Deighton AM1*, Szabo SM1, Korpach S1, Donato BMK2.
1 Broadstreet Health Economics & Outcomes Research, Vancouver, BC, CAN;
2 Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
Purpose: Obesity is highly prevalent in the US; and is linked to numerous other comorbid conditions, including type 2 diabetes mellitus (T2DM) and hypertension. Due to its prevalence and also the severity of associated complications, management of obesity is costly. However, even modest weight loss (5-10%) is associated with improvement in obesity-linked comorbidities. The aim here was to investigate the impact of changes in weight on the total costs of care among overweight and obese adults; with a particular focus on savings related to averting obesity-linked comorbidities.
Methods: A targeted review was performed using Medline/EMBASE to identify relevant publications of observational studies and economic models from the past 10 years. The focus was on data describing the impact of obesity and its complications on total costs of care in the United States. Available data were tabulated, and a gaps analysis performed.
Results: From 3,222 records identified, 63 manuscripts and 2 conference abstracts were included. Most studies reported on the total cost of care attributable to obesity by body mass index, or by the presence of comorbid T2DM. Data on costs associated with other obesity-linked comorbidities or according to the number of obesity-linked comorbidities present per patient, were sparse. However, available estimates highlighted the substantial incremental per person cost increase with the increasing number of comorbidities present. One study showed that patients with obesity, T2DM, hypertension, and depression incurred almost 7 times the cost of a person with obesity alone, which was largely driven by inpatient costs. Several economic model publications were identified that estimated total direct medical cost savings (overall and by obesity-linked comorbidity adverted) associated with weight loss. While modest weight loss was associated with substantial costs savings, additional and sustained weight loss lead to further reductions in costs.
Conclusions: Obesity does not occur in a silo; a recent US database study reported that up to 75% of overweight and obese adults have 2 or more obesity-linked comorbidities. Both obesity and its complications are challenging to manage, and are associated with extensive healthcare resource use and substantial costs. While many studies have documented the health benefits of modest weight loss in preventing downstream health outcomes, few have quantified the effect that this has on reducing costs. Future studies are needed to help document and quantify the cost of obesity-linked comorbidities over time.
Limor Ouzel-Yahalom*, Joshua A. Levine
Eli Lilly and Company, Indianapolis, IN, USA
Purpose: Tirzepatide, a novel, once-weekly, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, was recently approved in the US for the treatment of type 2 diabetes (T2D). The efficacy and safety of tirzepatide has been assessed in five global Phase 3 trials from the SURPASS program in a broad T2D population across the treatment continuum. The objective of this review is to summarize the Results from the completed SURPASS trials.
Method: Changes from baseline in glycosylated hemoglobin (HbA1c), fasting serum glucose, body weight, and proportion of of participants achieving HbA1c values of <7.0%, ≤6.5% and <5.7% (i.e., normoglycemia) were assessed in participants treated with tirzepatide (5 mg, 10 mg or 15 mg) from the SURPASS-1 (monotherapy vs placebo), SURPASS-2 (add-on to metformin vs semaglutide 1 mg), SURPASS-3 (add-on to metformin ± sodium glucose cotransporter 2 inhibitor [SGLT2i] vs insulin degludec), SURPASS-4 (± metformin ± sulfonylurea ± SGLT2i vs insulin glargine) and SURPASS-5 (add-on to basal insulin vs placebo) clinical trials. Study endpoints were 40 weeks for SURPASS-1, SURPASS-2, and SURPASS-5 and 52 weeks for SURPASS-3 and SURPASS-4. Safety was also assessed. Treatment comparisons were estimated using data while participants were on treatment and without rescue medications (i.e., efficacy estimand).
Results: In the Phase 3 SURPASS clinical trials in people with T2D, tirzepatide at doses of 5 mg, 10 mg and 15 mg demonstrated superior reductions in HbA1c, ranging from -1.87% to -2.59% compared to placebo (-0.93% to +0.04%), semaglutide (-1.86%), insulin deluded (-1.34%), and insulin glargine (-1.44%) at the primary timepoints of 40 and 52 weeks. A greater proportion of tirzepatide-treated participants achieved the ADA/EASD-recommended HbA1c target of <7.0% (81-97% of tirzepatide-treated participants) and AACE-recommended target of ≤6.5% (66-95% of tirzepatide treated participants), with 23-62% of tirzepatide-treated participants achieving normoglycemia (HbA1c <5.7%). Reductions from baseline in fasting serum glucose were significantly greater with tirzepatide at all doses (-43.6 mg/dL to -67.9 mg/dL) when compared with placebo (-38.9 mg/dL to +12.9 mg/dL) and semaglutide 1 mg (-48.6 mg/dL), and greater with tirzepatide 15 mg when compared with insulin glargine (-51.4 mg/dL). Greater reductions in fasting serum glucose were observed with insulin degludec (-55.7 mg/dL) when compared with tirzepatide 5 mg, but did not differ with tirzepatide 10 mg or 15 mg. Furthermore, tirzepatide at all doses demonstrated superior reductions in body weight, ranging from -6.2 kg to -12.9 kg (-6.6% to -13.9%) compared to placebo (-0.7 kg to +1.7 kg [-0.9% to +1.7%]), semaglutide 1 mg (-6.2 kg [-6.7%]), insulin degludec (+2.3 kg [+2.7%]), and insulin glargine (+1.9 kg [+2.2%]) at the primary timepoints of 40 and 52 weeks. The overall safety profile of tirzepatide was similar to that of the GLP-1 receptor agonist class. The most common adverse events were gastrointestinal (nausea, vomiting and diarrhea), mostly mild to moderate in severity, and decreased over time.
Conclusions: Across the diabetes treatment spectrum, tirzepatide has demonstrated significant HbA1c and weight reductions against all comparators.
Spomenka Ljubic*, Anamarija Jazbec, Ivona Cudina, Martina Tomic, Dario Rahelic
Vuk Vrhovac University Clinic, Merkur Clinical Hospital, School of Medicine, University of Zagreb
Purpose: Vitamin D deficiency is common in obese individuals, and that lower circulating concentrations may contribute to increase in metabolic risk. Absorption of vitamin B12, involved in the regulation of homocysteine (HCY) level, decreases with vitamin D deficiency. Increase in HCY level may increase cardiovascular risk (CVR), partly because of an impact on apo-lipoproteins and inflammatory markers. A possible association of vitamin D with visceral obesity and HCY was studied.
Method: HCY, 25-hydroxyvitamin D, vitamin B12, lipids, and other diabetes-related markers, including lipid accumulation product (LAP), were tested in 613 type 2 diabetic patients divided into four groups (1st group: LAP ≤ Q1; 2nd group: Q1 < LAP ≤ Med; 3rd group: Med < LAP ≤ Q3, 4th group: LAP ≥ Q3) according to LAP quartiles (Q1 = 28.5; Med = 50.59; Q3 = 80.64). LAP as an index, combining waist circumference and triglyceride, is related to risk of metabolic syndrome, diabetes and CVR. In all statistical tests: ANOVA, Tukey post hoc test, and stepwise multivariate linear regression, α=0.05 was considered as statistically significant.
Results: Significant difference in vitamin D and B12, and high-density lipoprotein (HDL) according to LAP groups was determined. HDL differed significantly between the 1st (1.56±0.27) and the 3rd (1.24±0.17), and between the 1st and the 4th (1.19±0.25) group, vitamin D between the 1st (67.21±11.87) and the 3rd (60.34±10.78), and between the 1st and the 4th (51.29±13.41) group, and vitamin B12 differed significantly between the 1st (319.33±158.71) and the 2nd (212.14±71.92) group. After stepwise regression two best predictive variables for vitamin D were glomerular filtration rate (GFR) (parR2=0.12) and LAP (parR2=0.07), for vitamin B12 HCY (parR2=0.07) and age (parR2=0.07), and for HCY GFR (parR2=0.23) and vitamin B12 (parR2=0.09).
Conclusions: Vitamins D differed according to quartiles of LAP, implying an influence of central obesity on their levels. LAP was one of the main predictors of vitamin D, and vitamin B12 was among best predictive variables for HCY. The relationship between vitamin D, vitamin B12 and HCY imply decreased vitamins D to be involved in increase in CVR.
Augusto Lavalle Cobo1, Michael Blaha2*, Angel Lanas3, Li Li4, Francesca Santilli5, Oliver Schnell6, Zhongwei Shi7, Dirk Sibbing8
Vuk Vrhovac University Clinic, Merkur Clinical Hospital, School of Medicine, University of Zagreb
Purpose: Vitamin D deficiency is common in obese individuals, and that lower circulating concentrations may contribute to increase in metabolic risk. Absorption of vitamin B12, involved in the regulation of homocysteine (HCY) level, decreases with vitamin D deficiency. Increase in HCY level may increase cardiovascular risk (CVR), partly because of an impact on apo-lipoproteins and inflammatory markers. A possible association of vitamin D with visceral obesity and HCY was studied.
Method: HCY, 25-hydroxyvitamin D, vitamin B12, lipids, and other diabetes-related markers, including lipid accumulation product (LAP), were tested in 613 type 2 diabetic patients divided into four groups (1st group: LAP ≤ Q1; 2nd group: Q1 < LAP ≤ Med; 3rd group: Med < LAP ≤ Q3, 4th group: LAP ≥ Q3) according to LAP quartiles (Q1 = 28.5; Med = 50.59; Q3 = 80.64). LAP as an index, combining waist circumference and triglyceride, is related to risk of metabolic syndrome, diabetes and CVR. In all statistical tests: ANOVA, Tukey post hoc test, and stepwise multivariate linear regression, α=0.05 was considered as statistically significant.
Results: Significant difference in vitamin D and B12, and high-density lipoprotein (HDL) according to LAP groups was determined. HDL differed significantly between the 1st (1.56±0.27) and the 3rd (1.24±0.17), and between the 1st and the 4th (1.19±0.25) group, vitamin D between the 1st (67.21±11.87) and the 3rd (60.34±10.78), and between the 1st and the 4th (51.29±13.41) group, and vitamin B12 differed significantly between the 1st (319.33±158.71) and the 2nd (212.14±71.92) group. After stepwise regression two best predictive variables for vitamin D were glomerular filtration rate (GFR) (parR2=0.12) and LAP (parR2=0.07), for vitamin B12 HCY (parR2=0.07) and age (parR2=0.07), and for HCY GFR (parR2=0.23) and vitamin B12 (parR2=0.09).
Conclusions: Vitamins D differed according to quartiles of LAP, implying an influence of central obesity on their levels. LAP was one of the main predictors of vitamin D, and vitamin B12 was among best predictive variables for HCY. The relationship between vitamin D, vitamin B12 and HCY imply decreased vitamins D to be involved in increase in CVR.
1. Baigent C, et al. Lancet 2009;373:1849–60.
2. Herlitz J, et al. Am J Cardiovasc Drugs 2010;10:125–41.
3. Park LG, et al. Digit Health. 2020; May 20;6:2055207620926844. doi: 10.1177/2055207620926844.
Jenna Theroux*, PharmD, Leigh Taylor, PharmD, BCACP, CDE, Christine Vaudo, PharmD, BCACP, Maileah Lawson, PharmD, BCACP, Leslie Mitchell, PharmD, BCACP
Wingate University School of Pharmacy,
Lahey Hospital & Medical Center,
Tufts Medical Center Community Care,
Edith Nourse Rogers Memorial Veterans Hospital
Purpose: Diabetes complications account for the seventh leading cause of death in the United States. Although glycemic control reduces these complications, only about half of patients with diabetes are achieving their glycemic targets, indicating the need for more innovative, cost-effective, motivational approaches to patient care. Shared Medical Appointments (SMA) have been defined as group visits in which several patients meet with the same provider at the same time. While several models of SMA exist, the goals behind this care model are similar: increase patients’ access to care and utilize peer to peer interaction to increase adherence, promote behavioral change, and improve outcomes, all while containing health care costs. Though literature has demonstrated the benefits of shared medical appointments (SMA) and pharmacist interventions on diabetes control and cardiometabolic risk factors separately, we aim to evaluate the impact of a solely pharmacist-led SMA on diabetes care.
Method: This retrospective study evaluated patients who participated in the pharmacist-led SMA pilot program, assessing the percentage of patients achieving the American Diabetes Association goal of hemoglobin A1C less than 7 percent and average hemoglobin A1c reduction. Secondary endpoints assessed percentage of patients achieving blood pressure (BP) less than 140/90 mmHg, percentage of patients receiving appropriate aspirin therapy, and percentage of patients receiving appropriate statin therapy in the review.
Results:
A total of 13 patients were analyzed. There was a 1.6% decrease in mean A1c after completion of the SMA program (9.4% to 7.8%, p=0.006). The percentage of patients achieving A1c <8% and BP <140/90 mmHg increased significantly (0% to 64%, p=0.001 and 46% to 100%, p=0.001, respectively). A significantly greater percentage of patients were up-to-date on urine albumin/creatinine lab and recommended immunizations (77% to 100%, p=0.001 and 62% to 85%, p=0.001, respectively) at the end of the program.
Conclusions: A pharmacist-led SMA program significantly improved hemoglobin A1c, BP, and was able to further improve screening and compliance with preventative measures. The satisfaction survey provided post-program produced positive Results with few suggestions for improvement, indicating the curriculum and program were well designed and/or well received.
Aysha Almas1*, Romaina Iqbal2, Abdul Ghani3, Zainab Samad1, Sania Sabir1, Khawar Kazmi4
1 Department of Medicine, Aga Khan University, Karachi, Pakistan
2 Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan
3 Institute of Public health, Quetta
4 National Institute of Cardiovascular Diseases, Karachi, Pakistan.
Purpose: The school environment plays an essential role in promoting health education and physical activity for children and adolescence. We aim to test feasibility of threefold health education program in children and its potential efficacy on physical activity and diet and cardio metabolic risk factors by including BP, BMI, and waist circumference
Method: The SHEPP was a parallel group feasibility intervention trial conducted in two schools over a 23-month period. All children aged 9-11 years enrolled from these schools were included. The SHEPP Intervention comprised of health education on healthy lifestyle and physical activity sessions for children, training of teachers and awareness sessions for parents conducted over 10 months. One school received intervention of SHEPP while the other school continued routine activity. Primary outcome was feasibility of SHEPP in terms of recruitment, retention, and treatment fidelity. Secondary outcomes were physical activity levels, dietary intake (of fruits, vegetable), and cardio metabolic risk factors (blood pressure, BMI, and waist circumference (WC)).
Results: A total of 1280 preadolescent children were assessed for eligibility and 1191 were found eligible. The overall recruitment n (%) was 982/1191(82.5 %) with 505(51.4) from SHEPP intervention school and 477(48.6) in Routine Activity school. The overall retention rate n (%) at 10 month follow up was 912/982(92.8), with 465/505(92) in SHEPP intervention school and 447/477(93.7) in routine activity school. In treatment fidelity 132/144(92) %) Physical activity sessions and all (100%) health education sessions were conducted for each of the twelve classes. Mean (SD) Seven-day Physical activity increased by134 (196) minutes in the SHEPP intervention school v 29.8(177) in the routine activity school (P value <0.001) from baseline to follow-up. Overall, there was increase in vegetable intake n (%) (>3 serving /day) in SHEPP intervention school (28(5.5) to 108(21.4)) from baseline to follow-up compared to routine activity school (36(7.5) to 71(14.9)). The Mean change (SD) in Systolic blood pressure was 1.3(12) mm Hg, in diastolic blood pressure was 2.2(19.0), BMI was -0.09(5.4) kg/ m2 and waist circumference was 6.2 cm in the intervention arm as versus -3.4(11.1) mm Hg in SBP, -4.3(9.9) mm Hg in DBP , -0.04((4.6) kg/m2 in BMI and 3.8 cm in WC in the control arm.
Conclusions: We found that intervention using SHEPP is feasible in schools and may help children to adopt a healthy lifestyle as they age by increasing physical activity. However, the potentially beneficial effect on BMI and BP needs a longer follow-up, more specifically at juncture of teenage and adulthood
Qianlan Xi MD1*, Leidy J Plaza Enriquez, MD1, Nusrat Uddin Tanni, MD1, Iani Parsias, MD, FACC2.
1 Department of Internal Medicine, Memorial Healthcare System, Hollywood, FL
2 Advanced Heart Failure and Transplant, Memorial Healthcare System, Hollywood, FL
Purpose: Roifman syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia, immunodeficiency, and retinal dystrophy. However, very rarely, with only one case reported, a patient with Roifman syndrome may develop cardiomyopathy in his/her lifetime. We reported a case of underdiagnosed Roifman syndrome manifested as non-ischemic cardiomyopathy to broaden further the association between non ischemic cardiomyopathy and genetic disorder Roifman syndrome and underscored the importance of whole genome sequencing in the diagnosis.
Methods: We reported a case with microcephaly, autoimmune polyglandular syndrome (APS) type 2 with primary adrenal insufficiency and hypothyroidism, retinitis pigmentosa, and recurrent ear infections during childhood presented with non-ischemic cardiomyopathy who was eventually diagnosed with Roifman syndrome by whole genome sequencing.
Results: Our patient is a 20-year-old male who was born with microcephaly and later as a child developed retinitis pigmentosa, recurrent ear infection, adrenal and thyroid insufficiency consistent with APS type 2. He presented with one month of worsening dyspnea on exertion and a near syncope episode. He was hypotensive (81/40 mmHg), tachycardiac (112 bpm) and hypoxic (85% on room air). Thyroid-stimulating hormone (TSH) was significantly elevated 70 mU/L. N-terminal-pro hormone B-type natriuretic peptide (NT pro-BNP) was 5340 pg/mL. A transthoracic echocardiogram (TTE) revealed left ventricular ejection fraction (LVEF) of 20% and severe left ventricle (LV) dilation. Cardiac catheterization ruled out obstructive coronary artery disease and cardiac MRI revealed nonspecific non ischemic cardiomyopathy with LVEF of 32% without infiltration or inflammation. Cardiac endomyocardium biopsy showed no histopathological abnormality. He was managed with mechanical ventilation for respiratory support, diuresis with inotropes (dobutamine) along with mechanical cardiac support with Impella (CP and RP) for cardiogenic shock, thyroid and steroid hormone replacement. He was then slowly weaned off mechanical cardiac support, pressors, and inotropes and started with guideline-directed medical therapy (GDMT). Unfortunately, his heart function didn’t improve despite normalization of thyroid function for which he had to receive MitraClip for severe mitral regurgitation, and an automatic implantable cardioverter defibrillator (AICD) implantation.
Initial Invitae cardiomyopathy comprehensive panel which we use commonly for cardiomyopathy-related genetic disorders screening was unable to detect any pathogenic variants. whole genome sequencing from Baylor Genetics for Undiagnosed Disease Network (UDN) was performed and revealed a compound heterozygous pathogenic variant in RNU4ATAC (NR_023343.1:n.118T>C, autosomal recessive (AR) inheritance, heterozygous, mother is heterozygous and father is negative, pathogenic; n.47T>G, mother is negative but father is heterozygous, variant of uncertain significance (VUS) ) which was considered to be pathogenic for Roifman syndrome and would explain this patient’s complicated medical history. His younger sister’s whole genome sequencing report revealed the same Results.
Conclusions: Our patient broadens further the association between non ischemic cardiomyopathy and genetic disorder Roifman syndrome. Thus, we underscore that cardiomyopathy might be part of the clinical manifestations of Roifman syndrome. In patients with non-ischemic cardiomyopathy but without clear etiology, associated with other clinical features like, spondyloepiphyseal dysplasia, immunodeficiency, growth retardation, or retinal anomaly, genetics should be involved and Roifman syndrome should be considered as a part of the differential diagnoses as other manifestations might be subtle and undiagnosed. The whole genome sequencing should be performed instead of the traditional cardiomyopathy comprehensive panel alone for the diagnosis confirmation. Meanwhile, in patients Roifman syndrome, cardiac manifestations should be monitored during their lifetime as it might be a later presentation. Annual cardiac evaluation, along with lifestyle modification, screening, and management of risk factors and comorbid conditions are recommended per guidelines.
Enrico De Belen, MD1, Divya Ganesan, MS1, David Paculdo, MPH1, Rosalynn Gill, PhD2, Nelson Trujillo, MD2, John W Peabody, MD PhD1,3,4*
1 QURE Healthcare, San Francisco, CA, USA;
2 SomaLogic Operating Co., Inc. Denver, CO, USA;
3 University of California, San Francisco, CA, USA;
4 University of California, Los Angeles, CA, USA
Purpose: One-third of the 462 million global patients with type 2 diabetes mellitus (T2DM) also have cardiovascular disease (CVD). Proper cardiovascular risk stratification (CVD) is critically important in patients with T2DM. Despite the known benefits of stratification to guide prevention and treatment, providers may not routinely incorporate this practice into their diagnostic and treatment decisions and, even if they do, they may not properly stratify their patient’s risk. Herein, we conducted a cross-sectional study to determine whether primary care and specialist physicians included risk assessment in their evaluation of T2DM patients and, if they did so, if they calculate risk accurately.
Methods: From a nationally representative roster of 12,500 primary care physicians (PCPs) and cardiologists, the QURE CVD Evaluation of Risk in Diabetes Mellitus Study (The QuiCER DM Study) sequentially invited physicians to participate. Between March and June 2022, after screening for eligibility, we enrolled 168 PCPs and 83 cardiologists. Eight PCPs and three cardiologists of the eligible participants withdrew or did not completing their cases, leaving 241 total participants. Males made up three-quarters of participants (76.4%), and the mean (+ S.D.) age was 57.8±9.1 years old. Most worked in either an urban or suburban setting (87.6%) and in private practice (79.5%). 81.3% of participants indicated they used at least one CV risk calculator in their everyday practice.
To determine the variation in risk determination among these providers we asked each participant to care for three simulated T2DM patients presenting with these common clinical scenarios: 3 or more CV risk factors, 2 CV risk factors, and chronic kidney disease (CKD). The primary outcome measures were the variation in clinical decisions among practicing PCPs and cardiologists in the assessment, use of existing risk stratification tools, and subsequent management of CV risk in patients with T2DM. More specifically, we aimed to determine 1) the frequency and accuracy of the two groups of specialists to correctly stratify the CV risk of T2DM patients and 2) what interventions were provided to target modifiable CV risk factors to attain the appropriate evidence-based goals.
Results: Overall, participants only performed half of all necessary items to care for these patients with quality-of-care scores averaging 49.4%±12.6% and ranging between 13% and 84%. By T2DM complication, we found participants performed best in T2DM patients with CKD (51.3%±13.7%) followed by cases with 2 CV risk factors (49.1%±12.2%) and 3+ CV risk factors (47.7%±11.8%). The +3.6% score difference in performance between the CKD patients and the 3+ CV risk factor patients was both clinically and statistically significant (p=0.007).
While 81.3% of participants reported using at least one cardiovascular risk estimator when taking care of T2DM patients, participants did not assess CV risk in 18.3% of cases and incorrectly stratified their patients’ risk in another 42.8% of cases or 61.1% overall. Only 38.9% of participants arrived at the correct CV risk stratification for their patients.
We saw significant differences in severity calculation by case type (p<0.001). CV risk score was either not calculated or incorrectly calculated 70.5% of the time for patients with 2 CV risk factors, while only 29.5% correctly calculated the CV risk. For patients with 3+ CV risk factors, participants either did not calculate or incorrectly calculated the CV risk 60.2% of the time, with only 39.8% assigning a correct CV risk. In the CKD cases, 52.7% did not calculate or incorrectly calculated CV risk, while 47.3% correctly did so.
Those who correctly identified a CV risk score were significantly more likely to order non-pharmacologic treatments, specifically advising on their patient’s nutrition (38.8% vs. 29.9%; p=0.013) and specifying the correct A1C target (37.7% vs. 15.6%; p<0.001). There was no difference, however, among those who correctly specified risk and those who did not when ordering pharmacologic treatments for their patients.
Conclusions: Using standardized simulated patients, this study confirmed a wide range of variability in how physicians evaluate, calculate, and manage CV risk factors in patients with T2DM. Despite 81.3% of participants indicating they used at least one cardiovascular risk estimator, we found only 38.9% of participants in this study correctly calculated and used the CV risk score for their patients. We conclude that this may be due to the numerous CV risk calculators available and by extension a lack of trust in the information from so many risk calculation Methods. Moreover, current risk tools do not provide patient specific, dynamic measure of patients’ responses to pharmacologic interventions or to healthier behaviors indicating there is an opportunity for a better method. This apparent gap indicates an opportunity to improve the quality of care in patients with T2DM.
DE. MacDougall*, M.P. McGowan, K.A. Wilemon, C.D. Ahmed, K.D. Myers
Family Heart Foundation, Pasadena CA
Purpose: Elevated lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is estimated to be present in 20% of the general population according to an NLA 2019 Scientific Statement, “Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come.” Nonetheless, this genetic lipoprotein is rarely assessed. This study aims to characterize individuals receiving Lp(a) measurement and their providers using an expansive, real-world US dataset.
Methods: The Family Heart Database™ includes diagnostic/procedural/prescription data from claims and/or laboratory data for >300 million individuals from the US who were screened or treated for any form of cardiovascular risk. This analysis dataset includes 112 million people with laboratory data from 2012-2019 from which a cohort of individuals with at least one Lp(a) measurement and sufficient healthcare data was identified. Demographics (mean+/-standard deviation), ASCVD history, and healthcare provider at time of Lp(a) measurement were characterized. Probable familial hypercholesterolemia (FH) status was determined using a validated machine learning model.
Results: Lp(a) was rarely measured; 0.3% (n=335,726) of individuals had at least one Lp(a) measurement; they were aged 59.9+/-39.7 years, female (52.5%); Black (7.8%), Hispanic (7.1%), White (53.6%) and Other/Unknown (31.5%). Risk factors included hypertension (53.7%), hyperlipidemia (50.6%) and diabetes (24.6%). Cardiovascular history included ASCVD-only (29.1%), Probable FH with ASCVD (1.2%), Probable FH without ASCVD (1.7%), diagnosed FH with ASCVD (0.4%), diagnosed FH without ASCVD (0.6%), or no ASCVD or FH (70.8%). A small number of healthcare providers (n=629 of 810,119; <0.1%) were responsible for ordering the Lp(a) lab tests for 50% of individuals with a measurement; these providers most frequently specialized in internal medicine (26%), family medicine (23%), and internal medicine/CVD (14%), or were physician assistants/advanced practice nursing providers/nurse practitioner (5%). Within this classification system, lipidology was not represented as a separate specialty.
Conclusions: Measurement of Lp(a) was rare within a large US healthcare dataset. Individuals who had Lp(a) assessed were older and had ASCVD risk factors; 31% had ASCVD. Ordering Lp(a) was concentrated within a very small number of all healthcare providers. Additional research is needed to characterize the barriers and facilitators related to ordering Lp(a) by healthcare providers for individuals with ASCVD and/or risk factors.
Deborah Bade Horn, DO1, MPH, MFOMA; Elizabeth Pash, PhD, RD, LDN2*; Megan Zhou, MS3; Lauren Broffman, PhD3; Damian Bialonczyk, PharmD3; Tzvi Doron, DO3; Elaine Chiquette, PharmD2
1 University of Texas McGovern Medical School, Houston, TX;
2 Gelesis, Inc. Boston, MA;
3 Ro, New York, NY
Purpose: Plenity is a non-systemic oral superabsorbent hydrogel (OSH) for the treatment of preobesity or obesity (BMI 25-40kg/m2) available by prescription and direct-to-consumer telehealth (Ro). This analysis describes the OSH telehealth population and differences in weight loss (WL) practices between patients (pts) with obesity (PwO) and preobesity (PwPO).
Methods: A cross-sectional, random sample of 20,000 patients who provided baseline health information, completed a structured online visit and received an OSH prescription were included and grouped as PwPO (BMI 25-29.9 kg/m2,n=6,426) or PwO (BMI 30-40 kg/m2,n=13,574), based on self-reported height and weight. Descriptive statistical analysis and tests of differences (χ 2, t-tests) were performed.
Results: Patients were 78% female, median age 43 ± SD 10.7 years (range 19-86), 35.9% had comorbidities, and 67.9% were PwO (mean BMI 32.4 kg/m2 ± SE 0.03). Females were more likely to be PwPO (34.2 vs 24.7% males; p<0.01), less likely to have a comorbidity (33.9 vs 42.9% males ;p<0.01) and less likely to believe weight negatively affected their health (91.5 vs 93.0% males; p<0.01). Over 90% tried at least 2 prior WL Methods before OSH (mean 3.4 vs 3.7 for PwO ,p=0.16). PwO were more likely than PwPO to have tried at least 3 to 5 prior WL Methods (p<0.01), including commercial WL plans (53.9 vs 43.6%;p<0.01), specialized diets (62.7. vs 59.3%; p<0.01) and prescription WL medications (34.1 vs 24.4%; p<0.01). Upon OSH initiation, most patients (62.5%) reported not following a specific diet, and significantly more PwPO engaged in aerobic and strength exercise 3-4 times/week compared to PwO (p<0.01).
Conclusions: Women represented most of the population utilizing OSH via telehealth. Data suggests they sought OSH at an earlier disease state compared to men, even with fewer comorbidities. Both PwPO and PwO actively tried to lose weight before OSH but through different Methods. Future studies are needed to determine whether this trend continues once OSH is more broadly available.
Frank Greenway1, Erika Matejkova2, Barry McLean3, Witold Zmuda4, Pawel Bogdanski5, Malgorzata Arciszewska6, Anna Bochenek-Mularczyk7, Harry Leider8, Damian Bialonczyk8*, Hassan Heshmati8
1 Pennington Biomedical Research Center, Baton Rouge, LA, USA;
2 Health & Care, sro, Prague, CZ;
3 Central Alabama Research, Birmingham, AL, USA;
4 Medicome Sp z o o, Oswiecim, PL;
5 Poznan University of Medical Sciences, Poznan, PL;
6 NZOZ Specjalistyczny Osrodek Internistyczno – Diabetologiczny, Bialystok, Poland;
7 Centrum Badawcze Wspolczesnej Terapii, Warszawa, Poland;
8 Gelesis, Inc., Boston, MA, USA
Purpose: Obesity is a worldwide pandemic causing increased morbidity and mortality. There is a need for alternative therapies that result in meaningful weight loss in addition to diet and exercise, without an increased safety risk, especially in people with type 2 diabetes (T2D).
Methods: LIGHT-UP (NCT03058029), a multicenter, double-blind, randomized, placebo-controlled study, assessed the effects of Gelesis200, a non-systemic, investigational superabsorbent hydrogel, in people with a body mass index (BMI) between 27 and 40 kg/m2, with prediabetes (PD) or T2D (untreated or treated) over 25 weeks. Participants were randomized to 2.10 g of Gelesis200 or placebo in capsules taken with water 10 minutes before lunch and dinner while given advice to support a 300 kcal/day energy-deficit diet with moderate-intensity physical activity. Co-primary efficacy endpoints were percent of participants with body weight (BW) loss ≥ 5% (Responders) and percent change in BW from baseline. Additional efficacy endpoints included change in waist circumference (WC). Data were analyzed using Logit models and analysis of covariance with multiple imputation (MI).
Results: The intention-to-treat (ITT) population included 254 adults (males 40.2%, females 59.8%, mean age 49.6 years, mean BMI 34.7 kg/m2, PD 50.8%, untreated T2D 4.3%, treated T2D 44.9%) from 36 investigational sites in Europe and North America. By using MI to include data from ITT population who did not complete the study, 55% of Gelesis200-treated participants were Responders vs. 34% in the placebo arm (P = 0.0004). Importantly, Gelesis200-treated participants had 2.83 higher adjusted odds as compared to placebo to become Responders, achieving the first primary endpoint of the study. The mean BW loss of the Responders was 10.5% (10.6 kg) and their mean WC reduction was 14.3 cm. Among the 171 participants who completed the study protocol requirements [per protocol (PP) population], 64% of Gelesis200-treated participants were Responders vs. 41% in the placebo arm (P = 0.0010). With respect to BW loss, the entire Gelesis200 treatment arm (including both Responders and non-Responders) demonstrated superiority over placebo after 25 weeks (BW loss of 6.3% vs. 3.6%, P = 0.0006 in the ITT-MI population and 6.9% vs. 4.1%, P = 0.0003 in the PP population), thereby achieving the second primary endpoint. The weight loss was similar between people with PD and T2D. No serious adverse events (AEs) related to Gelesis200 were observed. Overall, there were no significant differences in the incidence and severity of AEs between the 2 arms except for the incidence of constipation which was higher with Gelesis200 vs. placebo (14.3% vs. 3.9%) but with no severe cases. Less than 2% of the Gelesis200-treated participants dropped out of the study due to AEs, which was similar to the dropout rate in the placebo arm.
Conclusions: Gelesis200 is a promising new potential therapy for overweight and obesity in people with PD or T2D based on its favorable efficacy and safety data observed in the LIGHT-UP study.
Click to View this PosterM.P. McGowan1*, DE. MacDougall1, M.C. Card1, M. Cuchel2, P.C. Lee3, L.C Hudgins4, S.D. de Ferranti5, D. Staszak6, K.A. Wilemon1
1 Family Heart Foundation, Pasadena CA
2 University of Pennsylvania, Philadelphia, PA
3 Washington University in St. Louis, MO
4 The Rogosin Institute/ Weill Cornell Medical College, NY, NY
5 Harvard Medical School, Boston, MA
6 Atomo Inc, Austin, TX
Purpose: Homozygous Familial Hypercholesterolemia (HoFH) is a rare inherited condition associated with extremely elevated levels of serum low-density lipoprotein cholesterol (LDL-C) and risk of premature atherosclerotic cardiovascular disease (ASCVD) as early as the first decade of life. Clinical diagnosis is made based on LDL-C levels and the presence of positive family history and/or xanthomas. HoFH is most frequently caused by bi-allelic mutations in the low-density lipoprotein receptor (LDLR), but mutations in other genes in the LDLR pathway such as apolipoprotein B100 (APOB), proprotein convertase subtilisin/kexin 9 (PCSK9), and autosomal recessive hypercholesterolemia (ARH) adaptor protein can also result in the HoFH phenotype. The American Academy of Pediatrics (AAP) recommends lipid screening for children with a family history of ASCVD or FH at age 2 and universal screening between ages 9-11 and again between 17-21.
Methods: The current analysis includes a total of 67 HoFH patients enrolled at sites participating in the CASCADE FH® Registry, a multi-site patient registry created in 2013 by the Family Heart Foundation that tracks the characteristics, treatment patterns and clinical events in heterozygous [HeFH] and HoFH patients in the US. Twenty of forty registry sites contributed to this analysis. Here a comparison is made between 16 HoFH patients who were children (<18 years old) and 51 who were adults at time of enrollment into the CASCADE FH Registry.
Results: Age of diagnosis (median; IQR) was 2.0 years (2.0/3.5) in children and 12.6 years (4.1/26.5) in adults. Untreated levels of LDL-C (median; IQR) in the children were extremely elevated at 776 mg/dL (704/892) and significantly higher than untreated levels in the HoFH adults at 533 mg/dL (467/702) (p=0.001). At enrollment, 18.8% and 43.8% of the children had evidence of aortic valve stenosis (AS) and ASCVD, respectively whereas at enrollment 26% and 78% of adults had evidence of AS and ASCVD respectively. In children the median age of onset for ASCVD was 8.9 years (4.5/10.7) whereas the median age in adults was 30.5 (21.1/41.0). The earliest reported ASCVD diagnosis occurred at ages 2 and 3 years in children who underwent liver transplant at 4 and 8 years respectively. Two children underwent coronary artery bypass grafting at ages 6 and 14. Five subjects underwent liver transplant prior to age 18. Despite a more severe phenotype, children had not uniformly developed tendon xanthomas or corneal arcus and had younger family members with lower rates of ASCVD. Treatment reduced LDL-C substantially, but only 25% of children achieved LDL-C goal. In contrast, 32.4% of adults achieved their LDL-C goal. LDL-C goal attainment was defined as an LDL < 100 mg/dL or < 130 mg/dL in adults and children without documented ASCVD respectively and < 70 mg/dL for both adults and children with known ASCVD. Goal attainment was more likely with increased number of lipid lowering therapies prescribed (including medications and lipoprotein apheresis). It is notable that at present, there are greater therapeutic options for the treatment of adults versus children although clinical trials of HoFH agents are ongoing in children as young as 5 years of age.
Conclusions: HoFH patients enrolled in the CASCADE FH Registry as children were diagnosed earlier and had higher untreated LDL-C than their adult counterparts, they were also noted to develop ASCVD two decades prior to those enrolled as adults raising the possibility that only children with the most severe phenotypes are diagnosed before adulthood. Neither family history of ASCVD, nor physical findings (xanthomas or corneal arcus) reliably identified children. Moreover, at enrollment over half the children had evidence of ASCVD or AS. These findings make a compelling case for the completion of the ongoing clinical trials of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors and HoFH specific agents (lomitapide and evinacumab) in children as young as five years of age as well as rigorous compliance with AAP’s guidelines for screening at age 2 in children with a family history of FH or ASCVD (Pediatrics 2011). This should be followed by cascade family screening. Unfortunately, even routine screening between ages 9-11 is not routine in the US (Sleeth CM. Pediatrics 2020). A country-wide call for consistent screening is warranted. Only then, will all children with HoFH be consistently identified.
Livio Luzi1, Frank Greenway2, Erika Matejkova3, Barry Mclean4, Witold Zmuda5, Pawel Bogdanski6, Anders Sjödin7, Damian Bialonczyk8*, Harry Leider8, Hassan Heshmati8
1 University of Milan, Milan, Italy;
2 Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States;
3 Health & Care, sro, Prague, Czech Republic;
4 Central Alabama Research, Birmingham, Alabama, United States;
5 Medicome Sp z o o, Oswiecim, Poland;
6 Poznan University of Medical Sciences, Poznan, Poland;
7 University of Copenhagen, Frederiksberg C, Denmark;
8 Gelesis, Inc, Boston, Massachusetts, United States
Purpose: Postprandial hyperinsulinemia is associated with beta-cell dysfunction and development of type 2 diabetes. This analysis assessed the effect of Gelesis200 (GS200), an investigational oral superabsorbent hydrogel, on postprandial glucose and insulin response among people with prediabetes, in the LIGHT-UP study.
Methods: The LIGHT-UP study investigated the safety and efficacy of GS200 vs. placebo over 25 weeks in 254 participants with prediabetes or type 2 diabetes and a body mass index of 27-40 kg/m2. The analysis included participants with prediabetes who completed a 2-hr oral glucose tolerance test at baseline and Week 25 (42 participants per arm). Plasma glucose and serum insulin were measured at 15-30 minute intervals. Area under the curve (AUC) was calculated using the trapezoidal method and differences were assessed using ANCOVA model with weight loss as a covariate.
Results: Participants were 59.5% female, aged 47.1±11.7 years, with a fasting glucose of 104.6±10.4 mg/dL. Baseline insulin AUC was 13,005.8±6,895.2 μU/mL for GS200 and 13,233.8±8,268.9 μU/mL for placebo. At Week 25, insulin AUC was reduced by 17.0±8.2% in GS200 and increased by 5.0±8.0% in placebo arms (mean difference: -22.0±10.5%, P=0.04). Participants on GS200 had a greater reduction in postprandial insulin at T60 (-35.0±13.1 vs. -1.5±12.8 μU/mL for placebo, P=0.05) and T120 (-30.9±11.6 vs. 0.5±11.4 μU/mL for placebo, P=0.04), and a greater reduction in insulin Cmax vs. placebo (mean difference: -47.3±21.1 μU/mL, P=0.03). No significant differences were observed for postprandial glucose or HOMA-IR between arms.
Conclusions: Administration of GS200 in people with prediabetes significantly improved postprandial insulin secretion independently of weight loss.
Karl Finley1*, Melissa Magwire2, Anthony Hoovler1, Anup Sabharwal1, Carlos Campos3
1 Novo Nordisk, Inc., Plainsboro, NJ, USA;
2 Saint Luke’s Mid America Heart Institute, Kansas City, MO, USA;
3 Department of Family Medicine, UT Health San Antonio, San Antonio, TX, USA
Purpose: Heart failure with preserved ejection fraction (HFpEF) affects about half of patients with heart failure (HF). More than 50% of patients with HFpEF have a BMI ≥ 30 kg/m2. To understand the medical journey for patients with HFpEF who also have obesity, we mapped clinical touch points to understand provider roles and identify treatment decision drivers.
Methods: A cross-sectional study was conducted in the U.S. with patients with HFpEF and obesity and healthcare providers (primary care physicians, clinical cardiologists, HF specialists, HF clinic physicians). Here we report responses from total cardiologists (n=139) and patients (n=114).
Results: The majority (79%) of patients received an initial diagnosis of HFpEF from a cardiologist. Over half of cardiologists (55%) viewed themselves as coordinator of care for patients with HFpEF and obesity; 65% of patients viewed cardiologists as such. For newly diagnosed patients, cardiologists reported recommending lifestyle changes (91%), diuretics (87%), and beta blockers (76%); only 17% reported recommending anti-obesity medications. Most (92%) cardiologists reported discussing causes of HFpEF with their patients at the time of diagnosis. Among patients whose cardiologist discussed weight management, 74% of patients diagnosed by a cardiologist reported that their cardiologist explained the effect weight has on HFpEF. The majority of patients with HFpEF (66%) acknowledged that excess weight has contributed to their development of HFpEF. One third (32%) of patients with HFpEF and obesity who saw more than one provider who discussed weight loss reported that they viewed cardiologists as the most helpful providers in weight management. Only 17% of cardiologists reported receiving formal training in weight management; 74% reported interest in receiving additional training or support on weight management.
Conclusions: Patients with HFpEF and obesity are primarily diagnosed by cardiologists, and reported cardiologists provided an explanation of the link between HFpEF and obesity. There are opportunities to improve cardiologist focused obesity education and training to empower them to provide actionable strategies for weight loss.
Click to View this PosterDeepak L. Bhatt1, Harold E. Bays2, Michael Miller3, Teresa Parli4, Shibao Feng4, Lulu Sterling4, Cynthia L. Hartsfield4*, Germaine D. Agollah4, Hank Mansbach4, John J. P. Kastelein5
1 Brigham and Women’s Hospital, Division of Cardiovascular Medicine, Boston, MA;
2 Louisville Metabolic and Atherosclerosis Research Center, University of Louisville School of Medicine, Louisville, KY;
3 Corporal Michael J Crescenz VA Medical Center and Hospital of the University of Pennsylvania, Philadelphia, PA;
4 89bio Inc., San Francisco, CA;
5 Department of Vascular Medicine at the Academic Medical Center of the University of Amsterdam
Purpose: Pegozafermin (PGZ) is a long-acting glycopegylated recombinant analog of human fibroblast growth factor 21 (FGF21) being developed for severe hypertriglyceridemia (SHTG) and non-alcoholic steatohepatitis (NASH). FGF21, an endogenous stress hormone, regulates glucose and lipid metabolism and energy expenditure. This study evaluates the efficacy, safety, and tolerability of PGZ in subjects with SHTG.
Methods: ENTRIGUE is a Phase 2 double-blind, randomized 5-arm trial of pegozafermin at 4 different doses administered either once weekly or once every two weeks versus matching placebo for 8 weeks in subjects with triglycerides (TGs) ≥500 mg/dL and ≤2,000 mg/dL. Subjects could be on background lipid-modifying therapy (LMT), including statins, prescription fish oil, and/or fibrates. The primary endpoint was percent change in TGs from baseline. Prespecified secondary endpoints included additional lipids, liver fat fraction as assessed by MRI-PDFF (n=24), and markers of insulin sensitization. Non-parametric Methods compared pooled PGZ and individual dose groups with placebo.
Results: From November 2020 through February 2022, 489 patients were screened, with 85 subjects (17.4%) randomized and treated. Among those treated with pegozafermin, the distribution was as follows: 9mg QW, n=16; 18mg QW, n=17; 27mg QW, n=18; and 36mg Q2W, n=16. Baseline characteristics were balanced across dose groups with a mean TG of 733 mg/dL, 51% with T2D, and 55% on background LMT. There were significant reductions in median TGs for the pooled pegozafermin doses versus placebo (57.3% versus 11.9%); placebo-corrected reductions ranged from 29% to 53% across the four PGZ doses independent of LMT background status or T2D status. A total of 80% of PGZ treated subjects achieved a target TG level of <500mg/dL. At 27 mgs weekly, 75% of subjects achieved ≥ 50% reduction in TGs from baseline (p<0.001) and 31% normalized their TG levels to <150 mg/dL (p<0.01) at week 8. Significant decreases were also seen in both non-HDL-C and ApoB at the 27 mg dose (mean percent reductions 29% vs 1% placebo; p<0.001 and 16% vs 1% placebo; p<0.01 respectively). Concurrent increases in HDL-C (up to 25%) and adiponectin (up to 79%) were also observed, with no changes in LDL-C compared to placebo. In an MRI-PDFF sub-study (n=23 with follow-up assessment), liver fat was significantly reduced for the pooled arms versus placebo (35%, p=0.012) with 88% of PGZ subjects achieving ≥ 30% relative reduction from baseline. At week 8, improvements in HbA1c, fasting insulin, and plasma glucose were also observed in PGZ-treated subjects. The most common treatment-related AEs were nausea, diarrhea, and injection site reactions, all of which were mild-to-moderate. There were no serious adverse events related to study drug.
Conclusions: Pegozafermin significantly reduced triglycerides, non-HDL cholesterol, apoB, apoC3, and liver fat in subjects with SHTG, with the potential to positively impact other aspects of metabolic dysregulation. If these Results are confirmed in a Phase 3 trial, pegozafermin could be a promising new treatment for SHTG and NASH.
Naim Alkhouri1, Rohit Loomba2, Juan P Frias3, Shibao Feng4, Leo Tseng4, Germaine D Agollah4, Hank Mansbach4, Maya Margalit4, Cynthia L Hartsfield4*, Stephen Harrison5
1Arizona Liver Health, Tucson, AZ;
2USCD NAFLD Research Center, La Jolla, CA;
3Velocity??, Los Angeles, CA;
4 89bio Inc., Herzliya, Israel and San Francisco, CA,
5 Pinnacle Clinical Research, San Antonio, TX
Purpose: Metabolic derangements, such as aberrant lipid profile and insulin resistance, and co-morbidities such as obesity, metabolic syndrome and type 2 diabetes are common in NASH and are considered significant risk factors for cardiovascular (CV) morbidity and mortality in NASH patients, irrespective of fibrosis severity. Treatments for NASH would ideally address both liver injury and the metabolic disturbances contributing to liver pathology, however several NASH drug development programs have actually shown a negative impact on certain metabolic parameters such as LDL cholesterol (LDL-C). Pegozafermin (PGZ), a long-acting glycoPEGylated recombinant human FGF21 analog in development for NASH, significantly improved both liver and cardiometabolic parameters, with favorable safety and tolerability, in a Phase 1b/2a study in NASH.
Methods: In this open label cohort, 20 subjects with biopsy-proven NASH (NAS ≥4, fibrosis stage F2/F3) received SC PGZ 27 mg QW for 20 weeks. Key end points included histology, safety and tolerability. Change in metabolic parameters including hemoglobin A1c (HbA1c), body weight (BW), triglycerides (TG), non-HDL cholesterol (non-HDL-C), LDL-C and adiponectin was assessed at Week 20.
Results: Baseline (BL) characteristics (means) included age 58.4 years, HbA1c 6.6%, BW 104.6 kg, BMI 37.0 kg/m2, TG 170.0 mg/dL, non-HDL-C 125.9 mg/dL, LDL-C 92.0 mg/dL, HDL-C 43.4 mg/dL and adiponectin 3.55 μg/ml. 75% of subjects were female, and 85% had T2DM. 16/19 (84%) subjects who completed treatment took ≥1 antidiabetic agent (range 1–4 medications, including 15 on metformin and 5 on GLP-1 receptor agonists). Eleven of nineteen (subjects were treated with statins. At week 20, significant improvement in glycemic control, BW and lipid parameters were observed. HbA1c decreased by −0.5% (p <0.001) in the overall population. In subjects with BL HbA1c ≥6.5% (N = 10; mean BL HbA1 c = 7.3%), who were taking an average of 2 antidiabetic agents, HbA1c decreased by −0.9%, to a mean of 6.4% (p <0.01). BW decreased by −3.9% (p < 0.001). Adiponectin increased by 88.1% (p < 0.001). TG decreased by 26% in the overall population, and by 32% in subjects with elevated TG at BL (N = 11, mean BLTG 210 mg/dL; p < 0.001 for both comparisons). Non-HDL-C and LDL-C decreased by 18% (p < 0.001) and 13% (p < 0.05), respectively, and HDL-C increased by 23% (p < 0.001). Mean changes in serum lipids in subjects treated with statins were: TG-29.0%; non-HDL-C −22.1%; LDL −16.2% and HDL-C +35.4%.
Conclusions: PGZ (27 mg QW for 20 weeks) led to meaningful reduction in HbA1c and body weight and significant improvement in serum lipids in a cohort of NASH subjects with advanced fibrosis, most of whom had type 2 diabetes and significant metabolic derangements, many of whom were already on treatment for diabetes, hyperlipidemia or both. These benefits were additive to robust beneficial effects on liver histology and favorable safety and tolerability, and suggest a potential of PGZ to protect subjects with NASH not only from liver related outcomes, but also from CV risk. PGZ is currently being evaluated in NASH subjects (NAS ≥4, F2-F3) in the ongoing Phase 2b ENLIVEN study.
Rohit Loomba1, Naim Alkhouri2, Shibao Feng3, Leo Tseng3, Germaine D. Agollah3, Hank Mansbach3, Maya Margalit3, Cynthia L. Hartsfield3*, Stephen A. Harrison4
1 USCD NAFLD Research Center, La Jolla, CA;
2 Arizona Liver Health, Tucson, AZ;
3 89bio Inc., Herzliya, Israel and San Francisco, CA,
4Pinnacle Clinical Research, San Antonio, TX
Purpose: Pegozafermin (PGZ), a long-acting glycoPEGylated recombinant human FGF21 analog, had significant liver-related and cardiometabolic benefits, with favorable safety and tolerability, in a Phase 1b/2a study in NASH.
Methods: In this open label cohort, 20 subjects with biopsy-proven NASH (NAS ≥4, fibrosis stage F2/ F3) received SC PGZ 27 mg QW for 20 weeks. Key endpoints included histology [≥ 2-point improvement in NAS with ≥ 1 point improvement in ballooning or inflammation; NASH resolution without worsening of fibrosis, and ≥ 1 stage fibrosis improvement without worsening of NASH], and safety and tolerability at week 20 (W20). Change in liver fat (LF) and liver and metabolic markers were also assessed. Biopsies were read by one central reader at baseline (BL) and W20.
Results: BL characteristics included (means): Age 58.4 years, BMI 37.0 kg/m2, NAS 5.3 points, MRI-PDFF 21.1%, ALT 47.1 U/L, ProC3 19.3 ng/mL and Fibroscan™ VCTE score 14.3 kPa. 75% of subjects were female, 85% had T2DM, and BL fibrosis stage was F3 in 65% and F2 in 35% of subjects. 19/20 subjects completed treatment and had W20 biopsies. At W20, 74% of subjects had ≥ 2 pt reduction in NAS (mean absolute change -2.4 points); 32% and 26% had NASH resolution without fibrosis worsening and improved fibrosis without NASH worsening, respectively. There was a consistent improvement in NITs that assess fibrosis compared to BL [VCTE score -4.6 kPa (-31%; p<0.001), FAST score -0.47 (-76%; p<0.001)), FIB4 -0.29 (-19%; p<0.01) and ProC3 -4.3 ng/ml (-20%; p<0.001). 88% of subjects with BL FAST scores in the ‘rule-in’ or ‘indeterminate’ range had ‘rule-out’ FAST scores (≤ 0.35) at W20. At W20, mean relative reduction in MRI-PDFF was 65% (p<0.001), and 100% and 79% of subjects had ≥ 30% and ≥50% reductions, respectively. ALT decreased by 46% compared to BL (p<0.001); mean absolute decrease in ALT was -27.8 U/L in subjects with elevated ALT at BL, and ALT decreased ≥ 17 U/L in 71% of these subjects. At W20, significant improvement in HbA1c and lipids, weight loss and increased adiponectin were also observed in PGZ-treated subjects. PGZ was safe and well tolerated. There were no deaths, related SAEs or discontinuations due to AEs. Treatment related AEs reported in ≥10% of subjects included diarrhea, nausea, vomiting, injection site bruising, injection site erythema and decreased appetite; there were no reports of AEs grade ≥3, hypersensitivity, tremor or adverse effects on vital signs.
Conclusions: PGZ (27 mg QW for 20 weeks) led to meaningful changes in key histology endpoints and fibrosis-related NITs, reduction in liver fat by MRI-PDFF and decreased ALT in a cohort of NASH subjects with advanced fibrosis. In addition to these beneficial effects on liver health, PGZ significantly improved metabolic parameters, with good safety and tolerability.
Michael Castro*, Aditya Vijay, Navin Govind, Moh Barathan, Leticia Medina, Aravind Upadhyaya, Krishnaswami Vijayaraghavan
Arrowhead Internal Medicine, University of Arizona
Purpose: Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues to rise for almost all countries including high income countries. While traditional risk factors contribute to 90 % of CVD, there is a lack of understanding of the risk factors and engagement among patients to achieve the target goal to make a favorable impact on CVD. With advances in technology surpassing advances in medicine, an opportunity exists to utilize novel technology in education, training, and patient engagement, to prevent escalating risk of CVD. Systematic meta-analysis was recently performed to identify and measure the effectiveness of digital technology (mobile phones, the internet, software applications, wearables, etc.) interventions in randomized controlled trials and determine which behavior change constructs are effective at achieving risk factor modification in patients with CVD. The Results revealed that digital interventions may improve healthy behavioral factors (Physical Activity, healthy diet, and medication adherence) . However, they did not appear to reduce unhealthy behavioral factors (smoking, alcohol intake, and unhealthy diet, obesity education and measured physical activity ) and clinical outcomes (BMI, triglycerides, diastolic and systolic BP, and HbA1c). With novel technology such as Virtual Reality available mostly used in the gaming space, we now have an opportunity to utilize this immersive technology platform in the healthcare space for better patient engagement and experience as well as in education and training of medical and non-medical personnel that might result in better impact in reduction of risk factors and CVD mortality and morbidity.
Methods: This is a feasibility and efficacy study of the VR based simulation methodology for patient training and education of LIFE SIMPLE 7 prototype of American Heart Association. The primary objective is to provide hands on / experiential training to patients and to evaluate their skill set and compare the assessment with the standard of care. This study performed at a Primary care clinic included patients with preexistent CVD or risk factors for CVD. All patients were monitored for a total period of 1month Patients included were 18 years or older, Exclusion criteria was if they were unable to give informed consent or unwilling to participate. Informed consent, demographic, biometric and blood test data were collected. Thirty subjects were identified 2 weeks prior to enrollment of which twenty-six subjects were randomized 1:1 to either the VRV arm or standard of care arm (SOC) (printed educational materials provided and educated on LIFE’s SIMPLE 7 tools). For the VRV arm, a coordinator and two nurses were trained on the immersive HintVR platform to enable training to the patients via 3D lectures, Imitation training, and simulations on LIFE’s SIMPLE 7. The patients went through 2 sessions of 20 minutes each on the VRV plus downtime of 20 minutes for a total of one hour. Primary endpoint of patient experience quantified through Questionnaires were administered to capture acceptability, reliability, user friendliness, knowledge, self-assessment and patient experience pre and post intervention to all subjects. Comparisons were made between VRV and SOC arms
Results: Mean age was 70 with 54% participant of male gender. American Heart Association Life Simple 7 Mean Heart Score was 5.8 out of 10. CAD was prevalent in 20 % of the subjects, chronic kidney disease in 5 % and diabetes Type 2 in 25 %. Hypertension was present in 60 % of the population overall and tobacco abuse was present in 25 %. Statin use was noted in14 %, Calcium channel blocker use in 13 %,RAASi utilization in 38 % and Metformin use in 31%, There were no differences between the 2 arms of the study in these baseline characteristics. Mean cholesterol in this population was 199mg/dL, mean creatinine 0.9mg/dL ,and mean BP 124/71mmHg. Mean A1C FBS and body weight were 6.2%,104 mg and 180 lbs. respectively. No baseline differences were noted in these numerical variables ( see Table 1 and Table 2 ). Post intervention Knowledge Assessment Test revealed an improvement in foundation of knowledge on cholesterol in the VRV group ( p<0.05 ).Patient Experience Questionnaire assessing technology enabled engagement and empowerment showed statistical significance( Mann Whitney test ) favoring use of VRV in acceptability, user friendliness (rank16.3,p=0.0038), VRV technology being more helpful(rank14.8,p=0.046), more reliability(rank14.3,p=0.013), and more inspiring and motivational ( rank 16.2,p=0.001),. VRV arm also showed improved knowledge on medication(rank15.7, p=0.0085),enabled knowledge about salt and fluid restrictions(rank16.37, p=0.005) and improved knowledge on activity level ( rank 14.33, p= 0.013 ). Patient engagement was higher in VRV arm on education on hypertension, diabetes, activity, and cholesterol. Two third subjects in VRV arm mentioned increased education, motivation, and empowerment.
Conclusions: This study is amongst the first to examine the impact of an immersive technology-based intervention to change or modify behavior. In this UPLIFT trial, technology-based intervention to accomplish patient engagement , empowerment and enhancing foundation of knowledge was superior using the VRV immersive technology compared to the standard of care. There was an increase in trustworthiness, motivation, and inspiration from the information .VRV arm seem to provide education on adherence to medication and enabled their knowledge of their side effects and reason for reporting to nurses. It also increased knowledge on being compliant with salt and water intake if fluid retention were to occur. VRV arm showed an increase in knowledge base that enabled them to increase activity and muscle strengthening exercises. Patient engagement was higher in VRV arm on education on hypertension, diabetes, activity level and cholesterol. There are multiple barriers beyond access to care, such as availability of technology, communication resources, affordability of medications, affordability of good quality food and proximity to exercise programs. Participants in this study were positive about breaking these barriers through the VRV technology platform and many asked to purchase the headset for access on a continuum of storytelling of the content that was fun and exciting. Our study included a small sample size of mostly older participants in their sixties and seventies. Yet, the ethnicity , socioeconomic strata, and risk levels noted are consistent with the general population in Arizona and the United States. American Heart Association kicked off Life Essentials 8 that included sleep as another factor influencing CVD. An opportunity exists to include LE 8 in the next interventional trial using this immersive technology in a multi-center setting in a larger population and follow up to assess impact on Heart score ,QOL and CV events.
Anika Bilal, MD1*, Fanchao Yi, MS1, Gonzalo Romero Gonzalez, MD1, Mehreen Ali, MD2, Tina Thethi, MD1,3, Richard Pratley, MD1,3
1. AdventHealth Translational Research Institute, Orlando, Florida
2. AdventHealth Orlando, Florida
3. AdventHealth Diabetes Institute, Orlando, Florida
Purpose: The global population is ageing. In 2019, the number of people over 65 years of age with Type 2 diabetes (T2DM) was estimated to be 111 million and is projected to reach 276 million by 2045. Old age is an independent risk factor for cardiovascular (CV) disease and there is a two-to-four-fold increased risk of CV disease in patients with T2DM compared to the general population. Therefore, old age, diabetes, and CV disease is a challenging triad for clinicians.
Robust cardiovascular outcome trials (CVOTs) have been ongoing since 2008 when the U.S Food and Drug Administration (FDA) mandated CV safety trials for newer anti-hyperglycemic drugs. Since then, more than 28 CVOTs have been designed including more than 200,000 patients with T2DM and high CV risk. All these CVOTs measured three-point / four-point major adverse cardiovascular outcomes (MACE) including a composite of CV death, myocardial infarction (MI), stroke and/or unstable angina. All the newer anti-hyperglycemic drugs have demonstrated CV safety, and some even demonstrated a CV benefit, but data in older adults (≥ 65 years) is limited.
Older people with T2DM often have 10 to 20 or more years of productive life. With longer duration of diabetes, chances of increased complications, more hypoglycemic vulnerability, and polypharmacy it is imperative to use newer pharmacological agents with a favorable CV safety profile in this population. We designed this meta-analysis to study the CV outcomes of newer anti-hyperglycemic drugs in older adults at high risk of CV disease. This meta-analysis is registered with PROSPERO (ID CRD42021260167).
Methods: This systematic review was based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched PubMed and the Cochrane Central Register of Controlled Trials for randomized, controlled cardiovascular or renal outcome trials testing new anti-hyperglycemic agents (dipeptidyl peptidase-4 inhibitors [DPP-4i], glucagon-like peptide-1 receptor agonists [GLP-1RA], and sodium/glucose cotransporter 2 inhibitors [SGLT-2i]) in patients with T2DM. We restricted our search from March 1, 2008, to June 30, 2021. Trials were selected if they included at least 1000 adult participants, had at least 12 months follow-up, reported MACE as an outcome and had available data for sub-groups by age. The primary outcome included 3P-MACE and secondary outcomes included CV death, all-cause mortality (ACM), MI, and stroke
Two authors independently screened and extracted data from studies and evaluated risk of bias by using the Cochrane Collaboration tool. Conflicts were resolved by consensus/third author. Missing data was obtained from the corresponding authors of the studies. We obtained unpublished data from six studies for this analysis.
Trials were grouped according to three classes of anti-hyperglycemic drugs, with age sub-groups <65 years and ≥ 65 years. Random-effects models were used to estimate relative risk (RR) with 95% confidence interval (CI) for MACE, its components and all-cause mortality (ACM). The summary estimate was the weighted average. Inter-study heterogeneity was tested by the I2 index. A Chi-square test was done to assess differences between the age sub-groups (p-interaction). P-interaction was considered statistically significant at < 0.1. All analyses were applied using SAS (9.4) and R (4.10).
Results: SGLT-2i: Of 2,685 articles screened, five CVOTs (n=46,969, 45–50% ≥ 65 years old) were included. These were EMPA-REG (Empagliflozin), CANVAS and CREDENCE (Canagliflozin), DECLARE-TIMI 58 (Dapagliflozin) and VERTIS-CV (Ertugliflozin). Most participants were obese, mean HbA1c 8.1–8.3%, diabetes duration >10 years. For all the participants and for each age subgroup, SGLT-2is reduced risk of MACE (RR; 0.91[CI,0.85-0.98], I2=35%, p-interaction=0.42); CV death (RR;0.84[CI,0.73-0.96], I2=57%, p-interaction=0.29); and ACM (RR;0.86[CI,0.79-0.93], I2=24%, p-interaction=0.37) compared to placebo. SGLT-2i users had similar risk for MI and stroke compared to placebo. Heterogeneity was negligible (I2,0–30%) to moderate (I2,31–50%) for all outcomes except for CV death which showed considerable heterogeneity (I2 >50%)
GLP-1RA: Of 2,607 articles screened, eight CVOTs (n=60,080, 34–75% ≥ 65 years old) were selected. These were ELIXA (Lixisenatide), LEADER (Liraglutide), EXSCEL (Exenatide), HARMONY (Albiglutide), REWIND (Dulaglutide), SUSTAIN-6 (Once weekly subcutaneous Semaglutide) and PIONEER-6 (Daily oral Semaglutide), and AMPLITUDE-O (Efpeglenatide). Most participants were obese, mean HbA1c 7.3–8.9%, diabetes duration >10 years. For all participants and for the age-subgroups, GLP-1RAs significantly reduced risk of MACE (RR; 0.88[CI,0.82 – 0.94], I2=48%, p-interaction=0.61), stroke (RR;0.85[CI,0.75 – 0.97], I2=38%, p-interaction=0.35) and ACM (RR;0.89[CI,0.83-0.96], I2=22%, p-interaction=0.75). GLP-1RA users had similar risk for CV death and MI compared to placebo for overall population. Heterogeneity was negligible to moderate for all outcomes.
DPP-4i: Four CVOTs (n=33,063, 35 – 58% ≥ 65 years old) were selected after reviewing 1,866 records. Included trials were EXAMINE (Alogliptin), TECOS (Sitagliptin), CARMELINA and CAROLINA (Linagliptin). Study participants had mean BMI of 28 – 31 kg/m2, HbA1c was 7 – 8%, and diabetes duration of 6 –15 years. Use of DPP-4i was associated with no difference in risk of MACE (RR;1.0[CI,0.94–1.06]), CV death (RR;0.99[CI,0.90–1.08]), MI (RR;1.02[CI,0.91–1.14]), stroke (RR;0.94[CI,0.81–1.08]), or ACM (RR;0.99[CI,0.90 –1.09]). The results were consistent across both age subgroups for MACE (p-interaction=0.43), CV death (p-interaction=0.31), MI (p-interaction=0.68), stroke (p-interaction=0.22) and ACM (p-interaction=0.55).
Conclusions: Over the past two decades, robust CVOTs have been conducted in T2DM patients with high CV risk. These trials have played an important role in the paradigm shift from the gluco-centric diabetes management to one in which the risk for CV disease becomes the deciding factor for the next therapeutic steps. Older adults with diabetes are a uniquely heterogenous group with a high prevalence of comorbidities as well as high risk for hypoglycemia, which has been reported to increase risk of CV events. Newer anti-hyperglycemic drugs have demonstrated a safe CV profile and, in some cases, beneficial effects. Their safety across age subgroups (<65 years and ≥ 65 years) for different CV outcomes was confirmed in this study.
In this meta-analysis of three newer anti-hyperglycemic drug classes, data from five CVOTs with SGLT-2i, eight CVOTs with GLP-1RA and four CVOTs with DPP-4i was analyzed. When compared to standard of care, SGLT-2i significantly reduced the risk of MACE (9%), CV death (16%), and ACM (14%) in the overall population with no significant difference between the two age sub-groups (p-interaction > 0.1). GLP-1RA significantly reduced the risk of MACE (12%), stroke (15%), and ACM (11%) with no significant difference between the two age sub-groups (p-interaction > 0.1). Use of DPP-4i when compared to standard of care, had no effect on relative risk of MACE, CV death, MI, stroke, and ACM, with no significant difference between the two age sub-groups (p-interaction >0.1).
The results of this meta-analysis are reassuring and confirm that the overall CV safety profile of these drugs is unchanged in older individuals. Though all three classes can be used safely in older adults with high CV risk, use of SGLT-2i and GLP-1RA are preferred because of their demonstrated efficacy in reduction of adverse cardiovascular outcomes in all age sub-groups.
Jordan L. Saag*, Daniel Stirt, Dennis Gross, Andrea Espina Rey MPH, Bernard Gros, M.D.
University of Central Florida College of Medicine
Purpose: Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of morbidity and mortality in the United States. Management of LDL-C is crucial for the prevention of ASCVD events, such as stroke and myocardial infarction. Patients with ASCVD and comorbid diabetes mellitus show worse disease outcomes, often requiring more intense management. For this reason, in patients with both ASCVD and diabetes mellitus, proper management of LDL-C levels is integral for the prevention of future ASCVD events.
The American College of Cardiology (ACC) released new guidelines in 2018 for cholesterol management in patients with established ASCVD who are at very high risk of future events. In contrast to 2013 guidelines, the new guidelines highlight the addition of two new drug types to maximally tolerated statin therapy – ezetimibe and PCSK9 inhibitors.
The aim of this study is to determine if the use of ezetimibe and PCSK9 inhibitors, in combination with statin therapy, is statistically more effective than statin therapy alone in helping patients with diabetes mellitus achieve and maintain goal LDL-C levels. This will help assess if the 2018 ACC guidelines are more efficacious than the 2013 guidelines in managing ASCVD patients with Diabetes Mellitus.
Methods: A cohort study was done through a retrospective chart review at a large community-based cardiology practice. Patients were included in the study if they were between the ages 30-82 at baseline, had clinically established ASCVD, were considered “very high risk” for future ASCVD events, and had record of at least 2 lipid panels (not including baseline) between the collection dates of December 1, 2013, and December 31, 2019. Baseline LDL-C was defined by the most recent lipid panel before December 1, 2013. If that was not available, a lipid panel prior to September 30, 2015, was used as baseline if the patient was not taking ezetimibe or PCSK9 inhibitors at that time. Goal was defined as LDL-C less than 70 mg/dL or a greater than 50% reduction from baseline.
Data collected included all lipid panels, lipid lowering medications (dosage and duration), and demographic information. Patients were separated into 6 cohorts based on the therapy they received:
1. None
2. Statin
3. Ezetimibe
4. Statin + Ezetimibe
5. PCSK9 inhibitor +/- Statin
6. PCSK9 inhibitor & Ezetimibe +/- Statin
Patients could be included in multiple cohorts if they used different medication regimens over time. Sub-group analysis was performed using Fisher’s Exact Test and a P-value of <0.05 was considered significant.
Results: Overall, data from 300 patients was collected, with 102 of those being diabetics. Our primary analysis calculated the percentage of patients that achieved goal at any interval in their treatment history. Since patients could achieve goal on multiple different regimens, the number of data points exceeds 102. The results are as follows, “None” (0%), “Statin” (33.9%), “Ezetimibe” (21.1%), “Statin + Ezetimibe” (73.5%), “PCSK9 +/- Statin” (83.3%), “PCSK9 & Ezetimibe +/- Statin” (100%). Fisher’s Exact Test shows a significant difference in the ability to achieve goal between Statin vs. Statin + Ezetimibe (P < .001), Statin vs. PCSK9 +/- Statin (P < .001) and Statin vs. PCSK9 & Ezetimibe +/- Statin (P = .003). There is no significant difference between PCSK9 +/- Statin vs. Statin + Ezetimibe (P = .395), Statin + Ezetimibe vs. PCSK9 & Ezetimibe +/- Statin (P = .317), PCSK9 +/- Statin vs. PCSK9 & Ezetimibe +/- Statin (P = .557) and Statin vs. Ezetimibe (P = .398).
Patients that met goal were then analyzed to see they maintained goal at subsequent lipid panels. Patients were excluded if they lacked regimen continuity or if the lipid panel following goal fell outside the collection period. Consequently, the regimens “Ezetimibe” and “PCSK9 & Ezetimibe +/- Statin” were not included due to small sample size. Patients were included multiple times if they met and maintained goal on multiple regimens. In total, N=43 for this analysis. The results are as follows, “Statin” (61.5%), “Statin + Ezetimibe” (77.8%), and “PCSK9 +/- Statin” (100%). Fisher’s Exact Test showed a significant difference in the ability to achieve and maintain goal between Statin vs. PCSK9 +/- Statin (P = .039). However, there is no significant difference between Statin + Ezetimibe vs. PCSK9 +/- Statin (P = .130) and Statin vs. Statin + Ezetimibe (P = .433).
Conclusions: In summary, our analysis demonstrated that both Statin + Ezetimibe and PCSK9 inhibitor combination regimens were more effective that statin therapy alone in achieving goal. However, only PCSK9 inhibitors showed a greater ability to achieve and maintain goal for diabetic patients at very high risk for ASCVD events. When looking at the results, only 83.3% of patients who tried PCSK9 inhibitors were able to achieve goal, yet all of those that achieved goal were able to maintain it. This implies that PCSK9 inhibitors could be a superior long term adjunct treatment option for diabetic patients than ezetimibe, especially among those that show a response early on in treatment.
Overall, patients with diabetes mellitus are inherently at a heightened risk for adverse cardiovascular events. Our results show that statin therapy alone may be insufficient for a large proportion of patients, and there should be heightened consideration for diabetics under the umbrella of very high risk to be treated with combination therapy of Statin and ezetimibe or a PCSK9 inhibitor in accordance with the 2018 ACC guidelines.
Dr. Janet B. McGill, MD1, Dr. Rajiv Agarwal2*, Prof. Stefan D. Anker, MD3, Prof. Dr. George L. Bakris, MD4, Prof. Dr. Gerasimos Filippatos, MD5, Dr. Bertram Pitt, MD6, Prof. Luis M. Ruilope7-9,Prof. Andreas L. Birkenfeld, MD10,11, Dr. M. Luiza Caramori, MD, MSc, PhD12, Dr. Meike Brinker, MD13, Dr. Amer Joseph, MBBS14, Dr. Andrea Lage, MD15, Dr. Robert Lawatscheck, MD16, Charlie Scott, MSc17, Prof. Peter Rossing, MD18,19
1 Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
2 Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA
3 Department of Cardiology (CVK), and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany
4 Department of Medicine, University of Chicago Medicine, Chicago, IL, USA
5 National and Kapodistrian University of Athens, School of Medicine, Department of Cardiology, Attikon University Hospital, Athens, Greece
6 Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
7 Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research imas12, Madrid, Spain
8 CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain
9 Faculty of Sport Sciences, European University of Madrid, Madrid, Spain
10 Department of Diabetology, Endocrinology and Nephrology, University Clinic, Tübingen, Germany
11 Institute for Diabetes Research and Metabolic Diseases of Helmholtz Center Munich, University of Tübingen, Tübingen, Germany
12 Department of Medicine and Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
13 Cardiology and Nephrology Clinical Development, Bayer AG, Wuppertal, Germany
14 Research and Development, Clinical Development Operations, Bayer AG, Wuppertal, Germany
15 Cardiology and Nephrology Clinical Development, Bayer SA, São Paulo, Brazil
16 Medical Affairs & Pharmacovigilance, Pharmaceuticals, Bayer AG, Berlin, Germany
17 Data science and analytics, Bayer PLC, Reading, United Kingdom
18 Steno Diabetes Center Copenhagen, Herlev, Denmark
19 Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Purpose: Finerenone reduced the risk of cardiovascular (CV) and kidney outcomes, without affecting HbA1c, in CKD and T2D patients in the FIDELITY prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies. Here, we evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, and diabetes duration.
Methods: Patients with T2D and CKD (UACR ≥30–≤5000 mg/g and eGFR ≥25 mL/min/1.73 m2) were randomized to finerenone or placebo. Effects of finerenone vs placebo on CV (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained ≥57% eGFR decline from baseline, or renal death) composite outcomes were analyzed by baseline HbA1c quartiles, HbA1c variability (first year of treatment), and diabetes duration quartiles.
Results: In 13,026 patients included in the analysis, mean baseline HbA1c was 7.7% and diabetes duration was 15.4 years. Higher baseline HbA1c quartiles had longer diabetes duration and more diabetes-related complications. Risk reductions in the CV and kidney composite outcomes with finerenone vs placebo were consistent across HbA1c (p-interaction 0.52 and 0.09, respectively) and diabetes duration (p-interaction 0.12 and 0.75) quartiles. HbA1c variability in the first year of treatment was associated with higher cardiorenal risks; each 1 unit increase in mean absolute residual of HbA1c was associated with a 20% increased risk of a CV event (HR 1.20; 95% CI 1.07–1.35; p=0.0016) and a 36% increased risk of a kidney event (HR 1.36; 95% CI 1.21–1.52; p<0.001). The CV and kidney benefits of finerenone were not modified by HbA1c variability (p-interaction 0.48 and 0.09, respectively).
Conclusion: Greater variability in HbA1c was associated with increased risks of cardiorenal outcomes. Risk reductions in the CV and kidney outcomes with finerenone in patients with CKD and T2D were not modified by baseline HbA1c, HbA1c variability, or duration of diabetes
Gerasimos Filippatos1, Stefan D. Anker2, Bertram Pitt3, Peter Rossing4,5, Luis M. Ruilope6–8, Darren K. McGuire9, Ewa A. Jankowska10,11, Erin D. Michos12, Javed Butler13, Alfredo E. Farjat14, Peter Kolkhof15, Andrea Scalise16, Amer Joseph17, George L. Bakris18, Rajiv Agarwal19* on behalf of the FIDELIO-DKD and FIGARO-DKD Investigators
1 National and Kapodistrian University of Athens, School of Medicine, Department of Cardiology, Attikon University Hospital, Athens, Greece
2 Department of Cardiology (CVK), and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany
3 Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
4 Steno Diabetes Center Copenhagen, Herlev, Denmark
5 Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
6 Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research imas12, Madrid, Spain
7 CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain
8 Faculty of Sport Sciences, European University of Madrid, Madrid, Spain
9 The Division of Cardiology, University of Texas Southwestern Medical Center, and Parkland Health and Hospital System, Dallas, TX, USA
10 Institute of Heart Diseases, Wrocław Medical University, Wrocław, Poland
11 Institute of Heart Diseases, University Hospital in Wrocław, Wrocław, Poland
12 Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
13 The Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA
14 Data Sciences and Analytics, Bayer PLC, Reading, UK
15 Research and Development, Preclinical Research Cardiovascular, Bayer AG, Wuppertal, Germany
16 Bayer Hispania, S.L., Barcelona, Spain
17 Cardiology and Nephrology Clinical Development, Bayer AG, Berlin, Germany
18 Department of Medicine, University of Chicago Medicine, Chicago, IL, USA
19 Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA
Purpose: Patients with chronic kidney disease and type 2 diabetes (T2D) are at high risk of cardiovascular (CV) complications. FIDELITY, a prespecified pooled analysis of FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049), evaluated the efficacy and safety of finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) in patients with stage 1–4 chronic kidney disease and T2D. This study compared CV and kidney outcomes in primary and secondary prevention populations (by CV disease [CVD] history).
Methods : Patients with T2D, and either urine albumin-to-creatinine ratio (UACR) ≥30–<300 mg/g and estimated glomerular filtration rate (eGFR) ≥25–≤90 mL/min/1.73 m2, or UACR ≥300–≤5,000 mg/g and eGFR ≥25 mL/min/1.73 m2, treated with optimized renin–angiotensin system blockade, were randomized to finerenone or placebo. A composite CV outcome (CV death, nonfatal myocardial infarction, nonfatal stroke or heart failure hospitalization) and kidney outcome (kidney failure, sustained eGFR decrease ≥57% or renal death) were analyzed by CVD history (defined as prior atherosclerotic CVD). Safety was assessed by investigator-reported adverse events.
Results: Of 13,026 patients eligible for analysis, 5,935 (45.6%) had a history of CVD at baseline. Over a 3.0-year median follow-up, finerenone lowered the risk of the composite CV outcome vs placebo (HR 0.86; 95% CI 0.78–0.95), with no treatment modification by CVD history (HR 0.83 [95% CI; 0.74–0.94] in patients with a history of CVD; HR 0.91 [95% CI; 0.78–1.06] in patients without a history of CVD; Pinteraction=0.375). The effect of finerenone on the kidney outcome (HR 0.77; 95% CI; 0.67–0.88) was also not modified by history of CVD (HR 0.71 [95% CI; 0.57–0.88] and HR 0.81 [95% CI; 0.68–0.97]) in patients with and without CVD history, respectively; Pinteraction=0.325). Overall, adverse events did not differ between CVD subgroups, with a low incidence of hyperkalemia-related treatment discontinuation that was more frequent in the finerenone group but similar between patients with and without CVD history.
Conclusion: This prespecified pooled analysis shows that finerenone reduces the risk of CV and kidney outcomes consistently in patients with or without a history of CVD. These findings have provided further evidence to support the benefit of finerenone in primary and secondary CV prevention in patients across a broad spectrum of chronic kidney disease stages and T2D
Jeffrey V Lazarus¹, Abhishek Shankar Chandramouli², Kamal Kant Mangla³, Christin Rogers Marks⁴*, Zobair M Younossi⁵
1 Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain
2 Novo Nordisk Service Centre India Pvt Ltd, Bangalore, India
3 Novo Nordisk A/S, Søborg, Denmark
4 Novo Nordisk INC, New Jersey, USA
5 Center for Liver Disease, Inova Medicine, Falls Church VA, USA
Purpose: Non-alcoholic steatohepatitis (NASH) is estimated to be present in 3–6% of the US population and has been linked to end-stage liver disease, type 2 diabetes (T2D), and cardiovascular disease (CVD). The AWARE study aimed to describe the association of NASH with comorbidity severity scores and CVD comorbidities, which have not been widely studied previously.
Methods: Data were collected from a large US healthcare dataset covering October 1, 2015 to December 31, 2020. Records were included for adult patients diagnosed with NASH (using International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10 CM]), with no evidence of hepatitis B or C, excessive alcohol use, or liver transplant prior to NASH diagnosis, and with no evidence of pregnancy or cancer in the study period. ICD-CM coding was used to identify all diagnoses. Statistical significance of differences in comorbidities and severity scores between cirrhotic patients (CP) and non-cirrhotic patients (NCP) was assessed. Data are mean (standard deviation) unless otherwise stated.
Results: Of 4,989 patients identified, 489 had evidence of cirrhosis prior to NASH diagnosis, and 4,500 were non-cirrhotic. CPs were older than NCPs (mean age 59.6 [9.4] vs 52.2 [11.0] years), and a larger proportion were female (62.4% vs 55.2%) and had non-alcoholic fatty liver disease (NAFLD; 67.4% vs 56.5%). CPs compared to NCPs were also more progressed in terms of NASH-relevant biomarkers (aspartate transaminase:platelet ratio index, 1.09 [1.57] vs 0.62 [0.96]; Fib-4, 4.68 [5.28] vs 1.56 [1.42]; NAFLD fibrosis score, 1.74 [2.04] vs –1.13 [1.63]; all p<0.001 for NCPs vs CPs), and HbA1c (7.1% [1.5] vs 6.9% [1.7]). More CPs had comorbidities than NCPs (T2D, 73.4% vs 40.6%; chronic kidney disease, 17.8% vs 5.9%; diabetic neuropathy, 22.1% vs 6.8%; all p<0.001 for NCPs vs CPs). CVD comorbidities were significantly higher in CPs at baseline (73.0% vs 29.8%; p<0.001 for NCPs vs CPs), including atherosclerotic CVD (25.8% vs 13.1%; p<0.05 for CPs vs NCPs), as were severity scores for T2D (Adaptive Diabetes Complexity Severity Index, 0.4 [1.0] vs 0.1 [0.4]; p<0.001 for NCPs vs CPs) and comorbidities overall (Quan-Charlson Comorbidity Index, 4.4 [1.9] vs 1.9 [1.5]; p<0.001 for NCPs vs CPs).
Conclusion: This study found that patients with NASH are often not diagnosed until an advanced stage, suggesting the need for greater disease awareness to avoid diagnostic inertia and to better assess the burden associated with NASH. These data also suggest that NASH correlates with a higher risk of developing comorbidities, especially CVD and T2D, particularly as patients progress to cirrhosis.
Peter P. Toth, MD, PhD1, Alberico L. Catapano, MD (hc)*, PhD2, Bethany Helms, PharmD3, Lei Lei, PhD3, Michael J. Louie, MD, MPH, MSc3, George Bakris, MD4
1 CGH Medical Center, Sterling, IL, and The Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD
2 Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy and IRCCS MultiMedica, Milan, Italy
3 Esperion Therapeutics, Inc., Ann Arbor, MI
4 University of Chicago Medicine, Chicago, IL
Purpose: Patients with renal impairment and elevated levels of low-density lipoprotein cholesterol (LDL-C) are at very high risk for cardiovascular disease. Statins are safe and effective in this population but are often underutilized and underdosed; additional non-statin therapies to lower LDL-C are needed. Bempedoic acid is an ATP citrate lyase inhibitor that lowers LDL-C. The objectives of this study were to evaluate the safety and efficacy of bempedoic acid in patients with Stage 2 or Stage 3a+b renal impairment.
Methods: Data were pooled from four phase 3 studies in which patients were randomized 2:1 to bempedoic acid or placebo for 12–52 weeks. All studies permitted stable background
lipid-lowering therapy. In 2 studies, patients received background moderate- to high-intensity statin, and in 2 studies, patients had a history of statin intolerance and received low-dose or no statin. Patients were grouped by baseline estimated glomerular filtration rate
(eGFR [mL/min/1.73m2]) into the following renal function subgroups: Stage 1 (≥90), Stage 2 (60–89), or Stage 3a+b (30–59).
Results: A total of 3,619 (2,422 bempedoic acid; 1,197 placebo) patients were included in the analysis. Baseline Stage 2 or Stage 3a+b renal impairment was present in 63% and 15% of patients in each treatment arm, respectively; 22% of the patients had Stage 1 normal renal function at baseline. LDL-C lowering of bempedoic acid was similar across renal function subgroups, with significant reductions at week 12 from baseline in each subgroup: Stage 1 −20.8%, Stage 2 −18.8%, and Stage 3a+b −21.1% (P<.0001 vs placebo for each; interaction P=.4442). Significant reductions in apolipoprotein B levels were also observed with bempedoic acid treatment compared with placebo regardless of renal function (P<.0001). The overall pattern of adverse events was consistent across the renal function subgroups; any differences appeared to be driven by overall bempedoic acid vs placebo differences rather than by renal function at baseline. Creatinine levels were generally consistent within each renal function subgroup in both arms, with arm means varying by <7% at each assessed time point through 52 weeks.
Conclusion: Bempedoic acid was generally well tolerated among patients with Stage 2 or Stage 3a+b renal impairment and significantly lowered LDL-C regardless of renal function status.
Keith C. Ferdinand, MD1*, Erin D. Michos, MD, MHS2, P. Benjamin Everett, PhD3, Lei Lei, PhD3, Santosh Sanganalmath, MD, PhD3, Dean G. Karalis, MD4
1 Tulane Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA
2 Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD
3 Esperion Therapeutics, Inc., Ann
4 Division of Cardiology, Sidney Kimmel Medical College at Thomas Jefferson University Hospital, Philadelphia, PA
Purpose: Patients with hypercholesterolemia often have hypertension (HTN), further increasing cardiovascular disease risk. Statin treatment may affect blood pressure (BP) due to vascular effects. Bempedoic acid is an ATP citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C). The objectives of this study were to investigate the safety and lipid-lowering effect of bempedoic acid in patients with hypercholesterolemia and comorbid HTN.
Methods: Data were pooled from four phase 3 studies; patients were randomized 2:1 to bempedoic acid or placebo for 12–52 weeks. In 2 studies, patients also received moderate- to high-intensity statin, and in 2 studies, patients with statin intolerance received low-dose or no statin. Patients were grouped based on history of HTN, which was treated pharmacologically. Percent change from baseline to week 12 of LDL-C and other lipid parameters, vital signs, and adverse events were assessed. Moreover, in a 6 week,
1:1 randomized, phase 2 study (NCT02178098), the safety and efficacy of bempedoic acid were assessed in patients with uncontrolled HTN (BP ≥140/90 and ≤180/110 mmHg) not receiving statins or other lipid-lowering therapies.
Results: Of the 3,623 (2,425 bempedoic acid; 1,198 placebo) patients included, 78% had a history of HTN. At week 12, the placebo-corrected least squares (LS) mean (95% confidence interval) percent change in LDL-C was −19.2% (−20.9, −17.5; P<.0001) in patients with HTN and −20.9% (−24.2, −17.5; P<.0001) in patients without HTN (interaction P=.3697). Results were similar for apolipoprotein B levels (−13.0% [−14.5, −11.5; P<.0001] for patients with HTN and −15.3% [−18.0, −12.6; P<.0001] for patients without HTN [interaction P=.1586]). Overall, through 12–52 weeks, the bempedoic acid safety profile was similar in patients with or without HTN, with no clinically meaningful changes in BP. In the phase 2 study (n=143; mean baseline BP, 155/96 [standard deviation, 12/6] mmHg), the placebo-corrected LS mean (95% confidence interval) percent change in LDL-C was −24.2% (−30.3, −18.1; P<.0001) at week 6. Through 6 weeks of bempedoic acid treatment, 24-hour ambulatory BP monitoring showed no change from baseline in BP; bempedoic acid was generally well tolerated, with a consistent safety profile across treatment groups.
Conclusion: Regardless of HTN status, bempedoic acid was generally well tolerated and significantly lowered LDL-C, with no clinically meaningful BP changes.
Michael D. Shapiro, DO, MCR1, Pam R. Taub, MD2, Michael J. Louie, MD, MPH, MSc3, Lei Lei, PhD3, Christie M. Ballantyne, MD4*
1 Center for Prevention of Cardiovascular Disease, Wake Forest University School of Medicine, Winston-Salem, NC
2 Department of Cardiovascular Medicine, University of California San Diego School of Medicine, La Jolla, CA
3 Esperion Therapeutics, Inc., Ann Arbor, MI
4 Department of Medicine, Baylor College of Medicine
Purpose: Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular events. Bempedoic acid is an ATP citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. The objectives of this study were to assess the efficacy and safety of bempedoic acid in patients with and without MetS.
Methods: We investigated the lipid-lowering efficacy, safety, and effect of bempedoic acid on glycemic parameters and high-sensitivity C-reactive protein (hsCRP) according to baseline metabolic status, using pooled data (n=3,623) from four phase 3, double-blind studies in which patients were randomized 2:1 to bempedoic acid or placebo for 12–52 weeks. Patients with diabetes mellitus (n=1,114) were excluded from the analyses. MetS was defined using modified International Atherosclerosis Society guidelines; patients were categorized as having MetS if they had 3 of the 5 following criteria: increased waist circumference (body mass index [BMI] as a proxy for waist circumference), baseline triglycerides ≥150 mg/dL (or baseline use of triglyceride-lowering medication, which in this analysis included fibrates and nicotinic acid), baseline high-density lipoprotein cholesterol (HDL-C) <40 mg/dL for men or <50 mg/dL for women, baseline blood pressure ≥130/85 mmHg (or diagnosis of hypertension or medical history of hypertension), or baseline fasting plasma glucose (FPG) ≥100 mg/dL. Assessments included absolute or percent change from baseline to week 12 (data presented as least squares mean ± standard error unless otherwise indicated) in
LDL-C, other lipid parameters, hemoglobin A1c (HbA1c), FPG, and hsCRP (median [Q1, Q3]), as well as treatment emergent adverse events (TEAEs).
Results: 936 patients were categorized as having MetS, and 1,573 patients as not having MetS (nonMetS). Background statin intensity was similar between groups; most patients were taking either a high- or moderate-intensity statin. Baseline triglycerides, BMI, FPG, hsCRP, and non–HDL-C were higher in patients with MetS vs nonMetS. Bempedoic acid significantly lowered LDL-C at week 12 vs placebo and did so to a greater extent in patients with MetS vs nonMetS (placebo-corrected percent change from baseline of −22.3% MetS; −18.4% nonMetS; interaction P=.0472). Significant reductions from baseline to week 12 were observed with bempedoic acid vs placebo to a similar extent in both subgroups for total cholesterol (MetS: −11.7% ± 0.7 [bempedoic acid] vs 1.5% ± 0.9 [placebo]; nonMetS: −11.1% ± 0.4 [bempedoic acid] vs 1.3% ± 0.6 [placebo]), non–HDL-C (MetS: −12.8% ± 0.8 [bempedoic acid] vs 1.9% ± 1.2 [placebo]; nonMetS: −13.3% ± 0.5 [bempedoic acid] vs 2.6% ± 0.9 [placebo]), and apolipoprotein B (MetS: −10.7% ± 0.7 [bempedoic acid] vs 2.8% ± 1.1 [placebo]; nonMetS: −10.5% ± 0.5 [bempedoic acid] vs 4.0% ± 0.8 [placebo]). In patients with MetS, mean reductions were significantly greater with bempedoic acid vs placebo in HbA1c (−0.06% ± 0.01 [bempedoic acid] vs 0.01% ± 0.01 [placebo]) and FPG (−0.4 ± 0.4 mg/dL [bempedoic acid] vs 2.0 ± 0.7 mg/dL [placebo]), but were not significantly different in the nonMetS group (interaction P=.0003 [HbA1c] and .0017 [FPG]). Median hsCRP percent change from baseline was lowered with bempedoic acid vs placebo in both subgroups (MetS: −26.9% [−50.9, 8.4; bempedoic acid] vs −5.9% [−36.3, 41.2; placebo]; nonMetS: −15.8% [−48.4, 31.6; bempedoic acid] vs 4.8% [−30.8, 57.7; placebo]; insignificant interaction based on log of hsCRP absolute change). The incidence of TEAEs was comparable in both subgroups.
Conclusion: Overall, bempedoic acid demonstrated comparable safety in both metabolic subgroups and greater lowering of LDL-C, HbA1c, and FPG levels in patients with MetS vs nonMetS.
027 Five-year cardiometabolic outcomes following a very low carbohydrate intervention including nutritional ketosis delivered via continuous remote care in people with type 2 diabetes and prediabetes
McKenzie AL*, Athinarayanan SJ, VanTieghem M, Adams RN, Volk BM, Roberts C, Ratner RE, Volek J, Phinney S, Hallberg S
Virta Health, Ohio State University
Purpose: We previously reported the two-year durability of a very low carbohydrate intervention including nutritional ketosis (VLCI) delivered via continuous remote care (CRC) for safe, significant, and sustained reductions in glucose, weight, antihyperglycemic and antihypertensive medications, and broad cardiometabolic health improvements for people with type 2 diabetes (T2D), including achievement of diabetes remission among a quarter of participants treated two years. Similarly, we reported significant improvements in weight and components of metabolic syndrome in people with prediabetes (preD) with reversion to normoglycemia in more than half of participants over two years. Here, we evaluated effects of the VLCI via CRC over five years in people with T2D and preD.
Methods: People with T2D and preD who were initially enrolled in a two-year non-randomized, controlled trial and received the VLCI via CRC were offered continued participation in a three-year prospective follow up. Of 194 people with T2D completing the two-year trial, 169 (87.1%) consented to the extension and 122 (72.2%) were retained at five years. Fifty-eight (80%) of the preD cohort completing the two-year trial consented, and 78% completed five-year follow up. Among those who extended, baseline versus five-year changes in markers of metabolic health were assessed using LMM and ITT analysis. Changes in medications and percent of patients meeting glycemic targets among five-year completers with T2D and prevalence of weight loss (WL) thresholds and incidence of reversion to normoglycemia and progression to T2D among those with preD were described.
Results: At five years among people with T2D, there were sustained improvements in HbA1c (7.5 to 7.2%, 95%CI [-0.6, 0.0]), weight (116.4 to 107.6 kg, 95%CI [-11.0,-6.6]), and HOMA-IR (9.1 to 6.6, 95% CI [-3.5,-1.5]) concurrent with 46.6% deprescription of diabetes medications and 59.9% of medication other than metformin. Significant improvements in HDLc, ApoA-I, hs-CRP, and WBC and non-significant improvements in non-HDLc and triglycerides were observed. Total cholesterol, LDLc, and ApoB were unchanged. eGFR was stable at CKD-Stage2; in a subgroup with baseline CKD-Stage3, 6 of 10 improved to CKD-Stage2. The percent of patients meeting glycemic targets increased (A1c<7% with no medications except metformin from 7.5% to 23.3%; AACE A1c≤6.5% from 23.3% to 41.7%; A1c<6.5% with no medications except metformin increased from 11.7% to 32.5%). Twenty percent of five-year completers achieved diabetes remission. Among people with preD upon enrollment, there were sustained improvements in HOMA-IR (6.1 to 4.7, 95%CI [-2.5,-0.3]), weight (109.2 to 103.4 kg, 95%CI [-8.8,-2.8]), and BMI (38.8 to 36.6 kg/m2, 95%CI [-3.3,-1.1]). A1c was unchanged at 5.9%. Forty-eight percent maintained ≥5% WL, 32.8% ≥10% WL, 19.0% ≥15% WL, and 13.8% ≥20% WL. Crude incidence of progression to T2D was 2 cases per 100 person-years and crude incidence of first occurrence of reversion to normoglycemia among people with preD was 18.9 cases per 100 person-years. Estimated cumulative incidence of progression to T2D and reversion to normoglycemia was 12.2% and 55.6%, respectively.
Conclusion: Results demonstrate that a VLCI delivered via CRC elicits sustained, clinically meaningful cardiometabolic benefits to people with T2D and preD over five years, enabling remission of T2D and reversion to normoglycemia in those with preD. Nutritional changes drive rapid, durable, and significant improvements in cardiometabolic parameters and delivery through a continuous remote care model including health coaches and medical providers (physicians and NPs) facilitates sustainability of lifestyle changes and safe titration (largely deprescription) of medication in accordance with glucose changes. Given the broad metabolic health benefits observed, future research might explore the application of this treatment for related chronic conditions such as heart failure and chronic kidney disease
McKenzie AL*, Athinarayanan SJ, VanTieghem M, Adams RN, Volk BM, Roberts C, Ratner RE, Volek J, Phinney S, Hallberg S
Virta Health, Ohio State University
Purpose: We previously reported the two-year durability of a very low carbohydrate intervention including nutritional ketosis (VLCI) delivered via continuous remote care (CRC) for safe, significant, and sustained reductions in glucose, weight, antihyperglycemic and antihypertensive medications, and broad cardiometabolic health improvements for people with type 2 diabetes (T2D), including achievement of diabetes remission among a quarter of participants treated two years. Similarly, we reported significant improvements in weight and components of metabolic syndrome in people with prediabetes (preD) with reversion to normoglycemia in more than half of participants over two years. Here, we evaluated effects of the VLCI via CRC over five years in people with T2D and preD.
Methods: People with T2D and preD who were initially enrolled in a two-year non-randomized, controlled trial and received the VLCI via CRC were offered continued participation in a three-year prospective follow up. Of 194 people with T2D completing the two-year trial, 169 (87.1%) consented to the extension and 122 (72.2%) were retained at five years. Fifty-eight (80%) of the preD cohort completing the two-year trial consented, and 78% completed five-year follow up. Among those who extended, baseline versus five-year changes in markers of metabolic health were assessed using LMM and ITT analysis. Changes in medications and percent of patients meeting glycemic targets among five-year completers with T2D and prevalence of weight loss (WL) thresholds and incidence of reversion to normoglycemia and progression to T2D among those with preD were described.
Results: At five years among people with T2D, there were sustained improvements in HbA1c (7.5 to 7.2%, 95%CI [-0.6, 0.0]), weight (116.4 to 107.6 kg, 95%CI [-11.0,-6.6]), and HOMA-IR (9.1 to 6.6, 95% CI [-3.5,-1.5]) concurrent with 46.6% deprescription of diabetes medications and 59.9% of medication other than metformin. Significant improvements in HDLc, ApoA-I, hs-CRP, and WBC and non-significant improvements in non-HDLc and triglycerides were observed. Total cholesterol, LDLc, and ApoB were unchanged. eGFR was stable at CKD-Stage2; in a subgroup with baseline CKD-Stage3, 6 of 10 improved to CKD-Stage2. The percent of patients meeting glycemic targets increased (A1c<7% with no medications except metformin from 7.5% to 23.3%; AACE A1c≤6.5% from 23.3% to 41.7%; A1c<6.5% with no medications except metformin increased from 11.7% to 32.5%). Twenty percent of five-year completers achieved diabetes remission. Among people with preD upon enrollment, there were sustained improvements in HOMA-IR (6.1 to 4.7, 95%CI [-2.5,-0.3]), weight (109.2 to 103.4 kg, 95%CI [-8.8,-2.8]), and BMI (38.8 to 36.6 kg/m2, 95%CI [-3.3,-1.1]). A1c was unchanged at 5.9%. Forty-eight percent maintained ≥5% WL, 32.8% ≥10% WL, 19.0% ≥15% WL, and 13.8% ≥20% WL. Crude incidence of progression to T2D was 2 cases per 100 person-years and crude incidence of first occurrence of reversion to normoglycemia among people with preD was 18.9 cases per 100 person-years. Estimated cumulative incidence of progression to T2D and reversion to normoglycemia was 12.2% and 55.6%, respectively.
Conclusion: Results demonstrate that a VLCI delivered via CRC elicits sustained, clinically meaningful cardiometabolic benefits to people with T2D and preD over five years, enabling remission of T2D and reversion to normoglycemia in those with preD. Nutritional changes drive rapid, durable, and significant improvements in cardiometabolic parameters and delivery through a continuous remote care model including health coaches and medical providers (physicians and NPs) facilitates sustainability of lifestyle changes and safe titration (largely deprescription) of medication in accordance with glucose changes. Given the broad metabolic health benefits observed, future research might explore the application of this treatment for related chronic conditions such as heart failure and chronic kidney disease.
Junjie Luo, Mansur E. Shomali*, Abhimanyu Kumbara, Anand K. Iyer, and Guodong “Gordon” Gao
Carey Business School of Johns Hopkins University, Baltimore, MD, U.S.A. (JL, GG);
Welldoc, Inc. Columbia, MD, U.S.A. (MES, AK, AKI)
Purpose: Digital health tools which integrate continuous glucose monitoring (CGM) data can help people with diabetes make better self-management decisions regarding medications, food, weight, blood pressure, activity, and sleep. CGM data, however, is dense and complex. We applied the novel single-number summary metric GRI1 to a large data set of digital health tool2 users to study user behavior, engagement with the tool, and potential glycemia outcomes.
Methods: A real-world data set of 499 CGM users who were utilizing a digital health tool was created. The data were de-identified according to standard procedures. The GRI was calculated for the first 3 days and last 3 days of a 14-day observation period in those with at least 80% sensor wear time (n=381). A better glycemia outcome was defined as a GRI at endline being lower than GRI at baseline. People with diabetes can be mapped to GRI zones A (best glycemia) to E (worst glycemia). The digital health tool features were categorized into 4 categories: health, lifestyle, education, and medications.
Results: 55% of individuals had type 1 diabetes, and 45% had type 2 diabetes. 51% were female. The mean GRI of the population improved by 6 points (+/-29) during the first 14 days of use of the tool. Using logistic regression, for type 2 individuals, medications and lifestyle feature use increased the probability of improved glycemia. For type 1 individuals, CGM wear time was associated with increased probably of improved glycemia.
Conclusion: These data demonstrate how the GRI is a simple but powerful composite metric that can help characterize the behavior and outcomes of populations of CGM users. The patterns and insights impacting glycemic risk differed by type of diabetes. The GRI may be used by digital health software to coach individuals on self-management behavior and may provide decision support and population management tools to health care professionals.
Nicole L. Guthrie, MS,1* Martha Simmons, MD, PhD,1 Erin Rudolf,1 Björn Hansell, MD,1 Michelle Gearhart, PharmD,1 Mark A. Berman, MD,1 Paul Lupinacci, PhD,2 Christopher P. Cannon, MD,3,4 Judith Hsia, MD,4,5 Marc P. Bonaca, MD, MPH 4,5
1 Better Therapeutics, Inc,
2 D3,
3 Brigham and Women’s Hospital, Harvard Medical School,
4 CPC Clinical Research, e University of Colorado School of Medicine
Purpose: Successful adoption and maintenance of comprehensive behavioral changes to attenuate sequelae of Type 2 diabetes (T2DM) remain a challenge. Cognitive behavioral therapy (CBT) has been shown to improve glycemic control, however, the imbalance between the numbers of trained cognitive behavioral therapists and patients living with T2DM makes the broad provision of in-person CBT impractical. Digital therapeutics have the potential to increase access to behavioral interventions due to their inherent scalability and utilization outside of traditional brick-and-mortar constraints and were incorporated into American Diabetes Association clinical guidelines in 2021. BT-001 is a digital therapeutic designed as a scalable, engaging, and interactive mobile application (app) that provides personalized CBT to improve glycemic control. The pivotal trial described herein was designed to assess the efficacy and safety of BT-001 in a population generally representative of adults with T2DM in the United States being managed in a real world setting.
Method: Adults with hemoglobin A1c (HbA1c) >7% and <11% were randomized (1:1) to receive access to BT-001 or a control app. Treating clinicians were unblinded to HbA1c and allowed to adjust background medications consistent with standard of care. The primary efficacy endpoint was the treatment group difference in mean HbA1c change from baseline to Day 90 assessed by analysis of covariance; the secondary endpoint was change from baseline to Day 180. Safety outcomes were adverse events and adverse device effects. Other outcomes include medication use, biomarkers and patient-reported outcomes.
Results: A total of 668 randomized subjects completed the onboarding process which entailed downloading their assigned app and setting up an account. Mean age was 58 +/- 9 years, body mass index 35 +/- 7 kg/m2, median HbA1c 8.1%; 56% were female, 30% Black and 15% Latino. At 90 days, BT-001 significantly lowered HbA1c by 0.4% compared to the control app (p<0.001). A significant HbA1c decrease of 0.4% from baseline persisted at 180 days, with a 0.3% reduction vs. control (p=0.01) despite greater antihyperglycemic medication escalation in the control group. Statistically significant improvements in blood pressure, weight, mood, and quality of life were also observed. Adverse events were less frequent with BT-001 versus control and no adverse device effects were reported.
Conclusions: BT-001 significantly reduced HbA1c at 90 days with persistent reductions at 180 days versus control. Reductions were observed despite greater intensification of medical therapy in the control arm. Benefits extended to other cardiometabolic factors including weight and blood pressure and use was not associated with adverse events. These findings support the use of digital therapeutics as a scalable adjunct to pharmacotherapy to improve glycemic control and cardiometabolic risk factors in patients with T2DM
Jwan A. Naser, MBBS*; Sorin V. Pislaru, MD; Marius N. Stan, MD, Grace Lin, MD
Department of Cardiovascular Medicine and The Department of Endocrinology, Mayo Clinic, Rochester, Minnesota, USA
Purpose: Graves’ disease (GD) can both aggravate pre-existing cardiac disease and cause de-novo heart failure (HF), but large-scale studies are lacking. We aimed to investigate the incidence, risk factors, and outcomes of incident GD-related HF.
Methods: Patients with GD (2009-2019) were retrospectively included. HFrEF was defined by left ventricular ejection fraction<50% and Framingham criteria, while HFpEF was defined according to the HFA-PEFF criteria. HF due to ischemia, valve disorder or other structural heart disease was excluded. Proportional hazards regression was used to analyze risk factors and outcomes.
Results: Of 1371 patients with GD, HF occurred in 74 (5.4%) patients [31 (2.3%) HFrEF; 43 (3.1%) HFpEF]. In HFrEF, atrial fibrillation (AF) [HR 10.5 (3.0-37.3), p<0.001] and thyrotropin receptor antibodies (TRAb) level [HR 1.05 (1.01-1.09) per unit, p=0.007] were independent risk factors. In HFpEF, independent risk factors were COPD [HR 7.2 (3.5-14.6), p<0.001], older age [HR 1.5 (1.2-2.0) per 10 years, p=0.001], overt hyperthyroidism [HR 6.4 (1.5-27.1), p=0.01], higher BMI [HR 1.07 (1.03-1.10) per unit, p=0.001], and hypertension [HR 3.1 (1.3-7.2), p=0.008]. Risk of cardiovascular hospitalizations was higher in both HFrEF [HR 10.3 (5.5-19.4), p<0.001] and HFpEF [HR 6.7 (3.7-12.2), p<0.001]. However, only HFrEF was associated with increased risk of all-cause mortality [HR 5.17 (1.3-19.9), p=0.02] and ventricular tachycardia/fibrillation [HR 64.3 (15.9-259.7), p<0.001].
Conclusions: De-novo HF occurs in 5.4% of patients with GD and is associated with increased risk of cardiovascular hospitalizations and mortality. Risk factors include AF, higher TRAb, higher BMI, and overt hyperthyroidism.
Jwan A. Naser MBBS*, Austin M. Kennedy, Chieh-Ju Chao MD, Patricia A. Pellikka MD
Mayo Clinic, Rochester
Purpose: Hypertension is known to cause structural and functional alterations to the heart. The initial manifestation is usually left ventricular hypertrophy. Some patients progress to develop diastolic dysfunction while others develop heart failure with reduced ejection fraction (HFrEF). In this study, we aimed to develop a risk prediction model to identify patients with hypertension who are at risk of HFrEF.
Methods: Patients who underwent transthoracic echocardiography (TTE) with measurement of left ventricular global longitudinal strain (GLS) between 2008 and 2021 were identified retrospectively. Inclusion criteria were left ventricular ejection fraction (LVEF) ≥50% at baseline with no prior low LVEF <50% and being diagnosed with hypertension. Patients who received chemotherapy after the baseline TTE were excluded. Patients were randomly divided into training and testing sets in a 2:1 ratio. Comorbidities, demographics, and echocardiographic data were assessed, and the prediction model was developed using Cox proportional hazards regression.
Results: Overall, 3,661 patients were included [training set: 2,452; testing set: 1,209]. Median time to last follow-up was 1.5 (0.5-3.1) years. LVEF <50% developed in 190 (8%) patients at median 1.2 (0.5-2.9) years. Multivariable risk factors constituting the prediction model derived from the training set included left ventricular end-diastolic dimension [HR 1.06 (1.03-1.09) per 1 mm, p<0.001], heart rate [HR 1.02 (1.01-1.04) per 1 bpm, p<0.001], LVEF [HR 0.92 (0.90-0.95) per 1%, p<0.001], age [1.02 (1.01-1.03) per 1 year, p=0.003], left ventricular GLS [absolute value; HR 0.92 (0.88-0.96) per 1%, p<0.001], and right atrial pressure [HR 1.06 (1.02-1.11) per 1 mmHg, p=0.007]. The C-statistic for the model was 0.72 (95% CI 0.68-0.76) in the training set and 0.75 (95% CI 0.67-0.83) in the testing set.
Conclusions: A prediction model using GLS along with other echocardiographic data had good discrimination in identifying hypertensive patients who later developed HFrEF. These patients should be followed more closely, and more aggressive control of their blood pressure and other cardiovascular risk factors should be considered.
Opeyemi A. Adeniyi1*, Abayomi T. Olarinmoye1, Bukola A. Abiodun1, Adenike A. Eniade3, Omowumi Okedare3, Olanrewaju D. Eniade2,3
1. Department of Public Health, Faculty of Basic Medical Sciences, Adeleke University Ede, Osun State. Nigeria.
2. International Foundation Against Infectious Disease in Nigeria
3. Department of Epidemiology and Medical Statistics, University of Ibadan, Nigeria.
Purpose: Efforts to achieve the 2030 sustainable development goal (SGD) through the reduction of the mortality (33%) contributed by non-communicable diseases. It is however essential to sufficiently explore diseases such as diabetes and its comorbidities. Dyslipidaemia is a major complication of the deadly disease diabetes that causes about 1.6 million death every year. We examined the influence of demographic profile, lifestyle, and dietary pattern on Dyslipidaemia. We also assessed the gender differences in the risk factors of Dyslipidaemia among type-2 diabetes patients in LAUTECH teaching hospital, Osun-State, Nigeria.
Methods: A retrospective study was carried out among 143 diabetes patients attending the Diabetes Clinic of the LAUTECH Teaching Hospital. A structured instrument was used to extract data from the patient’s records. The outcome variable Dyslipidaemia was coded (Yes=1), (No=0). Also, demographic characteristics, lifestyle profiles, and dietary patterns were the explanatory variables. Descriptive statistics, Chi-square test, binary logistic regression, and interaction model were employed in this analysis. Risk factors were considered significant at P< 5%.
Results: Mean age of the respondents was 56.2 ±15.79 years. Majority (60.8%) were females and 67.8% were Christians. There was a preponderance (42.7%) of dyslipidaemia among diabetes patients. Dyslipidaemia was comparable among Female (43.7%) and Male (41.1%) participants, P=0.392. A lot 109 (76.8%) of the respondents reported a high level of carbohydrate intake. Similarly, high fats and oil intake (52.8%), and fibre intake (54.3%) were recorded among the participants. Animal fat was the common (65.7%) source of fats consumed by the respondents. Few (7.7%) of the participants smoke and about 19.3% take alcohol.
Similarly, a higher proportion of obese (61.1%) and overweight (47.1%) participants had dyslipidaemia compared to a lower proportion (27.3) who had normal BMI, p=0.005. Also, dyslipidaemia was common (61.3%) among diabetes patients who had a high level of fats and oil consumption compared to those (33.3%) who had a low level, p=0.000. Higher (81.8%) proportion of patients who smoke had dyslipidaemia compared to those (39.4%) who don’t smoke, p=0.006. Similarly, dyslipidaemia was more (59.3%) among those taking alcohol compared to those (38.1%) who were not taking alcohol, p=0.045. High intake of fats and oil (AOR: 2.49, 95%CI: 0.88 -7.05) was associated with the likelihood of dyslipidaemia. Also, a high intake of fibre (AOR: 0.15, 95%CI: 0.06-0.40) was protective for dyslipidaemia. The likelihood of dyslipidaemia was higher (AOR: 2.90, 95%CI: 1.05-8.07) among Christians compared to Muslim. The interaction model revealed that the effects of the risk factors such as religion, fat and oil intake, and Fibre intake on dyslipidaemia varied across gender.
Conclusions: Dyslipidaemia is prevalent among diabetes patients. The level of dyslipidaemia was similar across male and female diabetes patients. Identified risk factors were high-level intake of fat and oil, and low level of fibre intake. Other factors associated with dyslipidaemia among diabetes patients in this study are controllable factors. Factors such as BMI, level of engagement in physical activity, dietary pattern, smoking and alcohol intake. Intervention geared towards the improvement of lifestyle and the dietary pattern is needed among diabetes patients. Also, risk communication about the complication of diabetes is an essential need among diabetes patients without excluding religious gatherings.
Hyun Hwa Shin*, Min Hee Kim
Department of Family Medicine, College of Medicine, The Catholic University of Korea
Purpose: Menopause is one of the most important events in women life which changes the metabolism. While the correlation between metabolic syndrome and hyperuricemia in post-menopausal women has already been reported, the association in pre-menopausal women has not been studied. Thus, this study was designed to evaluate the association between hyperuricemia and metabolic risk components in Korean pre-menopausal women.
Methods: This study used data collected from the Korea National Health and Nutrition Examination Survey(KNHANES) 2016, which was conducted from January to December 2016. Total 2,958 (N=25,344,879) were examined among 4,305 women participants. A multiple logistic regression analysis was used to evaluate the association between hyperuricemia and metabolic risk components(by metabolic syndrome) in Korean pre-menopausal and post-menopausal women; presenting as odd-ratios (OR) with 95% confidence interval(95% CI).
Result: Among 2,958 participants, 57.6% (n=1,508) was pre-menopausal. In pre-menopausal women, hyperuricemia was associated with abdominal obesity (OR 6.35, 95% CI 3.42-11.80, P<0.001), high blood pressure (OR 3.67, 95% CI 1.86-7.21, P<0.001), hypertriglycemia (OR 3.53, 95% CI 1.68-7.39, P=0.001), and impaired fasting glucose (OR 2.15, 95% CI 1.10-4.20, P=0.026). After adjustment (Model 3), it was significantly associated with abdominal obesity (OR 4.30, 95% CI 1.02-18.04, P=0.046), high BP (OR 3.23, 95% CI 1.53-6.85, P=0.002), and hypertriglycemia (OR 3.08, 95% CI 1.40-6.78, P=0.005). In contrast, no metabolic risk was significantly associated with hyperuricemia in post-menopausal women.
Conclusions: In Korean pre-menopausal group, hyperuricemia was significantly associated with abdominal obesity, high blood pressure, and hypertriglycemia.
OKUNOWO Bolanle.O1*, OKUNOWO Adeyemi2,3, ADEGBOLA A2,3, FASANMADE Olufemi A2,4, OHWOVORIOLE Augustine E.2,4
1 Endocrinology, Diabetes and Metabolism division, department of Medicine. Lagos State University Teaching Hospital, Lagos; Nigeria.
2 College of Medicine, University of Lagos, Lagos, Nigeria.
3 Obstetrics and Gynecology department
4 Endocrinology, Diabetes and Metabolism division, department of Medicine. Lagos University Teaching Hospital, Lagos; Nigeria.
Purpose: The presence or absence of risk factors is often employed in screening for Gestational Diabetes Mellitus (GDM). The risk factors for GDM includes previous delivery of macrosomic babies, family history of type 2 diabetes mellitus, previous GDM among others. The impact of selective screening is yet to be fully evaluated in our environment. The aim of this study is to determine the impact of selective screening on diagnosis of gestational diabetes mellitus
Methods: The study was a prospective open cohort study carried out from 1st March to 30th November 2017 at the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria. Ethical approval for the study was obtained from LUTH ethical committee (ethical approval number AM/DCST/HREC/APP/862). Informed consent was obtained from all the participants before the commencement of the study.
All the pregnant women were categorized into either risk group or control group based on the presence or absence of clinical risk factors for GDM. All participant had 75g Oral Glucose Tolerance test (OGTT) done at 24 to 28 weeks gestation and follow up till delivery.
The data obtained were age, risk factors for GDM, fasting plasma glucose, one-hour post glucose load plasma glucose & two-hour post glucose load plasma glucose. The data were presented as mean, standard deviation, percentages & chi square. The p value ≤ 0.05 was considered significant
Results: Ninety pregnant women were screened for GDM. Forty-four women had risk factors for GDM while 46 were non risk group. Their mean age was 32.6± 5 years. The mean age for the risk & non-risk group were similar.
The overall prevalence of GDM using the IADPSG criteria was 23.3%. The percentage of women in the risk group with GDM was 38.6% while those women in the non-risk group with GDM was 8.7% which was statistically significant (p value 0.004).
The most commonly identified risk factors for GDM in this study were family history of type 2 diabetes mellitus, history of unexplained miscarriage & previous history of delivery of macrosomic babies.
Some women in the non-risk were diagnosed, even though the prevalence was lower than that observed among women with risk factors for GDM. Approximately one in ten women would have been missed if selective screening was employed in this study.
Most of the women in the non-risk group who were diagnosed with GDM were managed with medical nutritional therapy while majority of women in the risk group had insulin therapy.
Conclusions: The findings in our study further supports the idea of universal screening for GDM in order to avoid missed diagnosis
K.A. Wilemon1, C.D. Ahmed1*, M.P. McGowan1, D.E. MacDougall1, J.W. Knowles2, K.D. Myers1
1 Family Heart Foundation, Pasadena CA
2 Stanford University, Stanford, CA
Purpose: An ICD-10 code for Familial Hypercholesterolemia (FH), E78.01, became effective October 2016 following a proposal in 2013 to the ICD-10 Coordination and Maintenance Committee by the Family Heart Foundation. The code differentiated FH from other forms of elevated cholesterol, signaling the need for differential diagnosis of a condition in which management in the first two decades of life can substantially reduce the burden of aggressive atherosclerosis. This study aims to characterize the % of FH patients diagnosed with E78.01 in an expansive, real-world US dataset.
Methods: The Family Heart Database™ includes diagnostic/procedural/prescription data from claims and/or laboratory data for >300 million individuals from the US who were screened or treated for any form of cardiovascular risk. This analysis dataset includes 197 million people, including 22 million children, with diagnostic data from October 2016 through June 2020. The number of total (diagnosed + undiagnosed) FH patients within the dataset was estimated assuming an occurrence of 1:250 individuals. Patients with FH (E78.01) were counted if the diagnostic code was applied for a single in-patient claim or at least twice, >7 days apart, for an out-patient claim.
Results: The number of patients diagnosed with FH using E78.01 has increased substantially since 2016. During 2017 and 2018, use of the code was brisk and likely included previously and newly diagnosed individuals. Diagnosis was reduced dramatically with the onset of the COVID-19 pandemic corresponding with the marked reduction of in-person clinic visits and near halting of preventive care. By June 2020, 246,689 patients were diagnosed with FH representing 31.3% of the estimated total (diagnosed + undiagnosed) FH population of 787,886 within the dataset.
Compared with all individuals in the analysis dataset, those diagnosed with FH were substantially more likely to have atherosclerotic cardiovascular disease (40% versus 8%).
Conclusion: Prior to 2016, an estimated <1% of patients with FH in the US were diagnosed, but without an ICD code it was impossible to track. The number of patients diagnosed with FH (E78.01) has increased substantially since 2016. Within this large, real-world dataset of Americans, 31.3% of the estimated FH population had been diagnosed as of June 2020. However, despite clear screening guidelines, effective therapies, and classification of FH as a public health threat by the World Health Organization, most of the FH population remains undiagnosed, leaving these genetically vulnerable individuals at high risk for premature cardiovascular disease.
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