United States

Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrated clinically meaningful reductions in HbA1c and body weight that were significantly greater compared with semaglutide in patients with type 2 diabetes on background metformin. In a pre-specified subgroup analysis, we evaluated the efficacy and safety of tirzepatide in the Hispanic or Latino population of SURPASS-2.
In this open-label, 40-week, Phase 3 study (N=1878; mean baseline HbA1c 8.28%; BMI 34.2 kg/m²; Hispanic or Latino ethnicity 70%) participants were randomized 1: 1: 1: 1 to tirzepatide (5, 10, 15 mg; doses were double-blinded) or semaglutide (1 mg). Efficacy analyses included all randomised patients who received ≥1 treatment dose (modified intention-to-treat [mITT] population) while patients were on treatment without rescue therapy and excluding patients who discontinued study drug due to inadvertent enrollment (efficacy estimand). Safety analyses were performed in the mITT population, including all data from the start of treatment to the end of the safety follow-up. The least square mean (LSM) change from baseline was calculated within each subgroup using a mixed model for repeated measurements (MMRM) with country, baseline value, treatment group, visit, and treatment-by-visit interaction as the fixed effect, and patient as the random effect. MMRM for weight change also included baseline HbA1c group (≤8.5%, &gt;8.5%) as a covariate.
In patients of Hispanic or Latino ethnicity, the LSM change from baseline in HbA1c at 40 weeks was -2.11%, -2.46%, and -2.47% with tirzepatide 5, 10, and 15 mg, respectively, and -1.93% with semaglutide (all p&lt;0.001). The respective changes in patients not of Hispanic or Latino ethnicity were -2.03%, -2.14%, -2.43%, and -1.69% (all p&lt;0.001). Reductions in HbA1c were significantly greater for all tirzepatide doses compared with semaglutide in patients of both Hispanic or Latino and non-Hispanic or Latino ethnicity (all p≤0.027). In Hispanic or Latino patients, body weight change was -6.9 kg with tirzepatide 5 mg, -9.7 kg with 10 mg, -10.5 kg with 15 mg, and -5.6 kg with semaglutide (all p&lt;0.001). In non-Hispanic or Latino patients, the changes from baseline in body weight were -9.9 kg, -11.6 kg, -17.1 kg, and -7.5 kg, for the tirzepatide doses and semaglutide, respectively, (all p&lt;0.001). In both subgroups, reductions in body weight were significantly greater than semaglutide with all tirzepatide doses (all p≤0.013).
The most common adverse events were gastrointestinal in the tirzepatide and semaglutide arms, including nausea (Hispanic or Latino 11-17% and 13%; non-Hispanic or Latino 32-36% and 29%), diarrhoea (10-13% and 10%; 15-24% and 17%) and vomiting (4-7% and 7%; 10-16% and 12%).
Consistent with the primary SURPASS-2 results, in a Hispanic or Latino population with type 2 diabetes, tirzepatide demonstrated greater reductions from baseline in HbA1c and body weight than the selective GLP-1 receptor agonist semaglutide, with a comparable safety profile.

ENDO 2022

Efficacy and Safety of Tirzepatide Versus Semaglutide in a Hispanic or Latino Population: A Prespecified Subgroup Analysis of SURPASS-2

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrated clinically meaningful reductions in HbA1c and body weight that were significantly greater compared with semaglutide in patients with type 2 diabetes on background metformin. In a pre-specified subgroup analysis, we evaluated the efficacy and safety of tirzepatide in the Hispanic or Latino population of SURPASS-2.
In this open-label, 40-week, Phase 3 study (N=1878; mean baseline HbA1c 8.28%; BMI 34.2 kg/m²; Hispanic or Latino ethnicity 70%) participants were randomized 1: 1: 1: 1 to tirzepatide (5, 10, 15 mg; doses were double-blinded) or semaglutide (1 mg). Efficacy analyses included all randomised patients who received ≥1 treatment dose (modified intention-to-treat [mITT] population) while patients were on treatment without rescue therapy and excluding patients who discontinued study drug due to inadvertent enrollment (efficacy estimand). Safety analyses were performed in the mITT population, including all data from the start of treatment to the end of the safety follow-up. The least square mean (LSM) change from baseline was calculated within each subgroup using a mixed model for repeated measurements (MMRM) with country, baseline value, treatment group, visit, and treatment-by-visit interaction as the fixed effect, and patient as the random effect. MMRM for weight change also included baseline HbA1c group (≤8.5%, >8.5%) as a covariate.
In patients of Hispanic or Latino ethnicity, the LSM change from baseline in HbA1c at 40 weeks was -2.11%, -2.46%, and -2.47% with tirzepatide 5, 10, and 15 mg, respectively, and -1.93% with semaglutide (all p<0.001). The respective changes in patients not of Hispanic or Latino ethnicity were -2.03%, -2.14%, -2.43%, and -1.69% (all p<0.001). Reductions in HbA1c were significantly greater for all tirzepatide doses compared with semaglutide in patients of both Hispanic or Latino and non-Hispanic or Latino ethnicity (all p≤0.027). In Hispanic or Latino patients, body weight change was -6.9 kg with tirzepatide 5 mg, -9.7 kg with 10 mg, -10.5 kg with 15 mg, and -5.6 kg with semaglutide (all p<0.001). In non-Hispanic or Latino patients, the changes from baseline in body weight were -9.9 kg, -11.6 kg, -17.1 kg, and -7.5 kg, for the tirzepatide doses and semaglutide, respectively, (all p<0.001). In both subgroups, reductions in body weight were significantly greater than semaglutide with all tirzepatide doses (all p≤0.013).
The most common adverse events were gastrointestinal in the tirzepatide and semaglutide arms, including nausea (Hispanic or Latino 11-17% and 13%; non-Hispanic or Latino 32-36% and 29%), diarrhoea (10-13% and 10%; 15-24% and 17%) and vomiting (4-7% and 7%; 10-16% and 12%).
Consistent with the primary SURPASS-2 results, in a Hispanic or Latino population with type 2 diabetes, tirzepatide demonstrated greater reductions from baseline in HbA1c and body weight than the selective GLP-1 receptor agonist semaglutide, with a comparable safety profile.

technical paper

Introduction
Hyperglycemic emergencies, including diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS), are common reasons for hospitalization among adults with diabetes. Household income is a known determinant of health and impacts access to medications and health services. Outpatient services and medications impact readmission rates as medication nonadherence and inadequate follow-up are common underlying precipitants of DKA and HHS. This study outlined the trends in readmissions following initial hospitalization for hyperglycemic emergencies.
Methods
This was a longitudinal trend analysis of the National Readmission Database (NRD), which is the largest readmission database in the US. The study period was from 2010 to 2018, and involved adults with DKA and HHS as the principal discharge diagnosis. We excluded elective and December admissions. Using the unique visit linkage variable within the NRD, we estimated the 30-day all-cause readmission rate (30ACR) stratified by the median household income for the patient's zip code quartile (MHOI). Outcomes included comparing trends in 30ACR in DKA and HHS between the low-income quartile (LIQ) and high-income quartile (HIQ) as well as trends in 30-day DKA and HHS specific readmission rates between the LIQ and HIQ. We estimated the estimated annual percent change (APC) via logistic trend regression adjusted for age categories, sex, and MHOI.
Results
From 2010 to 2018, there was a trend towards increasing readmission rates overall. Among DKA hospitalizations, patients in the LIQ had a higher 30ACR compared to the HIQ (17.1% vs 12.3% in 2010 and 21.7% vs 15.3% in 2018). The LIQ patients also had a higher DKA-specific readmission rate over the period (7.2% vs 5.1% in 2010 and 7.6% vs 10.4% in 2018). The adjusted APC for DKA 30ACR was 1.6%, with the overall odds of readmission higher in the LIQ (adjusted odds ratio [aOR]: 1.50, 95% CI: 1.42 - 1.58, p<0.001) compared to the HIQ. Among HHS hospitalizations, patients in the LIQ had a higher 30ACR compared to the HIQ (12.2% vs 10.4% in 2010 and 14.8% vs 12.4% in 2018). The LIQ patients also had a higher HHS-specific readmission rate over the period (0.8% vs 0.6% in 2010 and 1.2% vs 1.1% in 2018). The adjusted APC for HHS 30ACR was 1.9%, with the overall odds of readmission higher in the LIQ (adjusted odds ratio [aOR]: 1.13, 95% CI: 1.02 - 1.26, p=0.025) compared to the HIQ.
Conclusion
There seem to be rising readmission rates following hyperglycemic emergency hospitalizations with significant disparity based on median household income. This difference is was higher DKA. Though the study design limits the elaboration on specific income-related factors that are at play, these findings establish the need for further exploring the barriers that predispose patients to readmissions to decrease healthcare utilization costs.

Widening Economic Disparity in Rates of Readmissions Following Hospitalizations for Hyperglycemic Emergencies Among US Adults over a Decade.

Background: Despite newer diabetes medications and technology being available, therapeutic inertia persists and there are more people living with "uncontrolled" diabetes than meeting A1c targets. Here we evaluate how the ECHO© model for diabetes management changed prescribing practices among participating primary care providers (PCPS).
Methodology: Three unique diabetes ECHO programs evaluated comfort or perception of prescribing practice changes for local community PCPs (n=74) in four regions (Illinois, District of Columbia, New Mexico, and Washington). One site representing two regions collected pre- and post-program participant surveys (n=45) while two sites collected post-program surveys only (n=29), in which respondents reported perceptions of changes resulting from participation in ECHO. Participants reported their use of technology (professional and personal continuous glucose monitoring (CGM) and insulin pumps) and medications (insulin and non-insulin).
Results: On a 4-point Likert scale, PCPs' (n=45) average self-reported prescription use for newer diabetes medications with cardiovascular indications increased from 3.07 (sometimes) to 3.84 (sometimes-always).

Combating Therapeutic Inertia: Project ECHO for Diabetes Improves Primary Care Providers' Comfort and Use of Diabetes Medication and Technology

Breast cancer is the most common invasive cancer in females worldwide and accounts for 16% of all female cancers, 22.9% of invasive cancers in women, and 18.2% of all cancer-related deaths worldwide. About 80% of these cancers, once established, depend on available estrogens (i.e., estradiol) to grow. The production of estrogens occurs via a catalytic process governed by the enzyme Aromatase. This process occurs primarily in the ovaries in pre-menopause, while in post-menopause, this occurs in peripheral tissues, including the breast. In patients whose cancers have specific hormone receptors, such as Estrogen Receptor positive (ER+), Progesterone Receptor positive (PR+), and Human Epidermal Growth Factor 2 Receptor positive (HER2+), these tumors can continue receiving nutrients and signals to grow, which provides targets for therapy. Although many of the currently available drugs for breast cancer seek to suppress this process and thus reduce available estrogens, they have numerous harmful side effects and have high rates of therapy failure due to the development of resistance. Therefore, new therapies and targets for this devastating disease are needed. We observed that breast tumors had increased estrogen production in postmenopausal women, leading us to question the cause of this increase. Further, the complete mechanism of aromatase action and the possibility of targetable cofactors remained previously unknown. Thus, we set out to identify the mechanism of Aromatase action to provide prognostic and therapeutic insight into this distressing disease. As Aromatase is an endoplasmic reticulum (ER) resident protein, we purified ER fractions from breast tissues, separated through 1D, and then each ten kDa fractions were further separated and analyzed through Mass-spectrometry to determine the cofactors associated with aromatase activity. We observed an 11 mer peptide LEVVVDQPMER, which on cloning resulted in a 207 amino acid protein not present in the database. This previously undiscovered protein is colocalized with Aromatase in the ER. We saw that knocking down its expression by siRNA in wild-type breast cells (MCF-12A) or tumorigenic MCF-7 or T47-D cells increased estradiol synthesis significantly without affecting aromatase expression. Further biochemical experiments showed that Aromatase and the 207 amino acid protein interacted directly without affecting the expression of other ER-resident proteins. Additionally, our experiments showed that the new protein is not hormonally stimulated or transcriptionally inhibited and thus, regulates the aromatase catalytic activity of estradiol synthesis. Therefore, we have termed this new protein "Aromatase Interacting Partner in Breast" (AIPB).

Cloning, Sequencing, and Characterization of Aromatase Interacting Partner in Breast (AIPB). A New Protein Regulating Estradiol Synthesis.

Estrogen receptor positive (ER+) breast cancer is the most common subtype among all breast cancers and is responsible for most breast cancer related deaths. Endocrine therapies, such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI), often given in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are initially effective but the majority of advanced ER+ breast cancers eventually become refractory to endocrine therapies. Therefore, understanding the underlying molecular mechanisms that enable or promote resistance to endocrine therapies may lead to novel therapeutic targets.Cancer cells have a high energy demand and as a result consume greater quantities of glucose to meet their energy and anabolic demands to support cell growth and proliferation. In this study, we used breast cancer cell models that are endocrine therapy sensitive and resistant and investigated the metabolic flux of glucose by growing the cells in the presence of the stable glucose isotope, UC13-Glucose. We measured the C13-labelled metabolites of glycolysis and the TCA cycle. Glucose consumption was higher in endocrine therapy resistant MCF7/LCC9 (LCC9) cells compared with parental MCF7 (MCF7) and estrogen independent, endocrine therapy sensitive MCF7/LCC1 (LCC1) cells. Notably, in LCC9 cells the m+4 and m+6 isotopomer of C-13 labelled citrate was absent. Further, in LCC9 cells, C-13 labelled fumarate was very low while the succinate: fumarate ratio was markedly higher. These results suggest that the TCA cycle is impaired in LCC9 cells and the conversion of succinate to fumarate is dysregulated. Succinate dehydrogenase (SDH) enzyme is responsible for catalytic conversion of succinate to fumarate. SDH is a multimeric protein comprised of four different subunits and SDH assembly factor 2 (SDHAF2), which is a tumor suppressor gene. Our study further showed that SDHAF2 protein was under expressed in LCC9 cells compared with LCC1 cells, likely contributing to lower SDH activity. Intriguingly, when SDH activity was inhibited using dimethylmalonate, the LCC9 were re-sensitized to both Fulvestrant and 4-hydroxytamoxifen. Data analysis of clinical samples shows that poor relapse free survival in ER+ breast cancer patients is correlated with lower expression levels of SDHAF2. Overall, this study suggests that targeting succinate metabolism may help to restore sensitivity to Fulvestrant and tamoxifen in endocrine therapy resistance in ER+ breast cancer cells.

Targeting Succinate Metabolism in Endocrine Therapy Resistant, ER Positive, Breast Cancer Cells

The transcription factor (TF) GRHL2 controls normal epithelial differentiation in different tissues. It is expressed in all breast cancer subtypes except those with a mesenchymal phenotype (claudin-low subtype), where its ectopic expression leads to induction of a mesenchymal-epithelial transition (MET) (1). Here we explored the mechanisms by which GRHL2 induces MET in claudin-low breast cancer cell lines using a combination of ChIP-seq and RNAseq analyses upon modulation of GRHL2 expression in mesenchymal and epithelial cell lines. Direct DNA binding by GRHL2 was enriched in proximity of genes positively regulated in mesenchymal cell lines, which include several epithelial TFs as well as an array of epithelial genes. Biotinylation and mass spectrometry analysis of membrane proteins confirmed surfaceome remodeling via induction of membrane proteins with roles in cell-cell contacts and adhesion. Repression of mesenchymal genes was mediated in part by direct induction of miRNAs targeting mesenchymal transcription factors. In addition, GRHL2 strongly induced expression of the cofactor VGLL1, whose expression is high in the triple-negative (TNBC) basal-like subtype. VGLL1 overexpression in mesenchymal cell lines and suppression in basal-like TNBC cells confirmed its role in mediating part of GRHL2 signaling, in particular via interaction with and modulation of TEAD transcription factors. In addition, GRHL2 also interacted with VGLL1 upon its induction in mesenchymal cells, recruiting it to some of its binding motifs, suggesting a multilayered cross-talk between GRHL2 and TEAD factors. Together, our results indicate that GRHL2 acts as a master regulator in the induction of TNBC epithelial differentiation via direct upregulation of epithelial transcription factors, miRNAs and TEAD cofactor VGLL1, resulting in both upregulation of epithelial genes and suppression of mesenchymal genes.(1) Cieply B. et al., Cancer Res. 2013 Oct. 1;73 (20): 6299-309

Direct and VGLL1-mediated gene regulation by GRHL2 during mesenchymal to epithelial transition in breast cancer

Breast cancer is the second leading cause of cancer related deaths in women in the United States, with most mortalities associated with recurrent metastasis. Interestingly, high cholesterol levels are associated with an increased risk of breast cancer recurrence and poor prognosis, while therapies that lower cholesterol concentrations are associated with a good prognosis. Previous work has identified a metabolite of cholesterol, 27-Hydroxycholesterol (27HC), as being able to promote the progression and metastasis of breast cancer. 27HC does so by acting on myeloid immune cells. Within the tumor microenvironment, macrophages are abundant cells in the myeloid lineage. When macrophages were treated with 27HC, their ability to activate T cells was impaired. Those T cells that were activated, had a decreased anti-cancer cytotoxic response. Subsequent work has identified the Liver X Receptor (LXR) as mediating the immune-suppressive effects of 27HC. However, the mechanism by which LXR activity within myeloid cells inhibits subsequent T cell activity is unknown.ABCA1 is a classic target gene of LXR and is known to facilitate cholesterol efflux from the cell. Our analysis of publicly available transcriptome indicates that ABCA1 expression within breast tumors is associated with good prognosis. These somewhat paradoxical observations suggest that ABCA1 exhibits a pro-immune and anti-cancer effect – opposite to what we would expect for LXR activation. Therefore, the goal of the current work is to determine the effect of manipulation of ABCA1 within macrophages and its consequent effect on T cells in vitro and in context to breast cancer metastasis. Our results to date indicate that knocking down ABCA1 using siRNA by targeting the 3' UTR decreased the expression of genes associated with macrophage function and interaction with T cells. Importantly, many of those effects were rescued by over- expression of ABCA1.In summary, our results indicate that although ABCA1 is a target gene of LXR, the induction of ABCA1 by LXR may be compensatory rather than driving the immunosuppressive effects of 27HC. Thus, we hypothesize that ABCA1 plays a pro-immune function and could be a potential therapeutic target to boost the immune system.

Role of ABCA1 in Myeloid Cell Function and Breast Cancer Progression

Background: Breast cancer (BC) is the most diagnosed cancer and the second-leading cause of cancer-associated death in women in the United States. BCs that express the estrogen and/or progesterone receptor (ER/PR) are treated with ER-targeting endocrine therapies that effectively reduce disease burden and extend lifespan. However, up to 50% of patients with ER+BCs will experience recurrence, often at a metastatic site, within 10 years of diagnosis. Novel targeted therapies are needed to treat both metastatic ER+BC resistant to current treatment strategies and chemoresistant ER-BCs.We identified chitinase 3–like-1 (CHI3L1/BRP-39/YKL-40) and prolactin inducible protein (PIP/GCDFP-15) as androgen receptor (AR)-regulated in BC. PIP is reported to be detectable in >90% of BCs, but its function in BC is not well-characterized. CHI3L1 is a glycosyl hydrolase family 18 protein member with reported roles in aging and numerous pathologies. During mammary gland involution, CHI3L1 contributes to a pro-tumorigenic wound-healing-like environment and increases macrophage infiltration. Further, CHI3L1 correlates with tumor-suppressive M2 macrophage infiltration in ER-BC. We previously reported that ER+ cells and patient-derived xenografts with activating mutations in the ESR1 gene encoding ER—a known mechanism of endocrine therapy resistance—had elevated AR and CHI3L1 gene and protein expression. Based on the above and our finding that metastatic BCs biopsies harboring ESR1 mutations exhibited increased AR expression, we hypothesized that AR regulation of CHI3L1 and PIP promote progression to metastatic disease in part through immune suppressive effects.Methods: A ConTra(V3) transcription factor binding site analysis was performed on CHI3L1 and PIP promoters. CHI3L1 and PIP were measured via immunohistochemistry in xenograft tumors in mice treated with or without the androgen dihydrotestosterone (DHT). Immunoblotting, immunohistochemistry, and immunofluorescence approaches were also utilized to assess CHI3L1 protein expression in DHT-treated, tamoxifen resistant (TAMR), and long term E2 deprived (LTED) ER+BC cells. CIBERSORT analysis was conducted on the Firehouse Legacy TCGA dataset. Macrophage efferocytosis assays were performed on an IncuCyte Live Cell Imaging system.Results: We identified highly conserved AR binding sites in the CHI3L1 and PIP promoters. CHI3L1 protein was elevated in TAMR and LTED BC cells, which was further elevated in BC cells with ESR1 mutations, as well as DHT-treated cells. Further, CHI3L1 and PIP were increased in xenograft tumors after DHT treatment. CIBERSORT analysis revealed that CHI3L1 and PIP high tumors had altered immune profiles, including differential macrophage levels. Finally, CHI3L1 and PIP treatment significantly reduced macrophage efferocytosis of BC cells (p ≤ 0.0001).Conclusions: Our work suggests that AR-mediated regulation of CHI3L1 and PIP may alter immune cell infiltration/function in BC and may be important in endocrine therapy resistant ER+BCs. Further characterization and manipulation of these AR-regulated proteins is underway to test the potential to target and reverse their immune suppressive functions.

Efficacy and Safety of Tirzepatide Versus Semaglutide in a Hispanic or Latino Population: A Prespecified Subgroup Analysis of SURPASS-2

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Widening Economic Disparity in Rates of Readmissions Following Hospitalizations for Hyperglycemic Emergencies Among US Adults over a Decade.

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