United States

Bimagrumab is a fully human, ligand-blocking antibody to activin receptors type IIA and type IIB that in obese diabetic patients has been shown to improve body composition dramatically. After 48 weeks of treatment (N=75, allocated 1: 1, bimagrumab intravenously (iv) 10 mg/kg/month: placebo), in the bimagrumab group total body fat mass decreased by 20.5% while at the same time, lean mass increased by 3.6%, both assessed by dual X-ray absorptiometry (DXA). At 24 weeks, fat mass loss was 16.5% in those treated with bimagrumab, while there was little effect on fat or lean mass in the placebo group at either timepoint. In a subset of patients who underwent magnetic resonance imaging, the fat loss effect was greatest for hepatic fat, with a 52% reduction from baseline to week 48, and for abdominal visceral fat, where a 34% decrease was observed over the same interval (Heymsfield SB et al. JAMA Open 2021;4: e2033457).
Most drugs for obesity are less effective in diabetics, so to evaluate the efficacy of bimagrumab on fat mass in non-diabetics, we undertook a pooled analysis of patient-level data from 6 clinical studies of bimagrumab previously conducted to assess muscle anabolic activity and/or clinical safety. Criteria for study selection included at least 24 weeks of therapeutic drug exposure, DXA performed at baseline and at least 2 additional time points. Studies that recruited patients with known, underlying primary diseases of adipose tissue or muscle were excluded. Of the 568 subjects in these 6 studies, 7 were identified as diabetic and excluded, leaving 561 subjects in 4 dose groups including placebo (N=204), 70 mg iv monthly (N=43), 210 mg iv monthly (N=75), or a top dose group comprising 700 mg iv once monthly or 10 mg/kg iv once monthly or 30 mg/kg iv q8w x 2 (total N=239). A dose- and time-dependent effect of bimagrumab on fat loss was observed and at the 24 week time point, the top dose group lost 14.6% (LS mean (95% CI) 13.2% - 16.0%) of total body fat mass, while the placebo group increased their fat mass by 2.4% (0.9% - 3.8%). Approximately 41% of the subjects in this pooled analysis were overweight or obese, which is a potential limitation of this study since all subjects in the diabetes study were overweight or obese, however this likely does not affect the conclusion since no effect of baseline BMI on % initial body fat lost at week 24 was seen. Thus, unlike most other drugs for obesity, the efficacy of bimagrumab is very similar in both diabetic patients and in non-diabetic patients.

ENDO 2022

The Dramatic Fat Mass Loss Caused by Bimagrumab is Similar in Diabetic and Non-diabetic Patients.

**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.

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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**
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**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. 

technical paper

INTRODUCTION: Diabetes prevalence continues to increase in the US, although the burden of diabetes varies by race/ethnicity. Diabetes prevalence is higher in US Asian compared to non-Hispanic White adults and Asian adults may develop diabetes at an earlier age. Some studies suggest that Asians with diabetes have reduced insulin secretory capacity, but lower rates of insulin use have also been reported. This study seeks to characterize insulin use in a large clinical population of US Asian and Pacific Islanders (PI) with diabetes.
METHODS: This cross-sectional observational study includes adult health plan members aged 45-79 years with diabetes prior to 2015 and receipt of diabetes pharmacotherapy in 2019. To estimate diabetes duration, those with diabetes identification during their first year of health plan membership (pre-existing diabetes) were excluded. Those without weight assessment in 2019 were also excluded. Race/ethnicity and Asian/PI subgroup were determined from self-reported data in health record databases. The primary outcome was insulin treatment in 2019, based on outpatient pharmacy records. Covariates included age, sex, BMI, diabetes duration, HbA1C, and calculated Charlson Comorbidity Index (CCI). A neighborhood deprivation index (NDI) was estimated using US Census data. Modified Poisson regression with robust variance was used to examine the association between ethnicity and insulin therapy, reporting relative risk (RR) with 95% confidence intervals (CI).
RESULTS: Among 81,692 adults with diabetes (47% female), 21,187 (26%) were Asian/PI, 32,435 (40%) non-Hispanic White, 8901 (11%) Black, 16,855 (21%) Hispanic/Latinx, and 2314 (3%) Other/unknown. Compared to other racial/ethnic groups, Asians were less likely to use insulin (25% of Asian vs. 38%, 39%, and 37% of non-Hispanic White, Black, and Hispanic/Latinx, respectively, p<0.01). Within Asian/PI subgroups, the prevalence of insulin use varied: Japanese (32%), Native Hawaiian/Pacific Islander (33%), Filipino (28%), South Asian (23%), Chinese (21%) and Southeast Asian (20%). However, age, sex, duration of diabetes, level of diabetes control (HbA1c), BMI, and comorbid burden also varied among these populations. In multivariable analyses adjusting for these covariates, non-Hispanic White (RR 1.4, CI 1.3-1.4), Black (RR 1.1, CI 1.1-1.2), and Hispanic (RR 1.2, CI 1.2-1.2) adults had a higher relative risk of insulin use when compared to Asian/PI adults in aggregate. However, among the different Asian/PI subgroups, with Chinese as reference, only Japanese adults were more likely to use insulin (RR 1.2, CI 1.1-1.3) with no differences seen for Filipino, other Southeast Asian, and Native Hawaiian/PI.
CONCLUSIONS: This study provides insight into use of diabetes pharmacotherapy and specifically insulin use among Asian/PI subgroups compared to other populations. The lower rate of insulin use observed among Asian/PI subgroups is consistent with past studies and is likely multifactorial. Further research is needed to understand barriers against insulin treatment which will help optimize treatment and reduce diabetes burden in this population.

Insulin Use Among Asian and Pacific Islander Adults with Diabetes Receiving Pharmacotherapy

Glycemic targets are not met by many individuals with type 1 diabetes (T1D), especially among adolescents and young adults (AYA). To date, research is limited regarding comfort with diabetes self-management in this vulnerable demographic preparing to transition from pediatric to adult care. The purpose of this study was to examine levels of self-reported comfort with diabetes management tasks among AYA with T1D, and to describe the relationships among comfort levels, sociodemographic factors, and HbA1c. As a part of a quality improvement initiative at an academic pediatric hospital, AYA aged 15-23 years old with T1D received a transition survey to self-assess their comfort level with sixteen different diabetes management tasks on a 5-point Likert scale during a routine diabetes care visit. A chart review was subsequently performed to obtain sociodemographic factors and HbA1c. Among 161 participants who completed the survey (median age 17, median diabetes duration 7 years, 82.3% white, 59% female, 66.5% with private insurance, and median HbA1c 8.8%), comfort with diabetes management tasks was generally rated highly (median overall comfort level of 4.5 out of 5) and did not differ by race or insurance type. Regression analysis revealed that higher self-reported comfort level with diabetes management tasks was associated with a higher HbA1c (p=0.006), after controlling for age, sex, race, insurance type, and diabetes duration. These findings suggested that self-reported comfort with independently managing T1D may not be a sufficient metric in assessing AYA patients' need for further intervention to optimize glycemic outcomes as they transition from pediatric to adult providers, and highlighted the importance of continuity of care to optimize diabetes management during this transitional period.

Association of HbA1c and Comfort with Diabetes Self-Management Among Adolescents and Young Adults with Type 1 Diabetes

Introduction: Obesity surgeries improve type 2 diabetes (T2D) in most cases, with effects frequently evident before substantial weight reduction. Therefore, this study hypothesizes that the increase in indolepropionic acid (IPA), a gut-derived tryptophan metabolite considered to be a potential biomarker for the development of T2D, might contribute to the metabolic benefits occurring after obesity surgery. Since sex impacts the pathogenesis of numerous diseases, including T2D, our objective was to investigate sex-specific effects on the changes in IPA in response to obesity surgery. Methods: One-hundred and twenty-one obese individuals (36 males and 85 females; age 48.4 ± 9.4 years; BMI 42.9 ± 5.3kg/m²) participants from the ongoing Kuopio OBesity Surgery (KOBS) Study, who were accepted for Roux-en-Y gastric bypass (RYGB) were included. Serum samples drawn after 12h fasting were available from both baseline and 1-year follow-up visits for measuring IPA by LC-QQQ-MS. Impaired fasting glucose (IFG) was defined as a fasting glucose level ≥5.6nmol/L. Results: Male and female participants had similar ages, BMI and IPA [93.2 (44.3 – 137.8) vs 67.0 (44.6 – 113.8) ng/dL, P=0.444, males and females respectively) at baseline. Weight loss after 1 year of RYGB was lower in males in comparison with females (19.8 vs 23.5%, P=0.014). A significant interaction between time and sex on IPA changes was found during the first year of RYGB (P=0.028). We observed an increase in IPA in females but not in males, especially in the youngest female group (median age <48.7 years). Fasting insulin interacted significantly with sex on the changes in IPA (P<0.001), but not fasting glucose (P=0.962). In addition, females had lower prevalence of IFG at 1-year (25 vs 57%, P=0.042, female and male participants respectively), which was associated with changes in IPA independently of weight loss. Conclusion: Our results suggest that changes in IPA concentrations may be associated with beneficial changes in glucose metabolism observed after obesity surgery in females. A comprehensive understanding of the sex-specific effects of the IPA could contribute to future non-surgical treatments for T2D.

Sex Differences in the Indolepropionic Acid Alterations in Response to Obesity Surgery

Introduction:
Hypertriglyceridemia is the third most common cause of acute pancreatitis, leading to increased morbidity and mortality. Hypocalcemia is a frequent complication of pancreatitis, attributed to saponification of calcium by the release of pancreatic lipase. Free fatty acids are released by the breakdown of triglycerides, then react with extracellular calcium, forming fatty acid salts that deposit in the retroperitoneum and reduce calcium availability.¹
We present a case of an adolescent female with recurrent episodes of acute pancreatitis, hypertriglyceridemia, and hypocalcemia. Her first presentation of pancreatitis coincided with new-onset type 2 diabetes, while this third episode with COVID-19.

Case:
An 18-year-old morbidly obese female with type 2 diabetes, hypertriglyceridemia, hepatomegaly, and recurrent acute pancreatitis was admitted for a third episode of pancreatitis secondary to severe hypertriglyceridemia.
On admission, triglycerides were 3213 mg/dL (reference 35-134mg/dL), lipase 12,721 units/L (145-226u/L), amylase 323 units/L (<106u/L), AST 90 units/L (10-26u/L), and ALT 109 units/L (19-49u/L). A1C was 7.5%, blood glucose 301 mg/dL, bicarbonate 25 mmol/L, and large urine ketones. Initial calcium was 8.7 mg/dL (9.0-10.7mg/dL) and albumin 4.0 gm/dL (3.8-5.6gm/dL). The next day, she developed hypocalcemia with numbness and tingling. Serum calcium was 5.3mg/dL, ionized calcium 0.74 mmol/L (1.12-1.37mmol/L), and albumin <0.6 gm/dL. 25-hydroxy vitamin D level was 16.5 ng/mL (30-100). QTc was 470 ms (350-440ms). She was transferred to pediatric intensive care and initiated on an insulin drip at 0.1 units/kg/hour for hypertriglyceridemia. She received four IV calcium gluconate boluses (1000-2000 mg each). Symptoms improved within one day. Triglycerides decreased to 642 mg/dL, calcium and albumin normalized, and subcutaneous insulin regimen was resumed. She started vitamin D 3000 IU daily and elemental calcium carbonate 26 mg/kg/day. During her hospitalization, she was found to be COVID-19 positive and had become hypoxemic requiring 2.5 liters of oxygen. Upon resolution, she was discharged with outpatient follow-up.
Of note, there is a strong maternal family history of type 2 diabetes and hypertriglyceridemia. The mother had three strokes in her forties. The patient has not previously undergone pancreatitis genetic testing.

Discussion:
To conclude, this case affirms the importance of detecting hypertriglyceridemia-induced pancreatitis early on and improved outcomes with insulin drips. It is important to determine triggers for recurrent pancreatitis in those with underlying genetic etiologies of hypertriglyceridemia. Additionally, it is crucial to monitor for secondary hypocalcemia, particularly given the risk for prolonged QT interval and ventricular arrhythmias. Lastly, the COVID-19 pandemic may be associated with more severe presentations of pancreatitis.

Recurrent Acute Pancreatitis Secondary to Hypertriglyceridemia in an Adolescent With Type 2 Diabetes, Symptomatic Hypocalcemia, and COVID-19 Infection

Background: Combination oral contraceptive medications may cause elevations of plasma renin activity and aldosterone levels.

Clinical Case:
A 20-year-old female with a past medical history of chronic migraines and allergic rhinitis was referred to endocrinology for evaluation of secondary hypertension after she was found to have elevated renin levels by her primary care physician. The patient was noted to be hypertensive during a tonsillectomy 4 months prior and had also experienced an increased frequency of headaches prompting an evaluation for secondary hypertension and the initiation of lisinopril 10 mg daily. Her other medications included levocetirizine, biotin, and the combined oral contraceptive pill (OCP) norgestimate-ethinyl estradiol (0.25 mg/0.035 mg).

Physical examination was remarkable for blood pressure 130/85mmHg, Pulse rate 77, BMI 30 kg/m², pale striae on upper arms, lower back and abdomen, and a slight fat pad on the posterior nape of her neck. Initial lab results revealed normal plasma sodium, potassium, metanephrines and normetanephrines, plasma renin activity (PRA) 70.657 ng/mL/h (0.167-5.380 ng/mL/h), aldosterone 18.9 ng/dL (0.0-30.0 ng/dL), and 8: 00 amcortisol 30.3 mcg/dL (6.2-19.4mcg/dL). Doppler ultrasound and magnetic resonance angiography excluded renal artery stenosis and abdominal renin-secreting tumors. Owing to concern about OCP interference with the measurements of PRA and aldosterone levels, these tests were repeated at the end of a seven-day OCP placebo pills and biotin withdrawal. Lab results revealed: PRA >178 ng/mL/h, aldosterone 15.3 ng/dL, 1 mg overnight dexamethasone suppression test cortisol 1.1 mcg/dL, and 24-hour urinary cortisol 22.4 mcg/L (normal value <24mcg/L). Subsequently, the patient agreed to discontinue OCP and biotin and have labs redrawn 6 weeks later, which revealed PRA of 0.9 ng/mL/h and aldosterone of 5.9 ng/dL. Her blood pressure also normalized off the oral contraceptive and lisinopril was successfully discontinued.

Conclusion:
This case report demonstrates the clinically significant impact of oral contraceptive medication on blood pressure, plasma renin activity and aldosterone levels. It's well known that oral contraceptives may cause elevations in PRA and aldosterone1 likely due to an upregulation of angiotensin mediated by the effect of ethinyl estradiol on the hepatocytes¹, albeit not previously reported of the magnitude found in our patient. The extreme elevations of PRA and aldosterone in our patient suggested a diagnosis of either renovascular hypertension, renin secreting neoplasm or coarctation of aorta all of which were excluded. The subsequent normalization of blood pressure, PRA and Aldosterone off oral contraception x 6 weeks confirmed that the OCP was the source of her hypertension and lab abnormalities. This case highlights the importance of identifying and omitting interfering medications when evaluating patients for secondary causes of hypertension.
References

Oelkers WK. Effects of estrogens and progestogens on the renin- aldosterone system and blood pressure. Steroids 1996;61: 166–71.

Effect of Oral Contraceptive Medication on Blood Pressure, Plasma Renin, and Aldosterone Levels

Background: Hyperparathyroidism, associated with calcium abnormalities has an increased probability of developing arrhythmias. However, there are very few studies to demonstrate the significance of hyperparathyroidism on Atrial Fibrillation (A-fib).
Methods:
This is a retrospective cohort study using the 2017-2018 National Inpatient Sample. Patients with a primary discharge diagnosis of A-fib were extracted with ICD10. Patients with hyperparathyroidism were extracted as a secondary diagnosis. Demographics, clinical complications were compared, and outcomes were assessed using linear and logistic regression models to adjust for confounders.
Results:
A total of 649,179 patients (Age >18) were identified with A-fib as the primary diagnosis, and amongst them, 6254 had hyperparathyroidism. Notably, the patients with Hyperparathyroidism and A-fib were more likely to be female and blacks (26.8 vs 8). In-hospital mortality was higher in A-fib patients with hyperparathyroidism (2%) compared to A-fib patients without hyperparathyroidism (0.84%), with a crude odds ratio of 2.4 and adjusted odds ratio of 2.65 (p<0.001). Mean length of stay (LOS) was greater in hyperparathyroidism patients (4.5 vs 3.2 days), with an adjusted odds ratio of 1.26, (p<0.001). Similarly, mean total charges were also significantly higher in hyperparathyroidism patients ($53792 vs $39128).
Conclusions:
Among patients with atrial fibrillation, those who have hyperparathyroidism as comorbidity are associated with more in-hospital mortality, LOS, and total charges. Further studies are required to study the causation of this association.

Impact of Hyperparathyroidism on Atrial fibrillation In-hospital Outcomes: A Nationwide Perspective

Plasma aldosterone concentration (PAC), renin levels and aldosterone-renin ratio (ARR) are used to screen for primary aldosteronism (PA). A recent study (Yozamp et al. Hypertension 2021) reported substantial intraindividual variability of PAC and ARR (using plasma renin activity) in the context of usual antihypertensive therapy. The intraindividual variability of PAC and direct renin concentration (DRC), a more widely used measurement of renin, in the absence of interfering medications is unknown but important where a single ARR is used to screen for PA.
The aim of this study was to evaluate the intraindividual variability of PAC, DRC and ARR in a cohort of patients with and without PA. Patients who attended an Endocrine Hypertension Service from May 2017 to July 2021 with at least two ARR measurements off interfering medications were retrospectively evaluated. While the measurements were performed at several hospital and community laboratories, the same analyser was used. PA was confirmed using the seated saline suppression test following an abnormal ARR >70 pmol/L: mU/L. PAC and DRC variability was calculated as coefficient of variation (CV=standard deviation/mean x 100) and percent difference (PD=difference between highest and lowest values/mean x 100).
A total of 223 patients were analysed (55% female, median age 52 years), including 162 with PA (25% with unilateral disease). Significant variability in both PAC and DRC was observed in the PA group (CV: 24%, 41%; PD: 46%, 76% respectively) and non-PA group (CV: 22%, 40%; PD: 38%, 65% respectively), which was higher than the assays' analytical variability. The ARR was also highly variable within individuals, in both the PA group (CV: 42%; PD: 74%) and non-PA group (CV: 37%; PD: 61%). Variability was not significantly different between PA subtypes, and persisted irrespective of age, gender and degree of hypertension. Sixty-two patients (39%) with PA could have had a missed diagnosis if the ARR had not been repeated, i.e., had at least one ARR <70 pmol/L: mU/L, while 28 (46%) without PA had at least one abnormal ARR > 70.
Intraindividual variability in PAC, DRC and ARR occurs in a significant number of patients being investigated for PA. These results support the need for at least two ARR on separate occasions before PA is excluded or further investigated.

To Repeat or Not to Repeat: The Question of Aldosterone and Renin Variability

Background: Natriuretic peptide (NP) hormones, atrial NP (ANP) and B-type NP (BNP), exert cardiovascular and metabolically protective effects. When measured by conventional immunoassay methods, NP levels are lower in obese, black, and insulin-resistant individuals, suggesting these groups may experience a relative NP deficiency. However, immunoassay measurements are likely poor determinants of physiologically relevant NPs as the immunoassay inadvertently captures predominantly inactive truncated peptides due to poor specificity and rapid degradation of the bioactive form. We have developed and validated a novel ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay¹ that specifically measures bioactive BNP (BNPMS) and ANP (ANPMS). Relationships between bioactive NPs measured by mass spectrometry (MS) with BMI, race, and glucose metabolism are not well-understood. Methods: We measured bioactive BNP and ANP using a novel UPLC-MS/MS assay in 26 veterans without heart failure, diabetes, or significant cardiac/pulmonary/renal/hepatic disease. We also determined BNP using conventional immunoassay (BNPia), age, sex, race, BMI, fasting glucose, and HbA1c. We assessed relationships of NPs with continuous variables using Spearman's correlation and multivariable linear regression, and with categorical variables using Wilcoxon rank-sum. Results: Among 26 veterans (aged 25-55, 69% male), 8 were lean (BMI 23.1 +/- 1.4 kg/m²) and 18 were obese (BMI 34 +/- 2.9 kg/m²). ANPMS was negatively associated with BMI (rs=-0.59, p=0.0015). Moreover, when analyzed by BMI category, ANPMS was lower in obese compared with lean individuals (mean 113.9 +/- 74.9 vs. mean 220 +/- 173.7 pg/mL, respectively, p=0.020). BNPMS was lower in blacks; all 5 black individuals had undetectably low BNPMS (<5 pg/mL), whereas whites had a higher mean BNPMS (19.3 pg/mL, p=0.011). BNPMS was negatively associated with fasting glucose (p=0.03) in multivariable regression models adjusted for age, sex, race, and BMI. BNPMS was not significantly associated with BNPia, possibly partially due to the large percentage whose BNPMS and/or BNPia was undetectably low (44% and 56%, respectively) in this non-heart failure cohort. Discussion: Using a novel UPLC-MS/MS technique, we found that ANPMS is lower in obesity, and BNPMS is lower in black individuals and in those with higher fasting glucose. Our results are consistent with relationships of NPs assessed by traditional immunoassay methods from large epidemiologic studies. Our findings are particularly striking as our sample size was relatively small compared with epidemiologic studies. Our analyses of bioactive NP levels by this specific methodology support the emerging hypothesis that obese and black individuals experience a relative NP deficiency. Future large-scale studies quantifying bioactive NPs by MS are warranted to refine the phenotyping of individuals with relative NP deficiency and determine whether relative NP deficiency contributes to greater cardiometabolic risk.
¹Reference: Dillon EM et al. Active BNP Measured by Mass Spectrometry and Response to Sacubitril/Valsartan. Journal of Cardiac Failure. 2021 Nov.

Bioactive natriuretic peptides measured by mass spectrometry and associations with BMI, race, and metabolic markers

Background and Aims: Portal venous pressure may begin to rise due to steatosis-induced changes in sinusoidal homeostasis in early stages of NASH and may contribute to progression of fibrosis and portal hypertension1. FGF21 is an endogenous hormone regulating carbohydrate, lipid and energy metabolism. FGF21 analogs improve liver and metabolic abnormalities in NASH. In a phase 1b/2a POC study in subjects with NASH, BIO89-100, a glycoPEGylated FGF21 analog, led to significant reductions in hepatic fat fraction (HFF) and liver volume (LV) by MRI-PDFF, with concurrent metabolic benefits and a favorable safety and tolerability profile. This post-hoc analysis assessed the effect of BIO89-100 on spleen volume (SV).
Methods: The trial enrolled 81 subjects with liver fat ≥10% by MRI-PDFF and biopsy-confirmed NASH or phenotypic NASH. Subjects were treated for 12 weeks in 6 cohorts (3, 9, 18 or 27mg QW; 18 or 36mg Q2W) or placebo. Key endpoints were safety, tolerability, pharmacokinetics, change in HFF by MRI-PDFF and liver and metabolic markers, and have been previously reported. SV was assessed by MRI at baseline, Day 50 and Day 92 in 16 BIO89-100-treated (pooled; 8 on 27 mg QW, 8 on 36 mg Q2W) and 18 placebo subjects.
Results: Median baseline (BL) characteristics for BIO89-100 subjects (N=16) and placebo subjects (N=18) were: age 47.6 vs 56.5 years, BMI 36.6 vs 33.5 kg/m2, ALT 53 vs. 29 IU/L, VCTE 8 vs 7.1 kPa, liver fat by MRI-PDFF 19.3% vs 19.7%; 56.3% vs 38.9% of subjects were male, and 25% vs 61% had T2DM. Median SV at BL was within normal limits: 232.6 (range 137.6 - 504.4) cm3 vs 170.9 (range 107.6 – 366.9) cm3. At BL, there were correlations between SV and LV (r=0.58), HOMA-IR (r=0.39), Adipo-IR (r=0.43), BMI (r=0.38) and VCTE score (r=0.40), and negative correlations between SV and HDL cholesterol (r=-0.48), adiponectin (r=-0.35) and platelet count (PC; r=-0.37). On day 92, reduced SV was observed in BIO89-100-treated subjects [percent change LS mean -11.8 vs -0.8 (p=0.002)]. Percent reduction in SV correlated with % reduction in HFF by MRI-PDFF (r=0.55), % reduction in liver fat volume (r=0.55), reduction in HOMA-IR (r=0.55) and % change in CK-18 (r=0.74); and absolute reduction in SV correlated with absolute change in ALT (r=0.48) and negatively correlated with PC (r=-0.75).
Conclusion: These preliminary data suggest that in non-cirrhotic NASH, a subclinical increase in SV, within the normal range, is associated with a worsening metabolic profile, increased liver stiffness and decreased PC. Normalization of liver fat and LV may be associated with decreased intrahepatic resistance and improved portal flow (PF), thus decreasing SV, and possibly improving insulin sensitivity. The role of SV measurement as a non-invasive tool for assessment of PF and the clinical significance of subclinical changes in SV

BIO89-100 Treatment Ameliorates a Subclinical Increase in Spleen Volume in Non-cirrhotic NASH in Correlation With Change in Liver Fat, HOMA-IR and Inflammatory Markers in a Phase 1b/2a, Placebo-Controlled, Double-Blind Proof of Concept Study

Background: The mammalian adrenal cortex is composed of the zona glomerulosa (ZG), zona fasciculata (ZF), and in some species the zona reticularis (ZR). Each layer is characterized by a specific steroidogenic enzyme expression pattern that leads to selective production of mineralocorticoids, glucocorticoids or adrenal androgens. ZG-specific expression of cytochrome P450 aldosterone synthase (Cyp11b2) and aldosterone biosynthesis are renin-angiotensin-dependent processes in which the Gq-signaling pathway is activated by angiotensin II (AngII). Gq-signaling can be exogenously activated using Gq-coupled designer receptors exclusively activated by designer drug (GqDREADD) technology. Using transgenic mice with targeted expression of GqDREADD to the adrenal cortex, we previously demonstrated that short-term receptor activation increased adrenal Cyp11b2 and aldosterone production. Herein, we hypothesized that prolonged activation of mouse adrenal cortex Gq-signaling would exacerbate the aldosterone levels and promote the transdifferentiation of ZF cells to ZG cells. Methods: Transgenic AS+/Cre hM3Dq (GqDREADD) female mice were engineered through crossing GqDREADD mice with Cyp11b2-regulated Cre recombinase mice. Mice were placed on a high sodium diet (to suppress physiologic renin) and orally provided the GqDREADD ligand, clozapine N-oxide (CNO; n=10) or control (n=8) for 6 weeks followed by collection of blood and adrenals. Mineralocorticoid levels were quantified using LC-MS/MS. Adrenal RNA was isolated and assessed by RNAseq for transcriptomic changes, and RT-qPCR analysis for ZG- and ZF-specific transcript markers, Cyp11b2 and Cyp11b1 (marker of ZF), respectively. Transcripts for β-catenin (Ctnnb1) and axin-2 (Axin2) (markers of the WNT signaling pathway) were also analyzed. Immunofluorescence (IF) studies examined adrenal expression of Cyp11b1 and Cyp11b2 in mice treated for 1 month. Results: CNO treatment caused plasma aldosterone to increase 613-fold from 7.9 ±2.5 pg/mL to 4810.7 ±1110.7 pg/mL (p<0.01). Levels of 18-hydroxycorticosterone increased 70-fold from 144.9 ±22.0 to 10143.2 ±1479.6 pg/mL (p<0.0001). Corticosterone levels were unaffected. RT-qPCR analysis showed adrenal Cyp11b2 transcripts to be 224-fold higher (p<0.0001) in the CNO-treated group while a 30 % decrease in Cyp11b1 levels was observed (p<0.01) compared to the controls. IF demonstrated hybrid ZF cells aberrantly expressing both Cyp11b2 and Cyp11b1. Within the normal mouse adrenal, the outer ZG exhibits high WNT/β-catenin (Ctnnb1) activation. To determine if chronic CNO treatment impacted overall adrenal WNT signaling, Ctnnb1 and Axin2 (a downstream β-catenin gene target) were examined. Analysis revealed no statistical difference in Ctnnb1 and Axin2 transcript levels in treated mice. RNAseq revealed that 242 transcripts were increased in adrenals from treated mice, while 109 decreased (>3-fold change; p<0.01). Induced transcripts include Cyp11b2 and its transcriptional regulators, Nr4a1 and Nr4a2. Conclusion: Overall, these findings demonstrate that chronic Gq-signaling is sufficient to cause ZF cells to produce aldosterone and express Cyp11b2. The findings also suggest that the adrenocortical WNT signaling pathway is not increased by the activation of Gq-signaling.

The Dramatic Fat Mass Loss Caused by Bimagrumab is Similar in Diabetic and Non-diabetic Patients.

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