The cost-effectiveness of dapagliflozin compared to DPP-4 inhibitors in the treatment of type 2 diabetes mellitus in the Netherlands.

AIM: When glycaemic control for people with type 2 diabetes is not achieved with metformin and sulfonylurea alone, adding another oral anti-diabetes drug, such as a sodium-glucose co-transporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4) inhibitor, is an alternative to starting insulin. The aim of this study is to determine the cost-effectiveness of dapagliflozin (an SGLT2 inhibitor) compared with DPP-4 inhibitors when added to metformin and sulfonylurea in people with type 2 diabetes in the Netherlands. METHODS: A cost-utility analysis is performed using the Cardiff diabetes model, a fixed-time increment stochastic simulation model informed by 'United Kingdom Prospective Diabetes Study 68' risk equations. The base-case analysis uses a 40-year time horizon, a Dutch societal perspective and differential discounting (4% for costs, 1.5% for effects). Inputs are obtained from the literature and Dutch price lists. Univariate and probabilistic sensitivity analysis are performed. RESULTS: Dapagliflozin is dominant compared with DPP-4 inhibitors, resulting in a €990 cost saving and a 0.28 quality-adjusted life year gain over 40 years. Cost savings are associated mainly with treatment costs and a reduced incidence of micro- and macrovascular complications, among others nephropathy, myocardial infarction and stroke. Results are robust to changes in input parameters. CONCLUSIONS: Dapagliflozin is a cost-saving alternative to DPP-4 inhibitors when added to metformin and sulfonylurea. The incidence of micro- and macrovascular complications is lower for people treated with dapagliflozin. Uncertainty around this outcome is low.

The impact of a multimodal intervention on emergency department crowding and patient flow.

OBJECTIVE: The objective of this study is to assess the impact of a multimodal intervention on emergency department (ED) crowding and patient flow in a Dutch level 1 trauma center. METHODS: In this cross-sectional study, we compare ED crowding and patient flow between a 9-month pre-intervention period and a 9-month intervention period, during peak hours and overall (24/7). The multimodal intervention included (1) adding an emergency nurse practitioner (ENP) and (2) five medical specialists during peak hours to the 24/7 available emergency physicians (EPs), (3) a Lean programme to improve radiology turnaround times, and (4) extending the admission offices' openings hours. Crowding is measured with the modified National ED OverCrowding Score (mNEDOCS). Furthermore, radiology turnaround times, patients' length of stay (LOS), proportion of patients leaving without being seen (LWBS) by a medical provider, and unscheduled representations are assessed. RESULTS: The number of ED visits were grossly similar in the two periods during peak hours (15,558 ED visits in the pre-intervention period and 15,550 in the intervention period) and overall (31,891 ED visits in the pre-intervention period vs. 32,121 in the intervention period). During peak hours, ED crowding fell from 18.6% (pre-intervention period) to 3.5% (intervention period), radiology turnaround times decreased from an average of 91 min (interquartile range 45-256 min) to 50 min (IQR 30-106 min., p < 0.001) and LOS reduced with 13 min per patient from 167 to 154 min (p < 0.001). For surgery, neurology and cardiology patients, LOS reduced significantly (with 17 min, 25 min, and 8 min. respectively), while not changing for internal medicine patients. Overall, crowding, radiology turnaround times and LOS also decreased. Less patients LWBS in the intervention period (270 patients vs. 348 patients, p < 0.001) and less patients represented unscheduled within 1 week after the initial ED visit: 864 (2.7%) in the pre-intervention period vs. 645 (2.0%) patients in the intervention period, p < 0.001. CONCLUSIONS: In this hospital, a multimodal intervention successfully reduces crowding, radiology turnaround times, patients' LOS, number of patients LWBS and the number of unscheduled return visits, suggesting improved ED processes. Further research is required on total costs of care and long-term effects.

Costs of non-small cell lung cancer in the Netherlands.

OBJECTIVES: Real-world resource use and cost data on non-small cell lung cancer (NSCLC) are scarce. This data is needed to inform health-economic modelling to assess the impact of new diagnostic and/or treatment technologies. This study provides detailed insight into real-world medical resource use and costs of stage I-IV NSCLC in the Netherlands. MATERIALS AND METHODS: A random sample of patients newly diagnosed with NSCLC (2009-2011) was selected from four Dutch hospitals. Data was retrospectively collected from patient charts. This data included patient characteristics, tumour characteristics, treatment details, adverse events, survival and resource use. Resource use was multiplied by Dutch unit costs expressed in EUR 2012. Total mean costs were corrected for censoring using the Bang and Tsiatis weighted complete-case estimator. Furthermore, costs of adverse events, costs per phase of NSCLC management and costs of second opinions are presented. RESULTS: Data was collected on 1067 patients. Total mean costs for NSCLC diagnosis, treatment and follow-up are €28,468 during the study period and €33,143 when corrected for censoring. Adverse events were recorded in the patient charts for 369 patients (41%) and 82 patients (9%) experienced an adverse event of grade III or higher. For these patients, adverse event-related hospital admissions cost on average €2,091. Mean total costs are €1,725 for the diagnostic period, €17,296 for first treatment line, and €13,236 for each later treatment line. Costs of providing a second opinion are €2,580 per patient. CONCLUSIONS: Total mean hospital costs per NSCLC patient are €33,143 for the total duration of the disease. Ignoring censoring in our data underestimates these costs by 14%. Main limitations of the study relate to the short follow-up time, staging difficulties and missing data. Its main strength is that it provides highly detailed, real-world data on the costs of NSCLC.

Real-world cost-effectiveness of cetuximab in locally advanced squamous cell carcinoma of the head and neck.

Clinical trial EMR 62202-006 demonstrates prolonged median locoregional control (24.4 vs. 14.9 months), progression-free survival (17.1 vs. 12.4 months) and overall survival (49.0 vs. 29.3 months) for patients who receive cetuximab added to the comparator radiotherapy for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). In the Netherlands, hospitals receive reimbursement for cetuximab conditional on cost-effectiveness in daily practice. To estimate the real-world incremental cost per quality adjusted life-year (QALY) gained for radiotherapy + cetuximab over radiotherapy alone in first line treatment of LA SCCHN, a Markov model is constructed with health states "alive without progression", "alive following progression" and "death". Transition probabilities per month are estimated from clinical trial data and retrospectively collected real-world data from two Dutch head and neck cancer treatment centres (2007-2010, n = 141). 5-year, 10-year and lifetime horizons are used, without and with discounting (4 % costs, 1.5 % effects) to calculate incremental cost-effectiveness ratios. Two scenarios explore different assumptions on prognosis of real-world versus trial patients. Adding cetuximab to radiotherapy results in increased costs and health gains in both scenarios and across each of the time horizons. Incremental costs per QALY gained range between 14,624 and 38,543 in the base-case. For a willingness to pay of 80,000 per QALY, the acceptability curves for the different scenarios show probabilities between 0.76 and 0.87 of radiotherapy + cetuximab being cost-effective compared to radiotherapy alone. Current results show the combined treatment of radiotherapy + cetuximab to be a cost-effective treatment option for patients with LA SCCHN.

Recurrent pancreatitis and chylomicronemia in an extended Dutch kindred is caused by a Gly154-->Ser substitution in lipoprotein lipase.

We report the molecular basis of familial chylomicronemia and recurrent pancreatitis in five members of a large Dutch family. All patients had normal plasma hepatic lipase and apoC-II levels, but absent lipoprotein lipase (LPL) catalytic activity and low LPL mass in postheparin plasma. The mutation in the LPL gene was characterized as a G715-->A substitution in the last nucleotide of exon 4, resulting in a substitution of Ser for Gly154. PCR amplification of exons 4 + 5 from the patients' mRNA, followed by direct sequencing, revealed normal splicing of intron 4. The mutation creates a BfaI restriction site that allows rapid screening of family members for the mutation. Reproduction of this mutation in LPL-cDNA by site-directed mutagenesis, followed by transient expression in COS-B cells, revealed production of a catalytically inactive enzyme. The Gly154-->Ser substitution appears in a conserved beta-sheet region, in close proximity to Asp156, which is part of the catalytic triad. These studies show that changes to residues close to Asp156 can have profound effects on catalytic activity of LPL.

Inhibition of carnitine palmitoyltransferase leads to induction of 3-hydroxymethylglutaryl coenzyme A reductase activity in rat liver.

The relation between carnitine palmitoyltransferase (CPT) activity and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity was investigated. Rats were treated with aminocarnitine or 1-carnitine overnight. In rats, in which CPT activity was inhibited by aminocarnitine, plasma and hepatic triacylglycerol contents were increased 5- to 6-fold. The plasma cholesterol concentration was unchanged, while the hepatic cholesterol content was lowered (-16%). Hepatic cholesterol synthesis, determined by following the incorporation of 14C-acetate and 3H2O into digitonin-precipitable sterols, in liver slices was increased 5- to 7-fold. HMG-CoA reductase activity in liver microsomes was increased to the same extent.

Phosphatidylinositol-linked FcRIII mediates exocytosis of neutrophil granule proteins, but does not mediate initiation of the respiratory burst.

In this report, we present data on the activation of different neutrophil effector functions by two distinct Fc-gamma receptors, FcRII and FcRIII. We and others have shown previously that IgG-dependent activation of phagocytosis and superoxide generation is mediated via FcRII. IgG-dependent exocytosis of granule proteins was assessed with Staphylococcus aureus Oxford opsonized with human IgG or with IgG-coated latex. Both anti-FcRII mAb and anti-FcRIII-F(ab')2 mAb inhibited this release, whereas the combination of these mAb inhibited this process more strongly than either mAb alone. This indicates that both FcRII and FcRIII are involved in IgG-dependent release of granule proteins. Cross-linking of the receptors by anti-FcR mAb and F(ab')2 fragments of goat-anti-mouse-Ig showed again that both FcRII and FcRIII mediate lysozyme release, whereas cross-linking of a control antigen (CD67) did not. By measuring the release of elastase and lactoferrin, we found that cross-linking of either FcRII or FcRIII induced release of both azurophilic and specific granules. Under these conditions, we did not measure any activation of the respiratory burst. When FcRIII was removed by treatment of neutrophils with glycosylphosphatidylinositol-specific phospholipase C, the lysozyme release induced by cross-linking of FcRIII was lower than the release from control neutrophils, whereas the release induced by cross-linking of FcRII was similar. Therefore, we conclude that IgG-dependent activation of neutrophils follows two distinct pathways: one via transmembrane FcRII, activating both the NADPH oxidase and the release of granule proteins (as was demonstrated previously by us and by others), and the other via phosphatidylinositol-linked FcRIII, activating exocytosis of granule proteins.