United States

Introduction: Cessation of denosumab(Dmab), a fully human monoclonal antibody to RANK-ligand, is associated with rises in bone remodelling, reductions in bone mineral density(BMD) and an increased fracture risk. We previously reported that BMD was stable following a switch from Dmab 60mg to 30mg in postmenopausal women with osteoporosis at a moderate fracture risk(1). The primary objective of this extension study is to evaluate the effect of switching patients from 30mg Dmab(6monthly) to IV Zoledronic acid (ZA), administered 6 months following the last dose of Dmab, in preventing bone loss in postmenopausal women with osteoporosis who are no longer at a high fracture risk.
Methods: Postmenopausal women with osteoporosis at a moderate or low fracture risk, previously on 30mg of Dmab 6monthly were switched to receive 5mg of IV ZA. Exclusion criteria included an additional skeletal disorder, prior fragility fracture, or use of oral steroids (daily in the past 12months). The primary endpoints were the mean percent change in BMD at the lumbar spine(LS), total hip(TH), femoral neck(FN) and 1/3radius(1/3R), as well as the percent change in alkaline phosphatase(ALP) at 24 months compared to baseline, following transition to IV ZA. Secondary outcomes were clinical fractures.
Results: 8 patients were included in the study. The mean duration of 30mg Dmab prior switching to IV ZA was 14.6 ± 2.8 months. Mean percent change in BMD at LS was -3.04(CI: 5.77, -0.32, p =0.033) and mean absolute change was -0.025gm/cm²(CI: -0.048, -0.002, p=0.038). The percent change at the TH was -2.64(CI: -4.97, -0.31, p=0.031) with a mean absolute change of -0.021 gm/cm²(CI: -0.040, -0.002, p=0.038). There were no statistically significant changes at the FN, or 1/3R sites at 24months post IV ZA. ALP showed 45.5% increase on average at 24months compared to baseline(95% CI: 14.1, 76.9, p=0.011). No clinical fractures were observed.
Conclusions: We observed a statistically significant decline in mean percent change in BMD at the LS and TH following a switch from 30mg Dmab to IV ZA at 24months following IV ZA administration. This is similar to the data seen following a switch from standard dose Dmab(60mg 6monthly) to IV ZA(2). The small decline in BMD seen maybe within the precision error of the assessment and this requires further evaluation in a larger number of patients. This was associated with a rise in ALP, however we did not observe any clinical fractures in this study.
References: 1.Khan A, et al. Efficacy of Low Dose Denosumab in Maintaining BMD in Postmenopausal Women With Osteoporosis Switching From 60mg to 30mg 6 Monthly: A Real World, Prospective Observational Study. JES. 2021 2.Everts‐Graber J, et al. A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains. JBMR. 2020

ENDO 2022

Transitioning From Low Dose Denosumab 30mg to IV Zoledronic Acid: Effect on BMD in Postmenopausal Women with Osteoporosis: A Prospective Observational Study

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technical paper

Background: Osteoporosis is a common comorbidity in patients with cystic fibrosis (CF); malabsorption, chronic glucocorticoid use, and chronic inflammation all contribute to increased bone resorption and decreased bone formation. Although lung transplantation (LTx) improves quality of life and short- and long-term outcomes of CF patients, there is little research examining long-term bone health outcomes following LTx in these patients.
Methods: We collected demographic and clinical data on patients who underwent LTx at a single institution between 2006-2019 and had bone mineral density (BMD) measured pre- and post-transplantation. We compared baseline characteristics, long-term BMD trends, and fracture incidence between the two patient populations. We also examined factors associated with post-LTx fractures in CF patients.
Results: Charts of 59 LTx recipients were reviewed including 30 with CF and 29 without CF. Compared with non-CF patients, patients with CF were significantly younger (32.8±10.0 vs. 56.7±10.7 years), had lower body mass index (19.7±3.0 vs. 26.7±4.4 kg/m²), and significantly lower baseline BMD Z-scores at the lumbar spine (-2.0±1.1 vs. -0.3±1.6), femoral neck (-1.6±0.8 vs. -0.7±1.0), and total hip (-1.6±0.8 vs. -0.7±1.0) (all p<0.001). BMD at all three sites declined significantly in both groups in the first year post-LTx. In subsequent years, and compared with non-CF patients, CF patients exhibited better BMD recovery relative to pre-transplantation, but continued to have lower BMD post-LTx. Post-transplant fractures were relatively common, occurring in 30% and 34% of CF and non-CF patients, respectively. Within the CF group, those who developed fractures after LTx were more likely to have lower baseline BMD T-scores at the femoral neck (p=0.017) and total hip (p=0.050), and lower pre-transplantation percent predicted forced expiratory volume in 1 second (FEV1%) (p=0.042).
Conclusions: Compared with their non-CF counterparts, CF patients undergoing lung transplantation start with significantly lower BMD pre-LTx but exhibit better BMD recovery post-LTx. Despite their younger age at transplantation, CF patients experience a similarly high rate of post-LTx fractures. In CF patients, lower BMD and worse FEV1% pre-LTx are associated with development of post-LTx fractures. These findings highlight the unique contribution of the CF disease process to bone health, as well as a clear need for better prevention and treatment of osteoporosis in CF patients before and after LTx.

Bone Health Outcomes Post-Lung Transplantation in Cystic Fibrosis Patients

The severity of liver fibrosis in patients with NAFLD is a strong predictor of cardiovascular mortality, independently of other well-known cardiovascular risk factors. However, the exact mechanisms leading to cardiovascular disease in patients with advanced liver fibrosis remain incompletely understood. As many of the apolipoproteins are synthesized in the liver, we hypothesized that lipoprotein composition may explain the association between liver disease and cardiovascular disease. Patients (n=185) underwent a liver proton magnetic resonance spectroscopy (¹H-MRS) to measure intrahepatic triglyceride accumulation and a percutaneous liver biopsy if they had NAFLD. Advanced lipid testing and lipoprotein subfractions were measured by ion mobility. ApoA-I containing particles (i.e., HDL) were isolated and a novel targeted proteomic approach utilizing multiple reaction monitoring (MRM) by liquid chromatography and tandem mass spectrometry (LC-MS/MS) was undertaken to measure HDL-bound proteins that are associated with lipid metabolism. Forty-five patients did not have NAFLD by ¹H-MRS and were used as controls for comparisons. One-hundred and forty patients had a liver biopsy, and 26 were diagnosed with advanced fibrosis. Patients with vs. without advanced fibrosis had similar clinical characteristics (Age: 54±9 vs. 52±11 years; sex: 77% vs. 76% males; BMI: 34.2±4.3 vs. 34.5±4.6 kg/m²). Patients with advanced fibrosis had lower HDL-C (34±8 vs. 38±9 mg/dl, p=0.024) and higher A1c (7.3±1.3% vs. 6.5±1.0%, p<0.001). No differences were observed in LDL or VLDL particle number or size between the groups. Patients with advanced fibrosis showed a mild reduction in HDL particle number, mainly driven by a reduction of small HDL particles (17269±3705 vs. 19057±4052 nmol/L, p=0.042). Despite this small difference in HDL particle number, a significant difference was observed in the proteomic signature of these particles. A panel of twenty-eight HDL-bound proteins were targeted and quantified by MRM LC-MS/MS. After adjustment for multiple comparisons based on a false discovery rate set at 10% (method of Benjamini-Krieger-Yekutieli), five proteins were found to be decreased in patients with advanced fibrosis (ApoC-I, ApoC-IV, ApoM, LCAT, and SAA4; all p<0.017). No differences were observed in these proteins in patients with vs. without NAFLD or steatohepatitis (NASH). The pCAD index [range from 0-100] is a well-validated model based on measurement of 5 HDL-associated apolipoproteins (Apolipoproteins A-I, C-I, C-II, C-III, and C-IV) that is associated with presence of coronary artery disease and cardiovascular mortality. We observed a stepwise increase in pCAD index with every stage of fibrosis among patients with NAFLD (F0: 84±3; F1: 88±3; F2: 90±6; F3-4: 97±1, p=0.037). Conclusion: Patients with NAFLD with advanced fibrosis showed significant differences in the apolipoproteomic composition of HDL particles, and this translated into increased cardiovascular risk based on pCAD index. Different lipoprotein composition and function may explain the link between liver disease and increased cardiovascular mortality in these patients.

Differences in HDL Particle Composition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD) and Advanced Liver Fibrosis May Explain Higher Cardiovascular Risk

Insulin resistance (IR)/compensatory hyperinsulinemia exert effects on the type and nature of blood lipids that contribute to the increased risk of atherosclerotic cardiovascular disease (ASCVD). Direct measurement of IR is labor-intensive and cannot be performed in a clinical setting. Previously, we modeled the utility of fasting insulin and C-peptide measurements (IR score) to inform the degree of insulin resistance in a large cohort of individuals without diabetes who had undergone direct measurement of whole-body IR. In the current study, we examined the associations of lipoprotein subfractions with IR and determined the usefulness of lipoprotein subfractions to identify insulin resistant individuals. A total of 527 persons (median age 50 years, 65% women, 93% non-Hispanic, and 70% white) underwent measurements of BMI, lipid panel, and lipoprotein subfractions by ion mobility (IM) as well as direct measurement of IR by steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Individuals in the top tertile of SSPG concentration were defined as being insulin resistant. A stepwise linear regression model was used to select a combination of lipoprotein subfractions that remained associated with SSPG after adjusting for BMI, age, sex, ethnicity, race, and triglyceride to HDL cholesterol ratio (TG/HDL-C). An IM score was calculated using linear combinations of the regression coefficients for IM lipoprotein subfractions. Similarly, scores were calculated for TG/HDL-C, the full model excluding the IM lipoprotein subfractions, and the full model that included all variables. The scores were evaluated for predicting the top tertile of SSPG by using area under the receiver operator characteristic curve (AUC) analysis and the positive predictive value (PPV) calculations where the highest 5% value of a score was considered a positive test. Several of the IM lipoprotein sub-fractions were associated with SSPG in a linear regression model after adjusting for BMI, age, sex, ethnicity, race, and TG/HDL-C. When predicting individuals in the top tertile of SSPG, the IM score and TG/HDL-C were similar (AUC=0.68 and 0.70 respectively; PPV=.59 and .59 respectively); however, when used together, they significantly improved the prediction of IR (AUC=0.73; PPV=0.70). Similarly, the score derived from the full stepwise model that included the IM score significantly improved the AUC and PPV when compared with the score from the model that excluded the IM score (AUC=0.84 vs. 0.81; PPV=0.89 vs 0.85). In conclusion, the IM score and TG/HDL-C are comparable in identifying insulin resistant individuals and their combination improves prediction of IR when combined with BMI and demographic data. Among patients who have undergone ion mobility testing, the IM score may assist prioritization of subjects for further testing by the IR score and aid in identification of persons at increased risk of ASCVD associated with IR.

The Relationship of Lipoprotein Fractions as Assessed by Ion Mobility and Insulin Resistance as Measured by the Insulin Suppression Test

The signaling lymphocytic activation molecule 1 (SLAMF1) exerts a role in regulating the immune response to some viruses and parasite infections. In the present study, we identified SLAMF1 as a potential therapeutic target and biomarker for Non-Alcoholic Fatty Liver Disease (NASH) in humans. We found that SLAMF1 is highly expressed in liver samples from mice and humans with NASH. Our data also show SLAMF1 is detected in plasma, and its levels correlate with the severity of the disease. To uncover a molecular role for SLAMF1 in hepatocytes, we treated two hepatocyte cell lines (HepG2 and HuH-7) and primary mouse hepatocyte with palmitic acid (PA) to induce lipotoxicity, characteristic of NASH. We found that PA treatment leads to a significant increase in SLAMF1 protein levels in the cell lines and primary hepatocytes. We found an increase in HepG2 cell apoptosis in response to PA treatment, and downregulation of SLAMF1 in hepatocytes with siRNA improved cell viability and reduced cytotoxicity, apoptosis, and the expression of inflammatory mediators. Moreover, we found that PA-treated HepG2 cells secrete SLAMF1 in the culture medium, which may be mediating part of these effects through paracrine action. Our findings suggest a role for SLAMF1 in NASH's pathogenesis and highlight SLAMF1 as a reliable clinical biomarker of the disease.

SLAMF-1 mediates Hepatocyte Death in Non-Alcoholic Fatty Liver Disease and is Plasma values correlates with the Severity of the Disease in Human

Introduction-Prediabetes is defined as Hba1c 5.7% - 6.4%, with an intermediate metabolic state and includes impaired glucose tolerance and impaired fasting glucose due to insulin resistance. While Type 2 Diabetes Mellitus is a well-established risk factor for cardiovascular disease, the possible link between Prediabetes and risk of Myocardial infarction (MI) has become a focus of interest in recent years. We wanted to evaluate if Prediabetes is independently associated with increased risk for MI.
Methods-We included adult patients admitted to teaching hospitals with a primary or secondary diagnosis of "acute myocardial infarction" from the National inpatient sample of 2016, 2017, and 2018. We created three separate multivariate logistic regression models with outcomes as MI, Percutaneous intervention (PCI), and CABG (Coronary artery bypass grafting).
Results-A total of 1,794,149 (95% CI 1,753,742-1,834,556) weighted hospitalizations with MI were included. Out of the 1.79 million patients with MI, 1% had Prediabetes. Prediabetes was greatly associated with increased odds for MI (OR 1.41, 95% CI 1.35-1.47, P=0.000). After adjusting for age, sex, race, family history of MI, dyslipidemia, hypertension, Diabetes, nicotine dependence, and obesity, Prediabetes was significantly associated with increased odds of MI (OR 1.25, 95% CI 1.20-1.31, P=0.000), increased odds of PCI (OR 1.45, 95% CI 1.37-1.53, P=0.000) and increased odds of CABG (OR 1.95, 95% CI 1.77-2.16, P=0.000).
Discussion- Our study shows that Prediabetes may be an independent risk factor for MI despite adjusting for the well-established risk factors. Coronary interventions such as PCI and CABG were highly associated with Prediabetes, suggesting macrovascular CAD. This growing evidence indicates the need to identify patients with Prediabetes and aggressively manage their cardiovascular risk factors to prevent MI. Although Prediabetes is commonly missed during coding and adds a limitation to this study, we would highlight that the association of Prediabetes with Myocardial Infarction, PCI, and CABG is a significant addition to the literature. Our study serves as a wake-up call for clinicians and patients to shift the focus to preventing Prediabetes and not just Diabetes. Our findings reinforce the importance of early recognition by screening and early intervention of Prediabetes by lifestyle changes and/or medications to decrease the risk of cardiovascular events.

Prediabetes is a Risk Factor for Myocardial Infarction-A National Inpatient Sample Study

Persons with HIV (PWH) who are well-treated on antiretroviral therapies (ART) have a 1.5-2.0 fold increased risk of cardiovascular disease (CVD) compared to persons without HIV (PWOH). A unique cardiovascular phenotype is seen in HIV such that traditional cardiovascular risk factors alone to do not account for this excess CVD risk. Coronary microvascular dysfunction may promote subendocardial ischemia and cardiomyocyte injury and provide a potential underlying mechanism for the atherosclerotic and myocardial disease prevalent in HIV. We assessed coronary microvascular function among those with HIV, comparing to those without HIV and with diabetes (DM).
39 PWH with no known history of CVD or DM, required to be on stable ART and virologically controlled (HIV viral load <200 copies/mL), underwent coronary ¹³N-ammonia PET/CT to evaluate coronary flow reserve (CFR)—a measure of microvascular dysfunction calculated by the ratio of peak coronary flow during regadenoson stress to rest. CFR was corrected using the rate pressure product, which integrates resting blood pressure and heart rate. A 0.1 unit reduction in CFR is associated with a 8% increase in hazard of CV events. Comparisons of CFR were made to PWOH from a database of higher risk clinical referrals who were matched approximately 2: 1 based on demographics and traditional risk factors and to those with diabetes and no known history of CVD recruited as part of a prior study evaluating CFR. Overall group comparisons for CFR were analyzed with the Wilcoxon/Kruskal-Wallis test, and if significant, the Mann-Whitney U test was employed for two-group comparisons.
PWH(74% male, age 55±7years, BMI 32±6kg/m², duration HIV 20±8years, duration ART 16±7years, CD4+ count 801±333cells/ul) were similar to PWOH(n=69, 74% male, age 55±8years, BMI 32±6kg/m²) and persons with DM(n=63, 63% male, age 55±8years, BMI 32±5kg/m²). CFR was significantly different among groups: PWOH 2.76(2.37,3.36), PWH 2.47(1.92,2.93), DM 2.31(1.98,2.84), overall P=.003. CFR was significantly reduced when comparing to PWH to PWOH(P=.02) as was DM to PWOH(P=.001) and did not differ when comparing PWH to DM(P=.68). Total cholesterol 182(168,205)mg/dL, LDL 108(77,127)mg/dL, triglycerides 159(88,219)mg/dL, and current tobacco use 23% were overall significantly higher among PWH (overall P<.03 for each comparison). Controlling for group status (PWH vs. PWOH) and either total cholesterol or current tobacco use, only group status remained significantly and independently related to CFR (group status P=.02 and .01, respectively).
Subclinical coronary microvascular dysfunction is present among asymptomatic, chronically infected PWH on ART who demonstrate good immunological control. This study demonstrates for the first time CFR is reduced compared to higher risk PWOH and comparable to those with DM, regardless of traditional CVD risk factors, and further highlights well-treated HIV as a CVD-risk enhancing factor similar to diabetes. The implications of reduced CFR in HIV warrants further investigation.

Coronary Microvascular Dysfunction is Present Among Well-Treated Asymptomatic Persons with HIV, Similar to Those with Diabetes

Introduction: Tirzepatide, the novel dual GIP/GLP-1 receptor agonist for the treatment of type 2 diabetes, has been shown to reduce HbA1c and weight, with more patients achieving HbA1c ≤6.5%, compared to placebo and active comparators in the phase 3 SURPASS 1-5 studies. This analysis compared the percentage of patients treated with tirzepatide achieving a composite endpoint of HbA1c <6.5% without weight gain and hypoglycemia in these studies.Methods: We compared the proportion of participants achieving the composite endpoint between the tirzepatide (5, 10, or 15 mg) and respective comparator groups while patients were on treatment and without rescue medication. Missing data was imputed based on observed data in the same treatment arm from subjects who had their efficacy measure at the endpoint visit assessed after early discontinuation of study drug. End of treatment HbA1c and weight were evaluated at week 40 (SURPASS-1, 2, 5) and week 52 (SURPASS-3, 4). Weight gain was defined as a change from baseline in weight <0.1 kg. Hypoglycemia included blood glucose level <54 mg/dL with symptoms of hypoglycemia or severe hypoglycemia.Results: In SURPASS-1, 2, 3, 4, and 5 significantly more patients treated with tirzepatide achieved the composite endpoint compared to placebo or comparator (P≤0.002). As a monotherapy in SURPASS-1, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than placebo (75%, 78%, 83%, and 5%, respectively; all P<0.001). As add-on to metformin in SURPASS-2, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than semaglutide (67%, 77%, 83%, and 59%, respectively; P=0.002, P<0.001, P<0.001, respectively). When compared to basal insulin in SURPASS-3, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than insulin degludec (63%, 76%, 82%, and 13%, respectively; all P<0.001). When added to 1-3 oral antihyperglycemics in SURPASS-4, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than insulin glargine (56%, 68%, 75%, and 10%, respectively; all P<0.001). As an add-on to basal insulin in SURPASS-5, significantly more patients treated with tirzepatide 5mg, 10mg, 15mg achieved the composite endpoint than placebo (63%, 70%, 76%, and 8% respectively; all P<0.001).Conclusions: Significantly more patients treated with tirzepatide achieved a composite endpoint of HbA1c <6.5% without weight gain or hypoglycemia than those treated with placebo, semaglutide, insulin degludec, or insulin glargine in the phase 3 SURPASS program.

Achievement of HbA1c <6.5% without weight gain and hypoglycemia in people with type 2 diabetes treated with tirzepatide across the phase 3 SURPASS program

Evidence from nonclinical studies suggests a role of cannabinoid-1 receptor (CB1) in the development of diabetic nephropathy (DN). Kidney CB1 expression is upregulated in podocytes and tubular cells in murine models of obesity and diabetes mellitus (DM). Inhibition by CB1 inverse agonists has been shown to ameliorate diabetes-induced albuminuria, inhibit kidney fibrosis and inflammation, and prevent podocyte dysfunction. Mouse models of DM have shown that genetic deletion of CB1 in podocytes or proximal tubular cells protects against glomerular and tubular dysfunction.
GFB-024 is a recombinant humanized monoclonal antibody functioning as a CB1-specific inverse agonist. Pharmacodynamic studies demonstrated that GFB-024 protects human podocytes in vitro. Targeting the CB1 pathway with GFB-024 is a potentially novel approach to protecting podocytes from injury in patients with CB1-associated DN.
In a phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial, we evaluated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of GFB-024 in up to 56 healthy overweight and obese (BMI 25 – 40 kg/m2) participants.
A total of 38 subjects have completed 5 cohorts in the SAD, receiving single doses of 5 mg to 300 mg administered subcutaneously. GFB-024 was well tolerated, and there were no dose-limiting adverse effects.
PK exposures achieved in the trial exceeded the estimated efficacious exposure, based on four different in vitro activity assays. Absorption was prolonged with flat exposure over the first 7 days, with a Tmax ranging from approximately 4-7 days. Elimination half-life was approximately 12-13 days, with exposures remaining in the estimated efficacious range at 28 days for all but the lowest dose tested.
In summary, GFB-024 was safe and well tolerated following single doses of up to 300 mg. PK analysis demonstrated potentially efficacious exposure, a prolonged absorption phase, and elimination half-life compatible with once-monthly dosing.

Phase 1, Randomized, Controlled Trial of GFB-024, a Once-Monthly CB1 Inverse Agonist, in Healthy Overweight and Obese Participants and in Participants with Type 2 Diabetes Mellitus

IntroductionAdherence to lifestyle modifications can prevent diabetes; however, this poses a challenge for most individuals. CGM is an effective tool for glycemic control and lifestyle modifications in patients with diabetes on insulin therapy. We explored the impact of CGM use in individuals with prediabetes.HypothesisIndividuals using CGM in addition to diabetes education will show improved adherence to lifestyle modifications and greater reduction of HbA1c as compared to those receiving diabetes education alone.Design57 individuals with prediabetes were randomized to use CGM for 3 months along with diabetes education (CGM group) or receive diabetes education alone (EDU group). Food frequency (UKDDQ) and physical activity (IPAQ) questionnaires were completed by participants at the beginning and at the end of the study (6 months). Primary outcomes were lifestyle modifications and changes in HbA1c. Secondary outcomes were changes in weight and blood pressure.ResultsBoth groups reported an increase in healthy food choices; however, EDU group performed better (EDU: 12.4 vs 9.2, p<0.01, CGM: 10.6 vs 9.5, p 0.08). Unhealthy food choices were reduced in both groups. CGM group reported a greater increase in moderate physical activity levels (CGM: 230 vs 61 minutes/week, p 0.01, EDU: 78.5 vs 48 minutes/week, p 0.22). Vigorous physical activity was reported by more individuals in CGM group than EDU (35% vs 4%). Greater reduction in mean HbA1c was noted in CGM group (5.7 vs 5.9%, p 0.05) compared to EDU (5.8 vs 5.9%, p 0.01). 33% of participants in both groups had normalization of HbA1c at the end of study. CGM group had greater reduction in weight (3.5 vs 0.8 lb, p 0.1) and systolic BP (12 vs 2.4 mmHg, p 0.01) than EDU. Irrespective of group assignment, the study population had improvement in all outcomes despite the beginning of COVID-19 pandemic during 4th month of the study. Smaller number of participants in the CGM group reported negative impact of the pandemic on their lifestyle modifications than EDU (Diet: 68% vs 80%, Physical activity: 48% vs 64%). Majority of CGM group participants were able to maintain lifestyle changes after discontinuing CGM use (Diet: 72%, Physical activity: 84%). On comparing both interventions, 56% of CGM group participants felt CGM to be more helpful than education for lifestyle modifications, while 40% felt both interventions helped equally.ConclusionsCGM use in addition to diabetes education resulted in improvement in physical activity, food choices, HbA1c, weight, and BP in individuals with prediabetes. The significance of diabetes education was noted by greater improvement in food choices in EDU group. CGM can be an effective tool for diabetes prevention with lifestyle modifications in prediabetes. The long-term impact of CGM use and cost-benefit analysis in high-risk patients needs to be explored further.

Impact of Continuous Glucose Monitoring (CGM) on Lifestyle Modifications in Individuals with Prediabetes

Post-bariatric hypoglycemia (PBH) is a rare disease characterized by recurrent episodes of severe, symptomatic hyperinsulinemic hypoglycemia (HH). The predominant form occurs after Roux-en-Y gastric bypass (RYGB). However, severe cases also present after other upper-gastrointestinal procedures. The mechanisms mediating PBH have long been debated, though a critical role for excessive postprandial secretion of glucagon-like peptide-1 (GLP-1) has been established. Avexitide (exendin 9-39) is a first-in-class GLP-1 receptor antagonist in development for treatment of PBH. Prior studies with avexitide administration have shown normalization of postprandial insulin concentrations and reductions in the occurrence of symptomatic hypoglycemia. In the Phase 2 multicenter PREVENT trial, avexitide administered to post-RYGB patients at a total daily dose of 60 mg [30mg twice daily (BID) or 60mg once daily (QD)] for 28 days was well-tolerated and demonstrated significant reductions in the rates of hypoglycemia, symptoms, and percent time in hypoglycemia. Based on the favorable safety and tolerability profile and dose-response relationship observed, we sought to evaluate whether higher doses of avexitide may further enhance the pharmacodynamic response. In addition, we sought to extend the evaluation to patients with HH after vertical sleeve gastrectomy, esophagectomy, gastrectomy or Nissen fundoplication. In this Phase 2b, open label, cross over study (NCT04652479), eligible patients included males and females (>18 years of age; BMI ≤40 kg/m²) with a history of recurrent hypoglycemia refractory to medical nutrition therapy (MNT) and exhibiting at least two severe hypoglycemia events while adhering to MNT over a 14-day period. Metabolic and symptomatic parameters were assessed by self-monitoring of blood glucose (SMBG), e-Diary, and blinded continuous glucose monitor (CGM) during 14 days of MNT as compared to 14 days of MNT + avexitide administered by subcutaneous injection at a dose of 45mg BID and 90mg QD in crossover design and random order, for a total of 28-days of treatment. An interim analysis (mixed-effect model) at ~50% completion was conducted (n=8). The primary and secondary endpoints were met with statistical significance. Compared with MNT alone, avexitide 45mg BID and 90mg QD reduced the rate of Level 1 hypoglycemia (SMBG<70 mg/dL) by 66% (p=0.022) and 74% (p=0.010); Level 2 hypoglycemia (SMBG <54 mg/dL) by 70% (p=0.003) and 93% (p=0.001); and Level 3 hypoglycemia (severe event characterized by altered mental and/or physical function requiring assistance) by 77% (p=0.002) and 93% (p=0.001), respectively. Objective assessment by blinded CGM corroborated SMBG/e-Diary results, demonstrating significant reductions in the rates of hypoglycemia and improvements in percent time in hypoglycemia. Responses were comparable across surgical subtypes. Greater improvements were consistently observed with once daily (90 mg QD) than twice daily (45 mg BID) dosing and exceeded those reported in the PREVENT trial. Avexitide was well-tolerated, with no serious adverse events. Complete study results will be presented.

Efficacy and Safety of Avexitide for Treatment of Hypoglycemia after Gastrointestinal Surgery; Assessment of Novel Dosing Regimens in an Expanded Indication

Transitioning From Low Dose Denosumab 30mg to IV Zoledronic Acid: Effect on BMD in Postmenopausal Women with Osteoporosis: A Prospective Observational Study

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