Cost-Effectiveness of Quadruple Therapy in Management of Heart Failure With Reduced Ejection Fraction in the United States.

BACKGROUND: The 2022 clinical guidelines for management of heart failure with reduced ejection fraction call for quadruple therapy. Quadruple therapy consists of an angiotensin receptor-neprilysin inhibitor (ARNi), sodium-glucose cotransporter-2 inhibitor (SGLT2i), mineralocorticoid receptor antagonist, and beta blocker. The ARNi and sodium-glucose cotransporter-2 inhibitor are newer additions to standard of care with the ARNi replacing ACE (angiotensin-converting enzyme) inhibitors and angiotensin II receptor blockers. METHODS: We investigate the cost-effectiveness of sequentially adding the SGLT2i and ARNi to form quadruple therapy as compared with the previous standard of care with ACE inhibitor/mineralocorticoid receptor antagonist/beta blocker. Using a 2-stage Markov model, we projected the expected lifetime discounted costs and quality-adjusted life years (QALYs) of a simulated cohort of US patients who underwent each treatment option and calculated incremental cost-effectiveness ratios. We assessed incremental cost-effectiveness ratios using criteria for health care value (<$50 000/quality-adjusted life year [QALY] indicating high-value, $50 000-150 000/QALY indicating intermediate value, and >$150 000/QALY indicating low-value) and a standard $100 000/QALY cost-effectiveness threshold. RESULTS: Compared with the previous standard of care, the SGLT2i addition had an incremental cost-effectiveness ratio of $73 000/QALY and weakly dominated the ARNi addition. The addition of both the ARNi and SGLT2i for quadruple therapy offered 0.68 additional discounted QALYs over the SGLT2i addition alone at a lifetime discounted cost of $66 700, resulting in an incremental cost-effectiveness ratio of $98 500/QALY. In sensitivity analysis varying drug prices, the incremental cost-effectiveness ratio for quadruple therapy ranged from $73 500/QALY using prices available to the US Department of Veterans Affairs to $110 000/QALY using drug list prices. CONCLUSIONS: While quadruple therapy offers intermediate value, it is borderline cost effective compared with adding the SGLT2i alone to previous standard of care. Thus, its cost-effectiveness is sensitive to a payer's ability to negotiate discounts off the increasing list prices for ARNI and SGLT2is. The demonstrated benefits of ARNi and SGLT2is should be weighed against their high prices in payer and policy considerations.

Association of Prescription Co-payment With Adherence to Glucagon-Like Peptide-1 Receptor Agonist and Sodium-Glucose Cotransporter-2 Inhibitor Therapies in Patients With Heart Failure and Diabetes.

Importance: Type 2 diabetes (T2D) and heart failure (HF) prevalence are rising in the US. Although glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve outcomes for these conditions, high out-of-pocket costs may be associated with reduced medication adherence. Objective: To compare 1-year adherence to GLP1-RA and SGLT2i therapies by prescription co-payment level in individuals with T2D and/or HF. Design, Setting, and Participants: This retrospective cohort study used deidentified data from Optum Insight's Clinformatics Data Mart Database of enrollees with commercial and Medicare health insurance plans. Individuals aged 18 years or older with T2D and/or HF who had a prescription claim for a GLP1-RA or SLGT2i from January 1, 2014, to September 30, 2020, were included. Exposures: Prescription co-payment, categorized as low (<$10), medium ($10 to<$50), and high (≥$50). Main Outcomes and Measures: The primary outcome was medication adherence, defined as a proportion of days covered (PDC) of 80% or greater at 1 year. Logistic regression models were used to examine the association between co-payment and adherence, adjusting for patient demographics, medical comorbidities, and socioeconomic factors. Results: A total of 94 610 individuals (mean [SD] age, 61.8 [11.4] years; 51 226 [54.1%] male) were prescribed GLP1-RA or SGLT2i therapy. Overall, 39 149 individuals had a claim for a GLP1-RA, of whom 25 557 (65.3%) had a PDC of 80% or greater at 1 year. In fully adjusted models, individuals with a medium (adjusted odds ratio [AOR], 0.62; 95% CI, 0.58-0.67) or high (AOR, 0.47; 95% CI, 0.44-0.51) co-payment were less likely to have a PDC of 80% or greater with a GLP1-RA compared with those with a low co-payment. Overall, 51 072 individuals had a claim for an SGLT2i, of whom 37 339 (73.1%) had a PDC of 80% or greater at 1 year. Individuals with a medium (AOR, 0.67; 95% CI, 0.63-0.72) or high (AOR, 0.68; 95% CI, 0.63-0.72) co-payment were less likely to have a PDC of 80% or greater with an SGLT2i compared with those with a low co-payment. Conclusions and Relevance: In this cohort study of individuals with T2D and/or HF, 1-year adherence to GLP1-RA or SGLT2i therapies was highest among individuals with a low co-payment. Improving adherence to guideline-based therapies may require interventions that reduce out-of-pocket prescription costs.

Primary Occurrence of Cardiovascular Events After Adding Sodium-Glucose Cotransporter-2 Inhibitors or Glucagon-like Peptide-1 Receptor Agonists Compared With Dipeptidyl Peptidase-4 Inhibitors: A Cohort Study in Veterans With Diabetes.

BACKGROUND: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in preventing major adverse cardiac events (MACE) is uncertain for those without preexisting cardiovascular disease. OBJECTIVE: To test the hypothesis that MACE incidence was lower with the addition of GLP1RA or SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) for primary cardiovascular prevention. DESIGN: Retrospective cohort study of U.S. veterans from 2001 to 2019. SETTING: Veterans aged 18 years or older receiving care from the Veterans Health Administration, with data linkage to Medicare, Medicaid, and the National Death Index. PATIENTS: Veterans adding GLP1RA, SGLT2i, or DPP4i onto metformin, sulfonylurea, or insulin treatment alone or in combination. Episodes were stratified by history of cardiovascular disease. MEASUREMENTS: Study outcomes were MACE (acute myocardial infarction, stroke, or cardiovascular death) and heart failure (HF) hospitalization. Cox models compared the outcome between medication groups using pairwise comparisons in a weighted cohort adjusted for covariates. RESULTS: The cohort included 28 759 GLP1RA versus 28 628 DPP4i weighted pairs and 21 200 SGLT2i versus 21 170 DPP4i weighted pairs. Median age was 67 years, and diabetes duration was 8.5 years. Glucagon-like peptide-1 receptor agonists were associated with lower MACE and HF versus DPP4i (adjusted hazard ratio [aHR], 0.82 [95% CI, 0.72 to 0.94]), yielding an adjusted risk difference (aRD) of 3.2 events (CI, 1.1 to 5.0) per 1000 person-years. Sodium-glucose cotransporter-2 inhibitors were not associated with MACE and HF (aHR, 0.91 [CI, 0.78 to 1.08]; aRD, 1.28 [-1.12 to 3.32]) compared with DPP4i. LIMITATION: Residual confounding; use of DPP4i, GLP1RA, and SGLT2i as first-line therapies were not examined. CONCLUSION: The addition of GLP1RA was associated with primary reductions of MACE and HF hospitalization compared with DPP4i use; SGLT2i addition was not associated with primary MACE prevention. PRIMARY FUNDING SOURCE: VA Clinical Science Research and Development and supported in part by the Centers for Diabetes Translation Research.

Brain Targeting of Citicoline Sodium via Hyaluronic Acid-Decorated Novel Nano-Transbilosomes for Mitigation of Alzheimer's Disease in a Rat Model: Formulation, Optimization, in vitro and in vivo Assessment.

Background: Alzheimer's disease (AD) is one of the furthermost advanced neurodegenerative disorders resulting in cognitive and behavioral impairment. Citicoline sodium (CIT) boosts the brain's secretion of acetylcholine, which aids in membrane regeneration and repair. However, it suffers from poor blood-brain barrier (BBB) permeation, which results in lower levels of CIT in the brain. Purpose: This study targeted to encapsulate CIT into novel nano-platform transbilosomes decorated with hyaluronic acid CIT-HA*TBLs to achieve enhanced drug delivery from the nose to the brain. Methods: A method of thin-film hydration was utilized to prepare different formulae of CIT-TBLs using the Box-Behnken design. The optimized formula was then hyuloranated via integration of HA to form the CIT-HA*TBLs formula. Furthermore, AD induction was performed by aluminum chloride (Alcl3), animals were allocated, and brain hippocampus tissue was isolated for ELISA and qRT-PCR analysis of malondialdehyde (MDA), nuclear factor kappa B (NF-kB), and microRNA-137 (miR-137) coupled with immunohistochemical amyloid-beta (Aß1-42) expression and histopathological finding. Results: The hyuloranated CIT-HA*TBLs formula, which contained the following ingredients: PL (300 mg), Sp 60 (43.97 mg), and SDC (20 mg). They produced spherical droplets at the nanoscale (178.94 ±12.4 nm), had a high entrapment efficiency with 74.92± 5.54%, had a sustained release profile of CIT with 81.27 ±3.8% release, and had ex vivo permeation of CIT with 512.43±19.58 µg/cm2. In vivo tests showed that CIT-HA*TBL thermogel dramatically reduces the hippocampus expression of miR-137 and (Aß1-42) expression, boosting cholinergic neurotransmission and decreasing MDA and NF-kB production. Furthermore, CIT-HA*TBLs thermogel mitigate histopathological damage in compared to the other groups. Conclusion: Succinctly, the innovative loading of CIT-HA*TBLs thermogel is a prospectively invaluable intranasal drug delivery system that can raise the efficacy of CIT in Alzheimer's management.

First-Line Therapy for Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists : A Cost-Effectiveness Study.

BACKGROUND: Guidelines recommend sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists as second-line therapy for patients with type 2 diabetes. Expanding their use as first-line therapy has been proposed but the clinical benefits may not outweigh their costs. OBJECTIVE: To evaluate the lifetime cost-effectiveness of a strategy of first-line SGLT2 inhibitors or GLP1 receptor agonists. DESIGN: Individual-level Monte Carlo-based Markov model. DATA SOURCES: Randomized trials, Centers for Disease Control and Prevention databases, RED BOOK, and the National Health and Nutrition Examination Survey. TARGET POPULATION: Drug-naive U.S. patients with type 2 diabetes. TIME HORIZON: Lifetime. PERSPECTIVE: Health care sector. INTERVENTION: First-line SGLT2 inhibitors or GLP1 receptor agonists. OUTCOME MEASURES: Life expectancy, lifetime costs, incremental cost-effectiveness ratios (ICERs). RESULTS OF BASE-CASE ANALYSIS: First-line SGLT2 inhibitors and GLP1 receptor agonists had lower lifetime rates of congestive heart failure, ischemic heart disease, myocardial infarction, and stroke compared with metformin. First-line SGLT2 inhibitors cost $43 000 more and added 1.8 quality-adjusted months versus first-line metformin ($478 000 per quality-adjusted life-year [QALY]). First-line injectable GLP1 receptor agonists cost more and reduced QALYs compared with metformin. RESULTS OF SENSITIVITY ANALYSIS: By removing injection disutility, first-line GLP1 receptor agonists were no longer dominated (ICER, $327 000 per QALY). Oral GLP1 receptor agonists were not cost-effective (ICER, $823 000 per QALY). To be cost-effective at under $150 000 per QALY, costs for SGLT2 inhibitors would need to be under $5 per day and under $6 per day for oral GLP1 receptor agonists. LIMITATION: U.S. population and costs not generalizable internationally. CONCLUSION: As first-line agents, SGLT2 inhibitors and GLP1 receptor agonists would improve type 2 diabetes outcomes, but their costs would need to fall by at least 70% to be cost-effective. PRIMARY FUNDING SOURCE: American Diabetes Association.

Association of Sodium-Glucose Cotransporter-2 Inhibitors With Incident Atrial Fibrillation in Older Adults With Type 2 Diabetes.

Importance: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have demonstrated many cardiovascular and kidney function benefits for patients with type 2 diabetes (T2D). However, the results of SGLT-2i use in primary prevention of atrial fibrillation (AF) were inconsistent in clinical trials, and incident AF was not a prespecified end point. Objective: To examine incident AF with initiation of an SGLT-2i compared with initiation of a dipeptidyl peptidase-4 inhibitor (DPP-4i) or a glucagonlike peptide-1 receptor agonist (GLP-1RA) among older adults (aged ≥66 years) with T2D in routine clinical practice. Design, Setting, and Participants: A population-based new-user cohort study included older adults with T2D who had no history of AF and were enrolled in Medicare fee-for-service from April 1, 2013, to December 31, 2018. Data analysis was performed from June 28 to December 1, 2021. Exposures: To control for potential confounding, new users of SGLT-2i were 1:1 propensity score (PS)-matched to new users of DPP-4is or GLP-1RAs in 2 pairwise comparisons based on 138 baseline covariates. Main Outcomes and Measures: The primary outcome was incident AF, defined as an inpatient diagnosis code for AF. Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years, with their 95% CIs, were estimated in the PS-matched groups. Results: New users of SGLT-2is were 1:1 PS-matched to new users of a DPP-4i (n = 74 868) or GLP-1RA (n = 80 475). Overall, the mean (SD) age of study participants was 72 (5) years, and 165 984 were women (53.4%). The risk of incident AF was lower in the SGLT-2i group than the matched DPP-4i group (HR, 0.82; 95% CI, 0.76 to 0.89; RD, -3.7; 95% CI, -5.2 to -2.2 per 1000 person-years) or the matched GLP-1RA group (HR, 0.90; 95% CI, 0.83 to 0.98; RD, -1.8; 95% CI, -3.2 to -0.3 per 1000 person-years). Results were consistent across several sensitivity and subgroup analyses. Conclusions and Relevance: The findings of this study suggest that the initiation of an SGLT-2i was associated with a reduced risk of incident AF compared with a DPP-4i or GLP-1RA. The results may be helpful when weighing the potential risks and benefits of various glucose level-lowering agents in older adults with T2D.

Trends in add-on medications following metformin monotherapy for type 2 diabetes.

BACKGROUND: Although metformin is generally universally recommended as a first-line pharmacologic therapy for most people living with type 2 diabetes, second-line and third-line choices can require a tailored approach to achieve optimal blood glucose and glycated hemoglobin levels. OBJECTIVE: To examine national trends in second- and third-line antihyperglycemic medications following metformin monotherapy, comparing 2015 and 2019. METHODS: This retrospective cohort analysis of deidentified pharmacy claims from a large national pharmacy benefits manager from January 1, 2015, to December 31, 2015, and again in January 1, 2019, to December 31, 2019, included adults (aged ≥ 18 years) continuously enrolled in commercial or Medicare insurance plans who filled an index metformin prescription in either year. Proportions of patients by second-line and third-line antihyperglycemic class were calculated. RESULTS: Second-line use of sulfonylureas (-10.1%; P < 0.001), combination drugs (-3.0%; P < 0.001), and dipeptidyl peptidase-4 inhibitors (-2.0%; P = 0.031) significantly declined, whereas second-line use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) (+4.9%; P < 0.001) and glucagon-like peptide-1 receptor agonists (GLP-1Ras) (+10.0%; P < 0.001) significantly increased. Similarly, third-line use of sulfonylureas declined (-5.5%; P = 0.005), whereas third-line use of SGLT2is (+3.4%; P = 0.005) and GLP-1RAs (+8.3%; P < 0.001) increased. Similar trends between 2015 and 2019 were found in commercial and Medicare subgroups. Among all groups in 2015 compared with 2019, sulfonylureas were the most prescribed second-line class and insulins the most common third-line class. Although SGLT2i and GLP-1RA together represented more than one-third of second-line and third-line prescriptions for commercially insured patients in 2019 (34.3% and 35.0%, respectively), these classes were less frequently prescribed in the Medicare subgroup (18% and 25.6%, respectively). CONCLUSIONS: This report provides updated second-line and third-line antihyperglycemic medication prescribing trends in the United States, which suggests that evidence-based guidelines are being used in practice to prevent complications and individualize diabetes care. DISCLOSURES: Ms Swart and Drs Peasah and Good are employed by UPMC Health Plan. Dr Neilson was employed by UPMC Health Plan at the time of the study. Drs Munshi and Henderson were employed by Evernorth at the time of the study.

Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study.

BACKGROUND: Evidence on the risk for cardiovascular events associated with use of first-line sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with metformin is limited. OBJECTIVE: To assess cardiovascular outcomes among adults with type 2 diabetes (T2D) who initiated first-line treatment with SGLT-2i versus metformin. DESIGN: Population-based cohort study. SETTING: Claims data from 2 large U.S. commercial and Medicare databases (April 2013 to March 2020). PARTICIPANTS: Patients with T2D aged 18 years and older (>65 years in Medicare) initiating treatment with SGLT-2i or metformin during April 2013 to March 2020, without any use of antidiabetic medications before cohort entry, were identified. After 1:2 propensity score matching in each database, pooled hazard ratios (HRs) and 95% CIs were reported. INTERVENTION: First-line SGLT-2i (canagliflozin, empagliflozin, or dapagliflozin) or metformin. MEASUREMENTS: Primary outcomes were a composite of hospitalization for myocardial infarction (MI), hospitalization for ischemic or hemorrhagic stroke or all-cause mortality (MI/stroke/mortality), and a composite of hospitalization for heart failure (HHF) or all-cause mortality (HHF/mortality). Safety outcomes including genital infections were assessed. RESULTS: Among 8613 first-line SGLT-2i initiators matched to 17 226 metformin initiators, SGLT-2i initiators had a similar risk for MI/stroke/mortality (HR, 0.96; 95% CI, 0.77 to 1.19) and a lower risk for HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up of 12 months. Initiators receiving SGLT-2i showed a lower risk for HHF (HR, 0.78; CI, 0.63 to 0.97), a numerically lower risk for MI (HR, 0.70; CI, 0.48 to 1.00), and similar risk for stroke, mortality, and MI/stroke/HHF/mortality compared with metformin. Initiators receiving SGLT-2i had a higher risk for genital infections (HR, 2.19; CI, 1.91 to 2.51) and otherwise similar safety as those receiving metformin. LIMITATION: Treatment selection was not randomized. CONCLUSION: As first-line T2D treatment, initiators receiving SGLT-2i showed a similar risk for MI/stroke/mortality, lower risk for HHF/mortality and HHF, and a similar safety profile except for an increased risk for genital infections compared with those receiving metformin. PRIMARY FUNDING SOURCE: Brigham and Women's Hospital and Harvard Medical School.

[Oral rehydration: experience in the management of patients with acute gastroenteritis in the emergency room at the Dr. Antonio Ortiz pediatric hospital]. / Rehidratación oral: experiencia en el manejo de pacientes con gastroenteritis aguda en la sala de emergencia hospital pediátrico Dr. Antonio Ortiz.

Oral rehydration solutions containing 50-90 mEq/L of sodium (Na+) have recently been recommended for the ambulatory management of children with acute diarrhea in the United States. We conducted a randomized study comparing the use of a commercial oral rehydration solution (Rehydralyte), containing 75 mEq/L of Na with the usual method of rehydration with an intravenous solution. Patients treated in the University Pediatric Hospital Emergency Room with acute diarrhea were randomly chosen to receive the oral rehydration solution (Rehydralyte) (Group A), control patients (Group B) were hydrated with the usual intravenous fluids, ie, Ringer's Lactate and then a solution of 56 mEq/L of Na. All patients received orientation about this modality of treatment. Both groups were compared as for weight gain, metabolic parameters, duration of diarrhea, impact on complications associated with use of intravenous solution and cost impact. When both groups were compared there were no differences in measurements of clinical, laboratory data and outcome. Advantages of oral rehydration on cost containment and less human suffering were demonstrated. It can be concluded that in Puerto Rican children oral rehydration solution containing 75 mEq/L Na may be used safely for the treatment of acute diarrhea on ambulatory basis.

Assessment of a general therapeutic protocol for the treatment of acute T-2 toxicosis in swine.

T-2 toxin, a trichothecene mycotoxin suspected of being used as a chemical warfare agent, was administered iv to swine at a dose of 3.6 mg/kg body weight (iv LD50 approximately 1.2 mg/kg). Four different therapeutic protocols were assessed for their efficacy in the treatment of the resultant acute T-2 toxicosis syndrome. One therapeutic protocol included the combined use of metoclopramide, activated charcoal, magnesium sulfate, dexamethasone sodium phosphate, sodium bicarbonate and normal saline. The other 3 protocols utilized the same agents less 1 of the following: the combination of activated charcoal and magnesium sulfate, sodium bicarbonate, or normal saline. All 4 treatment groups showed improved survival times compared to a positive T-2 control group. Within the limits of the study, it would appear that the removal of activated charcoal and magnesium sulfate was most detrimental to the T-2 toxin-dosed swine.

[Assessment of the effectiveness of hemodes in the treatment of the febrile variant of delirium tremens]. / K otsenke éffektivnosti gemodeza v terapii febril'nogo varianta beloi goriachki

The authors propose a complex scheme in the treatment of a febrile variant of delirium tremens. The main emphasis is made on the use of hemodez possessing an antitoxic property and normalizing metabolism. The use of the mentioned preparation along with neuroleptics and symptomatical therapy as was tried in 30 patients with delirium tremens, permitted to arrest acute disorders, the hyperthermic syndrome and normalize the vital functions of the organism. These measures excluded unfavourable lethal outcomes even in cases complicated by Gayet-Wernicke encephalopathy.