Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic ...needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear.
We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed.
Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements.
Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.
Abstract
Background
Acquired hypoparathyroidism (HPT) in adults is most commonly caused by post-surgical or autoimmune damage to the parathyroid glands. Genetic defects causing abnormal gland ...development, impaired parathyroid hormone (PTH) production or action are rare and typically diagnosed in childhood. Recent literature suggests surprisingly high prevalence of hypocalcemia in patients with SARS-CoV-2 infection and this finding is associated with poor outcomes. 1 We present a case of new onset HPT in a patient admitted with respiratory failure due to COVID-19.
Case presentation
A 63-year-old woman with history of obesity, GERD, asthma, presented to the ED with fever, cough, dyspnea, and diarrhea. She was found to have low O2 saturation, CXR revealed multifocal interstitial and airspace opacities. Her PCR SARS-CoV-2 test was positive and she was admitted to ICU. She was incidentally found to have severe hypocalcemia Ca 5.2 mg/dL (8.5 - 10.3 mg/dL), ionized Ca 2.46 mg/dL (4.50 - 5.10 mg/dL), albumin 3.7 g/dL (3.5 - 5. 0 g/dL). She denied any history of neck surgery, radiation or trauma and personal or family history of autoimmune or calcium disorders. Her calcium levels were normal over the past 4 years. She denied symptoms of hypocalcemia prior to presentation and reported leg cramps and finger numbness in the ED. Further work-up revealed PTH 13 pg/mL (15 - 65 pg/mL), 25-OH vitamin D 16 ng/mL (30 - 80 ng/mL), Mg 1.2 mg/dL (1.4 - 2.5 mg/dL), phosphorus 4.9 mg/dL (2.3 - 4.5 mg/dL), bicarbonate 26 mmol/L (22 - 32 mmol/L). Patient was started on Ca (IV and PO), Mg, and vitamin D replacement. PTH reassessment on days 6, 14, and 19 showed persistently low/inappropriately normal PTH (22, 14, and 8 pg/mL respectively) despite normalization of magnesium levels. Patient was discharged on Ca, Mg, and vitamin D supplementation with follow-up in Endocrinology clinic for further evaluation of her hypoparathyroidism progression.
Conclusion
SARS-CoV-2 infection causes a hypersensitive immune reaction and widespread inflammation. Emerging evidence suggests that this cytokine-mediated reaction and hypoxia associated with COVID-19 can affect the parathyroid glands, resulting in impaired PTH secretion. Furthermore, direct parathyroid tissue invasion and destruction by means of entry via angiotensin-converting enzyme 2 receptors has also been proposed 2. Hypocalcemia in our patient could be multifactorial, however we believe that COVID-19 induced HPT was the leading mechanism. We hope that further research explores this hypothesis and elucidates the underlying pathophysiology. References: 1 Martha JW, Pranata R. Hypocalcemia is associated with severe COVID-19: A systematic review and meta-analysis. Diabetes Metab Syndr. 2021 Jan-Feb;15(1): 337-342. 2 Abobaker A, Alzwi A. The effect of COVID-19 on parathyroid glands. J Infect Public Health. 2021;14(6): 724-725.
Presentation: No date and time listed
Introduction: Prior work has shown a linear relationship between breath acetone (BrACE) and capillary blood beta hydroxybutyrate (BOHB) in persons without diabetes. This innovative study investigates ...the correlation between capillary BOHB and BrACE in T1D during usual care and while taking an SGLT2 inhibitor in both insulin-sufficient and -deficient states. The primary outcome of the study is the correlation of capillary BOHB and BrACE. Methods: Participants provided written consent and were randomized to 2 weeks of usual care and 1 day of insulin withdrawal followed by 2 weeks of usual care plus dapagliflozin, 10 mg daily and 1 day of insulin withdrawal or the opposite sequence. Paired BOHB (Precision Xtra®, Abbott) and BrACE (Biosense®, Readout) were obtained 3X daily for 2 weeks, then hourly during supervised insulin withdrawal. Sick day rules were reviewed and insulin doses were minimally adjusted when taking dapagliflozin. The data was tested for normality and the Spearman's test was utilized due to non-normally distributed data. Results: Participant age was 48 ±18 years (mean ± SD), baseline A1c 7.0 ± 0.9%, and CGM time in range 70-180mg/dL 61 ± 18%. During outpatient care, BrACE and BOHB were weakly correlated both without dapagliflozin (n=689 paired readings; Spearman's ρ = 0.44; 95% CI: 0.37 to 0.50) and with dapagliflozin (n=718 paired readings; ρ = 0.32; 95% CI: 0.25 to 0.39). However, BrACE and BOHB were strongly correlated during supervised insulin withdrawal (n=246 paired values, ρ = 0.81; 95% CI: 0.77 to 0.85). In ROC analysis, BrACE of ≥ 5 demonstrated optimal sensitivity (93%) and specificity (87%) for detecting a capillary BOHB > 1.5 mmol/L. No serious adverse events occurred. Conclusion: In adults with T1D, BrACE monitoring provides a noninvasive estimate of ambient ketone levels when compared to blood BOHB but is more useful under supervised conditions with greater range of ketone production and less potential for interference with volatile organic compounds than in typical outpatient settings.
The relationship between mean glucose measured using a continuous glucose monitor (CGM) and hemoglobin A1c (A1C) was evaluated in adults with type 1 diabetes (T1D) or type 2 diabetes (T2D) . Data ...from participants enrolled in the MOBILE, DIAMOND, and WISDM trials and randomized to the CGM arm were used in the analysis. Follow-up visits collected A1C measured by a central laboratory at 8 months post-randomization in the MOBILE study and 6 months post-randomization in DIAMOND and WISDM studies. CGM data collected in the 91 days prior to the follow-up visit, when glucose control was thought to be relatively stable, was used to compute mean glucose. A least squares linear regression model estimated A1C using mean glucose as a predictor, and models were fit separately by diabetes type. 199 participants with T1D and 175 participants with T2D were included in the analysis. Mean age was 57±15 years among those with T1D and 58±years among those with T2D. Estimated A1C was similar but slightly higher for participants with T2D vs. T1D for the same mean glucose (Table) . Analyses restricting to White non-Hispanic cohort yielded similar results. Spearman partial correlation coefficients for mean glucose vs. A1C were 0.76 for T1D and 0.84 for T2D. Estimates of A1C based on CGM measured mean glucose were slightly higher for those with T2D compared with T1D.
Disclosure
M.Salam: Advisory Panel; Lilly Diabetes, Consultant; Neurocrine Biosciences, Inc., Research Support; Mylan N.V., Neurocrine Biosciences, Inc. R.Bailey: None. P.Calhoun: None. J.B.Mcgill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; Dexcom, Inc., Novo Nordisk. R.Beck: Consultant; Diasome, Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Research Support; Ascensia Diabetes Care, Beta Bionics, Inc., Bigfoot Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Roche Diabetes Care, Tandem Diabetes Care, Inc. D.A.Price: Employee; Dexcom, Inc.
Background: Maturity onset diabetes of the young type 5 (MODY5) is due to a mutation in the hepatocyte nuclear factor 1b (HNF1b) gene on chromosome 17q12. HNF1b mutations have been found in clear ...cell ovarian carcinomas (CCOC) while non-CCOC express this mutation rarely. 17q12 recurrent deletion syndrome presents with urogenital anomalies, MODY5, neurodevelopmental and psychiatric disorders. We report a patient with 17q12 recurrent deletion syndrome with MODY5, uterine abnormalities and low grade serous ovarian cancer.
Clinical Case: The female proband was diagnosed with diabetes at age 12. GAD65, islet cell and insulin auto-antibodies were negative, C-peptide was 2.7 ng/mL. Childhood history included strabismus, depression and chronic transaminitis with unremarkable liver biopsy. Mother’s medical history was notable for single kidney, partially-septated uterus, and diabetes. At age 25, the patient presented with abdominal pain. CT showed pancreatic atrophy, ascites, omental and peritoneal nodularity and calcifications. Tumor markers were normal except an elevated CA-125 of 240 U/mL. Short stature was noted, height 147 cm, BMI 27 kg/m2. Laparoscopy revealed bicornuate uterus, 2 cervices and vaginal septum. She underwent TAH-BSO, lymph node dissection and omentectomy for a stage IIIC low grade serous ovarian carcinoma. Chromosomal microarray analysis of the tumor revealed a pathogenic ∼1.8 Mb loss of 17q12, denoted arrhg19 17q12(34477479_36283807)x1.
Conclusion: While 17q12 has been described as a susceptibility locus in some ovarian cancers, ovarian cancer predisposition is not a reported feature of MODY5 or 17q12 recurrent deletion syndrome. The disease association reported here suggests that women with MODY5 should have periodic evaluation for ovarian cancer in addition to screening for gut and urogenital tract abnormalities. Patients with diabetes plus urogenital tract abnormalities or 17q12 deletion in an ovarian tumor should have genetic evaluation for MODY5.
Disclosure
L. Hollar: None. M. Salam: None. P.H. Thaker: Advisory Panel; Self; Clovis. Consultant; Self; AbbVie Inc., Celsion, Tesaro, UpToDate. Research Support; Self; Celsion, Merck & Co., Inc. Speaker’s Bureau; Self; Merck & Co., Inc., Tesaro. J.B. McGill: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc., Novo Nordisk Inc., Sanofi US. Research Support; Self; Dexcom, Inc., Medtronic, Novartis AG, Sanofi US. Speaker's Bureau; Self; Aegerion Pharmaceuticals, Dexcom, Inc., Janssen Pharmaceuticals, Inc., MannKind Corporation.
The relationship of mean glucose measured with continuous glucose monitoring (CGM) and hemoglobin A1c (HbA1c) shows considerable variability between individuals with diabetes and may be influenced by ...race-related factors. Whether the relationship of mean glucose with HbA1c varies according to type 1 diabetes (T1D) or type 2 diabetes (T2D) has not been well evaluated.
Data from 343 participants in four clinical trials (191 with T1D and 152 with T2D) were analyzed. Least squares linear regression models were fit with HbA1c as the dependent variable and mean glucose as the independent variable.
Mean age was 57 ± 15 years in the T1D cohort and 58 ± 10 years in the T2D cohort. The T1D cohort was 89% White non-Hispanic, 5% African American, 3% Hispanic, and 3% other or mixed race compared with 52%, 16%, 22%, and 9%, respectively, in the T2D cohort. The relationship between CGM-measured mean glucose and laboratory-measured HbA1c significantly differed between T1D and T2D cohorts, with HbA1c on average being higher with T2D than T1D for the same mean glucose (
= 0.002). However, this difference was largely attributable to the difference in the proportion of African Americans between T1D and T2D; and after stratifying by race, the mean glucose-HbA1c relationship showed only a small difference between T1D non-African Americans and T2D non-African Americans. The mean glucose-HbA1c relationship appeared similar for White non-Hispanic and Hispanic individuals.
HbA1c on average was higher in T2D than T1D for a given mean glucose, but after accounting for race, there was no meaningful difference in the mean glucose-HbA1c relationship comparing T1D and T2D. The mean glucose-HbA1c relationship differs in African American compared with White individuals, but does not appear to differ comparing White non-Hispanic to Hispanic individuals. The published glucose management indicator formula appears to be suitable for both T1D and T2D.
Objective: To determine the distribution of age of onset of T1DM in an adult cohort of patients with T1DM.
Methods: T1DM patients from an adult academic diabetes center provided informed consent, ...completed a questionnaire and gave permission for medical record review. Demographics included age, gender and race. T1DM diagnosis was confirmed by history, occurrence of DKA, C-peptide and/or positive T1DM autoantibodies. Patients with diabetes due to pancreatic disease, chemotherapy, genetic syndromes or unclear etiology were not included.
Results: Of the 1167 confirmed cases of T1DM, 563 (48.2%) were male and 604 (51.8%) were female; 107 (9.2%) were African-American and 1060 (90.8%) were Caucasian or other (<1% Asian). Mean age of participants was 46.9 +/- 16.2 years. T1DM was diagnosed at ages <1 to 78 years with mean age at onset of 21.3 +/- 14.4 years. Age at onset of <18 years occurred in 576 participants (49.4%), 18-30 years in 313 (26.8%), and >30 years in 278 (23.8%). Males and females age at onset of T1DM ≥18 years were 53.1% and 48.3% respectively, NS (p=0.11). African-Americans and non-African-Americans diagnosed with T1DM at ≥18 years: 52.3% and 50.5% respectively, NS (p=0.71). In a subset of patients with current age ≥30 (n=971), the mean age of onset of T1DM was 23.2+/-14.8 years.
Conclusion: In this cohort of adults with T1DM, over half of all patients were diagnosed at age ≥18 years, and 23.8% at age >30 years. This trend was consistent across race and gender and more pronounced in the subset with age ≥30 years. These findings challenge historical data that the mean age of onset of T1DM is in childhood. The strength of this dataset is accuracy of age of onset and diagnosis. The major limitation is that it is not population based. Because the reported age at onset of T1DM is highly dependent on the age of the cohort studied, epidemiologic studies of T1DM should include the entire age spectrum. Better awareness of T1DM in adults is needed to provide appropriate medical management and to ensure patient safety.
Disclosure
M. Salam: None. Y. Bao: None. C.J. Herrick: Stock/Shareholder; Spouse/Partner; Cardinal Health. J.B. McGill: Research Support; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Aegerion Pharmaceuticals. Consultant; Self; Bayer AG, Dexcom, Inc., Intarcia Therapeutics, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., MannKind Corporation. Research Support; Self; Novartis Pharmaceuticals Corporation. Consultant; Self; Novo Nordisk A/S. J. Hughes: None.
Type 1 diabetes (T1DM) is associated with other autoimmune diseases (AIDs), which may have serious health consequences. The epidemiology of AIDs in T1DM is not well defined in adults with T1DM. In ...this cross-sectional cohort study, we sought to characterize the incident ages and prevalence of AIDs in adults with T1DM across a wide age spectrum.
A total of 1,212 adults seen at the Washington University Diabetes Center from 2011 to 2018 provided informed consent for the collection of their age, sex, race, and disease onset data. We performed paired association analyses based on age at onset of T1DM. Multivariate logistic regression was used to evaluate the independent effects of sex, race, T1DM age of onset, and T1DM duration on the prevalence of an additional AID.
Mean ± SD age of T1DM onset was 21.2 ± 14.4 years. AID incidence and prevalence increased with age. Female sex strongly predicted AID risk. The most prevalent T1DM-associated AIDs were thyroid disease, collagen vascular diseases, and pernicious anemia. T1DM age of onset and T1DM duration predicted AID risk. Patients with late-onset T1DM after 30 years of age had higher risks of developing additional AIDs compared with patients with younger T1DM onset.
The prevalence of AIDs in patients with T1DM increases with age and female sex. Later onset of T1DM is an independent and significant risk factor for developing additional AIDs. Individuals who are diagnosed with T1DM at older ages, particularly women, should be monitored for other autoimmune conditions.
To evaluate glycemic outcomes in the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) randomized clinical trial (RCT) participants during an observational extension phase.
WISDM RCT was ...a 26-week RCT comparing continuous glucose monitoring (CGM) with blood glucose monitoring (BGM) in 203 adults aged ≥60 years with type 1 diabetes. Of the 198 participants who completed the RCT, 100 (98%) CGM group participants continued CGM (CGM-CGM cohort) and 94 (98%) BGM group participants initiated CGM (BGM-CGM cohort) for an additional 26 weeks.
CGM was used a median of >90% of the time at 52 weeks in both cohorts. In the CGM-CGM cohort, median time <70 mg/dL decreased from 5.0% at baseline to 2.6% at 26 weeks and remained stable with a median of 2.8% at 52 weeks (
< 0.001 baseline to 52 weeks). Participants spent more time in range 70-180 mg/dL (TIR) (mean 56% vs. 64%;
< 0.001) and had lower hemoglobin A1c (HbA1c) (mean 7.6% 59 mmol/mol vs. 7.4% 57 mmol/mol;
= 0.01) from baseline to 52 weeks. In BGM-CGM, from 26 to 52 weeks median time <70 mg/dL decreased from 3.9% to 1.9% (
< 0.001), TIR increased from 56% to 60% (
= 0.006) and HbA1c decreased from 7.5% (58 mmol/mol) to 7.3% (57 mmol/mol) (
= 0.025). In BGM-CGM, a severe hypoglycemic event was reported for nine participants while using BGM during the RCT and for two participants during the extension phase with CGM (
= 0.02).
CGM use reduced hypoglycemia without increasing hyperglycemia in older adults with type 1 diabetes. These data provide further evidence for fully integrating CGM into clinical practice. Clinicaltrials.gov (NCT03240432).
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