The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy.
...Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling.
Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) ×6, 140 or 280 mg every 2 weeks (Q2W) ×3, 420 mg every 4 weeks ×2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W ×3.
In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b).
In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.
Objective Serum markers measured early in pregnancy have been associated with the later diagnosis of gestational diabetes mellitus. To select an optimal early (<20 weeks) marker, we prospectively ...compared 3 serum markers examined simultaneously in a single cohort. Study Design A nested case-control design was used to evaluate the association of sex hormone-binding globulin, high-sensitive C-reactive protein, and measures of fasting glucose and insulin (homeostasis assessment model) obtained in the late first trimester and early second trimester of pregnancy with the diagnosis of gestational diabetes mellitus. Multivariate modeling and log likelihood ratios were used to identify the optimal biomarker associated with gestational diabetes mellitus. Results In both first and second trimester samples, sex hormone-binding globulin was lower and high-sensitive C-reactive protein higher among women who subsequently developed gestational diabetes mellitus. Similarly an elevated second-trimester homeostasis assessment model was associated with gestational diabetes mellitus. Multivariate analysis suggested that sex hormone-binding globulin measured from nonfasting first-trimester sera was the best predictor of gestational diabetes mellitus in our population. Conclusion Among 3 biomarkers examined prospectively, first-trimester nonfasting sex hormone-binding globulin appeared to be the optimal marker to predict subsequent gestational diabetes mellitus.
In 2003, the National Kidney Foundation introduced guidelines for the control of parathyroid hormone, calcium, and phosphorus in hemodialysis patients.
A cohort study was conducted of 22,937 incident ...hemodialysis patients who were identified from a large national provider between July 1, 2000, and June 30, 2002, and followed through June 30, 2004. Consistent achievement was determined (1) as the simultaneous control of multiple markers over time and (2) as the time in target for each marker during the first year of dialysis. Mortality risk was assessed with Cox proportional hazards models.
In the simultaneous control analysis, patients who achieved target for none of the markers had a 51% greater risk for death than those who achieved target for all three markers (reference group). Patients who achieved any target for any single marker had a 35 to 39% higher risk for death, and patients who achieved target for any two of the three markers had a 15 to 21% higher risk for death compared with the reference group. In the time in target analysis, patients with parathyroid hormone in target for 4 quarters had a 25% lower risk for death compared with those who did so for <or=1 quarter (reference group). Patients with calcium in target for 4 quarters had a 14% lower risk, and patients with phosphorus in target for 4 quarters had a 38% lower risk.
Consistent control of the markers of bone metabolism and disease within published targets is a strong predictor of survival in hemodialysis patients.
Women with a history of gestational diabetes mellitus (GDM) are at high risk for developing type 2 diabetes (diabetes mellitus, DM). The American Diabetes Association recommends regular postpartum ...diabetes screening for women with a history of GDM, but the American College of Obstetricians and Gynecologists (ACOG) is not as directive. We sought to examine postpartum glycemic testing in women diagnosed with GDM.
We conducted an observational cohort study of women diagnosed with GDM at one of two large academic medical centers between 2000 and 2001. Kaplan-Meier estimates of the time from delivery to the first postpartum DM screening tests were determined, and predictors of postpartum DM screening were examined using Cox proportional hazards testing.
Only 37% of eligible women underwent the postpartum diabetes screening tests recommended by the American Diabetes Association (fasting glucose or oral glucose tolerance test OGTT), with a median time from delivery to the first such testing of 428 days. By comparison, 94% of women underwent postpartum cervical cancer screening using a Papanicolaou (Pap) test, with a median time from delivery to Pap testing of 49 days. Even when random glucose testing was included in a broad definition of postpartum DM screening (random or fasting glucose, glycosylated hemoglobin, or OGTT), only two thirds of women (67%) received a postpartum glycemic assessment.
In the population studied, only 37% of women with a history of GDM were screened for postpartum DM according to guidelines published by the American Diabetes Association. Efforts to improve postpartum DM screening in this high-risk group are warranted.
Preeclampsia is far more common in women's first pregnancy but the mechanism of this association is unknown. Altered angiogenesis, marked by increased levels of circulating soluble fms-like tyrosine ...kinase (sFlt-1), an inhibitor of placental growth factor (PlGF) and vascular endothelial growth factor, has been implicated in the pathogenesis of preeclampsia. We tested the hypothesis that nulliparous women demonstrate increased sFlt-1 levels compared with multiparous women, suggesting an overall increase in relative antiangiogenesis during first pregnancies. We measured sFlt-1 and PlGF levels in early pregnancy serum samples from the first 2 completed pregnancies of 97 women who participated in the MOMS cohort study. Repeated measures analyses demonstrated that sFlt-1 levels were significantly increased in first compared with second pregnancies (877 ± 598 pg/mL vs 728 ± 399 pg/mL;
P
=
.01) but there was no significant difference in PlGF levels (45.3 ± 40.7 pg/mL vs 40.1 ± 31.9 pg/mL;
P
=
.14). After adjusting for age, gestational age, blood pressure, body mass index, smoking, and the interpregnancy time interval, the residual decrease in sFlt-1 levels from the first to the second pregnancy remained significant at 107 pg/mL (
P
=
.04). Significant interaction between ethnicity and pregnancy order on sFlt-1 levels was observed such that Hispanic women demonstrated greater sFlt-1 levels than white women during their first pregnancy but lower levels in their second pregnancies. Increased sFlt-1 secretion in first versus second pregnancies may account in part for the increased risk of preeclampsia among nulliparous women. Additional studies are needed to verify these findings and to further examine ethnic differences in angiogenesis factors and their potential impact on the incidence of preeclampsia.
Increased leukocyte count is a marker of inflammation that has been associated with the development of type 2 diabetes in prospective studies. Although gestational diabetes mellitus (GDM) and type 2 ...diabetes share certain pathophysiological mechanisms, few studies have examined inflammation and risk of GDM.
We prospectively examined routine leukocyte counts collected at the first prenatal visit in a cohort of 2,753 nulliparous euglycemic women, 98 (3.6%) of whom were later diagnosed with GDM. Subjects were divided into quartiles of leukocyte count, and the results of third-trimester glucose screening tests and the incidence of GDM among these quartiles were compared. Logistic regression was used to calculate univariate and multivariable-adjusted relative risks (RRs) of GDM according to leukocyte quartiles.
Leukocyte counts were increased among women who subsequently developed GDM compared with those who remained free of GDM (10.5 +/- 2.2 vs. 9.2 +/- 2.2 x 10(3) cells/ml; P < 0.01). There was a linear increase in postloading mean glucose levels (P for trend <0.01), the area under the glucose tolerance test curves (P for trend <0.01), and the incidence of GDM (quartile 1, 1.1; quartile 2, 2.5; quartile 3, 4.2; and quartile 4, 6.4%; P for trend <0.01) with increasing leukocyte quartiles. In the multivariable-adjusted analysis, the linear trend in the RR of GDM with increasing leukocyte quartiles remained statistically significant (quartile 1, reference; quartile 2, RR 2.3 95% CI 0.9-5.7; quartile 3, 3.3 1.4-7.8; quartile 4, 4.9 2.1-11.2; P for trend <0.01).
Increased leukocyte count early in pregnancy is independently and linearly associated with the results of GDM screening tests and the risk of GDM. Although overlap in the leukocyte count distributions precludes it from being a clinically useful biomarker, these data suggest that inflammation is associated with the development of GDM and may be another pathophysiological link between GDM and future type 2 diabetes.
IMPORTANCE: The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment ...with aducanumab, an amyloid-β (Aβ)–targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia. OBJECTIVE: To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021. INTERVENTIONS: Participants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy. MAIN OUTCOMES AND MEASURES: Brain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events. RESULTS: Of 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 35.2%), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 46.6%), confusion (15 14.6%), dizziness (11 10.7%), and nausea (8 7.8%). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ε4 allele carriers. Most events (479 of 488 98.2%) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ε4 carriers: 16 of 742 2.2%; noncarriers, 13 of 334 3.9%). ARIA-microhemorrhage and ARIA–superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively. CONCLUSIONS AND RELEVANCE: In this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache. TRIAL REGISTRATIONS: ClinicalTrials.gov Identifiers: NCT02484547, NCT02477800
Objectives The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin ...therapy. Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling. Methods Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) ×6, 140 or 280 mg every 2 weeks (Q2W) ×3, 420 mg every 4 weeks ×2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W ×3. Results In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b). Conclusions In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.
ABSTRACT—Altered angiogenesis and insulin resistance, which are intimately related at a molecular level, characterize preeclampsia. To test if an epidemiological interaction exists between these two ...alterations, we performed a nested case-control study of 28 women who developed preeclampsia and 57 contemporaneous controls. Serum samples at 12 weeks of gestation were measured for sex hormone binding globulin (SHBG; low levels correlate with insulin resistance) and placental growth factor (PlGF; a proangiogenic molecule). Compared with controls, women who developed preeclampsia had lower serum levels of SHBG (208±116 versus 256±101 nmol/L, P =0.05) and PlGF (16±14 versus 67±150 pg/mL, P <0.001), and in multivariable analysis, women with serum levels of PlGF ≤20 pg/mL had an increased risk of developing preeclampsia (odds ratio OR 7.6, 95% CI 1.4 to 38.4). Stratified by levels of serum SHBG (≤175 versus >175 mg/dL), women with low levels of SHBG and PlGF had a 25.5-fold increased risk of developing preeclampsia (P =0.10), compared with 1.8 (P =0.38) among women with high levels of SHBG and low levels of PlGF. Formal testing for interaction (PlGF×SHBG) was significant (P =0.02). In a model with 3 (n−1) interaction terms (high PlGF and high SHBG, reference), the risk for developing preeclampsia was as followslow PlGF and low SHBG, OR 15.1, 95% CI 1.7 to 134.9; high PlGF and low SHBG, OR 4.1, 95% CI 0.45 to 38.2; low PlGF and high SHBG, OR 8.7, 95% CI 1.2 to 60.3. Altered angiogenesis and insulin resistance are additive insults that lead to preeclampsia.
First-Trimester C-Reactive Protein and Subsequent Gestational Diabetes
Myles Wolf , MD, MMSC ,
Laura Sandler , BS ,
Karen Hsu , BA ,
Karen Vossen-Smirnakis , MD, PHD ,
Jeffrey L. Ecker , MD and
Ravi ...Thadhani , MD,MPH
From the Renal Unit, Department of Medicine and Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard
Medical School, Boston, Massachusetts
Abstract
OBJECTIVE —Systemic inflammation is associated with the development of type 2 diabetes. We tested the hypothesis that increased inflammation,
measured early in pregnancy, is associated with the subsequent development of gestational diabetes mellitus (GDM), a precursor
of type 2 diabetes.
RESEARCH DESIGN AND METHODS —We conducted a prospective nested case-control study in a pregnancy cohort. First-trimester C-reactive protein (CRP) levels
were measured using a high-resolution assay in 43 women who subsequently developed GDM and in a random sample of 94 women
who remained euglycemic throughout pregnancy. Median CRP levels were compared using Wilcoxon’s rank-sum test. Logistic regression
was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among CRP tertiles.
RESULTS —First-trimester CRP levels were significantly increased among women who subsequently developed GDM compared with control
subjects (3.1 vs. 2.1 mg/l, P < 0.01). The risk of developing GDM among women in the highest CRP tertile compared with the lowest tertile was 3.2 (95%
CI 1.2–8.8). After adjusting for age, race/ethnicity, smoking, parity, blood pressure, and gestational age at CRP sampling,
the risk of developing GDM among women in the highest compared with the lowest tertile was 3.6 (95% CI 1.2–11.4). When BMI
was included in the model, however, the association between increased CRP and GDM was attenuated (odds ratio for the highest
compared with lowest tertile 1.5 95% CI 0.4–5.5).
CONCLUSIONS —In women who develop GDM, there is evidence of increased inflammation during the first trimester. This association is mediated
in part by increased BMI. Larger studies are needed to verify these results.
CRP, C-reactive protein
CV, coefficient of variation
GDM, gestational diabetes mellitus
GLT, glucose-loading test
GTT, glucose tolerance test
IL-6, interleukin-6
MOMS, Massachusetts General Hospital Obstetric Maternal Study
OR, odds ratio
TNF, tumor necrosis factor.
Footnotes
Address correspondence and reprint requests to Myles Wolf, Bulfinch 127, 55 Fruit St., Massachusetts General Hospital, Boston,
MA 02114. E-mail: mswolf{at}partners.org .
Received for publication 27 March 2002 and accepted in revised form 13 November 2002.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
DIABETES CARE
PDF
