United States

The current treatment for growth hormone deficiency (GHD) requires daily subcutaneous injections, which can be burdensome. Somapacitan is a long-acting growth hormone (GH) derivative in development for once-weekly use in children with GHD.

REAL 3 (NCT02616562) is an ongoing, phase 2, multinational, randomised, open-label, controlled trial designed to investigate the efficacy and safety of somapacitan compared with daily GH (Norditropin®). Prepubertal children with GHD who were naïve to GH treatment received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) somapacitan, or daily GH 0.034 mg/kg/day (equivalent to 0.238 mg/kg/week; n=14) for 1 year. This was followed by a 2-year safety extension, in which all patients on somapacitan (n=45) received 0.16 mg/kg/week, while patients receiving daily GH remained on daily GH. In a further, ongoing 4-year long-term safety extension, patients treated with somapacitan remained on somapacitan (somapacitan/somapacitan, n=39) and all patients on daily GH switched to somapacitan 0.16 mg/kg/week (daily GH/somapacitan, n=11). Here, we present efficacy and safety results from the first year of the 4-year long-term safety extension.

At year 4, the mean (SD) height velocity (HV) was 7.4 (1.6) cm/year for the somapacitan/somapacitan group and 6.6 (1.6) cm/year for the daily GH/somapacitan group, compared with 8.3 (1.7) and 7.6 (2.0) cm/year for the somapacitan/somapacitan and daily GH groups, respectively, at year 3. The mean (SD) HV standard deviation score (SDS) was 1.55 (1.70) for the somapacitan/somapacitan group and 0.88 (1.61) for the daily GH/somapacitan group, and the mean (SD) change in height SDS from baseline was 2.85 (1.25) and 2.28 (0.97), respectively. The mean (SD) insulin-like growth factor-I SDS at year 4 was 1.29 (1.23) and 0.94 (1.60) for the somapacitan/somapacitan and daily GH/somapacitan groups, respectively.

During year 4, 20 patients (51.3%) experienced 84 adverse events (AEs) in the somapacitan/somapacitan group, and eight patients (72.7%) experienced 12 AEs in the daily GH/somapacitan group. The most common AE was nasopharyngitis, occurring in four patients (10.3%) in the somapacitan/somapacitan group and one patient (9.1%) in the daily GH/somapacitan group; all other AEs occurred in &lt;10% of patients in either group. Most AEs were mild or moderate and unlikely related to GH treatment. One severe AE (surgery for elbow fracture) occurred in the somapacitan/somapacitan group. No serious AEs were reported in year 4. Since previously reported in year 3, one patient in the somapacitan/somapacitan group experienced five injection-site reactions; none occurred in the daily GH/somapacitan group.

In conclusion, these year 4 data support the efficacy and safety results of somapacitan observed in the previous 3 years of the trial. In year 4, height-related outcomes were similar for patients who continued treatment with somapacitan and those who switched from daily GH to somapacitan. Somapacitan was well tolerated, and no safety signals were identified.

ENDO 2022

Once-Weekly Somapacitan in Growth Hormone Deficiency: 4-Year Efficacy and Safety Results from REAL 3, a Randomised Controlled Phase 2 Trial

**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. 

The current treatment for growth hormone deficiency (GHD) requires daily subcutaneous injections, which can be burdensome. Somapacitan is a long-acting growth hormone (GH) derivative in development for once-weekly use in children with GHD.

REAL 3 (NCT02616562) is an ongoing, phase 2, multinational, randomised, open-label, controlled trial designed to investigate the efficacy and safety of somapacitan compared with daily GH (Norditropin®). Prepubertal children with GHD who were naïve to GH treatment received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) somapacitan, or daily GH 0.034 mg/kg/day (equivalent to 0.238 mg/kg/week; n=14) for 1 year. This was followed by a 2-year safety extension, in which all patients on somapacitan (n=45) received 0.16 mg/kg/week, while patients receiving daily GH remained on daily GH. In a further, ongoing 4-year long-term safety extension, patients treated with somapacitan remained on somapacitan (somapacitan/somapacitan, n=39) and all patients on daily GH switched to somapacitan 0.16 mg/kg/week (daily GH/somapacitan, n=11). Here, we present efficacy and safety results from the first year of the 4-year long-term safety extension.

At year 4, the mean (SD) height velocity (HV) was 7.4 (1.6) cm/year for the somapacitan/somapacitan group and 6.6 (1.6) cm/year for the daily GH/somapacitan group, compared with 8.3 (1.7) and 7.6 (2.0) cm/year for the somapacitan/somapacitan and daily GH groups, respectively, at year 3. The mean (SD) HV standard deviation score (SDS) was 1.55 (1.70) for the somapacitan/somapacitan group and 0.88 (1.61) for the daily GH/somapacitan group, and the mean (SD) change in height SDS from baseline was 2.85 (1.25) and 2.28 (0.97), respectively. The mean (SD) insulin-like growth factor-I SDS at year 4 was 1.29 (1.23) and 0.94 (1.60) for the somapacitan/somapacitan and daily GH/somapacitan groups, respectively.

During year 4, 20 patients (51.3%) experienced 84 adverse events (AEs) in the somapacitan/somapacitan group, and eight patients (72.7%) experienced 12 AEs in the daily GH/somapacitan group. The most common AE was nasopharyngitis, occurring in four patients (10.3%) in the somapacitan/somapacitan group and one patient (9.1%) in the daily GH/somapacitan group; all other AEs occurred in <10% of patients in either group. Most AEs were mild or moderate and unlikely related to GH treatment. One severe AE (surgery for elbow fracture) occurred in the somapacitan/somapacitan group. No serious AEs were reported in year 4. Since previously reported in year 3, one patient in the somapacitan/somapacitan group experienced five injection-site reactions; none occurred in the daily GH/somapacitan group.

In conclusion, these year 4 data support the efficacy and safety results of somapacitan observed in the previous 3 years of the trial. In year 4, height-related outcomes were similar for patients who continued treatment with somapacitan and those who switched from daily GH to somapacitan. Somapacitan was well tolerated, and no safety signals were identified.

technical paper

Treatment of persistent short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that can be burdensome for patients and caregivers. Once-weekly somapacitan is a long-acting GH currently in phase 3 development for replacement therapy in children with GH deficiency. We report the 26-week results of the first phase 2, multinational, randomized, open-label, controlled, dose-finding trial (NCT03878446) investigating the efficacy and safety of somapacitan as treatment for short stature in children born SGA compared with daily GH (Norditropin®, Novo Nordisk A/S). A total of 62 (35.5% female) GH-treatment-naïve, prepubertal children received 0.16, 0.20 or 0.24 mg/kg/week subcutaneous (s.c.) somapacitan, or 0.035 or 0.067 mg/kg/day s.c. daily GH for 26 weeks (main phase). All children are subsequently included in an extension to this trial.
The primary outcome was annualized height velocity (HV). At week 26, the estimated mean HV was: 8.9, 11.0 and 11.3 cm/year for 0.16 mg/kg/week (n=12), 0.20 mg/kg/week (n=13) and 0.24 mg/kg/week (n=12) somapacitan, respectively, versus 10.3 and 11.9 cm/year for 0.035 mg/kg/day (n=12) and 0.067 mg/kg/day (n=13) daily GH, respectively. A dose-dependent response in the estimated mean HV was observed with both somapacitan and daily GH. The effect of somapacitan on HV was not statistically significantly different compared with daily GH. A similar pattern was observed for change from baseline in height standard deviation score (SDS) and change from baseline in HV SDS. Consistent dose-dependent increases were observed in insulin-like growth factor-I (IGF-I) SDS with both somapacitan and daily GH. Exposure-response modeling of somapacitan exposure versus HV and IGF-I SDS vs. HV indicated an exposure-dependent increase in HV for both these parameters.
Somapacitan was well tolerated at all doses investigated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to glucose metabolism, and no detection of anti-drug antibodies in any of the dose groups.
In conclusion, all investigated doses of weekly somapacitan were efficacious and well tolerated throughout the study period. Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, a somapacitan dose of 0.24 mg/kg/week appears as the most efficacious dose, providing similar efficacy, safety and tolerability to daily GH 0.067 mg/kg/day after 26 weeks of treatment.

Once-Weekly Somapacitan Versus Daily Growth Hormone in Children Born Small for Gestational Age: Results From a Randomized Phase 2 Trial

Background
MRIs of the brain in patients with short stature have shown a number of abnormalities. Some of these radiological findings can have clinical significance. Here we have looked at MRI results in such a population.

Objective
To review the value and significance of the prevalence of all abnormal MRI findings of children with short stature who are to undergo growth hormone therapy (GHT).

Materials and methods
This study involved a retrospective review of MRI findings in all children prescribed GHT within a pediatric health network's database from Jan 2020 to Aug 2021. Post-gadolinium contrast enhanced brain and pituitary MRIs utilizing 2 mm slices were used to calculate pituitary volume. Pituitary volume was calculated using the ellipsoid formula (LxWxH/2). Pediatric patients diagnosed with non-acquired GHD or ISS, with MRIs having been performed between Jan 2020 and Aug 2021 and having been prescribed GHT by Aug 2021 were included in this study. Patients who experienced other endocrine abnormalities such as SGA, Turner Syndrome, and Noonan Syndrome were excluded. Patients with obstruction of sellar and parasellar religion due to movement artifacts or magnetic interference on their MRIs were also excluded.

Results
Of one hundred and twelve patients found, eighty one met criteria for inclusion in this study. Of the eighty one MRIs reviewed, twenty eight children, 34.6%, had normal pituitary anatomy and fifty three, 65.4%, had a pituitary abnormality. Out of the fifty three with a pituitary abnormality, forty three subjects, 81.1%, were determined to have a small pituitary volume, including significant pituitary hypoplasia. Ten subjects (18.9%) had an enlarged pituitary volume (pituitary hyperplasia). Of these ten patients who had an enlarged pituitary volume, eight were pubertal (80%). Nine children with a pituitary abnormality (16.9%) had additional structural anomalies on their MRIs. One had a small left frontal developmental venous anomaly. Two had Rathke's cleft cysts. Two had pars intermedia cysts. One had a small right parietal developmental venous anomaly. One had a small left parietal developmental venous anomaly. One had a left cerebellar tonsillar ectopia bordering on chiari malformation (.5 mm away on the coronal plane). One had a small lobulation (semi-bulbous projection) of the anterior pituitary gland, superior and anterior to the infundibular stalk.

Conclusion
Prevalence of brain abnormalities in children with short stature who are to undergo GHT is significant and warrants MRI evaluations in these subjects.

The Prevalence of Abnormalities in Cranial MRIs in Children with Short Stature Prior to Growth Hormone Therapy

Background: Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. People with ACH are at risk for several significant co-morbidities, including foramen magnum stenosis, obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, and a propensity towards obesity. PROPEL is a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development as a therapeutic option for ACH. Here we describe the medical complications reported as medical history in the PROPEL study.
Methods: Children with ACH between the ages of 2.5 and 10 years are eligible for enrollment in PROPEL and are evaluated at screening/baseline, month 3, month 6, and every 6 months thereafter. Medical history collected at screening/baseline is summarized using system organ class and preferred terms.
Results: A total of 86 children with ACH (60% female, mean±SD age 6.1±2.5 years) have been enrolled to date at 19 sites in Europe, Australia and North America. Fifty-eight children had undergone surgical and medical procedures with a mean of 2.9 procedures per child (1–11 surgeries/subject). The most common procedures were pressure-equalizing ear tube insertion, adenoidectomy and tonsillectomy. Twenty-one (24%) children had undergone at least 1 surgery (1–5 surgeries/child) for spine or cranial decompression. History of infections and respiratory disorders were reported in 46 (53%) and 40 (47%) children, respectively, the most common being ear infections and obstructive sleep apnea. Musculoskeletal disorders were described in 33 (38%) children, with kyphosis being the most common. Hydrocephalus was reported in 2 children, while 4 had ventriculomegaly without intracranial hypertension. Congenital cardiovascular abnormalities were found in 4 children, 2 of whom presented with patent ductus arteriosus and 2 had patent foramen ovale. A comprehensive summary of medical histories will be presented at the conference.
Conclusions: The PROPEL study has a planned total enrollment of 200 children and seeks to contribute to the deeper understanding of the natural history of ACH. Data described here highlight the significant complications and high number of interventions that children with ACH undergo throughout infancy and childhood. This stresses the importance of expert management of this complex condition.

Medical History of Children Enrolled in PROPEL: A Prospective Clinical Assessment Study in Children with Achondroplasia

Background: Families often seek medical care for a child's short stature due to concerns about how short stature affects psychosocial function in childhood and projected into adulthood. However, height is a poor predictor of psychosocial adjustment, and there is a critical gap in our understanding of how patient and parent characteristics alter the potential impact of being short.
Hypothesis: We hypothesized that among healthy youth undergoing medical evaluation for short stature, youth quality of life (QoL) and self-esteem would be associated with youth and parental characteristics rather than height.
Methods: Healthy youth aged 8-14 years who underwent provocative GH testing in our Growth Center and a parent participant each completed surveys at or around the time of testing. Surveys collected demographic data; youth and parent report of youth health-related QoL (PedsQL and Quality of Life in Short Stature Youth [QoLISSY]); youth reports of self-esteem (Self-Perception Profile for Children [SPP]), coping skills (Coping Strategies Inventory), and social support (Social Support Scale for Children); and parent reports of perceived environmental threats (World Out There), goals for their child (Achievement Goals), and autonomy support (Parents As Social Context Questionnaire). Clinical data were extracted from the patients' electronic health records. Continuous variables were summarized as mean ± SD. Univariate models with Holm-Bonferroni correction of significance level 0.05 assessed the marginal effect of each factor on QoL and self-esteem outcomes. Multivariable linear regression models with stepwise selection approaches were used to identify significant predictors of QoL and self-esteem.
Results: Participants included 60 youth (15 female/45 male; age 11.77 ± 1.93 years; 50% prepubertal, 37% Tanner 2, 13% Tanner 3; height Z-score -2.18 ± 0.61) and their parents (55 female/5 male; age 45.65 ± 7.25 years). In multivariable regression, the youth PedsQL physical domain was associated positively with grade in school and perceived friend support. The youth PedsQL psychosocial domain was associated positively with perceived support from classmates and friends, but negatively with disengaged coping. The youth QoLISSY total score was associated positively with perceived support from classmates. Youth's global self-esteem (SPP) was associated positively with perceived classmate support and mid-parental height Z-score. Parent report of youth psychosocial QoL (PedsQL) was associated positively with perceived classmate support. None of the other analogous parent assessment outcomes were associated with the QoL or self-esteem outcomes. Neither youth height nor height Z-score was associated with any of the QoL or self-esteem outcomes.
Conclusions: Perceived social support and coping skills were associated with QoL and self-esteem in healthy short youth, whereas youth height was not, and constitute an important potential area of clinical intervention.

PATIENT AND PARENT CHARACTERISTICS RELATED TO QUALITY OF LIFE AND SELF-ESTEEM IN HEALTHY YOUTH UNDERGOING PROVOCATIVE GH TESTING

Introduction: Randomized clinical trials identified a small increased risk of acute pancreatitis in patients using glucagon-like peptide-1 receptor agonist (GLP1- RA) therapy. As a result, GLP-1RA therapy is generally avoided in patients with a history of acute pancreatitis. The aim of this report was to evaluate the real-world experience of GLP-1RA therapy in patients with a history of acute pancreatitis.
Methods: A retrospective chart review was conducted (2010-2019) using the enterprise-wide electronic health record (EHR) system. Patients with a history of acute pancreatitis and a subsequent encounter diagnosis of acute pancreatitis (ICD-9/ ICD-10 codes), after exposure to GLP-1R, were identified. Exposure to GLP-1RA was defined as a documented prescription for GLP-1RA in the EHR. Patients were followed until the date of recurrent acute pancreatitis (RAP) or censoring. Categorical and continuous variables were summarized using N (%) and mean (SD), respectively.
Results: A total of 161 patients were identified, 50.9% were female, 56.6% Caucasian, with mean age (years) 54 (±13) and mean BMI 35 kg/m² (±8). Type 2 diabetes, hypertension, and obesity were present in 92.5% (N=149), 86.3% (N=139), and 73.9% (N=119), respectively. The mean duration of follow-up for all patients was 28.2 months (±24.6). The etiologies of the first documented episode of pancreatitis prior to GLP-1RA exposure were gall stones (N=49, 30.4%), alcoholism (N=21, 13%), hypertriglyceridemia (N=9, 5.6%), medication-induced N=5 (3.1%), and the remaining cases (N=77, 47.8%) were classified as idiopathic. Among these 161 patients, N=16 (9.9%) had a second episode of pancreatitis after GLP1-RA exposure. The mean duration of exposure to GLP-1RA prior to RAP was 10.8 months (±7.2). RAP was attributed to GLP 1-RA exposure N=6 (37.5%), alcohol intake N=2 (12.5%), hypertriglyceridemia N=3 (18.8%), oral hypoglycemic agent N=1 (6.2%), ampulla stenosis N=1 (6.2%), and the remaining N=3 (18.8%) were considered idiopathic.
Conclusions: Among 161 patients with a history of acute pancreatitis exposed to GLP-1RA, a total of 16 (9.9%) cases of RAP were identified, but only N=6 (4%) of these were determined attributable to GLP-1RA exposure. The overall rate of RAP among our cohort of GLP-1RA exposed patients (9.9%) is similar to the overall rate of RAP reported in the literature (12.7%), regardless of the underlying etiology or drug exposure.¹ Acute pancreatitis related to drug exposure is a diagnosis of exclusion; thus, it is certainly possible that some of the cases in our report considered idiopathic were actually related to GLP-1RA exposure. While caution needs to be exercised, our data would support the use of GLP-1RA in patients with a history of acute pancreatitis, on an individualized basis, where the benefits are considered to outweigh the risks.
References: 1) Mallick et al. Differences between the outcome of recurrent acute pancreatitis and acute pancreatitis. JGH Open. 2018 Jun 6;2(4): 134-138.

Risk of Pancreatitis After Glp-1 Receptor Agonist in Individuals With Known History of Pancreatitis

INTRODUCTION: The cause-effect relationships of dysbiosis and type 2 diabetes are complex and remain to be elucidated, very likely a two-way interaction. The aim of the study was to evaluate intestinal microbiota composition in patients with type 2 diabetes.MATERIAL and METHODS: This is a case-control study among patients with type 2 diabetes. Individuals were eligible if they were aged ≥18 years, were newly diagnosed with type 2 diabetes, had HbA1c levels ≥6.5 and ≤10.0%, and have been treated for oral antidiabetic agents for 3 months. The primary endpoint was the change from baseline in intestinal microbiota compositon after 12 weeks of treatment and comparison with healthy controls. Secondary endpoints were; change from baseline in intestinal microbiota composition after 12 weeks of oral antidiabetic monotherapy and comparison with healthy controls.  A minimum of 5 mL fresh stool sample was collected at Day O of the study and 12 weeks later in a 15 mL Falcon tube and rapidly transferred to −80 °C to be stored in an upright position until DNA extraction. The V3 and V4 regions of the 16S rRNA gene were amplified following the 16S Metagenomic Sequencing Library Preparation. RESULTS: During the study period, 44 eligible patients were planned to enroll the study. Detailed analysis has been performed in 24 patients with type 2 diabetes (receiving oral antidiabetic treatment, metformin or linagliptin) and 10 age-matched healthy controls. The Chao-1 and Shannon Index were lower in the type 2 diabetes group before and after treatment groups (p<0.01 for both). PCoA plots were constructed to demonstrate separation of groups of samples for unweighted UniFrac distance, weighted UniFrac distance, and Bray–Curtis dissimilarity distance and no statistically significant differences between or within the type 2 diabetes and healthy control groups. At the first visit (before treatment), at phylum level, Bacteroidetes abundance have been observed in diabetic group, while Actinobacteria and Firmicutes in healthy controls. At genera level, we observed Gemmiger and Collinsella predominance in diabetes group; however, Faecalibacterium, Bacteroides and Alistipes in healthy controls. After 12 weeks of treatment, at genera level, Lactobacillus, Rothia and Collinsella increased in type 2 diabetes group however, microbiota composition was still different comparing the healthy controls. In patients receiving 12 weeks of metformin, Prevotella and Lactobacillus increased at genera level while Dialister and Ruminocococcus decreased. DISCUSSION: We report that there is a substantial change in the composition of the gut microbiota in patients with type 2 diabetes. We observed the beneficial effects as relative abundance of short chain fatty acid producing bacteria increased (eg, Prevotella, Lactobacillus) in metformin group. The interaction of the anti-diabetic drugs with gut microbiota have been less studied, further studies will highlight the clinical effect of these alteration in intestinal microbiota composition in diabetes.

Intestinal microbiota composition in patients with type 2 diabetes and effects of 12 weeks of oral anti-diabetic treatment

Abstract:
Introduction: Approximately 50% of obese Black patients presenting with diabetic ketoacidosis (DKA) at new-onset of diabetes have immunologic and metabolic features of type 2 diabetes, also called ketosis-prone diabetes (KPDM). With intensive insulin treatment, ~70% have improvements in beta-cell function and insulin sensitivity and achieve diabetes remission. The definition of remission in KPDM has been heterogeneous with our group defining remission as HbA1c < 7%, fasting blood glucose (BG) < 130 mg/dl and random BG < 180 mg/dl while off insulin injections for at least 1 week. In 2021, the American Diabetes Association (ADA) consensus recommended that the definition of diabetes remission as HbA1c < 6.5% or a fasting BG < 126 mg/dl while off medications for > 3 months. We hypothesized that patients who achieved the more intensive ADA definition of remission (HbA1c < 6.5%) will have longer time in remission compared to our previous non-intensive definition of remission (HbA1c 6.5-7%).
Methods: Forty obese Black patients (BMI ≥ 28 kg/m²) with newly diagnosed diabetes and unprovoked DKA had intensive insulin therapy until HbA1c < 7% without insulin therapy for at least one week. Patients were followed until hyperglycemia relapse (HbA1c > 6.5% or fasting BG > 126 mg/dl and/or requiring antidiabetic medications). Baseline characteristics and clinical time to hyperglycemia relapse-free survival were compared between patients with HbA1c < 6.5 (n= 24) and HbA1c 6.5-7% (n=16).
Results: Age, sex, family history of type 2 diabetes, BMI, HbA1C, weight change and insulin doses received between the two groups (HbA1c < 6.5 vs 6.5-7%) did not differ significantly. Median follow-up overall was 404 days with a range of 7-1099 days. In patients that experienced a hyperglycemia relapse, bivariate analysis shows that median days to hyperglycemia relapse was longer in HbA1c < 6.5% (411 days, range (17-804) vs HbA1c 6.5-7% (126 days, range (7-391), p= 0.05) but without a statistical difference. Survival analysis showed that time in remission did not statistically differ between the two groups (log rank, p=0.6853).
Conclusion: In obese Black patients with KPDM, HbA1c < 6.5% at time of insulin discontinuation does not prolong diabetes compared to patients that achieved HbA1c 6.5-7%, suggesting that predictors of prolonged remission may differ among diverse populations with diabetes.

New American Diabetes Association Definition of Diabetes Remission Does not Correlate with Time in Remission in Ketosis-Prone Diabetes

Background: While a well-established relationship between diabetes and breast cancer exists, it remains unclear how diabetes impacts breast cancer outcomes. This study aims to determine the impact/association of diabetes and hyperglycemia on cancer progression and mortality in individuals with metastatic breast cancer.
Methods: Patients with metastatic breast cancer between 2010-2021 were identified using the metastatic breast cancer database at a single academic center. The Research Patient Data Registry, a data warehouse of all patients receiving care in the hospital network was then used to determine the diabetes status of each participant. A participant was categorized as having diabetes if they fulfilled pre-specified criteria (international classification of diseases (ICD) 9 or 10 code for diabetes, or a hemaglobin A1c ≥6.5%, or a random blood glucose (RBG) ≥200 mg/dL and documented use of glucose-lowering agents), while controls were defined as individuals who did not fulfill the previous criteria. We evaluated the effects of diabetes on 1) overall survival (OS) and 2) the interval from initiation of first-line metastatic therapy to initiation of a second-line regimen due to documented progression of disease (a surrogate measure of progression-free survival). The impact of glycemic control on OS and duration of first-line therapy was also assessed.
Results: We compared 244 patients with diabetes (median age 57.6 years) to 244 patients without diabetes, who were matched for age, gender, ethnicity and hormone-receptor (HR) status. OS at 5 years (diabetes: 54%, CI; 47-62% vs. controls: 56%, CI; 49-63%, p=0.65) and freedom from initiating a second-line regimen at 2 years (diabetes: 43%, CI; 36-50% vs. controls: 44%, CI; 36-51%, p=0.33) were not statistically different between groups. However, in an 8-year landmark subgroup analysis, OS was better amongst controls than those with diabetes (diabetes [n=27]: 67%, CI; 48-86% vs. Controls [n=28]: 87%, CI; 73-100%, p=0.047at 10 years). Poor glycemic control (median RBG >180 mg/dL or median HbA1c >7%) was not associated with increased mortality at 5 years but was associated with a trend towards worse freedom from initiating a second-line regimen at 2 years when compared to good glycemic control. In a sub-group analysis based on HR status, there were no differences in OS at 5 years, or freedom from initiating a second-line regimen at 2 years between the two glycemic groups (≤180 mg/dL vs >180 mg/dL on two or more occasions in a month) for any of the HR subgroups.
Conclusions: These data provide some reassurance that hyperglycemia may not be a major contributor to overall mortality in the first 5 years, in most individuals with metastatic breast cancer. However, amongst longer-term survivors, diabetes was associated with worse survival, suggesting that individualized diabetes and glycemic goals should, therefore, be considered in patients with metastatic breast cancer.

The effects of diabetes and glycemic control on cancer outcomes in individuals with metastatic breast cancer

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.

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

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.

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