenal mass. Greater harmonization between Imaging and Endocrine Societies could lead to more consistent and optimized clinical practice.

Predictors of Type 2 Diabetes (T2D) Remission using Digital Twin Technology Based on Artificial Intelligence (AI) and Internet of Things (IoT) Technologies

Joshi S, presented a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 13^th May 2022. The objective of this study is to find pre-intervention anthropometric and biochemical characteristics that predict diabetes remission after using AI-based IoT technology, as well as post-intervention parameters that improve in remission patients.

TPT is a mobile app and intervention based on the proprietary Whole-Body Digital Twin (WBDT) enabled precision treatment. TPT was completed by 167 T2D patients over the course of 180 days. Remission was defined as an A1C result of less than 6.5 % for at least 90 days without the usage of diabetes medication. Using this criterion, 141 of the 167 patients (84.4%) experienced diabetic remission (group R).

The results of the study suggest that patients in the R group had a shorter duration of diabetes at baseline than those in the non-remission Group (NR group). For Time Below Range, the difference in change in R was better than NR after 180 days. Body weight, LDL-C, HDL-C, TGs, and sdLDL levels were all comparable at the start and after the intervention. In NR, the end mean A1C was 6.3 %, compared to 5.5% in R.

The study concludes that the diabetes remission by TPT intervention is reliably predicted and have a shorter duration of diabetes, lower A1C, eA1C, GMI, and TAR2 at baseline. TPT is a promising diabetes remission lifestyle strategy.

Updated Guidelines on Management of Primary Hyperparathyroidism

Khan A, presented about primary hyperparathyroidism in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 12^th May 2022. The primary objective was to discuss how to diagnose and treat primary hyperparathyroidism (PHPT)and manage its complications. The diagnosis of hyperparathyroidism is usually first suspected because of:

• An elevated serum calcium concentration
• Calcium to creatinine clearance ratio >0.02
• UCaX PCr / Ucr X Pca
• FHH- inactivating mutation of casr
• Mildly high Ca and PTH, hypocalciuria CCCR<0.01 ( sensitivity 85%, specificity 88% for FHH)

Symptomatic PHPT is correlated with skeletal and renal complications that may incorportae osteitis fibrosa cystica and/or fractures, chronic kidney disease, nephrolithiasis and/or nephrocalcinosis. Asymptomatic PHPT exhibits no overt symptoms; typically discovered by biochemical screening. Two forms of asymptomatic PHPT are described following analysis are with target organ involvement and without target organ involvement. In normocalcemic PHPT, skeletal or renal complications may or may not exist in those whose presentation fits this definition. PHPT can be evaluated with

• Biochemical: Measure adjusted total serum calcium (ionized if normocalcemic PHPT is a consideration), phosphorus, intact PTH, 25OHD, creatinine
• Skeletal: Three-site DXA (lumbar spine, hip, distal 1/3 radius); imaging for vertebral fractures [vertebral fracture assessment (VFA) or vertebral X-rays]; Trabecular Bone Score if available
• Renal: eGFR or, preferably, creatinine clearance, 24-hour urinary calcium and for biochemical risk factors for stones; imaging for nephrolithiasis/nephrocalcinosis. Retrospective X-sectional study in 109 PHPT patients evaluated pre and post PTX showed that PTX prevents decline in renal function
• Non-classical manifestations (neurocognitive, quality of life, cardiovascular): There are no data to support routine evaluation for these manifestations
• Genetic: genetic evaluation should be considered for patients < 30 years old, those with multi-gland disease by history or imaging, and/or those with a family history of hypercalcemia and/or a syndromic disease

Theupgraded recommendations for surgical management of PHPTare: Surgery is recommended if one or more of the following is present:

• Serum calcium > 1 mg/dL (0.25 mmol/L) above the upper limit of normal
• Skeletal involvement: A fracture by VFA or vertebral X-ray or BMD by T-score ≤ -2.5 at any site or
• Renal involvement: eGFR or creatinine clearance 250 mg/day in women; > 300 mg/day in men) or Nephrocalcinosis or nephrolithiasis by X-ray, ultrasound, or other imaging modality • 6.1.3.3 Hypercalciuria (e.g. > 250 mg/day in women; > 300 mg/day in men)
• Age < 50 years (no other indications are necessary; age < 50 years is a sufficient indication)
• If no aforementioned guidelines are met, PTX is still an option with concurrence of the patient and physician and if there are no contraindications

The Ungraded Panel Recommendations  for role of non-surgical/medical management of PHPT (limited by quality of available evidence from RCT’s) are:

• Alendronate and denosumab can be used to increase bone density if there are no contraindications
• Cinacalcet can be used to reduce the serum calcium concentration into the normal range if there are no contraindications
•  
• Calcium intake/supplementation should follow the Institute of Medicine nutritional guidelines: 800 mg/day for women < 50 and men < 70 years old; 1000 mg/day for women > 50 and men > 70 years old
• Vitamin D supplementation: the panel recommends levels of 25OHD > 30 ng/mL and < the upper limit of normal for the laboratory reference range (e.g., < 50 ng/mL)
• Estrogen has been shown to increase BMD. Its effect on the reduction of serum calcium is inconsistent
• Raloxifene cannot be recommended because the data are insufficient to reach any conclusions

Updated recommendations of management of PHPT during pregnancy are:

• Mild cases should be managed by maintaining good hydration and monitoring calcium levels
• Bisphosphonates and denosumab should not be used
• Data are very limited on use of cinacalcet
• Consider surgery in the 2nd trimester for patients with serum calcium > 11.0 mg/dl and for whom surgery is not contraindicated
• Preoperative imaging should be limited to ultrasound
• If surgery is deferred, the neonate should be closely monitored for hypocalcemia
• If surgery is deferred, PTX should be done after delivery, and before a subsequent pregnancy

PTX is an appealing choice for asymptomatic PHPT. Those not meeting the revised guidelines or unable or unwilling to begin with surgery can be safely followed. N-BP and Dmab may yield skeletal protection. Cinacalcet decreases PTH and calcium frequently into normal range. Analysing with annual serum calcium, creatinine clearance and BMD 1-2 yrs advised.

Self-Care for the Medical Provider During a Global Pandemic

Swiner CN, talked about self care among medical provider at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 12^th May 2022. The learning objectives of the session were to evaluate how the COVID-19 pandemic has impacted our ability to achieve work-life balance, discuss how the superwo(man) complex and imposter syndrome affects us and summarize strategies to aid enhance work-life balance/integration. Researchers based their results on more than 20,000 respondents at 124 institutions across the country. Burnout, workload, fear of infection, anxiety or depression due to COVID-19 and the number of years in practice were correlated with intent to decrease work hours or leave. 1 in 5 doctors plan exit in 2 years, via AMA in Jan. 2022 due to stress, grief, getting sick, undervalued/underpaid, decreased support, overworked. If 1/3 of nurses and doctors leave, hospitals won’t have enough staff to care for patients. Burnout is the disorder of disengagement, disconnecting from work, friends, family & health. Burnout develops when someone is dealing with a high level of stress however doesn’t have access to adequate resources, such as social support, helpful advice, feedback from friends or colleagues, or control over how they spend their time. The impact syndrome is an internal experience of intellectual phoniness that appears to be especially prevalent and intense among a select sample of high achieving women. What can a person do is practicing positive self-talk, learn how to accept & believe compliments, make a strength list, remind yourself how great you are, realize that perfection is not realistic and ask for help. Self-preservation is very important aspect, set boundaries for your life, you are worthy & deserving and stop giving yourself away for free.

The strategies should be established to aid work/life balance and can include few things like  the roles of the support staff should be known, call patients only if essential, don’t let others take benefit of your kindness, have a procedure to keep up with findings, schedule f/u appointments instead of promising phone calls, and be an effective  communicator, go somewhere on vacay with precautions of covid norms, take mental health days, fire horrible patients, invest or start a business/write a book, hire support, pack a fun bag in your trunk, have allies and mentors. The ultimate strategy is to get a therapist.

Current and Future Treatments for Nonalcoholic Fatty Liver Disease (NAFLD)

Cusi K, talked about NAFLD in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 12^th May 2022. Nonalcoholic steatohepatitis (NASH) treatment is recommended in intermediate and high risk patients. Also, diabetic drugs Pioglitazone and GLP-RA were recommended in these patients of criteria. Current treatments for patients with NAFLD (not FDA approved but that can be used for patients with obesity or diabetes) were lifestyle interventions and bariatric surgery, GLP-1RA and Pioglitazone. Pioglitazone increases adiponectin (Adipose Tissue function) and reduces visceral and hepatic fat in subjects with NASH. Piogliatazone significantly decreases NASH in all patients included in RCTs (2016) and significantly lowers the risk of liver fibrosis in NASH.

 Future options to enhance the efficacy of pioglitazone and reduce weight gain are low-dose pioglitazone (15 mg/day; UF NIH study) and combination therapy: a) SGLT2i: (e.g., EMPA-REG Extend) b) GLP-1RA: (e.g., SUSTAIN-2: PIO + semagutide). Low dose pioglitazone is associated with minimal weight gain in patients with T2DM.

The dual obesity and diabetes epidemics will worsen in the coming decade and will further fuel the epidemic of NASH and liver cirrhosis. NASH cirrhosis may be prevented by early diagnosis in PCP and endocrinology clinics, but still significant clinical inertia exists. Current treatments remain underutilized to treat obesity and T2DM. They reverse the fundamental defects associated with obesity (excess fat mass; GLP-1RAs) and with T2DM (dysfunctional adipose tissue, insulin resistance; PIO) that cause NAFLD. Many treatments are in development and  potentially will be available within the next 2 years.

The Risks and Benefits of Other Therapies

Stanton RC, talked about ACE inhibitors and ARB in diabetic kidney disease in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 12^th May 2022. The aims of the session were to discuss the new ideas on the dosing of ACEi and ARBs for managing Diabetic Kidney Disease, evaluate the risks and benefits of newer hypoglycemic drugs for treatment of diabetic kidney disease (DKD), evaluate proposed mechanisms underlying renoprotection given by newer hypoglycemic drugs for DKD. Renin-Angiotensin-Aldosterone System Inhibitors are pillar of treatment for DKD. Decreasing urine albumin level is a goal for slowing progression of kidney disease and reducing CV Risk. Liraglutide lowers urine albumin level but no change in eGFR. Dulaglutide is reported to be reno-protective in AWARD-7 study but only in macro-albuminuria (UACR >300 mg/g). Based on AMPLITUDE-O Trial, Efpeglenatide is recently reported to improve kidney outcomes. GLP1 Agonists have CV benefits, lead to lowering of the urine albumin level, and appear to slow rate of decline in eGFR. FLOW Study with Semaglutide (Estimated enrollment of 3508; to be completed in 2024) will certainly aid in determining reno-protective effects of GLP-1 RA. DPP-4 Inhibitors had no clear unique renal benefit; although there may be subgroups that benefit such as people with high urine protein levels. As per CREDENCE trial, Canagliflozin slowed decline in eGFR and improved albuminuria. Dapagliflozin showed CV and renal benefits in CKD in diabetic and non-diabetic patients. The CREDENCE and DAPA-CKD Results (EMPA Kidney was recently stopped early due to positive results) combined with the positive cardiovascular results are understandably extremely exciting for new treatments for people with DM, Heart Disease, and CKD. The risks involved with SGLT2i were euglycemic ketoacidosis, genital mycotic infections, UTI, extracellular fluid volume depletion. SGLT2 Inhibitors provide highly significant benefits for people with CV disease. All recent guidelines are recommending their use as first line agents with Metformin if Diabetic Kidney Disease is present. Combination of SGLT2 Inhibitor with RAAS Inhibition may be more reno-protective as compared to either alone.

There is a world-wide epidemic of DKD. Early detection and aggressive interferences can slow the evolution and development of DKD. Currently, a very exciting era of discovery is proceeding that will continue to lead to new mechanistic insights and new treatments to manage this very serious complication of diabetes mellitus.

 Achievement of HbA1c <6.5% with ≥5% Weight Loss and without Hypoglycemia in Patients with Type 2 Diabetes Treatment with Tirzepatide: A Post Hoc Analysis of the SURPASS 1-5 Studies

Thieu V, presented a study on Tirzepatide in a session at American Association of Clinical Endocrinology on 12^th May, 2022.  Tirzepatide is a once weekly GIP/GLP-1 receptor agonist for the treatment of people with type 2 diabetes (T2D) and in phase 3 clinical trials, it showed substantial reductions in HbA1c and body weight.

In this post-hoc analysis, evaluation of SURPASS 1 to 5 studies were done to achieve a triple composite of HbA1c <6.5% with ≥5% weight loss without clinically significant hypoglycaemia or severe hypoglycaemia. At the end of the treatment, HbA1c and weight were evaluated.

The efficacy data analysis set included data from randomly assigned participants who were exposed to at least one drug. End of treatment HbA1c and weight were evaluated at week 40 (SURPASS 1, 2, 5) and week 52 (SURPASS 3, 4). Hypoglycaemia was evaluated post baseline up to Week 40 (SURPASS-1, -2, -5) or Week 52 (SURPASS-3, -4).

Of the participants in SURPASS 1 to-5 treated with any dose of tirzepatide, 46-79% of patients achieved HbA1c< 6.5% with ≥5% weight loss in comparison to 2-44% of patients treated with placebo or active comparators. HbA1c <6.5% with no hypoglycemia was achieved in 58-85% of patients as compared to 8-63% of patients treated with placebo or active comparators. 39-77% achieved the triple endpoint of HbA1c <6.5%, ≥5% weight loss, and no hypoglycemia.

The results suggests that higher number of patients treated with tirzepatide achieved HbA1c <6.5% with ≥5% weight loss and without hypoglycemia compared to placebo, semaglutide 1 mg or basal insulin. The triple endpoint of HbA1c, weight loss and no hypoglycaemia was achieved by more than 50% of patients for tirzepatide 10 and 15 mg dose.

Diabetes Mellitus and COVID-19: A Not So Sweet Combination

Khine A, presented a study on severity of COVID-19 infection and HbA1c levels in a session at American Association of Clinical Endocrinology on 12^th May, 2022. The risk factors for increased severity of COVID-19 infection are diabetes mellitus and hyperglycaemia. However, the connection between DM and COVID-19 is not well understood.

The objective of the current study is to investigate whether there is any correlation between HbA1c levels and COVID-19 infection severity. The primary outcomes assessed was mortality and the secondary outcomes assessed were need for intubation, need for intensive care unit (ICU) level of care, increased hospital length of stay.

The study was conducted as a retrospective cohort study with a total of 317 patients. The results of the study suggest that there is no significant correlation between elevated HbA1c and severity of COVID-19 infection. No significant correlation with found with mortality, need for intubation, need for ICU level of care and increased hospital length of stay.

The study concludes that further studies are needed to identify possible predictors of COVID-19 severity in order to appropriately manage these patients.

Use of Sulfonylurea Based on Diet Recall

Panchal D, presented a study on use of sulfonylurea base on diet in a session at American Association of Clinical Endocrinology on 12^th May, 2022. When it comes to possibility of hypoglycemia, sulfonylureas are the most potent oral diabetes agents and to avoid hypoglycaemia, sulfonylurea agent has to be selected based on diet composition and pattern of the patient.

In this study, sulfonylurea group of drugs were offered to type 2 diabetes patients not able to achieve glycemic goal with maximum tolerated dose with two non-sulfonylurea group of oral anti-diabetes agents for 3 months. Sulfonylureas were used based on patients’ diet, particularly meal pattern and carbohydrate percentage in each meal. A total of 286 patients were included in this trial. These patients were divided into three groups:

• Group A with three major meals per day consists of 228 patients
• Group B with two major meals per day consists of 42 patients
• Group C with one major meal per day consists of 16 patients

The results of the study suggest that 72.7% (281) patients were able to achieve target HbA1c at 3 month and 88.1% (254) patients achieved target HbA1c at six months.

The study concludes that the use of sulfonylurea drugs as per the diet pattern particularly meal pattern and percent of carbohydrate, can achieve glycaemic control with minimum risk of hypoglycaemia in type 2 diabetes patients.

Energy Metabolism in a Weight Reduced State

Jakicic J, presented a study on the components of energy expenditure in a session at American Association of Clinical Endocrinology on 12^th May, 2022.  The components of energy expenditure are voluntary structured physical activity, voluntary non- structured physical activity, non-voluntary physical activity, thermic effect of food, and resting energy expenditure.

The 24-hour physical activity spectrum consists of low-energy expenditure at the extreme left and high-energy expenditure at the extreme right. The spectrum consists of sleep, sedentary behavior, light intensity physical activity, moderate intensity physical activity, and vigorous intensity physical activity.

With moderate dietary restriction, physical activity can enhance short-term weight loss by 20-25% which is above what can be achieved with the moderate dietary restriction alone. If there is a severe dietary restriction, physical activity will have minimum effect on weight loss above what can be achieved with severe dietary restriction.

When it comes to sleep, get adequate amounts of volume and quality of sleep, decrease sedentary behavior to increase light moderate and vigorous intensity physical activity. Light physical activity includes engaging in lifestyle, household, and occupational activity to enhance light intensity physical activity. Moderate and vigorous intensity physical activity engaging in leisure-time moderate-to-vigorous physical activity, and when possible, increase moderate-to-vigorous household and occupational physical activity.  

The given results suggest that as physical activity increases in terms of moderate to vigorous physical activity, weight loss occurs. The 24-hour physical activity spectrum consists of low energy expenditure activities and high-energy expenditure activities.