HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN.

Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFß pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (<70 years if hypertensive; all ages if non-hypertensive), (2) thoracic aortic aneurysm (all adults with Z score >3.5 or 2.5-3.5 if non-hypertensive or hypertensive and <60 years; all children with Z score >3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives.

Translational Medicine: Towards Gene Therapy of Marfan Syndrome.

Marfan syndrome (MFS) is one of the most common inherited disorders of connective tissue caused by mutations of the fibrillin-1 gene (FBN1). Vascular abnormalities, such as the enlargement of the aorta with the risk of life-threatening rupture are frequently observed. However, current treatment is limited and therapeutic options focus solely on symptomatic therapy. Gene therapy focuses on genetically modifying cells to produce a therapeutic effect and may be a promising treatment option for MFS. Here, we first provide an overview of the historical background and characterization of MFS. Subsequently, we summarise current gene therapy options and possible translational concepts for this inherited disorder that affects connective tissue.

Treatment of the aortic root in acute aortic dissection type A: insights from the German Registry for Acute Aortic Dissection Type A.

OBJECTIVES: Surgery of the aortic root in acute aortic dissection type A (AADA) remains a topic of vague evidence since the extend of dissection and surgeons' capability and interpretation of the disease vary remarkably. We aimed to interpret root operation strategies in the German Registry for Acute Aortic Dissection cohort. METHODS: German Registry for Acute Aortic Dissection collected the data of 56 centres between July 2006 and June 2015. A total of 3382 patients undergoing operations for AADA were included and divided into 3 groups according to aortic root procedure types: supracommissural replacement (SCR), conduit replacement (CR) and valve sparing root replacement (VSRR). RESULTS: Patients in SCR (2425, 71.7%) were significantly older than CR (681, 20.1%) and VSRR (276, 8.2%) (63.4 vs 57.5 vs 54.2 years; P < 0.001), more female (38.9% vs 32.0% vs 26.1%; P < 0.001) and presented with less aortic regurgitation (26.3% vs 57.1% vs 56.5%; P < 0.001). VSRR presented with slightly less multiple organ malperfusion (11.6% vs 12.0% vs 10.9%; P = 0.045) and were more often diagnosed for Marfan syndrome (2.4% vs 5.1% vs 9.1%; P < 0.001). Thirty-day mortality was lower for VSRR (11.6%) compared to SCR (16.1%) and CR (19.8%; P = 0.010). Despite longer procedural times, multivariable regression showed no influence of total arch replacement for VSRR on mortality compared to CR (odds ratio 0.264; 95% confidence interval, 0.033-2.117; P = 0.21). CONCLUSIONS: SCR remains the procedure of choice in elderly and compromised patients. Extended root preservation techniques may be applied even in combination with extended aortic arch surgery for selected patients for AADA with promising early outcomes.

Treatment of the Aortic Root in Acute Aortic Dissection Type A: Insights from the German Registry for Acute Aortic Dissection Type A (GERAADA) Registry.

OBJECTIVES: Surgery of the aortic root in acute aortic dissection type A (AADA) remains a topic of vague evidence since the extend of dissection and surgeons' capability and interpretation of the disease vary remarkably. We aimed to interpret root operation strategies in the German Registry for Acute Aortic Dissection (GERAADA) cohort. PATIENTS AND METHODS: GERAADA collected the data of 56 centers between July 2006 and June 2015. A total of 3382 patients undergoing operations for AADA were included and divided into three groups according to aortic root procedure types: supracommissural replacement (SCR), conduit replacement (CR) and valve sparing root replacement (VSRR). RESULTS: Patients in SCR (2425, 71.7%) were significantly older than CR (681, 20.1%) and VSRR (276, 8.2%) (63.4 vs 57.5 vs 54.2 yrs; p < 0.001), more female (38.9 vs 32.0 vs 26.1%; p < 0.001) and presented with less aortic regurgitation (26.3 vs 57.1 vs 56.5%; p < 0.001). VSRR presented with slightly less multiple organ malperfusion (11.6 vs 12.0 vs 10.9%; p = 0.045) and were more often diagnosed for Marfan syndrome (2.4 vs 5.1 vs 9.1%; p < 0.001). Thirty-day mortality was lower for VSRR (11.6%) compared to SCR (16.1%) and CR (19.8%; p = 0.010). Despite longer procedural times multivariable regression showed no influence of total arch replacement for VSRR on mortality compared to CR (OR 0.264; 95% CI, 0.033-2.117; p = 0.21). CONCLUSIONS: SCR remains the procedure of choice in elderly and compromised patients. Extended root preservation techniques may be applied even in combination with extended aortic arch surgery for selected patients for AADA with promising early outcomes.

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme.

AIMS: To evaluate the efficacy and safety of oral semaglutide versus comparators by patient characteristic subgroups in patients with type 2 diabetes. MATERIALS AND METHODS: Change from baseline in glycated haemoglobin (HbA1c) and body weight, and achievement of HbA1c <7.0% with oral semaglutide 7 mg, oral semaglutide 14 mg, flexibly dosed oral semaglutide (flex) and comparators were assessed across baseline subgroups (age, race, ethnicity, diabetes duration, body mass index and HbA1c) from the PIONEER programme. Treatment differences were analysed using a mixed model for repeated measurements for continuous variables and a logistic regression model for the binary endpoint. Pooled safety data were analysed descriptively. RESULTS: Changes from baseline in HbA1c and body weight, and the odds of achieving HbA1c <7.0%, were greater with oral semaglutide 14 mg/flex (n = 1934) and higher or similar with oral semaglutide 7 mg (n = 823) versus comparators (n = 2077) across most subgroups. Changes in HbA1c with oral semaglutide 14 mg/flex were greater for patients with higher baseline HbA1c (HbA1c >9.0%: -1.7% to -2.6%; HbA1c <8.0%: -0.7% to -1.2%). In some trials, Asian patients experienced greater HbA1c reductions with oral semaglutide 14 mg/flex (-1.5% to -1.8%) than other racial groups (-0.6% to -1.6%). The overall incidence of adverse events (AEs) with oral semaglutide was similar to that with comparators and was consistent across subgroups. More gastrointestinal AEs were observed with oral semaglutide, versus comparators, across subgroups. CONCLUSIONS: Oral semaglutide demonstrated consistently greater HbA1c and body weight reductions across a range of patient characteristics, with greater HbA1c reductions seen at higher baseline HbA1c levels.

Human hematopoietic microenvironments.

Dormancy of hematopoietic stem cells and formation of progenitors are directed by signals that come from the bone marrow microenvironment. Considerable knowledge has been gained on the murine hematopoietic stem cell microenvironment, while less so on the murine progenitor microenvironment and even less so on these microenvironments in humans. Characterization of these microenvironments is decisive for understanding hematopoiesis and finding new treatment modalities against bone marrow malignancies in the clinic. However, it is equally challenging, because hematopoietic stem cells are difficult to detect in the complex bone marrow landscape. In the present study we are characterizing the human hematopoietic stem cell and progenitor microenvironment. We obtained three adjacent bone marrow sections from ten healthy volunteers. One was used to identify a population of CD34+/CD38- "hematopoietic stem cells and multipotent progenitors" and a population of CD34+/CD38+ "progenitors" based on immunofluorescence pattern/intensity and cellular morphology. The other two were immunostained respectively for CD34/CD56 and for CD34/SMA. Using the combined information we performed a non-computer-assisted quantification of nine bone marrow components (adipocytes, megakaryocytes, bone surfaces, four different vessel types (arteries, capillaries, sinusoids and collecting sinuses), other "hematopoietic stem cells and multipotent progenitors" and other "progenitors") within 30 µm of "hematopoietic stem cells and multipotent progenitors", "progenitors", and "random cell profiles". We show that the microenvironment of the "hematopoietic stem cells and multipotent progenitors" is significantly enriched in sinusoids and megakaryocytes, while the microenvironment of the "progenitors" is significantly enriched in capillaries, other "progenitors", bone surfaces and arteries.

Once-Daily Oral Semaglutide Versus Injectable GLP-1 RAs in People with Type 2 Diabetes Inadequately Controlled on Basal Insulin: Systematic Review and Network Meta-analysis.

INTRODUCTION: The relative efficacy and safety of once-daily oral semaglutide vs. injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in subjects with type 2 diabetes (T2D) inadequately controlled on basal insulin were assessed using network meta-analysis (NMA). METHODS: A systematic literature review (SLR) was performed to identify randomised controlled trials of GLP-1 RAs in this population. Data at 26 ± 4 weeks were extracted for efficacy and safety outcomes feasible for the NMA: change from baseline in glycated haemoglobin (HbA1c), weight and blood pressure; HbA1c target levels (< 7.0% and ≤ 6.5%); composite endpoint; incidence of nausea, vomiting or diarrhoea. Comparators of interest were all licensed doses of dulaglutide, exenatide, liraglutide, lixisenatide and once-weekly injectable semaglutide. RESULTS: The NMA included seven trials. Once-daily oral semaglutide 14 mg was associated with significantly greater HbA1c reductions vs. most comparators (treatment differences: - 0.42 to - 1.32%); differences vs. once-weekly injectable semaglutide (0.5 mg and 1 mg doses) were not statistically significant. Once-daily oral semaglutide 14 mg was associated with significantly greater weight reductions vs. exenatide 2 mg and lixisenatide 20 µg (- 2.21 and - 2.39 kg respectively); non-statistically significant weight reductions in favour of once-daily oral semaglutide 14 mg were observed vs. all other comparators except once-weekly injectable semaglutide 1 mg. Similar trends were observed for the proportion of subjects achieving HbA1c < 7.0% and ≤ 6.5% and the composite endpoint. Once-daily oral semaglutide 14 mg was associated with similar odds of experiencing nausea, vomiting or diarrhoea vs. all comparators. CONCLUSION: Once-daily oral semaglutide 14 mg, as an add-on to basal insulin, is an efficacious treatment for reducing HbA1c and weight and meeting glycaemic targets at 26 ± 4 weeks. Once-daily oral semaglutide 14 mg also offers the option of an oral treatment with similar or better efficacy and similar tolerability vs. most injectable GLP-1 RAs.

AAV-mediated AP-1 decoy oligonucleotide expression inhibits aortic elastolysis in a mouse model of Marfan syndrome.

AIMS: Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome. METHODS AND RESULTS: Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography.Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs. CONCLUSION: This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.

Gender-related differences in patients with acute aortic dissection type A.

OBJECTIVE: Acute aortic dissection type A can occur in both genders at any age. Our aim was to report differences in presentation, treatment, and outcome in female and male patients with acute aortic dissection type A. METHODS: Between July 2006 and June 2015, 56 centers participating in the German Registry for Acute Aortic Dissection Type A reported on a total of 3380 patients. As many as 1234 (37%) were women and 2146 (63%) were men. We compared their clinical features and events occurring within 30 days after surgery. RESULTS: Women were significantly older than male patients (65.5 ± 12.7 years vs 59.2 ± 13.3 years; P < .001). Aortic dissection extended down to the abdominal aorta in 43% men and 39% women (P = .01). Visceral (4.9% vs 7.3%; P = .006) and renal malperfusion (7.7% vs 10.6%; P = .006) were more frequently diagnosed in men. Aortic roots were replaced more frequently in men (22% vs 18%; P < .001). Different aortic arch repair strategies were distributed similarly in both genders. The incidence of new hemiplegia or hemiparesis was also similar in men and women (P = .24). Thirty-day mortality did not differ between women and men (16.3% vs 16.6%; P = .18). In a logistically mixed-effect model, gender revealed no influence on 30-day mortality (odds ratio, 1.15; 95% confidence interval, 0.92-1.44; P = .21). CONCLUSIONS: Aortic dissection type A occurs almost twice as frequently in men. Women develop aortic dissection later in life. Despite women and men presenting at different ages and exhibiting varying dissection and malperfusion patterns, and the fact that men undergo complex proximal aortic repair more frequently, outcomes are similar in both genders.

Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence.

Primary melanomas >1 mm thickness are potentially curable by resection, but can recur metastatically. We assessed the prognostic value of T cell fraction (TCFr) and repertoire T cell clonality, measured by high-throughput-sequencing of the T cell receptor beta chain (TRB) in T2-T4 primary melanomas (n=199). TCFr accurately predicted progression-free survival (PFS) and was independent of thickness, ulceration, mitotic rate, or age. TCFr was second only to tumor thickness in its predictive value, using a gradient boosted model. For accurate PFS prediction, adding TCFr to tumor thickness was superior to adding any other histopathological variable. Furthermore, a TCFr >20% was protective regardless of tumor ulceration status, mitotic rate or presence of nodal disease. TCFr is a quantitative molecular assessment that predicts metastatic recurrence in primary melanoma patients whose disease has been resected surgically. This study suggests that a successful T cell-mediated antitumor response can be present in primary melanomas.

AAV-mediated TIMP-1 overexpression in aortic tissue reduces the severity of allograft vasculopathy in mice.

BACKGROUND: Allograft vasculopathy (AV) is the primary limiting factor for long-term graft survival. An increased activity of matrix metalloproteinases (MMPs) contributes to neointima formation in AV and represents a potential therapeutic target. Adeno-associated virus (AAV)-mediated gene therapy comprises a potentially benign vector model for the long-term expression of MMP antagonists. METHODS: Aortic allografts from DBA/2 mice were incubated with control buffer, AAV-enhanced green fluorescence protein (EGFP), or tissue inhibitor of metalloproteinases 1 (TIMP-1)-loaded AAV (AAV-TIMP-1) and transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg body weight) was administered daily. Explantation as well as histomorphometric and immunohistochemical evaluation was performed after 30 days. Matrix metalloproteinase (MMP) activity was visualized by gelatin in situ zymography. RESULTS: Intima-to-media area ratio and neointima formation were significantly reduced in the AAV-TIMP-1 treatment group compared with those in the control group (by 40%; p < 0.001) and the AAV-EGFP group (by 38.2%; p < 0.001). TIMP-1 overexpression positively affected several pathomechanisms for the development of AV both in vitro and in vivo as compared to that in the control groups: endothelium integrity was preserved as shown by zona occludens 1 and occludin staining; MMP9 expression and activity were significantly reduced (p = 0.01); and smooth muscle cell migration was significantly reduced as smooth muscle actin positive cells predominantly remained in the aortic media in the treatment group (p = 0.001). Moreover, macrophage infiltration was markedly reduced by 49% in the AAV-TIMP-1 group (p < 0.001). CONCLUSION: Immediate post-harvesting allograft incubation with AAV-TIMP-1 reduces neointima formation and macrophage infiltration, constituting a possible adjunct therapeutic strategy to preserve graft function after transplantation.

Imaging-Based 4D Aortic Pressure Mapping in Marfan Syndrome Patients: A Matched Case-Control Study.

BACKGROUND: Marfan syndrome predisposes to aortic aneurysm, dissection, and rupture. We sought to investigate aortic 4-dimensional (4D) relative pressure maps derived from 4D flow cardiovascular magnetic resonance to identify disease characteristic alterations of the intraaortic pressure field in Marfan patients with aortic root dilation compared with age- and sex-matched healthy controls. METHODS: This prospective case-control study included 11 Marfan patients with aortic root dilation (31 ± 5 years, 5 female) and 11 age- and sex-matched healthy controls (31 ± 8 years, 5 female) undergoing 4D flow cardiovascular magnetic resonance of the thoracic aorta. 4D relative pressure maps were computed and compared between groups for 8 aortic regions. RESULTS: Aortic root diameters were significantly larger in patients compared with controls (43 vs 31 mm, P < .001), but not in the proximal descending aorta (23 vs 21 mm, P = .19). Regional pressure gradients over the cardiac cycle were significantly altered in Marfan patients with significantly higher minimum pressure gradients in the proximal ascending aorta (-44.3 vs -97.0 mm Hg/m, P < .001) and significantly lower maximum pressure gradients in the proximal descending aorta (55.1 vs 82.3 mm Hg/m, P < .01). The latter finding was associated with pathologic vortical flow patterns. Regional pressure gradient at mid systole significantly correlated with aortic diameter (proximal ascending aorta: r = 0.73, P < .001; proximal descending aorta: r = -0.59, P = .004). CONCLUSIONS: Noninvasive 4D pressure mapping derived from 4D flow cardiovascular magnetic resonance revealed significant alterations of spatiotemporal pressure characteristics in the thoracic aorta of Marfan patients. These alterations were most pronounced in the proximal ascending aorta and the proximal descending aorta, corresponding to the regions where aortic dissections often originate in Marfan patients.

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts.

Transplant vasculopathy (TV), characterized by obstructive lesions in affected vessels, represents one of the long-term complications of cardiac transplantation. Activation of the transcription factor activator protein-1 (AP-1) is implicated in smooth muscle cell (SMC) phenotypic switch from contractile to synthetic function, increasing the migration and proliferation rate of these cells. We hypothesize that adeno-associated virus (AAV)-mediated delivery of an RNA hairpin AP-1 decoy oligonucleotide (dON) might effectively ameliorate TV severity in a mouse aortic allograft model. Aortic allografts from DBA/2 mice ex vivo transduced with modified AAV9-SLR carrying a targeting peptide within the capsid surface were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg BW) was administered daily. AP-1 dONs were intracellularly expressed in the graft tissue as small hairpin RNA proved by fluorescent in situ hybridization. Explantation after 30 days and histomorphometric evaluation revealed that AP-1 dON treatment significantly reduced intima-to-media ratio by 41.5% (p < 0.05) in the grafts. In addition, expression of adhesion molecules, cytokines, as well as numbers of proliferative SMCs, matrix metalloproteinase-9-positive cells, and inflammatory cell infiltration were significantly decreased in treated aortic grafts. Our findings demonstrate the feasibility, efficacy, and specificity of the anti-AP-1 RNA dON approach for the treatment of allograft vasculopathy in an animal model. Moreover, the AAV-based approach in general provides the possibility to achieve a prolonged delivery of nucleic-acids-based therapeutics in to the blood vessel wall.

Extensive aortic surgery in acute aortic dissection type A on outcome - insights from 25 years single center experience.

BACKGROUND: This single center study compares the different surgical techniques used in the treatment of acute aortic dissection type A (AADA) analyzing the influence of the extent of the surgical approach on outcome. METHODS: From 1988 to 2012, 407 patients were operated for AADA. The cohort was divided into subgroups according to the surgical approach. These groups were compared with the supracommissural replacement group (SCR; n = 141). Groups included aortic valve sparing techniques (AVS; n = 29), Composite replacement (COMP; n = 119), COMP with total arch replacement (COMP+TAR; n = 27) and SCR with TAR (n = 75). RESULTS: Compared to SCR alone, operation (p = 0.005), bypass-, cross-clamp and circulatory arrest times were longer in SCR + TAR (all p < 0.001). Moreover, operation, bypass and cross clamp times were longer in COMP+TAR (p = 0.003, p = 0.002 and p < 0.001 respectively). COMP alone and AVS required longer cross-clamp time, too (p < 0,001 and p = 0.002, respectively). Overall 30-day mortality was 21% with the observed lowest rate after AVS (14%, SCR 18%, COMP 25%) but differences in 30-day mortality were not statistically significant. The estimated 10-year survival was 42%, especially AVS demonstrated a good 10-year survival (69%). David technique was superior to Yacoub technique concerning incidence of redo interventions (p = 0.036). Risk factors for early mortality included age, circulatory arrest, general malperfusion, bypass and operation time. Circulatory arrest per se was revealed as risk factor for long-term survival. CONCLUSIONS: Within our single center retrospective study concomitant aortic root repair or aortic arch replacement for AADA demonstrated acceptable early and long-term survival. Circulatory arrest, long bypass and operation times per se might be important risk factors for early mortality. AVS techniques can be performed safely and have good outcomes in acute aortic dissection repair.

Evaluation of the Cost Per Patient Achieving Treatment Targets with Oral Semaglutide: A Short-Term Cost-Effectiveness Analysis in the United States.

INTRODUCTION: Oral semaglutide is the first orally administered glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes, and has been evaluated in the PIONEER clinical trial program. These trials assessed the proportions of patients achieving single and composite endpoints, encompassing glycemic control [defined in terms of glycated hemoglobin (HbA1c)], weight loss, and hypoglycemia. The present study assessed the cost of control with oral semaglutide versus empagliflozin, sitagliptin, and liraglutide in the US. METHODS: Four endpoints were evaluated: (1) HbA1c ≤ 6.5%; (2) HbA1c < 7.0%; (3) ≥ 1.0%-point HbA1c reduction and weight loss ≥ 3.0%; and (4) HbA1c < 7.0% without hypoglycemia and without weight gain. The proportions of patients achieving each endpoint were sourced from the PIONEER 2, 3 and 4 trials. Treatment costs were accounted over an annual time-period in 2019 US dollars (USD), based on wholesale acquisition cost. Cost of control was calculated by dividing treatment costs by the proportion of patients achieving each target. RESULTS: Oral semaglutide was consistently associated with the lowest cost of control for all four endpoints. For the targets of HbA1c ≤ 6.5% and HbA1c < 7.0%, oral semaglutide 14 mg was associated with lower cost of control than empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg by USD 15,036, 14,697, and 6996, respectively, and USD 931, 346 and 4497, respectively. For the double composite endpoint, cost of control was lower with oral semaglutide 14 mg by USD 525, 32,277 and 13,011, respectively versus empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg. For the triple composite endpoint, cost of control was lower with oral semaglutide 14 mg by USD 1255, 7510 and 5774, respectively. CONCLUSION: Oral semaglutide was associated with lower cost of bringing patients with type 2 diabetes to four clinically-relevant treatment targets versus empagliflozin, sitagliptin, and liraglutide in the US. FUNDING: Novo Nordisk A/S.