Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes.

AIMS: Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, has been shown to lower glycated hemoglobin (HbA1c), weight, blood pressure and serum uric acid in clinical trials. Plasma lipids were also evaluated as exploratory variables. The goal of this study was to estimate the long-term cardiovascular (CV) and microvascular outcomes of dapagliflozin added to the standard of care (SOC) versus SOC using simulation methodology. METHODS: The Archimedes Model, a validated model of human physiology, diseases and healthcare systems, was used to model a type 2 diabetes mellitus (T2DM) population derived from National Health and Nutrition Examination Survey (NHANES) with HbA1c 7-10%, taking a single oral antidiabetic agent [metformin, sulfonylureas SU or thiazolidinedione (TZD)] at the beginning of the trial. A 20-year trial was simulated comparing dapagliflozin 10 mg, given in addition to SOC, with SOC alone. SOC was based on American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) 2012 guidelines and included diet, metformin, SU, TZD, dipeptidyl peptidase-4 (DPP-4), glucagon-like peptide-1 (GLP-1), and insulin therapies, with usage levels reflective of those in NHANES. Dapagliflozin effects were derived from phase 3 clinical trial results. End points included CV and microvascular outcomes. RESULTS: Over a 20-year period, patients on dapagliflozin were projected to experience relative reductions in the incidence of myocardial infarction (MI), stroke, CV death, and all-cause death of 13.8, 9.1, 9.6 and 5.0%, respectively, and relative reductions in the incidence of end-stage renal disease (ESRD), foot amputation, and diabetic retinopathy of 18.7, 13.0 and 9.8%, respectively, when compared with SOC. CONCLUSIONS: On the basis of simulation results, adding dapagliflozin to currently available treatment options is projected to further decrease the CV and microvascular complications associated with T2DM.

Effect of desvenlafaxine on mood and climacteric symptoms in menopausal women with moderate to severe vasomotor symptoms.

OBJECTIVE: To assess effects of desvenlafaxine (administered as desvenlafaxine succinate) on secondary outcomes of mood, climacteric symptoms, and treatment satisfaction in postmenopausal women with moderate to severe menopausal vasomotor symptoms (VMS). METHODS: A 12-week, multicenter, double-blind, placebo-controlled trial was conducted in postmenopausal women with ≥ 50 moderate to severe hot flushes per week. Participants were randomly assigned to desvenlafaxine 100 mg/day, desvenlafaxine 150 mg/day, or placebo. Secondary outcome efficacy variables included Profile of Mood States (POMS), Greene Climacteric Scale (GCS), and Menopausal Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) scores. Change from baseline in POMS total mood disturbance (TMD) score and subdomain scores were evaluated using analysis of covariance, adjusting for treatment and study site as factors and baseline score. GCS total and subdomain scores were analyzed similarly. Treatment satisfaction was analyzed using the row mean score test. RESULTS: A total of 458 women were enrolled. At week 12, desvenlafaxine 100 mg/day significantly improved POMS TMD scores (p <0.001) and four of six POMS subdomains compared with placebo (all p ≤ 0.005). Women taking desvenlafaxine 100 mg/day experienced significantly greater improvement in GCS total scores (p <0.001) and five of six subdomains (all p ≤ 0.029) compared with placebo. Treatment with desvenlafaxine 100 mg/day resulted in significantly greater treatment satisfaction overall and in six of seven additional MS-TSQ items (all p ≤0.042). Desvenlafaxine 150-mg/day results were similar. CONCLUSIONS: Desvenlafaxine treatment improved mood and climacteric symptoms in postmenopausal women with moderate to severe VMS compared with placebo, and more women were satisfied with desvenlafaxine treatment than with placebo.

Hot flush symptom-free days with bazedoxifene/conjugated estrogens in postmenopausal women.

OBJECTIVE: The aim of this study was to examine the number of hot flush symptom-free days in symptomatic postmenopausal women treated with bazedoxifene/conjugated estrogens (BZA/CE). METHODS: In this 12-week, randomized, double-blind, placebo-controlled, phase-3 study, 322 postmenopausal women aged 40-65 years with an intact uterus who had ≥ seven moderate-to-severe daily hot flushes (or ≥ 50 per week) were randomized to BZA 20 mg/CE 0.45 or 0.625 mg or placebo. Subjects recorded the incidence and severity of hot flushes on daily diary cards. In this secondary analysis, the number of days per week without hot flushes from baseline to week 12 was determined. The percentage of women who experienced no hot flushes at week 12 was also evaluated. RESULTS: From baseline to week 12, the number of days per week without moderate-to-severe hot flushes or without any hot flushes steadily increased for women treated with BZA 20 mg/CE 0.45 or 0.625 mg versus placebo. In addition, the rate of increase in days per week without any hot flushes was significantly greater with either BZA/CE dose than with placebo (p < 0.0001). Compared with placebo, the percentage of women who experienced no moderate-to-severe hot flushes or no severe hot flushes at week 12 was greater with BZA 20 mg/CE 0.45 mg (p < 0.01 and p < 0.05, respectively) and BZA 20 mg/CE 0.625 mg (p < 0.001 for both). CONCLUSIONS: BZA/CE increased the number of hot flush symptom-free days and the proportion of women without hot flushes over 12 weeks of therapy.

Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention.

Postmenopausal women with vasomotor and vaginal symptoms are commonly treated with estrogens or combined estrogen/progestin therapy (hormone therapy). However, hormone therapy is associated with some safety and tolerability concerns and its benefit/risk profile may vary for women based on their time since menopause. The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator with one or more estrogens, with the goal of relieving menopausal symptoms and preserving bone mineral density without stimulating the breast or endometrium. Bazedoxifene/conjugated estrogens (BZA/CE) is the first TSEC in clinical development. BZA 20 mg/CE 0.45 and 0.625 mg have been shown in phase-3 clinical trials to significantly improve hot flushes and vulvar/vaginal atrophy measures in symptomatic postmenopausal women and to prevent bone loss in postmenopausal women at risk for osteoporosis while ensuring endometrial safety. These doses of BZA/CE have also demonstrated significant improvements in quality-of-life scores, sleep parameters, and treatment satisfaction compared with placebo. BZA 20 mg/CE 0.45 and 0.625 mg showed high cumulative rates of amenorrhea and low rates of breast pain, similar to those with placebo. The favorable treatment effects seen with BZA/CE were generally consistent in women < 5 or ≥ 5 years since menopause. Based on its demonstrated efficacy and safety in women both closer to or further from menopause, BZA/CE may be an appropriate alternative to hormone therapy for the treatment of menopausal symptoms and the prevention of osteoporosis.

Alzheimer's disease: the strength of association of costs with different measures of disease severity.

OBJECTIVE: To identify Alzheimer's disease (AD) severity measures for use in cost-effectiveness models that effectively capture the impact of AD on costs. METHODS: A review of the literature and data abstraction from papers that present 1) mean AD costs (direct, indirect, or total) by disease severity, defined using measure of cognition, functional status, and behavior; and/or 2) the results of regression analyses that estimate the strength of the association between AD costs and disease severity. RESULTS: All papers reviewed showed that mean total costs increase with disease severity regardless of severity-measurement method. The relative difference in mean total costs between patients with severe disease compared to those with moderate disease, or moderate disease compared to mild disease, was fairly consistent across studies, suggesting that any of the disease-severity measures may be used to broadly categorize patients by cost. However, when regression analysis included multiple disease-severity measures, independent associations with costs were noted for the different measures. Cognitive and functional status measures were consistently associated with direct costs, whereas functional status and behavioral measures were consistently associated with indirect costs and caregiver hours. CONCLUSIONS: Either multidimensional disease-severity measures, or a single disease-severity measure, that capture the impact of cognition, functional status, and behavior on costs are needed for cost-effectiveness models.