Tirzepatide 10 and 15 mg vs semaglutide 2.0 mg: A long-term cost-effectiveness analysis in patients with type 2 diabetes in the United States.

BACKGROUND: Tirzepatide is a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes (T2D) treatment. OBJECTIVE: To compare the long-term cost-effectiveness of tirzepatide 10 mg and 15 mg vs semaglutide 2.0 mg, an injectable glucagon-like peptide-1 receptor agonist, in patients with T2D from a US health care payer perspective. METHODS: The PRIME T2D Model was used to project clinical and cost outcomes over a 50-year time horizon. Baseline cohort characteristics and treatment effects were sourced from a published adjusted indirect treatment comparison that used data from the SURPASS-2 and SUSTAIN FORTE trials. Patients were assumed to intensify to insulin therapy at a hemoglobin A1c of greater than 7.5%. Costs and health state utilities were derived from published sources. Future costs and clinical benefits were discounted at 3% annually. RESULTS: Tirzepatide 10 mg and 15 mg were associated with improved quality-adjusted life-expectancy (10 mg: 0.085 quality-adjusted life-years [QALYs], 15 mg: 0.121 QALYs), higher direct costs (10 mg: USD 5,990, 15 mg: USD 6,617), and incremental cost-effectiveness ratios of USD 70,147 and 54,699 per QALY gained, respectively, vs semaglutide 2.0 mg. Both doses of tirzepatide remained cost-effective vs semaglutide 2.0 mg over a range of sensitivity analyses. CONCLUSIONS: Long-term projections using the PRIME T2D model and based on treatment effects from an adjusted indirect treatment comparison indicate that tirzepatide 10 mg and 15 mg are likely to be cost-effective vs semaglutide 2.0 mg for the treatment of T2D in the United States.

Lysophospholipid acyltransferases orchestrate the compositional diversity of phospholipids.

Lysophospholipid acyltransferases (LPLATs), in concert with glycerol-3-phosphate acyltransferases (GPATs) and phospholipase A1/2s, orchestrate the compositional diversity of the fatty chains in membrane phospholipids. Fourteen LPLAT enzymes which come from two distinct families, AGPAT and MBOAT, have been identified, and in this mini-review we provide an overview of their roles in de novo and remodeling pathways of membrane phospholipid biosynthesis. Recently new nomenclature for LPLATs has been introduced (LPLATx, where x is a number 1-14), and we also give an overview of key biological functions that have been discovered for LPLAT1-14, revealed primarily through studies of LPLAT-gene-deficient mice as well as by linkages to various human diseases.

Long-term cost-effectiveness analysis of tirzepatide versus semaglutide 1.0 mg for the management of type 2 diabetes in the United States.

AIM: To evaluate the long-term cost-effectiveness of tirzepatide (5, 10 and 15 mg doses), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, versus semaglutide 1.0 mg, an injectable glucagon-like peptide-1 receptor agonist, based on the results of the head-to-head SURPASS-2 trial, from a US healthcare payer perspective. MATERIALS AND METHODS: The PRIME Type 2 Diabetes Model was used to make projections of clinical and cost outcomes over a 50-year time horizon. Baseline cohort characteristics, treatment effects and adverse event rates were derived from the 40-week SURPASS-2 trial. Intensification to insulin therapy occurred when HbA1c reached 7.5%, in line with American Diabetes Association recommendations. Direct costs in 2021 US dollars (US$) and health state utilities were derived from published sources. Future costs and clinical benefits were discounted at 3% annually. RESULTS: All three doses of tirzepatide were associated with lower diabetes-related complication rates, improved life expectancy, improved quality-adjusted life expectancy and higher direct costs versus semaglutide. This resulted in incremental cost-effectiveness ratios of US$ 75 803, 58 908 and 48 785 per quality-adjusted life year gained for tirzepatide 5, 10 and 15 mg, respectively, versus semaglutide. Tirzepatide remained cost-effective versus semaglutide over a range of sensitivity analyses. CONCLUSIONS: Long-term projections based on the SURPASS-2 trial results indicate that 5, 10 and 15 mg doses of tirzepatide are likely to be cost-effective versus semaglutide 1.0 mg for the treatment of type 2 diabetes in the United States.

Cost-effectiveness analysis of ferric carboxymaltose versus iron sucrose for the treatment of iron deficiency anemia in patients with inflammatory bowel disease in Spain.

Background: Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD) and can result in reduced quality of life and increased healthcare costs. IDA is treated with iron supplementation, commonly with intravenous iron formulations, such as ferric carboxymaltose (FCM), and iron sucrose (IS). Methods: This study assessed the cost-effectiveness of FCM compared with IS, in terms of additional cost per additional responder in patients with IDA subsequent to IBD in the Spanish setting. An economic model was developed to assess the additional cost per additional responder, defined as normalization or an increase of ⩾2 g/dl in hemoglobin levels, for FCM versus IS from a Spanish healthcare payer perspective. Efficacy inputs were taken from a randomized controlled trial comparing the two interventions (FERGIcor). Costs of treatment were calculated in 2021 Euros (EUR) using a microcosting approach and included the costs of intravenous iron, healthcare professional time, and consumables. Cost-effectiveness was assessed over one cycle of treatment, with a series of sensitivity analyses performed to test the robustness of the results. Results: FCM was more effective than IS, with 84% of patients achieving a response compared with 76%. When expressed as number needed to treat, 13 patients would need to switch treatment from IS to FCM in order to achieve one additional responder. Costs of treatment were EUR 323 with FCM compared with EUR 470 with IS, a cost saving of EUR 147 with FCM. Cost savings with FCM were driven by the reduced number of infusions required, resulting in a reduced requirement for healthcare professional time and use of consumables compared with the IS arm. Conclusion: The present analysis suggests that FCM is less costly and more effective than IS for the treatment of IDA subsequent to IBD in Spain and therefore was considered dominant.

Cost of Severe Hypoglycemia and Budget Impact with Nasal Glucagon in Patients with Diabetes in Spain.

INTRODUCTION: Severe hypoglycemic events (SHE) represent a clinical and economic burden in patients with diabetes. Nasal glucagon (NG) is a novel treatment for SHEs with similar efficacy, but with a usability advantage over injectable glucagon (IG) that may translate to improved economic outcomes. The economic implications of this usability advantage on SHE-related spending in Spain were explored in this analysis. METHODS: A cost-offset and budget impact analysis (BIA) was conducted using a decision tree model, adapted for the Spanish setting. The model calculated average costs per SHE over the SHE treatment pathway following a treatment attempt with IG or NG. Analyses were performed separately in three populations with insulin-treated diabetes: children and adolescents (4-17 years) with type 1 diabetes (T1D), adults with T1D and adults with type 2 diabetes (T2D), with respective population estimates applied in BIA. Treatment probabilities were assumed to be equal for IG and NG, except for treatment success following glucagon administration. Epidemiologic and cost data were obtained from Spanish-specific sources. BIA results were presented at a 3-year time horizon. RESULTS: On a per SHE level, NG was associated with lower costs compared to IG (children and adolescents with T1D, EUR 820; adults with T1D, EUR 804; adults with T2D, EUR 725). Lower costs were attributed to reduced costs of professional medical assistance in patients treated with NG. After 3 years, BIA showed that relative to IG, the introduction of NG was projected to reduce SHE-related spending by EUR 1,158,969, EUR 142,162,371, and EUR 6,542,585 in children and adolescents with T1D, adults with T1D, and adults with insulin-treated T2D, respectively. CONCLUSIONS: In Spain, the usability advantage of NG over IG translates to potential cost savings per SHE in three populations with insulin-treated diabetes, and the introduction of NG was associated with a lower budget impact versus IG in each group.

The PRIME Type 2 Diabetes Model: a novel, patient-level model for estimating long-term clinical and cost outcomes in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: The growing burden of diabetes mellitus and recent progress in understanding cardiovascular outcomes for type 2 diabetes (T2D) patients continue to make the disease a priority for healthcare decision-makers around the world. Our objective was to develop a new, product-independent model capable of projecting long-term clinical and cost outcomes for populations with T2D to support health economic evaluation. METHODS: Following a systematic literature review to identify longitudinal study data, existing T2D models and risk formulae for T2D populations, a model was developed (the PRIME Type 2 Diabetes Model [PRIME T2D Model]) in line with good practice guidelines to simulate disease progression, diabetes-related complications and mortality. The model runs as a patient-level simulation and is capable of simulating treatment algorithms and risk factor progression, and projecting the cumulative incidence of macrovascular and microvascular complications as well as hypoglycemic events. The PRIME T2D Model can report clinical outcomes, quality-adjusted life expectancy, direct and indirect costs, along with standard measures of cost-effectiveness and is capable of probabilistic sensitivity analysis. Several approaches novel to T2D modeling were utilized, such as combining risk formulae using a weighted model averaging approach that takes into account patient characteristics to evaluate complication risk. RESULTS: Validation analyses comparing modeled outcomes with published studies demonstrated that the PRIME T2D Model projects long-term patient outcomes consistent with those reported for a number of long-term studies, including cardiovascular outcomes trials. All root mean squared deviation (RMSD) values for internal validations (against published studies used to develop the model) were 1.1% or less and all external validation RMSDs were 3.7% or less. CONCLUSIONS: The PRIME T2D Model is a product-independent analysis tool that is available online and offers new approaches to long-standing challenges in diabetes modeling and may become a useful tool for informing healthcare policy.HIGHLIGHTSThe PRIME Type 2 Diabetes (T2D) Model is a new, product-independent simulation model.The model offers new approaches to long-standing challenges in diabetes modeling.PRIME T2D Model projects outcomes consistent with those from clinical trials.The model is designed to be a useful tool for informing healthcare policy in T2D.

Cost-Effectiveness of Hybrid Closed Loop Insulin Pumps Versus Multiple Daily Injections Plus Intermittently Scanned Glucose Monitoring in People With Type 1 Diabetes in The Netherlands.

INTRODUCTION: Hybrid closed loop (HCL) insulin pump systems and intermittently scanned continuous glucose monitoring (IS-CGM) are increasingly used by individuals with type 1 diabetes (T1D). The aim of the analysis was to compare the long-term cost-effectiveness of the MiniMed 670G HCL system versus IS-CGM plus multiple daily injections of insulin (MDI) or continuous subcutaneous insulin infusion (CSII) in adults with T1D in the Netherlands. METHODS: The analysis was performed using the IQVIA CORE Diabetes Model with clinical input data sourced from observational studies. Simulated patients were assumed to have a baseline HbA1c of 7.8%. Use of the MiniMed 670G system was assumed to reduce HbA1c by 0.4% and confer a quality-of-life (QoL) benefit through reduced fear of hypoglycemia (FoH). The analysis was performed from a societal perspective over a lifetime time horizon; future costs and clinical outcomes pertaining to the Netherlands were used and discounted at 4% and 1.5% per annum, respectively. RESULTS: Use of the MiniMed 670G HCL system was projected to improve mean quality-adjusted life expectancy by 2.231 quality-adjusted life years (QALYs) versus IS-CGM. Total mean lifetime costs were EUR 13,683 higher with the MiniMed 670G system resulting in an ICER of EUR 6133 per QALY gained. Sensitivity analyses revealed findings to be sensitive to changes in assumptions around severe hypoglycemic event rates and the (QoL) benefit associated with reduced FoH. CONCLUSIONS: Over patient lifetimes, for adults with long-standing T1D in the Netherlands, use of the MiniMed 670G system is projected to be cost-effective versus IS-CGM plus MDI or CSII.

Evaluation of the cost and medical resource use outcomes associated with nasal glucagon versus injectable glucagon for treatment of severe hypoglycemia in people with diabetes in Canada: a modeling analysis.

OBJECTIVES: Treatments for severe hypoglycemia aim to restore blood glucose through successful administration of rescue therapy, and choosing the most effective and cost-effective option will improve outcomes for patients and may reduce costs for healthcare payers. The present analysis aimed to compare costs and use of medical services with nasal glucagon and injectable glucagon in people with type 1 and 2 diabetes in Canada when used to treat severe hypoglycemic events when impaired consciousness precludes treatment with oral carbohydrates using an economic model, based on differences in the frequency of successful administration of the two interventions. METHODS: A decision tree model was prepared in Microsoft Excel to project outcomes with nasal glucagon and injectable glucagon. The model structure reflected real-world decision-making and treatment outcomes, based on Canada-specific sources. The model captured the use of glucagon, emergency medical services (EMS), emergency room, inpatient stay, and follow-up care. Costs were accounted for in 2019 Canadian dollars (CAD). RESULTS: Nasal glucagon was associated with reduced use of all medical services compared with injectable glucagon. EMS call outs were projected to be reduced by 45%, emergency room treatments by 52%, and inpatient stays by 13%. Use of nasal glucagon was associated with reduced direct, indirect, and combined costs of CAD 1,249, CAD 460, and CAD 1,709 per severe hypoglycemic event, respectively, due to avoided EMS call outs and hospital costs, resulting from a higher proportion of successful administrations. CONCLUSIONS: When a patient with type 1 or type 2 diabetes is being treated for a severe hypoglycemic event when impaired consciousness precludes treatment with oral carbohydrate, use of nasal glucagon was projected to be dominant versus injectable glucagon in Canada reducing costs and use of medical services.

Update and nomenclature proposal for mammalian lysophospholipid acyltransferases, which create membrane phospholipid diversity.

The diversity of glycerophospholipid species in cellular membranes is immense and affects various biological functions. Glycerol-3-phosphate acyltransferases (GPATs) and lysophospholipid acyltransferases (LPLATs), in concert with phospholipase A1/2s enzymes, contribute to this diversity via selective esterification of fatty acyl chains at the sn-1 or sn-2 positions of membrane phospholipids. These enzymes are conserved across all kingdoms, and in mammals four GPATs of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family and at least 14 LPLATs, either of the AGPAT or the membrane-bound O-acyltransferase (MBOAT) families, have been identified. Here we provide an overview of the biochemical and biological activities of these mammalian enzymes, including their predicted structures, involvements in human diseases, and essential physiological roles as revealed by gene-deficient mice. Recently, the nomenclature used to refer to these enzymes has generated some confusion due to the use of multiple names to refer to the same enzyme and instances of the same name being used to refer to completely different enzymes. Thus, this review proposes a more uniform LPLAT enzyme nomenclature, as well as providing an update of recent advances made in the study of LPLATs, continuing from our JBC mini review in 2009.

Evaluation of the Cost-Effectiveness of Iron Formulations for the Treatment of Iron Deficiency Anaemia in Patients with Inflammatory Bowel Disease in the UK.

INTRODUCTION: In patients with inflammatory bowel disease (IBD), iron deficiency anaemia (IDA) can impair quality of life and increase healthcare costs. Treatment options for IDA-associated IBD include oral iron and intravenous iron formulations (such as ferric carboxymaltose [FCM], ferric derisomaltose [FD, previously known as iron isomaltoside 1000], and iron sucrose [IS]). The present analysis compared the cost-effectiveness of FCM versus FD, IS, and oral iron sulfate in terms of additional cost per additional responder in the UK setting. METHODS: Cost-effectiveness was calculated for FCM versus FD, IS, and oral iron individually in terms of the additional cost per additional responder, defined as haemoglobin normalisation or an increase of ≥2 g/dL in haemoglobin levels, in a model developed in Microsoft Excel. Relative efficacy inputs were taken from a previously published network meta-analysis, since there is currently no single head-to-head trial evidence comparing all therapy options. Costs were calculated in 2020 pounds sterling (GBP) capturing the costs of iron preparations, healthcare professional time, and consumables. RESULTS: The analysis suggested that FCM may be the most effective intervention, with 81% of patients achieving a response. Response rates with FD, IS, and oral iron were 74%, 75%, and 69%, respectively. Total costs with FCM, FD, IS, and oral iron were GBP 296, GBP 312, GBP 503, and GBP 56, respectively. FCM was found to be more effective and less costly than both FD and IS, and therefore was considered dominant. Compared with oral iron, FCM was associated with an incremental cost-effectiveness ratio of GBP 2045 per additional responder. CONCLUSIONS: FCM is likely to be the least costly and most effective IV iron therapy in the UK setting. Compared with oral iron, healthcare payers must decide whether the superior treatment efficacy of FCM is worth the additional cost.

Projecting the long-term benefits of single pill combination therapy for patients with hypertension in five countries.

OBJECTIVE: To project the 10-year clinical outcomes associated with single pill combination (SPC) therapies compared with multi-pill regimens for the management of hypertension in five countries (Italy, Russia, China, South Korea and Mexico). METHODS: A microsimulation model was designed to project health outcomes between 2020 and 2030 for populations with hypertension managed according to four different treatment pathways: current treatment practices (CTP), single drug with dosage titration then sequential addition of other agents (start low and go slow, SLGS), free choice combination with multiple pills (FCC) and combination therapy in the form of a single pill (SPC). Model inputs were derived from the Global Burden of Disease 2017 dataset. Simulated outcomes of mortality, chronic kidney disease (CKD), stroke, ischemic heart disease (IHD), and disability-adjusted life years (DALYs) were estimated for 1,000,000 patients on each treatment pathway. RESULTS: SPC therapy was projected to improve clinical outcomes over SLGS, FCC and CTP in all countries. SPC reduced mortality by 5.4% in Italy, 4.9% in Russia, 4.5% in China, 2.3% in South Korea and 3.6% in Mexico versus CTP and showed greater reductions in mortality than SLGS and FCC. The projected incidence of clinical events was reduced by 11.5% in Italy, 9.2% in Russia, 8.4% in China, 4.9% in South Korea and 6.7% in Mexico for SPC versus CTP. CONCLUSIONS: Ten-year projections indicated that combination therapies (FCC and SPC) are likely to reduce the burden of hypertension compared with conventional management approaches, with SPC showing the greatest overall benefits due to improved adherence.

Lipidomic Analyses Reveal Specific Alterations of Phosphatidylcholine in Dystrophic Mdx Muscle.

In Duchenne muscular dystrophy (DMD), lack of dystrophin increases the permeability of myofiber plasma membranes to ions and larger macromolecules, disrupting calcium signaling and leading to progressive muscle wasting. Although the biological origin and meaning are unclear, alterations of phosphatidylcholine (PC) are reported in affected skeletal muscles of patients with DMD that may include higher levels of fatty acid (FA) 18:1 chains and lower levels of FA 18:2 chains, possibly reflected in relatively high levels of PC 34:1 (with 16:0_18:1 chain sets) and low levels of PC 34:2 (with 16:0_18:2 chain sets). Similar PC alterations have been reported to occur in the mdx mouse model of DMD. However, altered ratios of PC 34:1 to PC 34:2 have been variably reported, and we also observed that PC 34:2 levels were nearly equally elevated as PC 34:1 in the affected mdx muscles. We hypothesized that experimental factors that often varied between studies; including muscle types sampled, mouse ages, and mouse diets; may strongly impact the PC alterations detected in dystrophic muscle of mdx mice, especially the PC 34:1 to PC 34:2 ratios. In order to test our hypothesis, we performed comprehensive lipidomic analyses of PC and phosphatidylethanolamine (PE) in several muscles (extensor digitorum longus, gastrocnemius, and soleus) and determined the mdx-specific alterations. The alterations in PC 34:1 and PC 34:2 were closely monitored from the neonate period to the adult, and also in mice raised on several diets that varied in their fats. PC 34:1 was naturally high in neonate's muscle and decreased until age ∼3-weeks (disease onset age), and thereafter remained low in WT muscles but was higher in regenerated mdx muscles. Among the muscle types, soleus showed a distinctive phospholipid pattern with early and diminished mdx alterations. Diet was a major factor to impact PC 34:1/PC 34:2 ratios because mdx-specific alterations of PC 34:2 but not PC 34:1 were strictly dependent on diet. Our study identifies high PC 34:1 as a consistent biochemical feature of regenerated mdx-muscle and indicates nutritional approaches are also effective to modify the phospholipid compositions.

Iron Formulations for the Treatment of Iron Deficiency Anemia in Patients with Inflammatory Bowel Disease: A Cost-Effectiveness Analysis in Switzerland.

INTRODUCTION: Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD) and can result in reduced quality of life and increased healthcare costs. IDA is treated with iron supplementation, either with oral iron therapy (OI) or intravenous iron formulations, including ferric carboxymaltose (FCM), iron isomaltoside 1000 (IIM), and iron sucrose (IS). This analysis compared the cost-effectiveness of FCM versus IIM, IS, and OI in terms of additional cost per additional responder in Switzerland. METHODS: A health economic model was developed to assess the additional cost per additional responder, defined as normalization or an increase of at least 2 g/dL in hemoglobin levels, for FCM versus IIM, IS, and OI. To date, no single head-to-head trial comparing all therapies is available, and therefore relative efficacy data were taken from a published network meta-analysis. Costs of treatment were calculated in 2020 Swiss francs (CHF) using a microcosting approach, and included the costs of iron, healthcare professional time, and consumables. Costs are also presented in euros (EUR) based on an exchange rate of CHF 1 = EUR 0.94. RESULTS: Response rates with FCM, IIM, IS, and OI were 81%, 74%, 75%, and 69%, respectively, with FCM projected to be the most effective treatment. FCM was associated with cost savings of CHF 24 (EUR 23) versus IIM and of CHF 147 (EUR 138) versus IS, and increased costs by CHF 345 (EUR 324) versus OI. Therefore FCM was considered dominant versus both IIM and IS, improving clinical outcomes with cost savings. FCM was associated with an incremental cost-effectiveness ratio of CHF 2970 (EUR 2792) per additional responder versus OI. CONCLUSIONS: FCM was projected to be the most cost-effective intravenous iron therapy in Switzerland, increasing the number of responders and leading to cost savings for healthcare payers.

Smart Insulin Pens are Associated with Improved Clinical Outcomes at Lower Cost Versus Standard-of-Care Treatment of Type 1 Diabetes in Sweden: A Cost-Effectiveness Analysis.

INTRODUCTION: Real-world evidence has demonstrated improved glycemic control and insulin management following introduction of smart insulin pens in a Swedish type 1 diabetes (T1D) population. To understand the implications for healthcare costs and expected health outcomes, this analysis evaluated the long-term cost-effectiveness of introducing smart insulin pens to standard-of-care T1D treatment (standard care) from a Swedish societal perspective. METHODS: Clinical outcomes and healthcare costs (in 2018 Swedish krona, SEK) were projected over patients' lifetimes using the IQVIA CORE Diabetes Model to estimate cost-effectiveness. Clinical data and baseline characteristics for the simulated cohort were informed by population data and a prospective, noninterventional study of a smart insulin pen in a Swedish T1D population. This analysis captured direct and indirect costs, mortality, and the impact of diabetes-related complications on quality of life. RESULTS: Over patients' lifetimes, smart insulin pen use was associated with per-patient improvements in mean discounted life expectancy (+ 0.90 years) and quality-adjusted life expectancy (+ 1.15 quality-adjusted life-years), in addition to mean cost savings (direct, SEK 124,270; indirect, SEK 373,725), versus standard care. A lower frequency and delayed onset of complications drove projected improvements in quality-adjusted life expectancy and lower costs with smart insulin pens versus standard care. Overall, smart insulin pens were a dominant treatment option relative to standard care across all base-case and sensitivity analyses. CONCLUSIONS: Use of smart insulin pens was projected to improve clinical outcomes at lower costs relative to standard care in a Swedish T1D population and represents a good use of healthcare resources in Sweden.

Biosynthetic Enzymes of Membrane Glycerophospholipid Diversity as Therapeutic Targets for Drug Development.

Biophysical properties of membranes are dependent on their glycerophospholipid compositions. Lysophospholipid acyltransferases (LPLATs) selectively incorporate fatty chains into lysophospholipids to affect the fatty acid composition of membrane glycerophospholipids. Lysophosphatidic acid acyltransferases (LPAATs) of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family incorporate fatty chains into phosphatidic acid during the de novo glycerophospholipid synthesis in the Kennedy pathway. Other LPLATs of both the AGPAT and the membrane bound O-acyltransferase (MBOAT) families further modify the fatty chain compositions of membrane glycerophospholipids in the remodeling pathway known as the Lands' cycle. The LPLATs functioning in these pathways possess unique characteristics in terms of their biochemical activities, regulation of expressions, and functions in various biological contexts. Essential physiological functions for LPLATs have been revealed in studies using gene-deficient mice, and important roles for several enzymes are also indicated in human diseases where their mutation or dysregulation causes or contributes to the pathological condition. Now several LPLATs are emerging as attractive therapeutic targets, and further understanding of the mechanisms underlying their physiological and pathological roles will aid in the development of novel therapies to treat several diseases that involve altered glycerophospholipid metabolism.

Druggable Lysophospholipid Signaling Pathways.

Lysophosphatidic acid (LPA) has major roles as a bioactive signaling molecule, with multiple physiological and pathological roles being described in almost every major organ system. In this review we discuss LPA signaling pathways as emerging drug targets for multiple conditions relevant to human health and disease. LPA signals through the six G protein-coupled receptors LPA1-6, and several of these receptors along with the LPA-producing enzyme including autotaxin (ATX) are now established as therapeutic targets with potential to treat various human diseases as exemplified by several LPA signaling targeting compounds now in clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. Several crystal structures of LPA receptors and ATX have been solved, which will accelerate development of highly selective and effective LPA signaling targeting compounds. We also review additional bioactive lysophospholipid (LPL) signaling molecules including lysophosphatidylserine and lysophosphatidylinositol, which represent the next wave of LPL druggable targets. An emerging theme in bioactive LPL signaling is that where the ligand is produced and how it is delivered to the cognate receptor are critical determinants of the biological responses. We will also discuss how connecting the production and function of bioactive LPLs will identify new therapeutic strategies to effectively target LPL signaling pathways.

Impact of Stigma on People Living with Chronic Hepatitis B.

BACKGROUND: People with chronic infectious diseases such as hepatitis B can face stigma, which can influence everyday life as well as willingness to engage with medical professionals or disclose disease status. A systematic literature review was performed to characterize the level and type of stigma experienced by people infected with hepatitis B virus (HBV) as well as to identify instruments used to measure it. METHODS: A literature review was performed using the PubMed, Embase and Cochrane Library databases to identify studies describing HBV-related stigma. For inclusion, articles were required to be published in full-text form, in English and report quantitative or qualitative data on HBV-related stigma that could be extracted. RESULTS: A total of 23 (17 quantitative and 6 qualitative) articles examined HBV-related stigma. The scope of the review was global but nearly all identified studies were conducted in countries in the WHO Southeast Asia or Western Pacific regions or within immigrant communities in North America. Several quantitative studies utilized tools specifically designed to assess aspects of stigma. Qualitative studies were primarily conducted via patient interviews. Internalized and social stigma were common among people living with chronic HBV . Some people also perceived structural/institutional stigma, with up to 20% believing that they may be denied healthcare and up to 30% stating they may experience workplace discrimination due to HBV. CONCLUSION: HBV-related stigma is common, particularly in some countries in Southeast Asia and the Western Pacific region and among Asian immigrant communities, but is poorly characterized in non-Asian populations. Initiatives are needed to document and combat stigma (particularly in settings/jurisdictions where it is poorly described) as well as its clinical and socioeconomic consequences.

Evaluation of the Clinical and Economic Burden of Poor Glycemic Control Associated with Therapeutic Inertia in Patients with Type 2 Diabetes in the United States.

INTRODUCTION: Therapeutic inertia refers to the failure to initiate or intensify treatment in a timely manner and is widespread in type 2 diabetes (T2D) despite the well-established importance of maintaining good glycemic control. The aim of this analysis was to quantify the clinical and economic burden associated with poor glycemic control due to therapeutic inertia in patients with T2D in the USA. METHODS: The IQVIA CORE Diabetes Model was used to simulate life expectancy, costs associated with diabetes-related complications, and lost workplace productivity in US patients. Baseline glycated hemoglobin (HbA1c) levels were 7.0% (53 mmol/mol), 9.0% (75 mmol/mol), 11.0% (97 mmol/mol) 13.0% (119 mmol/mol), or 15.0% (140 mmol/mol), with targets of 6.5% (48 mmol/mol), 7.0% (53 mmol/mol), 8.0% (64 mmol/mol), or 9.0% (75 mmol/mol) depending on baseline HbA1c, across several delayed intensification scenarios (values above target were defined as poor control). The burden associated with intensification delays of 1, 2, 3, 5, and 7 years was estimated over time horizons of 1-30 years. Future costs and clinical benefits were discounted at 3% annually. RESULTS: In a population of 13.4 million patients with T2D and baseline HbA1c of 9.0% (75 mmol/mol), delaying intensification of therapy by 1 year was associated with a loss of approximately 13,390 life-years and increased total costs of US dollars (USD) 7.3 billion (1-year time horizon). Longer delays in intensification were associated with a greater economic burden. Delaying intensification by 7 years was projected to cost approximately 3 million life-years and USD 223 billion over a 30-year time horizon. CONCLUSION: Therapeutic inertia is common in routine clinical practice and makes a substantial contribution to the burden associated with type 2 diabetes in the USA. Initiatives and interventions aimed at preventing therapeutic inertia are needed to improve clinical outcomes and avoid excess costs.