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Recent progress in "on-the-fly" trajectory simulations of molecular reactions, using different electronic structure methods is discussed, with analysis of the insights that such calculations can provide and of the strengths and limitations of the algorithms available. New developments in the use of both ab initio and semi-empirical electronic structure algorithms are described. The emphasis is on: (i) calculations of electronic properties along the reactive trajectories and the unique insights this can contribute to the processes; (ii) electronic structure methods recently introduced to this topic to improve accuracy, extend applicability or enhance computational efficiency. The methods are presented with examples, including new results, of reactions of both isolated molecules and of molecules in media, mostly clusters. Possible future directions for this fast growing field are suggested.

Key words: angioplasty; dialysis; elderly; hypertension; renal artery stenosis [ABSTRACT FROM PUBLISHER]

Introduction: This study aimed to assess the effects of a monoclonal antibody (mAb) combination on symptoms, daily function, and overall health-related quality of life., Methods: We analyzed patient-reported outcomes data from symptomatic outpatients in a phase 1/2/3 trial. Patients with confirmed SARS-CoV-2 infection and ≥ 1 risk factor for severe COVID-19 received mAb treatment (casirivimab plus imdevimab 1200 mg) or placebo. Prespecified exploratory assessments included time to sustained symptoms resolution, usual health, and return to usual activities (assessed daily for 29 days). The trial was conducted from September 2020 to February 2021, prior to widespread COVID-19 vaccination programs and Omicron-lineage variants against which casirivimab + imdevimab is not active., Results: In this analysis 736 outpatients received mAb and 1341 received placebo. Median time to sustained symptoms resolution was consistently shorter with mAb versus placebo (≥ 2 consecutive days: 14 vs 17 days, [nominal p = 0.0017]; ≥ 3 consecutive days: 17 vs 21 days, [nominal p = 0.0046]). Median time to sustained return to usual health and usual activities were both consistently shorter with mAb versus placebo (≥ 2 consecutive days: 12 vs 15 days [nominal p = 0.0001] and 9 vs 11 days [nominal p = 0.0001], respectively; ≥ 3 consecutive days: 14 vs 18 days [nominal p = 0.0003] and 10 vs 13 days [nominal p = 0.0041], respectively)., Conclusions: mAb treatment against susceptible SARS-CoV-2 strains improved how patients feel and function, as evidenced by shortened time to sustained symptoms resolution and return to usual health and activities. Future studies are warranted to assess the patient experience with next generation mAbs., Clinicaltrials: GOV: Registration number, NCT04425629; Submission date June 11, 2020., (© 2024. The Author(s).)

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study., Methods: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks., Results: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related., Conclusions: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918., Competing Interests: Disclosures A.W. reports payment or honoraria for lectures, presentations, speakers’ bureaus, article writing, or educational events from Novartis and Algorithm; participation in a data safety monitoring board or advisory board for Amryt Pharma; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for Novartis; and research support for pharmaceutical trials from Amgen, Regeneron Pharmaceuticals, Inc, Novartis, Silence Therapeutics, Esperion, and Ultragenyx. S.G.-P. reports receiving research support from Amgen. S.A., J.M., S.B., P.B., R.T.G., B.H., and R.P. are employees of and stockholders in Regeneron Pharmaceuticals, Inc. E.A.B. is a steering committee member for the REDUCE-IT (Amarin) and PROMINENT (Kowa) trials, and receives research support from Regeneron Pharmaceuticals, Inc. He has received speaking or consulting honoraria from 89Bio, Amarin, Amgen, Amryt, Dalcor, Esperion, Immunovant, Ionis, Merck, New Amsterdam, and Pfizer. M.-J.C. reports honoraria from AstraZeneca, Merck Sharp & Dohme, Pfizer, Amgen, and Sanofi. C.B.-S. reports honoraria for presentations from the National Association of Continuing Medical Education and the Cardiometabolic Health Congress. S.B. reports funding or consulting fees from Amgen, Altimmune, Axcella, Regeneron Pharmaceuticals, Inc, Ionis Pharmaceuticals, Boehringer Ingelheim, Esperion, Lilly, Madrigal, Merck, and Novartis. J.B. reports funding or consulting fees from Regeneron Pharmaceuticals, Inc. P.M.M. reports receipt of research grants to his institution for the participation in the ODYSSEY OUTCOMES trial, as well as financial fees for serving as a medical monitor for the trial and associated support for travel related to trial meetings from Sanofi; consulting fees from Regeneron Pharmaceuticals, Inc, Amgen, Esperion, Kaneka, and Stage II Innovations; advisor fees from Novartis for serving on their advisory committee; and research grants to his institution from Ionis, FH Foundation, GB Life Sciences, Aegerion, Amgen, Kowa, Novartis, and Regeneron Pharmaceuticals, Inc. The other authors report no conflicts.

Metadynamics is a powerful method to accelerate molecular dynamics simulations, but its efficiency critically depends on the identification of collective variables that capture the slow modes of the process. Unfortunately, collective variables are usually not known a priori and finding them can be very challenging. We recently presented a collective variables-free approach to enhanced sampling using stochastic resetting. Here, we combine the two methods, showing that it can lead to greater acceleration than either of them separately. We also demonstrate that resetting Metadynamics simulations performed with suboptimal collective variables can lead to speedups comparable with those obtained with optimal collective variables. Therefore, applying stochastic resetting can be an alternative to the challenging task of improving suboptimal collective variables, at almost no additional computational cost. Finally, we propose a method to extract unbiased mean first-passage times from Metadynamics simulations with resetting, resulting in an improved tradeoff between speedup and accuracy. This work enables combining stochastic resetting with other enhanced sampling methods to accelerate a broad range of molecular simulations., (© 2024. The Author(s).)

Background: Virologic determinants of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were defined in a post hoc analysis of prospectively studied vaccine- and infection-naïve individuals at high risk for coronavirus disease 2019 (COVID-19)., Methods: This phase 3 COVID-19 prevention trial (NCT04452318) with casirivimab and imdevimab was conducted in July 2020-February 2021, before widespread vaccine availability. Placebo-treated participants who were uninfected (SARS-CoV-2 quantitative reverse transcription polymerase chain reaction [RT-qPCR] negative) and seronegative were assessed weekly for 28 days (efficacy assessment period [EAP]) for COVID-19 symptoms and SARS-CoV-2 infection by RT-qPCR of nasopharyngeal swab samples and for serostatus by antinucleocapsid immunoglobulin (Ig) G. Regression-based modeling, including causal mediation analysis, estimated the effects of viral load on seroconversion., Results: Of 157/1069 (14.7%) uninfected and seronegative (for antispike IgG, antispike IgA, and antinucleocapsid IgG) participants who became infected during the EAP, 105 (65%) seroconverted. The mean (SD) maximum viral load of seroconverters was 7.23 (1.68) log 10 copies/mL vs 4.8 (2.2) log 10 copies/mL in those who remained seronegative; viral loads of ∼6.0   log 10 copies/mL better predicted seroconversion. The mean of the maximum viral load was 7.11 log 10  copies/mL in symptomatic participants vs 5.58 log 10  copies/mL in asymptomatic participants. The mean duration of detectable viral load was longer in seroconverted vs seronegative participants: 3.24 vs 1.63 weeks., Conclusions: Maximum SARS-CoV-2 viral load is a major driver of seroconversion and symptomatic COVID-19, with high viral loads (∼6.0 log 10  copies/mL) better predicting seroconversion. Serology underestimates infection rates, incidence, and prevalence of SARS-CoV-2 infection., Competing Interests: Potential conflicts of interest. M.X., K.-C.C., B.H., and B.J.M. are Regeneron Pharmaceuticals, Inc., employees/shareholders and report grants from BARDA. M.P.O. and G.A.H. are Regeneron Pharmaceuticals, Inc., employees/stockholders who report having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., as well as a pending patent application, and report grants from BARDA. A.T.H. is a Regeneron Pharmaceuticals, Inc., employee/stockholder and a Pfizer stockholder and has a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., and reports grants from BARDA. E.F.-N. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals, Inc., and reports having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., as well as a pending patent application, and reports grants from BARDA. F.I. and J.D.H. are Regeneron Pharmaceuticals, Inc., employees/stockholders who report having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., and report grants from BARDA. P.H. is a former Regeneron Pharmaceuticals, Inc., employee and current stockholder and reports grants from BARDA. M.A.M. reports being an employee of the federal government, which, as part of USG, through Operation Warp Speed, supported the clinical trial network involved in implementation of this effort. M.S.C. reports a relationship with the National Institutes for Health for study funding and Regeneron Pharmaceuticals, Inc., for drug studies; reports receiving consulting fees from Aerium for a Scientific Advisory Board and Atrea for a Medical Advisory Board; reports receiving payment for lectures from NY Course, MJH Life Sciences, Clinical Care Solutions, Virology Education, Amgen, Medscape, and UpToDate; reports receiving payment for an educational panel from AstraZeneca and GSK; reports receiving support for attending meetings with Krog Healthcare-GSK and Trinity Health Sciences; and has a leadership role for the HIV Prevention Trials Network, COVID-19 Prevention Network., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19)., Methods: Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020-April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients., Results: Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log 10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was -0.69 (95% confidence interval [CI], -1.25 to -.14) log 10 copies/mL for IC patients and -0.31 (95% CI, -.42 to -.20) log 10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%)., Conclusions: IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695., Competing Interests: Potential conflicts of interest. S. S.-K., J. M., V. M. C., A. M., M. H., S. A., R. B., and B. H. are employees/stockholders of Regeneron Pharmaceuticals, and report grants from BARDA. E. M. reports payments to his institution received from the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH), National Institute of General Medical Sciences/NIH, SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Pfizer, Chemic Labs/KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc/National Cancer Institute. E. O.-O. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals, and reports grants from BARDA. M. P. O. and G. A. H. are employees/stockholders of Regeneron Pharmaceuticals and report having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application; and report grants from BARDA. A. T. H. is an employee/stockholder of Regeneron Pharmaceuticals, a former Pfizer employee and current stockholder, has a patent pending with Regeneron Pharmaceuticals, and reports grants from BARDA. F. M. M. reports payments to his institution received from Regeneron Pharmaceuticals, F2G, Gilead, Merck, Shire, Syneos, and the Bill & Melinda Gates Foundation; reports grants or contracts from Ansun, Chimerix, Cidara, Scynexis, Shire (a Takeda company), WHISCON, AlloVir, Amplyx, F2G, Gilead, and Merck; reports consulting fees from AlloVir, Amplyx, Avir, Emcure, F2G, Gilead, Janssen, Kyorin, Merck, Regeneron, ReViral, Symbio, United Medical, ADMA Biologics, Astellas, Behring, Cidara, Octapharma, Partner Therapeutics, Shionogi, Shire (a Takeda company), and Siemens Healthineers; reports payment for honoraria from Basilea, Merck, and Merck Sharp & Dohme Europe; and reports grants from BARDA. E. F.-N. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals and reports having a patent pending, which has been licensed and receiving royalties from Regeneron Pharmaceuticals, as well as a pending patent application; and reports grants from BARDA. J. D. H. is an employee/stockholder of Regeneron Pharmaceuticals and has a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals. D. M. W. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals and reports having a pending patent application; and reports grants from BARDA., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Chronic pain is prevalent but difficult to treat in patients undergoing hemodialysis (HD). Effective and safe analgesics are limited in this patient population. Our aim in this feasibility study was to evaluate the safety of sublingual oil based medical cannabis for pain management in patients undergoing HD., Methods: In a prospective randomized, double-blind, cross-over design, patients undergoing HD with chronic pain were assigned to one of three arms: BOL-DP-o-04-WPE whole-plant extract (WPE), BOL-DP-o-04 cannabinoid extraction (API) or placebo. WPE and API contained trans-delta-9-‏tetrahydrocannabinol (THC) and cannabidiol (CBD) in a 1:6 ratio (1:6, THC:CBD). Patients were treated for 8 weeks, with subsequent 2-week wash out, followed by a cross-over to a different arm. The primary endpoint was safety., Results: Eighteen patients were recruited and 15 were randomized. Three did not complete drug titration period due to adverse events (AEs) and one patient died during titration due to sepsis (WPE). Of those who completed at least one treatment period, seven patients were in the WPE arm, five in the API and nine receiving placebo. The most common AEs were sleepiness, which improved after dose reduction or patient adaptation. Most AEs were mild to moderate and resolved spontaneously. Serious AEs considered related to study drug included one episode of accidental overdose (WPE) leading to hallucinations. Liver enzymes were stable during cannabis treatment., Conclusions: Short-term medical cannabis use in patients treated with HD was generally well tolerated. The safety data supports further studies to assess the overall risk-benefit of a treatment paradigm utilizing medical cannabis to control pain in this patient population., Competing Interests: N.A. is an employee of BOL Pharma Ltd. N.V. and B.H. are former employees of BOL Pharma Ltd. O.M. is a former employee of BOL; Advisory Board: Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Novartis, AstraZeneca, Bayer, BOL Pharma; Research grant: Novo Nordisk, AstraZeneca; Speakers Bureau: Novo Nordisk, AstraZeneca, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Objective: To assess the real-world effectiveness of casirivimab and imdevimab (CAS+IMD) versus no COVID-19 antibody treatment among patients diagnosed with COVID-19 in the ambulatory setting, including patients diagnosed during the Delta-dominant period prior to Omicron emergence., Design: Retrospective cohort study., Setting: Komodo Health closed claims database., Participants: 13 273 128 patients diagnosed with COVID-19 (December 2020 through September 2021) were treated with CAS+IMD or untreated but treatment eligible under the Emergency Use Authorization (EUA). Each treated patient was exact and propensity score matched without replacement to up to five untreated EUA-eligible patients., Interventions: CAS+IMD., Primary and Secondary Outcome Measures: Composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalisation. Kaplan-Meier estimators were used to calculate outcome risks overall and across subgroups: age, COVID-19 vaccination status, immunocompromised status, and timing of diagnosis (December 2020 to June 2021, and July to September 2021). Cox proportional hazards models were used to estimate adjusted HRs (aHRs) and 95% CIs., Results: Among 75 159 CAS+IMD-treated and 1 670 338 EUA-eligible untreated patients, 73 759 treated patients were matched to 310 688 untreated patients; matched patients were ~50 years, ~60% were women and generally well balanced across risk factors. The 30-day risk of the composite outcome was 2.1% and 5.2% in the CAS+IMD-treated and CAS+IMD-untreated patients, respectively; equivalent to a 60% lower risk (aHR 0.40; 95% CI, 0.38 to 0.42). The effect of CAS+IMD was consistent across subgroups, including those who received a COVID-19 vaccine (aHR 0.48, 95% CI, 0.41 to 0.56), and those diagnosed during the Delta-dominant period (aHR 0.40, 95% CI, 0.38 to 0.42)., Conclusions: The real-world effectiveness of CAS+IMD is consistent with the efficacy for reducing all-cause mortality or COVID-19-related hospitalisation reported in clinical trials. Effectiveness is maintained across patient subgroups, including those prone to breakthrough infections, and was effective against susceptible variants including Delta. ., Competing Interests: Competing interests: All authors are employees and stockholders of Regeneron Pharmaceuticals, Inc., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Data on real-world effectiveness of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) for the treatment of coronavirus disease 2019 (COVID-19) are limited. The objective of this study was to assess the effectiveness of SC CAS+IMD versus no antibody treatment among patients with COVID-19., Methods: This retrospective cohort study linked Komodo Health and CDR Maguire Health and Medical data. Patients diagnosed with COVID-19 in ambulatory settings (August 1-October 30, 2021) treated with SC CAS+IMD were exact- and propensity score-matched to fewer than five untreated treatment-eligible patients and followed for the composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalization. Kaplan-Meier estimators were used to calculate outcome risk overall and across subgroups. Cox proportional-hazards models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI)., Results: Of 13,522 patients treated with CAS+IMD, 12,972 were matched to 41,848 untreated patients. The 30-day composite outcome risk was 1.9% (95% CI 1.7-2.2) and 4.4% (95% CI 4.2-4.6) in the treated and untreated cohorts, respectively; treated patients had a 49% lower relative risk of the composite outcome (aHR 0.51; 95% CI 0.46-0.58) and a 67% relative risk of 30-day mortality (aHR 0.33, 95% CI 0.18-0.60). Effectiveness was consistent across vaccination status and various subgroups., Discussion: Patients with COVID-19 benefitted from treatment with SC CAS+IMD versus untreated patients. The results were consistent across subgroups of patients, including older adults, immunocompromised patients, and patients vaccinated against COVID-19. Results were robust across numerous sensitivity analyses., Conclusion: SC CAS+IMD is effective in reducing 30-day COVID-19-related hospitalization or mortality in real-world outpatient settings during the Delta-dominant period., (© 2022. The Author(s).)

Background: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction., Methods: REAL-TIMI 63B (A Randomized, Placebo‑controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012., Results: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P =0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P =0.30). There was no significant difference in treatment emergent serious adverse events., Conclusions: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03578809.

Aims: Reverse cholesterol transport (RCT) removes cholesterol and stabilizes vulnerable plaques. In addition, high-density lipoprotein (HDL) may be cardioprotective in acute myocardial infarction (MI). Lecithin-cholesterol acyltransferase (LCAT) may enhance RCT. The objective of this study was to investigate the pharmacokinetics, pharmacodynamics, and safety of multiple ascending doses of recombinant human LCAT (MEDI6012) to inform a Phase 2b programme., Methods and Results: This was a randomized, blinded, placebo-controlled, dose-escalation Phase 2a study of MEDI6012. Patients were randomized into one of four cohorts (40, 120, 300 mg IV weekly ×3 doses, or 300 mg IV-push, 150 mg at 48 h and 100 mg at 7 days). All cohorts were planned to randomize 6:2 (MEDI6012 vs. placebo). The primary endpoints were baseline-adjusted area under the curve (AUC) from 0 to 96 h post dose 3 (AUC 0-96 h) for HDL-C, HDL cholesteryl ester (HDL-CE), and total cholesteryl ester (CE). The primary safety endpoints were treatment-emergent adverse events. A total of 32 patients were randomized. MEDI6012 significantly increased AUC 0-96 h for HDL-C, HDL-CE and CE in a graded fashion with increasing doses. Relative to placebo, MEDI6012 increased HDL-C at Day 19 by 66% (95% CI 33-99, P = 0.014) with 120 mg and 144% (95% CI 108-181, P < 0.001) with 300 mg. An IV-push increased HDL-C by 40.8% at 30 min. Overall adverse events were similar between groups with no severe, life-threatening/fatal adverse events, or neutralizing antibodies., Conclusions: Multiple ascending doses of MEDI6012 were safe and well tolerated and significantly increased HDL-C, HDL-CE and CE in a dose-related manner. These data support the ongoing Phase 2b programme investigating MEDI6012 in ST-elevation MI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021.)

Objective: Functional HDL (high-density lipoprotein) particles that facilitate cholesterol efflux may be cardioprotective. EL (endothelial lipase) hydrolyzes phospholipids promoting catabolism of HDL and subsequent renal excretion. MEDI5884 is a selective, humanized, monoclonal, EL-neutralizing antibody. We sought to determine the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of MEDI5884 in patients with stable coronary artery disease. Approach and Results: LEGACY was a phase 2a, double-blind, placebo-controlled, parallel-design trial that randomized 132 patients with stable coronary artery disease receiving high-intensity statin therapy to 3 monthly doses of 1 of 5 dose levels of MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary end point was the safety and tolerability of MEDI5884 through the end of the study (day 151). Additional end points included change in HDL cholesterol and cholesterol efflux from baseline to day 91, hepatic uptake of cholesterol at day 91, changes in various other lipid parameters. The incidence of adverse events was similar between the placebo and MEDI5884 groups. In a dose-dependent manner, MEDI5884 increased HDL cholesterol up to 51.4% ( P <0.0001) and global cholesterol efflux up to 26.2% ([95% CI, 14.3-38.0] P <0.0001). MEDI5884 increased HDL particle number up to 14.4%. At the highest dose tested, an increase in LDL (low-density lipoprotein) cholesterol up to 28.7% ( P <0.0001) and apoB (apolipoprotein B) up to 13.1% ( P =0.04) was observed with MEDI5884. However, at the potential target doses for future studies, there was no meaningful increase in LDL cholesterol or apoB., Conclusions: Inhibition of EL by MEDI5884 increases the quantity and quality of functional HDL in patients with stable coronary artery disease on high-intensity statin therapy without an adverse safety signal at the likely dose to be used. These data support further clinical investigation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03351738.

Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.

Objective: Cotadutide, a dual GLP-1 and glucagon receptor agonist, is under development for nonalcoholic steatohepatitis (NASH) and chronic kidney disease with type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes., Research Design and Methods: In this phase 2b study, 834 adults with BMI ≥25 kg/m 2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A 1c [HbA 1c ] of 7.0%-10.5% [53-91 mmol/mol]) were randomized to double-blind cotadutide 100 μg ( n = 100), 200 μg ( n = 256), or 300 μg ( n = 256); placebo ( n = 110); or open-label liraglutide 1.8 mg ( n = 110)-all administered subcutaneously. Coprimary end points were changes in HbA 1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed., Results: Cotadutide significantly decreased HbA 1c and body weight at weeks 14 and 54 versus placebo (all P < 0.001). Improvements in lipid profile, AST and ALT levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score were observed with cotadutide 300 μg versus placebo, but not with liraglutide. Weight loss with cotadutide 200 μg was similar to that with liraglutide 1.8 mg and greater with cotadutide 300 μg versus liraglutide 1.8 mg. The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time., Conclusions: Cotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH., (© 2021 by the American Diabetes Association.)

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

Trapped bosons exhibit fundamental physical phenomena and are at the core of emerging quantum technologies. We present a method for simulating bosons using path integral molecular dynamics. The main difficulty in performing such simulations is enumerating all ring-polymer configurations, which arise due to permutations of identical particles. We show that the potential and forces at each time step can be evaluated by using a recurrence relation which avoids enumerating all permutations, while providing the correct thermal expectation values. The resulting algorithm scales cubically with system size. The method is tested and applied to bosons in a 2-dimensional (2D) trap and agrees with analytical results and numerical diagonalization of the many-body Hamiltonian. An analysis of the role of exchange effects at different temperatures, through the relative probability of different ring-polymer configurations, is also presented., Competing Interests: The authors declare no competing interest.

The anharmonic frequencies of O-H, C-H, and N-H stretching modes of hydrogen-bonded glycine-H 2 O complexes are calculated using ab initio classical separable potential approximation. In this approach, ab initio molecular dynamic simulations are used to determine an effective classical potential for each of the normal modes of the system. The frequencies are calculated by solving the time-independent Schrödinger equation for each mode using time-averaged potentials. Three complex structures are studied, which differ in the location of the water molecule on the amino acid. Significant differences are found between the spectra of the three structures, and signatures of individual complexes are established. It is demonstrated that anharmonic effects are essential in the discrimination between different structures, while frequency differences at the harmonic level are much smaller. Intensities are also computed and found to carry information on differences between structures, but the role of anharmonicity in this is small.

Aims/hypothesis: Cardiovascular disease is the leading cause of morbidity and mortality in people with type 2 diabetes. MEDI4166 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and glucagon-like peptide-1 (GLP-1) analogue fusion molecule designed to treat patients with type 2 diabetes who are at risk for cardiovascular disease. In this completed, first-in-human study, we evaluated the safety and efficacy of single or multiple doses of MEDI4166 in participants with type 2 diabetes., Methods: In this phase 1 study that was conducted across 11 clinics in the USA, eligible adults had type 2 diabetes, a BMI of ≥25 kg/m 2 to ≤42 kg/m 2 , and LDL-cholesterol levels ≥1.81 mmol/l. Participants were randomised 3:1 to receive MEDI4166 or placebo using an interactive voice/web response system, which blinded all participants, investigators and study site personnel to the study drug administered. In 'Part A' of the study, five cohorts of participants received a single s.c. injection of MEDI4166 at 10 mg, 30 mg, 100 mg, 200 mg or 400 mg, or placebo. 'Part B' of the study consisted of three cohorts of participants who received an s.c. dose of MEDI4166 once weekly for 5 weeks at 50 mg, 200 mg or 400 mg, or placebo. The primary endpoint in Part A was safety. The co-primary endpoints in Part B were change in LDL-cholesterol levels and area under the plasma glucose concentration-time curve (AUC 0-4h ) post-mixed-meal tolerance test (MMTT) from baseline to day 36. The pharmacokinetics and immunogenicity of MEDI4166 were also evaluated., Results: MEDI4166 or placebo was administered to n = 30 or n = 10 participants, respectively, in Part A of the study, and n = 48 or n = 15 participants, respectively, in Part B. The incidence of treatment-emergent adverse events (TEAEs) were comparable between MEDI4166 and placebo in both Part A (60% vs 50%) and Part B (79% vs 87%) of the study. Common TEAEs with MEDI4166 included injection-site reactions, diarrhoea and headache; there was no evidence for dose-related increases in TEAEs. In Part B of the study, at all tested doses of MEDI4166, there was a significant decrease in LDL-cholesterol levels vs placebo (least squares mean [95% CI]; MEDI4166 50 mg, -1.25 [-1.66, -0.84]; MEDI4166 200 mg, -1.97 [-2.26, -1.68]; MEDI4166 400 mg, -1.96 [-2.23, -1.70]; placebo, -0.03 [-0.35, 0.28]; all p < 0.0001). However, there were no clinically relevant reductions or significant differences between MEDI4166 vs placebo in glucose AUC 0-4h post-MMTT (least squares mean [95% CI]; MEDI4166 50 mg, -10.86 [-17.69, -4.02]; MEDI4166 200 mg, -4.23 [-8.73, 0.28]; MEDI4166 400 mg, -2.59 [-7.14, 1.95]; placebo, -4.84 [-9.95, 0.28]; all p > 0.05). MEDI4166 was associated with a pharmacokinetic profile supportive of weekly dosing and an overall treatment-induced anti-drug antibody-positive rate of 22%., Conclusions/interpretation: MEDI4166 was associated with an acceptable tolerability profile and significantly decreased LDL-cholesterol levels in a dose-dependent manner in overweight or obese patients with type 2 diabetes. However, there were no significant reductions in postprandial glucose levels at any dose of MEDI4166., Trial Registration: ClinicalTrials.gov NCT02524782 FUNDING: This study was funded by MedImmune LLC, Gaithersburg, MD, USA.

Aims: MEDI0382 is a balanced glucagon-like peptide-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus and non-alcoholic steatohepatitis. The primary objective was to assess the safety of MEDI0382 in healthy subjects., Methods: In this placebo-controlled, double-blind, Phase 1 study, healthy subjects (aged 18-45 years) were randomized (3:1) to receive a single subcutaneous dose of MEDI0382 or placebo after ≥8 h of fasting. The study consisted of six cohorts that received study drug at 5 μg, 10 μg, 30 μg, 100 μg, 150 μg or 300 μg. The primary objective was safety and tolerability. Secondary endpoints included assessments of pharmacokinetics and immunogenicity. All subjects were followed for up to 28 days., Results: A total of 36 subjects received MEDI0382 (n = 6 per cohort) and 12 subjects received placebo (n = 2 per cohort). Treatment-emergent adverse events (TEAEs) occurred more frequently with MEDI0382 vs. placebo, which was mostly due to an increased occurrence at MEDI0382 doses ≥150 μg. All TEAEs were mild or moderate in severity. The most common TEAEs were vomiting, nausea and dizziness. There appeared to be a dose-dependent increase in heart rate with MEDI0382 treatment. MEDI0382 showed linear pharmacokinetic profile (time to maximum plasma concentration: 4.50-9.00 h; elimination half-life: 9.54-12.07 h). No immunogenicity was observed in the study., Conclusions: In this single-dose, Phase 1 study in healthy subjects, the safety and pharmacokinetic profiles of MEDI0382 support once-daily dosing and further clinical development of MEDI0382., (© 2018 The British Pharmacological Society.)

Background: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury., Methods: In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days)., Results: Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported., Conclusions: The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.

Introduction: This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies (N = 4632) summarizes saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens., Methods: Patients received saxagliptin 5 mg/d or control as either monotherapy (n = 1196 vs placebo), add-on therapy (n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy (n = 619 vs control monotherapy). Patients with renal impairment received saxagliptin 2.5 mg/d or placebo (n = 164)., Results: Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: -0.55% [-0.63%, -0.47%]) and when used as monotherapy (-0.52% [-0.63, -0.40%]), add-on (-0.55% [-0.69%, -0.40%] vs placebo; -0.72% [-0.88%, -0.56%] vs uptitrated sulfonylurea), initial combination therapy (-0.54% [-0.73%, -0.35%] vs control monotherapy), and in patients with renal impairment (-0.42% [-0.75%, -0.09%]). Similar reductions in A1C versus control were noted for patients <65 years (-0.55% [-0.67%, -0.43%]) and ≥65 years (-0.54% [-0.69%, -0.38%]) and for men (-0.54% [-0.69%, -0.40%]) and women (-0.55% [-0.64%, -0.47%]) across treatment regimens. More patients achieved A1C <7% (39% vs 23%) and A1C ≤6.5% (24% vs 14%) with saxagliptin than with placebo or active-control treatment. Saxagliptin versus control was associated with a reduction in glucagon area under the curve (AUC) from baseline and increases in insulin AUC, C-peptide AUC, and the homeostasis model assessment of β-cell function., Conclusion: Results of this meta-analysis demonstrate the consistency of saxagliptin efficacy in different subgroups of patients with T2D across treatment regimens., Funding: AstraZeneca.

Objective: Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy., Research Design and Methods: We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial., Results: At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m 2 (BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA 1c (r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well., Conclusions: Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control., (© 2017 by the American Diabetes Association.)

Introduction: Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). The recommended dose of the dipeptidyl peptidase-4 inhibitor saxagliptin is 2.5 mg in patients with moderate or severe renal impairment (creatinine clearance ≤50 mL/min). In this post hoc analysis, we assessed the effect of saxagliptin 2.5 and 5 mg/day versus placebo on glycemic measures in patients with T2D and estimated glomerular filtration rate 45-60 mL/min/1.73 m(2)., Methods: Efficacy and safety data were pooled from nine 24-week, randomized, placebo-controlled clinical trials., Results: The majority (56-61%) of patients were women aged <65 years with glycated hemoglobin (A1C) 8.1-8.2%; half of the patients had a T2D duration ≥5 years. Mean change from baseline in A1C was significantly greater with saxagliptin 2.5 (-0.6%, P = 0.036 vs placebo) and 5 mg/day (-0.9%, P < 0.001 vs placebo) compared with placebo (-0.2%). There were numerically greater reductions in fasting plasma glucose and 2-h postprandial glucose, and a significantly greater proportion of patients achieved A1C <7% with saxagliptin 5 mg/day (44.8%) compared with placebo (20.0%, P = 0.004 vs placebo). The incidence of hypoglycemia was not significantly different across groups (16.2% in the saxagliptin 5-mg/day, 12.2% in the saxagliptin 2.5-mg/day, and 11.3% in the placebo groups)., Conclusion: These results suggest that saxagliptin 2.5 and 5 mg/day improve glycemic control and are generally well tolerated in patients with T2D and moderate CKD., Trial Registration: ClinicalTrials.gov identifier, NCT00121641, NCT00316082, NCT00698932, NCT00918879, NCT00121667, NCT00661362, NCT00313313, NCT00295633, NCT00757588., Funding: AstraZeneca, Gaithersburg, MD, USA.

Objective: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study., Research Design and Methods: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied., Results: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia., Conclusions: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: Patients with type 2 diabetes have an increased risk of bone fractures, the predisposing factors for which are unknown. Treatment with thiazolidinediones (TZDs) further increases the incidence of osteoporotic fractures. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, fractures were considered an adverse event of special interest, and information regarding fractures was collected., Research Design and Methods: We compared the incidence of fractures among the 8,280 patients who were assigned to treatment with saxagliptin with that in the 8,212 patients who were assigned to placebo. We further analyzed the participants' baseline characteristics and fracture risk., Results: During a median follow-up of 2.1 years, 241 patients (2.9%) in the saxagliptin group and 240 (2.9%) in the placebo group experienced a fracture (hazard ratio [HR] 1.00 [95% CI 0.83-1.19]). Event rates for fractures were the same in both treatment arms: 14.7 per 1,000 patient-years in the entire population and 14.0 in the on-treatment population (first event only). Fracture risk was similar in patients treated with saxagliptin or placebo across different subgroups defined by race, cardiovascular risk, and renal function. A multivariable Cox regression analysis showed that risk of fracture was associated with female sex (P < 0.0001), longer diabetes duration (P < 0.0001), older age (P = 0.002), major hypoglycemic events (P = 0.01), noncompliance with study drug (P = 0.01), and treatment with TZDs (P = 0.03)., Conclusions: In a large population of older patients with type 2 diabetes, treatment with saxagliptin was not associated with an increased risk of fractures. The association between longer diabetes duration and increased risk of bone fracture is an intriguing finding., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin treatment., Research Design and Methods: Patients receiving treatment with stable metformin (stratum A) (screening HbA1c level 8.0-11.5% [64-102 mmol/mol]) or stable metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor (stratum B) (HbA1c 7.5-10.5% [58-91 mmol/mol]) for ≥8 weeks received open-label saxagliptin 5 mg/day and metformin for 16 weeks (stratum A) or 8 weeks (stratum B) (saxagliptin replaced any DPP-4 inhibitor). Patients with inadequate glycemic control (HbA1c 7-10.5% [53-91 mmol/mol]) were randomized to receive placebo or dapagliflozin 10 mg/day plus saxagliptin and metformin. The primary end point was the change in HbA1c from baseline to week 24. Secondary end points included fasting plasma glucose (FPG) level, 2-h postprandial glucose (PPG) level, body weight, and proportion of patients achieving an HbA1c level of <7% (53 mmol/mol)., Results: Treatment with dapagliflozin add-on to saxagliptin plus metformin resulted in a greater mean HbA1c reduction than placebo (-0.82 vs. -0.10% [-9 vs. -1.1 mmol/mol], P < 0.0001). Significantly greater reductions in FPG level, 2-h PPG level, and body weight were observed, and more patients achieved an HbA1c level of <7% (53 mmol/mol) with treatment with dapagliflozin versus placebo. Adverse events were similar across treatment groups, with a low overall risk of hypoglycemia (∼1%). Genital infections developed in more patients with dapagliflozin treatment (5%) than with placebo (0.6%)., Conclusions: Triple therapy with dapagliflozin add-on to saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin therapy., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: The objective of this study was to assess the efficacy and safety of triple therapy with saxagliptin add-on versus placebo add-on to dapagliflozin plus metformin in adults with type 2 diabetes., Research Design and Methods: Patients on stable metformin (≥1,500 mg/day) for ≥8 weeks with glycated hemoglobin (HbA1c) 8.0-11.5% (64-102 mmol/mol) at screening received open-label dapagliflozin (10 mg/day) plus metformin immediate release (IR) for 16 weeks. Patients with inadequate glycemic control (HbA1c 7-10.5% [53-91 mmol/mol]) were then randomized to receive placebo (n = 153) or saxagliptin 5 mg/day (n = 162) in addition to background dapagliflozin plus metformin IR. The primary efficacy end point was change in HbA1c from baseline to week 24., Results: There was a significantly greater reduction in HbA1c at 24 weeks with saxagliptin add-on (-0.51% [-5.6 mmol/mol]) versus placebo (-0.16% [-1.7 mmol/mol]) add-on to dapagliflozin plus metformin (difference, -0.35% [95% CI -0.52% to -0.18%] and -3.8 [-5.7 to -2.0 mmol/mol], respectively; P < 0.0001). Reductions in fasting plasma glucose and 2-h postprandial glucose were similar between treatment arms. A larger proportion of patients achieved HbA1c <7% (53 mmol/mol) with saxagliptin add-on (35.3%) versus placebo add-on (23.1%) to dapagliflozin plus metformin. Adverse events were similar between treatment groups. Episodes of hypoglycemia were infrequent in both treatment arms, and there were no episodes of major hypoglycemia., Conclusions: Triple therapy with the addition of saxagliptin to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with type 2 diabetes inadequately controlled with dapagliflozin plus metformin., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To examine the safety and cardiovascular (CV) effects of saxagliptin in the predefined elderly (≥65 years) and very elderly (≥75 years) subpopulations of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial., Research Design and Methods: Individuals ≥40 years (n = 16,492; elderly, n = 8,561; very elderly, n = 2,330) with HbA1c ≥6.5% (47.5 mmol/mol) and ≤12.0% (107.7 mmol/mol) were randomized (1:1) to saxagliptin (5 or 2.5 mg daily) or placebo in a double-blind trial for a median follow-up of 2.1 years., Results: The hazard ratio (HR) for the comparison of saxagliptin versus placebo for the primary end point (composite of CV mortality, myocardial infarction, or ischemic stroke) was 0.92 for elderly patients vs. 1.15 for patients <65 years (P = 0.06) and 0.95 for very elderly patients. The HRs for the secondary composite end points in the entire cohort, elderly cohort, and very elderly cohort were similar. Although saxagliptin increased the risk of hospitalization for heart failure in the overall saxagliptin population, there was no age-based treatment interaction (P = 0.76 for elderly patients vs. those <65 years; P = 0.34 for very elderly patients vs. those <75 years). Among saxagliptin-treated individuals with baseline HbA1c ≥7.6% (59.6 mmol/mol), the mean change from baseline HbA1c at 2 years was -0.69%, -0.64%, -0.66%, and -0.66% for those ≥65, <65, ≥75, and <75 years old, respectively. The incidence of overall adverse events (AEs) and serious AEs was similar between saxagliptin and placebo in all cohorts; however, hypoglycemic events were higher for saxagliptin versus placebo regardless of age., Conclusions: The SAVOR-TIMI 53 trial supports the overall CV safety of saxagliptin in a robust number of elderly and very elderly participants, although the risk of heart failure hospitalization was increased irrespective of age category. AEs and serious AEs as well as glycemic efficacy of saxagliptin in elderly patients are similar to those found in younger patients., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)