Once-weekly glucagon-like peptide-1 receptor agonists vs dipeptidyl peptidase-4 inhibitors: cardiovascular effects in people with diabetes and cardiovascular disease.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have proven cardiovascular benefits, are recommended in people with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). However, there is limited real-world evidence comparing the effects of once-weekly (OW) GLP-1 RAs and dipeptidyl peptidase-4 inhibitors (DPP-4is). This observational cohort study (1/1/2017-9/30/2021) used data from the Optum Clinformatics® Data Mart to compare time to incident clinical cardiovascular outcomes, health care resource utilization (HCRU), and medical costs in new adult users of OW GLP-1 RAs and DPP-4is with T2D and ASCVD. METHODS: Time to occurrence of ischemic stroke, myocardial infarction (MI), or their composite and ASCVD-related and all-cause HCRU and medical costs were investigated. Baseline characteristics were balanced using inverse probability of treatment weighting. Survival analyses were conducted to compare risks during exposure. RESULTS: OW GLP-1 RA users (weighted N = 25,287) had 26%, 22%, and 24% lower risk of ischemic stroke, MI, and their composite, respectively, compared with DPP-4i users (weighted N = 39,684; all P < 0.01). Compared with DPP-4i users, OW GLP-1 RA users had 25% and 26% lower ASCVD-related and all-cause hospitalization costs, 19% and 23% lower ASCVD-related and all-cause medical costs, 23% and 27% fewer ASCVD-related and all-cause hospitalizations, 13% and 8% fewer ASCVD-related and all-cause outpatient visits, and 8% fewer all-cause ER visits (all P < 0.01). CONCLUSIONS: In adults with T2D and ASCVD, OW GLP-1 RAs are associated with reduced stroke and MI risks and ASCVD-related and all-cause HCRU and costs vs DPP-4is.

Pregnancy Outcomes in Patients Exposed to OnabotulinumtoxinA Treatment: A Cumulative 29-Year Safety Update.

BACKGROUND AND OBJECTIVES: A previous publication of pregnancy outcomes in onabotulinumtoxinA-exposed mothers demonstrated that the prevalence of major fetal defects (0.9%, 1/110) was comparable with background rates in the general population. There is continued interest to better understand the safety of onabotulinumtoxinA during pregnancy. This analysis evaluated pregnancy outcomes after onabotulinumtoxinA exposure to provide a cumulative 29-year update. METHODS: The Allergan Global Safety Database was searched from January 1, 1990, to December 31, 2018. Data from women (younger than 65 years or unknown) during pregnancy or ≤3 months before conception treated with onabotulinumtoxinA were assessed to estimate birth defect prevalence rates of live births only from prospective pregnancies. RESULTS: Of 913 pregnancies, 397 (43.5%) were eligible with known outcomes. Maternal age was known in 215 pregnancies: 45.6% were 35 years or older. Indication was known in 340 pregnancies: most frequent were aesthetic (35.3%) and migraine/headache (30.3%). The timing of exposure was known in 318 pregnancies: 94.6% were before conception or during the first trimester. OnabotulinumtoxinA dose information was known in 242 pregnancies; most (83.5%) were exposed to <200 U. Of 195 prospective pregnancies with 197 fetuses, there were 152 (77.2%) live births and 45 (22.8%) fetal losses (32 spontaneous, 13 elective). Of 152 live births, 148 (97.4%) had normal outcomes and 4 had abnormal outcomes. Among the 4 abnormal outcomes, there were 1 major birth defect, 2 minor fetal defects, and 1 birth complication. The prevalence rate for overall fetal defects was 2.6% (4/152, 95% CI 1.0%-6.6%) and 0.7% (1/152, 95% CI 0.1%-3.6%) for major fetal defects (3%-6% in the general population). Among cases of live births and known determinable exposure times, there was 1 birth defect with preconception exposure and 2 with first-trimester exposure. DISCUSSION: Although subject to reporting bias due to the nature of the postmarketing database review, this 29-year retrospective analysis of safety data in pregnant women exposed to onabotulinumtoxinA demonstrates that the prevalence rate of major fetal defects among live births is consistent with the rates reported in the general population. Although there are limited data available for second-trimester and third-trimester exposure, this updated and expanded safety analysis provides important real-world evidence to health care providers and their patients. CLASSIFICATION OF EVIDENCE: This analysis provides Class III data that demonstrate that the prevalence rate of major fetal defects among live births subsequent to in utero onabotulinumtoxinA exposure is comparable with the reported background rates.

Real-World Evidence for Control of Chronic Migraine Patients Receiving CGRP Monoclonal Antibody Therapy Added to OnabotulinumtoxinA: A Retrospective Chart Review.

INTRODUCTION: Combination use of onabotulinumtoxinA and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) has the potential to be more effective than either therapy alone for migraine prevention. METHODS: This retrospective, longitudinal chart review included adults with chronic migraine treated at one clinical site with ≥ 2 consecutive cycles of onabotulinumtoxinA and ≥ 1 month of subsequent combination treatment with CGRP mAbs. Charts at time of mAb prescription (baseline) and up to four visits ~ 3, 6, 9, and 12 months post-baseline were reviewed for safety, tolerability, and outcome measures (monthly headache days [MHDs], headache intensity, and migraine-related disability [MIDAS]). RESULTS: Of 300 charts reviewed, 257 patients met eligibility criteria (mean age: 50 years; 82% women). Average headache frequency was 21.5 MHDs before initiation of onabotulinumtoxinA and 12.1 MHDs before adding CGRP mAb therapy. Prescribed mAbs were erenumab (78%), fremanezumab (6%), and galcanezumab (16%). Over the entire study, patients discontinued CGRP mAb more frequently than onabotulinumtoxinA (23 vs. 3%). Adverse events occurred in 28% of patients, most commonly constipation (9%). Compared with onabotulinumtoxinA alone (baseline), MHDs decreased significantly at all visits (mean decrease: 3.5-4.0 MHDs over ~ 6-12 months of combination treatment); 45.1% of patients had clinically meaningful improvement in migraine-related disability (≥ 5-point reduction in MIDAS score) after ~ 6 months. CONCLUSIONS: In this real-world study, combination treatment with onabotulinumtoxinA and CGRP mAbs was well tolerated, with no new safety signals identified, and was associated with additional clinically meaningful benefits. More real-world and controlled trials should be considered to further assess safety and potential benefits of combination treatment. Video abstract: Real-world data suggests that CGRP inhibitors improve onabotulinumtoxinA efficacy for chronic migraine (MP4 20,067 kb).

Characteristics and Cardiovascular Disease Event Rates among African Americans and Whites Who Meet the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Trial Inclusion Criteria.

PURPOSE: Determine the risk for cardiovascular disease (CVD) events among adults with clinically evident CVD who meet the inclusion criteria for the FOURIER clinical trial on PCSK9 inhibition in a real-world database. METHODS: We analyzed data from 2072 African American and 2972 white REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants 45-85 years of age with clinically evident CVD. Study participants meeting the FOURIER inclusion criteria (one major or two minor cardiovascular risk factors, fasting LDL cholesterol ≥ 70 mg/dL or non-HDL cholesterol ≥ 100 mg/dL, triglycerides ≤ 400 mg/dL, and taking statin) were followed for CVD events (myocardial infarction, stroke, coronary revascularization, and CVD death) from baseline in 2003-2007 through 2014. RESULTS: Overall, 771 (37.2%) African Americans and 1200 (40.4%) whites met the FOURIER inclusion criteria. The CVD event rate per 1000 person years was 60.6 (95% CI 53.6-67.6) among African Americans and 63.5 (95% CI 57.7-69.3) among whites. The risk for CVD events among adults meeting the FOURIER inclusion criteria was higher for those with a history of multiple cardiovascular events (hazard ratios among African Americans and whites 1.34 [95% CI 1.05-1.71] and 1.34 [1.10-1.63], respectively), a prior coronary revascularization (1.44 [1.13-1.84] and 1.23 [1.00-1.52], respectively), diabetes (1.38 [1.08-1.76] and 1.41 [1.15-1.72], respectively), reduced glomerular filtration rate (1.63 [1.26-2.11] and 1.29 [1.03-1.62], respectively), and albuminuria (1.77 [1.37-2.27] and 1.33 [1.07-1.65], respectively). CONCLUSIONS: The CVD event rate is high among African Americans and whites meeting the FOURIER inclusion criteria. Characteristics associated with a higher CVD risk may inform the decision to initiate PCSK9 inhibition.

How well can familial hypercholesterolemia be identified in an electronic health record database?

BACKGROUND: Familial hypercholesterolemia (FH) is a condition characterized by high cholesterol levels and increased risk for coronary heart disease (CHD) that often goes undiagnosed. The Dutch Lipid Network Criteria (DLNC) are used to identify FH in clinical settings via physical examination, personal and family history of CHD, in addition to the presence of deleterious mutations of the LDLR, ApoB, and PCSK9 genes. Agreement between clinical and genetic diagnosis of FH varies. While an ICD diagnosis code was not available for coding FH until 2016, Systematized Nomenclature of Medicine (SNOMED) clinical concept codes, including genetic diagnoses, for FH have been utilized in electronic health records (EHRs). OBJECTIVE: To evaluate the concordance of identifying FH via SNOMED and ICD-10 CM codes vs the DLNC in an EHR database. METHODS: Using the Practice Fusion EHR database, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value were calculated comparing an FH cohort identified via SNOMED and ICD-10 CM codes to one identified via the DLNC. RESULTS: Among 907,616 patients with hypercholesterolemia, 2,180 were identified as FH via SNOMED code (zero were identified via ICD-10 CM), 259 had a DLNC score 6-8 (probable FH), and 45 had a DLNC score >8 (definite FH). Compared to DLNC score >8, the sensitivity, specificity, and PPV of the FH SNOMED code were 84.4%, 99.4%, and 6.4%, respectively. Compared to DLNC score ≥6, the sensitivity was 36.8% and the specificity was 99.5% with a PPV of 18.7%. CONCLUSION: Compared to the clinical criteria for FH, identification of FH patients via SNOMED diagnosis codes had high sensitivity and specificity, but low PPV. The discordance of these two techniques in identifying FH patients speaks to the challenges in identifying FH patients in large electronic databases such as administrative claims and EHR.

Project Baiterek: A Patient Access Program to Improve Clinical Outcomes and Quality of Life in Children with Type 1 Diabetes in Kazakhstan.

Diabetes is a key driver in the rise of noncommunicable diseases globally. It causes expensive and burdensome short- and long-term complications, with both an economic and social impact. In many countries, however, access to care and disease management in type 1 diabetes is suboptimal, increasing the risk for complications. In 2011, Project Baiterek was initiated as a collaborative effort between the Kazakhstan Ministry of Health, industry (Medtronic Plc), local physicians, and the Diabetes Association of the Republic of Kazakhstan to enhance patient access to continuous subcutaneous insulin infusion (CSII) therapy. It was the first countrywide project to provide equity and universal access to insulin pump therapy among children with type 1 diabetes, increasing pump use from zero to two-thirds of this population in less than 3 years. The project also involved instigating longitudinal data collection, and long-term clinical outcomes continue to be monitored. Here, we provide an overview of the clinical, quality-of-life, and economic outcomes to date associated with providing CSII therapy to children with type 1 diabetes in Kazakhstan. Initial clinical data show that CSII therapy improved clinical outcomes and quality of life for patients entered into the program and that CSII therapy was cost-effective relative to multiple daily injection therapy. The positive outcomes of Project Baiterek provide a template for similar patient access programs in other settings, and its framework could be adapted to initiatives to change health care infrastructures and standards of care for other noncommunicable diseases.

Alteration of endothelial function markers in women with gestational diabetes and their fetuses.

OBJECTIVE: We tested the hypothesis that women with gestational diabetes mellitus (GDM) and their fetuses would demonstrate alterations in markers of endothelial nitric oxide synthase (eNOS) uncoupling, oxidative stress, and endothelial dysfunction and these changes would correlate with the levels of hyperglycemia through a pilot observational case-control study of women with GDM and their fetuses. METHODS: Levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), C-reactive protein (CRP), nitric oxide (NO), eNOS, p22-phox, and SOD gene expression, and endothelial progenitor cells (EPC) counts in both maternal and cord blood were measured at the time of delivery in women with and without GDM. RESULTS: We demonstrated the presence of decreased maternal circulating EPC counts, increased soluble adhesion molecules in maternal blood, decreased SOD expression in both maternal and cord blood and increased eNOS expression in both maternal and cord blood in women with GDM. CONCLUSIONS: These data suggest that the molecular mechanisms behind oxidative stress in women with GDM and their fetuses appear similar to those hypothesized for non-pregnant adults with type 2 diabetes mellitus (DM).

Prevalence of noncardiac structural anomalies in twin-twin transfusion syndrome.

OBJECTIVES: Compared to singleton pregnancies, monochorionic twins have increased rates of perinatal morbidity and mortality, believed due in part to both twin-twin transfusion syndrome and an increased risk of congenital anomalies. Here we describe the prevalence of noncardiac structural anomalies in monochorionic twins with twin-twin transfusion syndrome who underwent laser surgery. METHODS: In a retrospective study of 221 consecutive cases of twin-twin transfusion syndrome treated with laser surgery, noncardiac anomalies were identified by review of antepartum and neonatal medical records. RESULTS: Of 377 live-born twins, 19 (5.0%) had a noncardiac anomaly. This rate was increased for donor versus recipient twins (8.5% versus 2.0%; P < .01). The presence of an anomaly was unrelated to the Quintero stage, the presence of donor intrauterine growth restriction, or 30-day survival of the donor or recipient. CONCLUSIONS: The prevalence of noncardiac anomalies in pregnancies complicated by twin-twin transfusion syndrome who underwent laser surgery was higher in donors versus recipients.

One-hour post-glucola results and pre-pregnancy body mass index are associated with the need for insulin therapy in women with gestational diabetes.

OBJECTIVE: The purpose of this study was to analyze the relationship of 1-h post-glucola (PG) screening results and the need for insulin therapy in women with gestational diabetes (GDM). METHODS: The study group was comprised of women with GDM treated at a single institution during calendar years 2000-2004. Women with singleton, term (≥ 37 weeks gestation), liveborn fetuses were included. The association of 1-h PG results and other perinatal risk factors to the need for subsequent insulin therapy was analyzed using multivariable logistic regression models. RESULTS: Of the 1451 women were included in the analysis, 18.1% required insulin treatment. The mean 1-h PG result was 170.0 ± 26.1 mg/dl (range 140-414 mg/dl). We determined that a 1-h PG ≥ 190 mg/dl (p < 0.0001), an obese body mass index (BMI) (p < 0.0001), an overweight BMI (p = 0.0019), prior GDM (p = 0.0019), and prior macrosomia (p = 0.0210) were each highly associated with the need for subsequent insulin therapy during the pregnancy. CONCLUSIONS: A 1-h PG ≥ 190 mg/dl was strongly associated with the need for insulin therapy in women with GDM. These data may be helpful in counseling and managing women with GDM.

A prospective, randomized, multicenter trial of amnioreduction vs selective fetoscopic laser photocoagulation for the treatment of severe twin-twin transfusion syndrome.

OBJECTIVE: The objective of the study was to examine the effect of selective fetoscopic laser photocoagulation (SFLP) vs serial amnioreduction (AR) on perinatal mortality in severe twin-twin transfusion syndrome (TTTS). STUDY DESIGN: This was a 5 year multicenter, prospective, randomized controlled trial. The primary outcome variable was 30 day postnatal survival of donors and recipients. RESULTS: There was no statistically significant difference in 30-day postnatal survival between SFLP or AR treatment for donors at 55% (11 of 20) vs 55% (11 of 20) (P = 1.0, odds ratio [OR] 1, 95% confidence interval [CI] 0.242 to 4.14) or recipients at 30% (6 of 20) vs 45% (9 of 20) (P = .51, OR 1.88, 95% CI 0.44 to 8.64). There was no difference in 30 day survival of 1 or both twins on a per-pregnancy basis between AR at 75% (15 of 20) and SFLP at 65% (13 of 20) (P = .73, OR 1.62, 95% CI 0.34 to 8.09). Overall survival (newborns divided by the number of fetuses treated) was not statistically significant for AR at 60% (24 of 40) vs SFLP 45% (18 of 40) (P = .18, OR 2.01, 95% CI 0.76 to 5.44). There was a statistically significant increase in fetal recipient mortality in the SFLP arm at 70% (14 of 20) vs the AR arm at 35% (7 of 20) (P = .25, OR 5.31, 95% CI 1.19 to 27.6). This was offset by increased recipient neonatal mortality of 30% (6 of 20) in the AR arm. Echocardiographic abnormality in recipient twin Cardiovascular Profile Score is the most significant predictor of recipient mortality (P = .055, OR 3.025/point) by logistic regression analysis. CONCLUSION: The outcome of the trial did not conclusively determine whether AR or SFLP is a superior treatment modality. TTTS cardiomyopathy appears to be an important factor in recipient survival in TTTS.