Efficacy and safety of dapagliflozin in patients with type 2 diabetes and concomitant heart failure.

AIM: We investigated the efficacy and safety of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF). METHODS: Data for patients randomized to dapagliflozin 10mg or placebo with a history of HF were pooled from five clinical trials. HbA1c, weight and systolic blood pressure (SBP; two studies) were examined up to 52weeks using longitudinal repeated-measures models. Composite cardiovascular outcomes, hospitalizations for HF (HHF), and adverse events (AEs) were also assessed. RESULTS: Patients (mean age 64years, T2DM duration ~14years, HbA1c 8.2%, ~50% with New York Heart Association Class ≥II) received dapagliflozin (N=171) or placebo (N=149). Dapagliflozin produced clinically meaningful placebo-adjusted reductions in HbA1c (-0.55%; 95% confidence interval [CI]: -0.80, -0.30), weight (-2.67kg; 95% CI: -3.88, -1.47), and SBP (-2.05mmHg; 95% CI: -5.68, 1.57) over 52weeks. HHF was rare, but numerically lower with dapagliflozin (n=1 [0.6%]) vs placebo (n=7 [4.7%]). Point estimates for hazard ratios of composite cardiovascular outcomes favored dapagliflozin vs placebo, although 95% CIs crossed unity. CONCLUSIONS: Dapagliflozin produced clinically meaningful reductions in HbA1c, weight, and SBP in patients with T2DM and HF, and was well tolerated.

Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis.

BACKGROUND: A pre-specified meta-analysis of cardiovascular (CV) events from 21 phase 2b/3 dapagliflozin clinical trials was undertaken to characterise the CV profile of dapagliflozin. This showed no increase in CV risk with dapagliflozin compared with control (placebo or comparator treatment) with or without background glucose-lowering therapies. The analysis reported here aimed to characterise the CV profile of dapagliflozin in subgroups of patients in these 21 studies grouped by degree of CV risk, based on both baseline and in-study risk factors (including hypoglycaemic events), with a focus on major adverse CV events (MACE). METHODS: Patients with type 2 diabetes, both overall and with different levels of CV risk, including CV disease (CVD) history, age and other CV risk factors, were analysed. A further analysis compared CV risk in patients who experienced a hypoglycaemic event prior to MACE and those who did not. Analyses were based on time to first event using a Cox proportional hazards model stratified by study comparing dapagliflozin versus control. RESULTS: In total, 9339 patients were included in this meta-analysis; 5936 patients received dapagliflozin 2.5-10 mg (6668 patient-years) and 3403 received control (3882 patient-years). Dapagliflozin is not associated with increased CV risk and results further suggest the potential for a beneficial effect both in the overall population [Hazard Ratio (HR) 0.77; 95 % CI (0.54, 1.10) for MACE] and in those with a history of CVD [HR 0.80 (0.53, 1.22)]. These findings were consistent in patients with varying degrees of CV risk, including age, number and type of CVD events in medical history and number of CV risk factors present. Furthermore, there was no increased risk of MACE in patients who experienced a hypoglycaemic event compared with those who did not. CONCLUSIONS: There was no suggestion of increased risk for MACE with dapagliflozin compared with control in any of the populations investigated. In addition, the results suggest the potential for a beneficial CV effect which is consistent with the multifactorial benefits on CV risk factors associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Self-administered symphysis-fundus measurements analyzed with a novel statistical method for detection of intrauterine growth restriction: a clinical evaluation.

OBJECTIVE: To assess the ability of self-administered symphysis-fundus measurements used with the Shiryaev-Roberts statistical method (SR method) to identify growth-restricted (IUGR) fetuses and compare it with the traditional SF method (symphysis-fundus measurements used with a population-based reference curve). DESIGN: Longitudinal study. SETTING: Pregnant women attending primary antenatal care centres. POPULATION: From a population of 1 888 women with singleton ultrasound-dated pregnancies, we analyzed data from 1 122 women. METHODS: Weekly self-administered SF measurements from gestational week 25 until delivery were analyzed according to the SR method. Neonatal morbidity and small for gestational age (SGA) were used as proxies for IUGR. Small for gestational age was defined as a birthweight less than two standard deviations (SD) and <10th percentile. We assessed the sensitivity of the SR and the SF methods to detect neonatal morbidity and SGA. MAIN OUTCOME MEASURES: Birth-related mortality, respiratory distress, hypoglycemia, Apgar score ≤6 at five minutes, pH ≤7.00 in the umbilical artery, neonatal care, preterm delivery, operative delivery for fetal distress and SGA. Results. For the SR method, the sensitivity for neonatal morbidity was between 6.0 and 36.4%, for SGA <2SD 36.8%, and for SGA <10th percentile 20.9%. The SF method had a sensitivity between 6.0 and 13.8% for neonatal morbidity, 52.3% for SGA <2SD and 28.6% for SGA <10th percentile. CONCLUSIONS: The SR and the SF methods had low sensitivities for neonatal morbidity.

Relative growth estimated from self-administered symphysis fundal measurements.

OBJECTIVE: To establish absolute- and relative-growth reference curves for the detection of intrauterine growth restriction from weekly self-administered symphysis-fundus (SF) measurements and to assess the influence of fetal sex, maternal obesity and parity. DESIGN: Prospective longitudinal study. SETTING: Pregnant women from six primary antenatal care centres. POPULATION: Three hundred women with singleton ultrasound dated pregnancies. METHODS: Weekly self-administered SF measurements from gestational week 25 until delivery were obtained. A linear mixed longitudinal model was used to estimate the absolute SF growth using the natural logarithm (lnSF). Relative lnSF growth was calculated as the lnSF measurement in one gestational week subtracted by the lnSF measurement in the previous gestational week. The influence of fetal sex, maternal obesity and parity was assessed in regression models and by a graphical display. MAIN OUTCOME MEASURES: Absolute lnSF and relative lnSF growth curves and influence of fetal sex, maternal obesity and parity on these. RESULTS: SF measurements from 191 women were used to establish an SF-growth reference. The absolute lnSF growth was influenced by maternal obesity, and for fetal sex and parity, borderline significance was recorded; while there was no evidence that the relative lnSF growth could depend on these variables. CONCLUSIONS: Weekly self-administered SF measurements can be obtained and used to estimate SF growth. Relative growth of the lnSF height seems to be independent of fetal sex, maternal obesity and parity.

Self-administered measurement of symphysis-fundus heights.

BACKGROUND: Antenatal identification of infants small for gestational age (SGA) improves their perinatal outcome. Repeated measurement of symphysis-fundus (SF) heights performed by midwives is the most widespread screening method for detection of SGA. However, the inefficiency of this method necessitates improved practices. Earlier start and more frequent SF measurements, which could be accomplished by self-administered measurements, might improve the ability to detect deviant growth. The present study was set up to evaluate whether pregnant women can reliably perform SF measurements by themselves. METHOD: Forty healthy women with singleton and ultrasound-dated pregnancies from 2 antenatal clinics in Uppsala, Sweden, were asked to perform 4 consecutive SF measurements once every week, from 20 to 25 weeks of gestation until delivery. The self-administered SF measurements were recorded and systematically compared with midwives' SF measurements. RESULTS: Thirty-three pregnant women performed self-administered SF measurements over a 14-week period (range: 1-21). The SF curves constructed from self-administered SF measurements had the same shape as previously constructed population-based reference curves. The variance for self-administered SF measurements was higher than that of the midwives. CONCLUSIONS: Pregnant women are capable of measuring SF heights by themselves, but with higher individual variance than midwives. Repeated measurements at each occasion can compensate for the higher variance. The main advantage of self-administered SF measurements is the opportunity to follow fetal growth earlier and more frequently.

A CUSUM framework for detection of space-time disease clusters using scan statistics.

Several methods for timely detection of emerging clusters of diseases have recently been proposed. We focus our attention on one of the most popular types of method; a scan statistic. Different ways of constructing space-time scan statistics based on surveillance theory are presented. We bridge the ideas from space-time disease surveillance, public health surveillance and industrial quality control and show that previously suggested space-time scan statistics methods can be fitted into a general CUSUM framework. Crucial differences between the methods studied are due to different assumptions about the spatial process. An example is the specification of the spatial regions of interest for a possible cluster, another is the increased rate to be detected within a cluster. We evaluate the detection ability of the methods considering the possibility of a cluster emerging at any time during the surveillance period. The methods are applied to the detection of an increased incidence of Tularemia in Sweden.

Are flexible designs sound?

Flexible designs allow large modifications of a design during an experiment. In particular, the sample size can be modified in response to interim data or external information. A standard flexible methodology combines such design modifications with a weighted test, which guarantees the type I error level. However, this inference violates basic inference principles. In an example with independent N(mu, 1) observations, the test rejects the null hypothesis of mu < or = 0 while the average of the observations is negative. We conclude that flexible design in its most general form with the corresponding weighted test is not valid. Several possible modifications of the flexible design methodology are discussed with a focus on alternative hypothesis tests.

Symphysis-fundus measurements for detection of small for gestational age pregnancies.

BACKGROUND: In Sweden measurements of the symphysis-fundus (SF) distance are used to detect small for gestational age (SGA) pregnancies. The aim of this study was to evaluate the efficiency of Swedish ultrasound-based SF reference curves in detecting SGA pregnancies. METHODS: To assess the sensitivity for detection of SGA pregnancies we performed a case-control study. Through the Swedish Medical Birth Register we identified all singleton SGA infants born in Uppsala in 1993-1997 and randomly recruited non-SGA singleton infants as controls. We included 169 term and 73 preterm SGA cases and 296 controls, all born at term. The reference curves constructed by Steingrimsdottir (S curve) and Kieler (K curve) were evaluated. Gestational age at the first alarm in the preterm SGA group was recorded. RESULTS: In term pregnancies the S curve showed a sensitivity of 32% and specificity of 90% at a cut-off of -2 SDs. The corresponding values for the K curve were 51% and 83%, respectively. In preterm SGA pregnancies the sensitivity of the S curve was 49% and of the K curve 58%. The first alarm below 2 SDs was noted before 32 weeks in 37% with the S curve and 43% with the K curve for preterm SGA pregnancies. CONCLUSIONS: Both tested Swedish SF reference curves had low sensitivities for term SGA pregnancies. Sensitivity was higher for the preterm group and SF measurements seem to be better for detecting the most severe cases of SGA.

Do policy changes in the pharmaceutical reimbursement schedule affect drug expenditures? Interrupted time series analysis of cost, volume and cost per volume trends in Sweden 1986-2002.

The last decades increasing pharmaceutical expenditures in Sweden and other western countries have created a need for reforms to reduce the trend. The aim was to analyse if reforms concerning the pharmaceutical reimbursement scheme in Sweden during the years 1986-2002 were associated with changes in cost, volume and cost per volume of pharmaceuticals. Effects of changes in the reimbursement schedule during the study period were evaluated for all registered pharmaceuticals in Sweden and for five indicator drug groups. Five policy changes during the study period were assessed. Three concerned increased patient co-payment (January 1, 1991; January 1, 1995 and June 1, 1999), one the introduction of reference based pricing and increased co-payment (January 1, 1993) and one a new structure of the reimbursement schedule (January 1, 1997). The National Corporation of Swedish Pharmacies provided pharmaceutical delivery data for all Swedish pharmacies. Possible breaks in the trend associated with the investigated reforms were analysed with linear segmented regression analysis. This showed that increased co-payments were not associated with changed level or slope of cost and volume. The new reimbursement schedule was associated with a decreased level of cost and volume, both for all drugs combined and for several of the indicator drug groups. It was also associated with an increased slope for both volume and cost in some indicator drug groups and for all drugs. Introduction of reference based pricing was associated with a reduced slope of cost/defined daily doses (DDD) in all of the indicator drug groups and for all drugs. The analysis showed that major changes in the reimbursement system such as the introduction of a new reimbursement schedule and reference based pricing were associated with reductions in cost and volume for the new reimbursement schedule and cost per volume for reference based pricing.

What are the obstacles to generic substitution? An assessment of the behaviour of prescribers, patients and pharmacies during the first year of generic substitution in Sweden.

PURPOSE: The aim of the present study was to investigate obstacles to generic substitution and savings achieved during the first year after Sweden introduced generic substitution in October 2002. METHODS: Normal prescriptions encompassed by generic substitution were included. Data on dispensed prescriptions in the Vastra Gotaland region was obtained from the National Corporation of Swedish Pharmacies. The outcome variables were investigated in three categories of drugs represented by two indicator drugs each. RESULTS: In total, 501,400 dispensed prescriptions of six indicator drugs were analysed. The prescriber opposed substitution in 1-8% of the dispensed prescriptions, varying between the indicator drugs. Patients declined substitution more frequently when the average saving per substitution was low. Substitution occurred most frequently in indicator drugs where the average saving per substitution was high. The total possible saving was 26 million Swedish krona (Swedish krona 1=U.S. $0.13) for the indicator drugs. The actual saving achieved by substitution was on average 60% of the total possible savings and was largely dependent on the extent to which the pharmacies kept the cheapest brand in stock. CONCLUSIONS: Generic substitution has been implemented in practice although it did not reach full dividend during the first year. The potential savings from extended use of generic substitution are substantial.

Surveillance in longitudinal models: detection of intrauterine growth restriction.

A new methodology for online detection of intrauterine growth restriction (IUGR) is proposed where traditional methods for statistical surveillance are applied. Here, deficient growth rate is used to detect IUGR instead of the common surrogate measure "small for gestational age" (SGA). Fetal growth is estimated by repeated measurements of symphysis-fundus (SF) height. At each time point the new method, based on the Shiryaev-Roberts method, is used to evaluate the growth in SF height. We use Swedish data to model a normal growth pattern, which is used to evaluate the capability of the new method to detect IUGR in comparison with a method used in practice today. Results from simulations indicate that the new method performs considerably better than the method used today. We also illustrate the effect of some important factors which influence the detection ability and illuminate the tendency of the method used today to misclassify SGA cases as IUGR.

Expression of delta opioid receptor mRNA and protein in the rat cerebral cortex and cerebellum is decreased by growth hormone.

Hormones released from the pituitary have been shown to regulate the expression of different proteins in the central nervous system. We wanted to examine whether peripheral administration of bovine growth hormone (bGH) regulates the expression of delta-opioid receptor (DOR) in the cerebral cortex and cerebellum. Expression of the DOR protein was quantified using Western blot densitometry. DOR mRNA was quantified with a solution hybridization RNase protection assay. Hypophysectomized (Hx) and untreated normal female rats were included in the study. All Hx rats were hormonally treated with cortisol (400 microg/kg/day) and L-thyroxine (10 microg/kg/day) for 19 days. Hypophysectomy resulted in a threefold increase in cerebral cortex and a twofold increase in cerebellum of the DOR protein compared with normal rats. One subgroup of Hx rats received bGH (1 mg/kg body weight) as a daily subcutaneous injection for 19 days. This treatment normalized the levels of DOR protein in the cerebral cortex and cerebellum. Immunohistochemical experiments showed that GH decreased DOR expression especially in layers II-VI in cerebral cortex and in stratum moleculare in cerebellum. Quantification of DOR mRNA by solution hybridization RNase protection assay corresponded to the DOR protein measurements. We conclude that the expression of DORs in cerebral cortex and cerebellum is regulated by GH.