Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins.

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.

Predicting gestational diabetes: choosing the optimal early serum marker.

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.

Postpartum diabetes screening in women with a history of gestational diabetes.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies.

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.

Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia.

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 < or =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 (< or =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 (PlGFxSHBG) 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 follows: low 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.