Double-blind Clinical Studies Research Articles

Pharmacokinetics, safety, and efficacy of daridorexant in Japanese subjects: Results from phase 1 and 2 studies.

Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. We report results from the first two randomised, double-blind clinical studies of daridorexant in Japanese subjects. In the Phase 1 study, daridorexant (10, 25, 50 mg) or placebo were administered in the morning for 4 days in 24 young (mean age 26.9 years) and 24 older (mean age 69.7 years) healthy Japanese adults. Daridorexant reached a peak plasma concentration within 1.0 h across every dose and age group. For all doses, the mean plasma concentration of daridorexant showed a similar change between the age groups. Exposure parameters increased dose-dependently with minimal/no accumulation upon repeated dosing. The terminal half-life was ~8 h. In the Phase 2, four-period, four-way crossover study, 47 Japanese subjects (mean age 50.4 years) with insomnia disorder were randomised to receive four treatments (daridorexant 10, 25, 50 mg, placebo) during four treatment periods, each consisting of two treatment nights (5-12 day washout between treatment periods). Subjects continued their fourth treatment for 12 further days. A statistically significant dose-response relationship (multiple-comparison procedure-modelling, p < 0.0001) was found in the reduction of polysomnography-measured wake after sleep onset (WASO; primary endpoint) and latency to persistent sleep (secondary endpoint) from baseline to days 1/2. Statistically significant dose-response relationships were also observed for secondary subjective endpoints from baseline to days 1/2 (sWASO, latency to sleep onset). All daridorexant doses were well tolerated, with no treatment discontinuations and no next-morning residual effects. These results supported further investigation of daridorexant in Japanese patients with insomnia disorder.

Clinical Benefits of Therapeutic Interventions Targeting Mitochondria in Parkinson's Disease Patients.

Parkinson's disease is the second most common neurodegenerative disease. Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson's disease, and several treatments targeting mitochondria have been tested in these patients to delay disease progression and tackle disease symptoms. Herein, we review available data from randomised, double-blind clinical studies that have investigated the role of compounds targeting mitochondria in idiopathic Parkinson's disease patients, with a view of providing patients and clinicians with a comprehensive and practical paper that can inform therapeutic interventions in this group of people. A total of 9 compounds have been tested in randomized clinical trials, but only exenatide has shown some promising neuroprotective and symptomatic effects. However, whether this evidence can be translated into daily clinical practice still needs to be confirmed. In conclusion, targeting mitochondrial dysfunction in Parkinson's disease is a promising therapeutic approach, although only one compound has shown a positive effect on Parkinson's disease progression and symptoms. New compounds have been investigated in animal models, and their efficacy needs to be confirmed in humans through robust, randomised, double-blind clinical trials.

Preliminary clinical study of mucoadhesive propolis gel to gingival disorders control in patients with fixed orthodontic appliances.

Aims: Gingival hyperplasia (GH) etiology is diverse and ranges from acute or chronic inflammatory processes and is commonly observed in patients with fixed orthodontic appliances. Propolis has been globally studied and has anti -inflammatory and antimicrobial properties, however, there are few clinical studies involving orthodontics. Study design: This clinical study aims to obtain preliminary evidence of an oral gel containing 5% Brazilian propolis (BPG) in GH and gingivitis control on patients with fixed orthodontic appliances. Place and Duration study: Clinic Orthodontics, Faculty of Dentistry/UFMG, Belo Horizonte, Brazil, from March to October 2013. Methodology: Thirty patients were selected, but only 10 participated and reached the end of the study. The patients were submitted to questionnaire and a complete prophylaxis of dental structures before initiating the gel use(T0) and they were instructed to use the gel two times daily after brushing (morning and evening) during 30 days (T30). Patients were evaluated considering plaque and gingival index and photographs collection of first premolars - measuring gingiva of the clinical crown area. The SPSS version 18.0 statistical program, Shapiro Wilk normality test, presenting a normal or parametric distribution and all analyzes were performed using Student's t Test for paired samples. Results: BPG show statistically significant reduction of GBI and GSI (GB1 p =0.207; GB2 p = 0.122), respectively. Conclusion: Considering this study model, 5% propolis gel had effective in reducing GH and gingivitis. However, a double blind and randomized clinical studies with higher number of patients should be made to give greater credibility for gel use.

The efficacy of administration of prazosin in reducing the risk of recurrent urethral obstruction in male cats

PICO Question In male cats presenting with urethral obstruction, does administration of prazosin compared with no administration of prazosin reduce the incidence of recurrent urethral obstruction within the first month of initial presentation? Clinical bottom line Category of research Treatment. Number and type of study designs reviewed A total of three studies were included in this appraisal. Two of which were prospective double-blind clinical studies and one retrospective study. Strength of evidence Weak. Outcomes reported Both double-blind studies found no significant difference between prazosin administration and the development of recurrent urethral obstruction (rUO) when compared with a placebo. Both studies, however, did report that cats had a shorter urinary catheterisation time with prazosin administration. The retrospective study found no association between prazosin administration and the risk of rUO and found that after 14 days post discharge, significantly more 73/302 (24%) cats that received prazosin had experienced rUO compared to 11/86 (13%) of cats that did not. One study found side effects to the administration of prazosin which may be detrimental to the overall recovery. Conclusion Administration of prazosin does not reduce the risk of rUO within 30 days of presentation. However, the strength of evidence is weak and would benefit from further clinical studies. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

Identification of a human blood biomarker of pharmacological 11β-hydroxysteroid dehydrogenase 1 inhibition.

11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) catalyses the oxoreduction of cortisone to cortisol, amplifying levels of active glucocorticoids. It is a pharmaceutical target in metabolic disease and cognitive impairments. 11β-HSD1 also converts some 7oxo-steroids to their 7β-hydroxy forms. A recent study in mice described the ratio of tauroursodeoxycholic acid (TUDCA)/tauro-7oxolithocholic acid (T7oxoLCA) as a biomarker for decreased 11β-HSD1 activity. The present study evaluates the equivalent bile acid ratio of glycoursodeoxycholic acid (GUDCA)/glyco-7oxolithocholic acid (G7oxoLCA) as a biomarker for pharmacological 11β-HSD1 inhibition in humans and compares it with the currently applied urinary (5α-tetrahydrocortisol + tetrahydrocortisol)/tetrahydrocortisone ((5αTHF + THF)/THE) ratio. Bile acid profiles were analysed by ultra-HPLC tandem-MS in blood samples from two independent, double-blind placebo-controlled clinical studies of the orally administered selective 11β-HSD1 inhibitor AZD4017. The blood GUDCA/G7oxoLCA ratio was compared with the urinary tetrahydro-glucocorticoid ratio for ability to detect 11β-HSD1 inhibition. No significant alterations were observed in bile acid profiles following 11β-HSD1 inhibition by AZD4017, except for an increase of the secondary bile acid G7oxoLCA. The enzyme product/substrate ratio GUDCA/G7oxoLCA was found to be more reliable to detect 11β-HSD1 inhibition than the absolute G7oxoLCA concentration in both cohorts. Comparison of the blood GUDCA/G7oxoLCA ratio with the urinary (5αTHF + THF)/THE ratio revealed that both successfully detect 11β-HSD1 inhibition. 11β-HSD1 inhibition does not cause major alterations in bile acid homeostasis. The GUDCA/G7oxoLCA ratio represents the first blood biomarker of pharmacological 11β-HSD1 inhibition and may replace or complement the urinary (5αTHF + THF)/THE ratio biomarker.

BIOMIMETIC MATERIALS IN PEDIATRIC DENTISTRY FROM PAST TOFUTURE

With the arrival of technology, during the last two decades, numerous changes have been made in the field of restorative dentistry. Biomimetic materials, with their biocompatible nature and excellent physico-chemical properties are widely used nowadays. They can function as long lasting esthetic and restorative materials, cements, root repair materials, root canal sealers and filling materials, which have the advantages of enhanced biocompatibility, high strength, sealing ability and antibacterial properties. New biomimetic materials have demonstrated the ability to overcome some of the significant limitations of earlier generation materials. Although in vitro studies, the uses of biomimetic materials in restorative dentistry endodontic have given encouraging results, randomized and double-blind clinical studies of sufficient length with these materials are needed to confirm long-term success following their use.

Effects of Pear Extracts on Microbiome and Immunocytokines to Alleviate Air Pollution-Related Respiratory Hypersensitivity.

Pears are ancient functional foods for modern times. Particularly, Korean pears (Pyrus pyrifolia cv.) have been used as folk medicine for respiratory diseases and have strong potential for the treatment of hazardous aerosol-related diseases. Thus, the effects of pear ethanol extracts on air pollution-related respiratory hypersensitivity were studied by toxicokinetics, pro-inflammatory cytokines, and microbiomics in preclinical and randomized double-blind clinical studies. The mild-asthma subjects, who lived in the same city, Seoul, Korea, were separated into the placebo and the treatment (pear extracts, as brix 55; arbutin 5.01 mg and chlorogenic acid 0.18 mg/3 mL per day) groups for 4 weeks (n = 20). As results, there were positive associations between urinary 2-naphthol (NT) or 1-hydroxypyrene (OHP), exposure biomarkers for polyaromatic hydrocarbons in PM2.5, and pro-inflammatory cytokines, interleukin (IL)-4 or IgE, respectively, in the human subjects. The pear extracts somewhat reduced 2-NT and 1-OHP levels. The proportions of fiber-degrading bacteria that stimulate growth of beneficial microflora for immune defense, that is, Bifidobacterium and Eubacterium, were significantly higher in the pear consuming group than in the placebo group. Moreover, pro-inflammatory cytokines, including IgE, IL-4, IL-5, and IL-13, were significantly suppressed by the pear extracts in the preclinical tests of the ovalbumin-induced asthma mice. Thus, we suggest that air pollution-related respiratory hypersensitivity can be alleviated by Korean pear extracts by modulation of microbiome and immunocytokines.

Effect of Proprietary Chinese Medicine on Coronary Microvascular Dysfunction in Patients with Microvascular Angina: A Systematic Review and Meta-Analysis.

Microvascular angina (MVA) has received increasing attention and interest in recent years, but there are still some shortcomings in the diagnosis and treatments at current stage. In recent years, several studies have confirmed the efficacy of proprietary Chinese medicines (PCMs) in improving MVA symptoms; however, there is no systematic review and meta-analysis to comprehensively assess the efficacy of PCMs in this area. Investigating the clinical efficacy of proprietary Chinese medicines for treating MVA and coronary microvascular function. We looked up articles from January 1, 2012, to the present from eight databases. Then, we screened the literature and followed the 2019 version 2 of Cochrane risk of bias tool for systematic review. The Stata/SE 15.0 software was used for the meta-analysis. There are 21 studies, including 1,641 patients who were included in this review. According to the results, the combination of PCMs and conventional MVA treatment was able to further enhance clinical efficacy [RR = 1.28, 95% CI (1.20, 1.36), p < 0.001], prolong the time of duration on the treadmill exercise testing (TET) [SMD = 1.49, 95% CI (0.63, 2.36), p = 0.001] and improve levels of NO [SMD = -1.77 95% CI (-2.11, -1.43), p < 0.001]. At the same time, PCMs could also decrease the microvascular resistance index (IMR) [SMD = -1.79, 95% CI (-2.58, -1.00), p < 0.001)], serum level of hs-CRP [SMD = -1.21, 95% CI (-1.84, -0.58), p < 0.001] and ET-1 [SMD = -1.77 95% CI (-2.11, -1.43), p < 0.001]. Regards to medication safety, a total of 27 adverse events occurred, including 10 cases in the intervention group and 17 cases in the control group. The study suggests that the combination of PCMs and conventional MVA treatment enhances clinical efficacy and could better improve coronary microvascular function. In the future, we expect more high-quality, randomized, double-blind clinical studies to validate the safety, and efficacy of PCMs to provide valuable evidence-based medicine (EBM) for the treatment of MVA with PCMs.

Impact of anti-oestrogen therapy on lipoprotein(a) in postmenopausal women: a systematic review and meta-analysis of double-blind placebo-controlled clinical studies.

The potential mechanisms of endocrine therapy for thrombosis remain currently unclear, and more studies are warranted for further investigation and elucidation. However, high plasma concentration of lipoprotein(a) (Lp(a)) is a recognized prothrombotic factor. The aim of our study was to systematically evaluate the effect of different anti-oestrogen therapy on plasma Lp(a) level in postmenopausal women. A systematic literature search was conducted in multiple electronic databases to identify the randomized, double-blind, placebo-controlled clinical studies on this topic. Effect size for changes in Lp(a) was expressed as mean difference (MD) and 95% confidence intervals (CI). Data were pooled from 10 clinical trials comprising 24 treatment arms, which included 2049 women (1128 women in the active-treated arms and 921 women in the control arms). Meta-analysis of data suggested that anti-oestrogen therapy in women significantly reduced Lp(a) [MD = -5.92% (95%CI: -9.05%,-2.8%)]. This observation is of both clinical and pathophysiological relevance, also in view that the identification of molecular determinants and cellular pathways implicated in Lp(a) synthesis and metabolism is still of concern as a critical issue in lipidology and CV prevention.

Het gebruik van antipsychotica bij therapieresistente obsessief-compulsieve stoornis: een systematische literatuurstudie

The use of antipsychotics in refractory obsessive-compulsive disorder: a systematic review Obsessive-compulsive disorder (OCD) is a psychiatric diagnosis, characterized by obsessions and/or compulsions. The primary pharmacological treatment consists of selective serotonin reuptake inhibitors (SSRIs). In practice, only 40% to 60% of the patients reaches clinical response on SSRI treatment. The objective of this literature study is to make an analysis of the literature concerning the efficacy of antipsychotic augmentation in refractory OCD. A systematic literature search was performed in the PubMed and Web of Science databases. The inclusion criteria (among others) were limited to double-blind, randomized and placebo-controlled clinical studies (RCTs). Twelve RCTs were included: 3 studies comparing risperidone to a placebo, 1 comparing aripiprazole to a placebo, 2 comparing olanzapine to a placebo, 1 comparing paliperidone to a placebo, 4 comparing quetiapine to a placebo and 1 comparing quetiapine to clopramine and a placebo. A descriptive analysis and an overview of the results were drawn up. There is rather limited scientific evidence for augmentation treatment with antipsychotics in refractory OCD. Each of the included trials individually shows a certain positive effect, but they globally have several shortcomings. Especially the heterogeneity between the different trials makes a comparative analysis difficult. There is a need for more well-designed and homogeneous research in this field. Due to the lack of evidence, it is rather premature to formulate recommendations on antipsychotic augmentation.

Efficacy and safety of Tanreqing injection combined with antibiotics against Streptococcus pneumoniae pneumonia: A systematic review and meta-analysis.

Tanreqing injection (TRQ) is a traditional Chinese medicine injection. The goal of this study was to assess the clinical efficacy and safety of TRQ injection in combination with azithromycin or ceftriaxone, as well as azithromycin or ceftriaxone alone, in treating Streptococcus pneumoniae pneumonia (SPP). The randomized controlled trial (RCT) of TRQ injection combined with antibiotics versus antibiotics alone in the treatment of SPP was retrieved from Chinese and English databases (the control group was treated with antibiotics alone, while the experimental group received TRQ injection combined with antibiotics). The retrieval period was from the database's inception through February 2022. The data was extracted using the Cochrane Collaboration Network Quality Evaluation Standards, the methodological quality of the included literature was assessed, and the outcome indicators were calculated using RevMan5.4.1 software. A total of 25 RCTs were collected, including 2057 patients. TRQ injection combined with antibiotics significantly improved clinical efficacy and reduced defervescence time, lung rale disappearance time, cough disappearance time, disappearance time of chest pain, and average hospitalization time when compared to control group, according to meta-analysis results (p < 0.05). In the treatment of SPP, TRQ injection combination with antibiotics can significantly improve the total effect rate when compared to standard western medicine. Due to the low quality of the randomized controlled trials included in this investigation, more high-quality, multi-center, large-sample, prospective, randomized, double-blind clinical studies are needed to confirm the aforementioned conclusions.

Herbals and Plants in the Treatment of Pancreatic Cancer: A Systematic Review of Experimental and Clinical Studies.

Background: Pancreatic cancer represents the most lethal malignancy among all digestive cancers. Despite the therapeutic advances achieved during recent years, the prognosis of this neoplasm remains disappointing. An enormous amount of experimental (mainly) and clinical research has recently emerged referring to the effectiveness of various plants administered either alone or in combination with chemotherapeutic agents. Apart from Asian countries, the use of these plants and herbals in the treatment of digestive cancer is also increasing in a number of Western countries as well. The aim of this study is to review the available literature regarding the efficacy of plants and herbals in pancreatic cancer. Methods: The authors have reviewed all the experimental and clinical studies published in Medline and Embase, up to June 2021. Results: More than 100 plants and herbals were thoroughly investigated. Favorable effects concerning the inhibition of cancer cell lines in the experimental studies and a favorable clinical outcome after combining various plants with established chemotherapeutic agents were observed. These herbals and plants exerted their activity against pancreatic cancer via a number of mechanisms. The number and severity of side-effects are generally of a mild degree. Conclusion: A quite high number of clinical and experimental studies confirmed the beneficial effect of many plants and herbals in pancreatic cancer. More large, double-blind clinical studies assessing these natural products, either alone or in combination with chemotherapeutic agents should be conducted.

Dual Trigger with Gonadotropin Releasing Hormone Agonist and Human Chorionic Gonadotropin of Fresh Autologous Cycles in High Responders: A Systematic Review

Background:The purpose of the current study was to investigate the effect of co-administration of human chorionic gonadotropin (hCG) with gonadotropin releasing hormone agonist (GnRH-a) trigger (dual trigger) in high responders for fresh autologous cycles in order to investigate the pregnancy outcomes and rates of ovarian hyperstimulation syndrome (OHSS) in comparison to GnRH-a trigger alone.Methods:A systematic search was performed in PubMed and Ovid MEDLINE from inception through February 2020. The included materials were case-control, cohort and, cross-sectional studies as well as clinical trials in which the outcomes of dual trigger with GnRH-a were compared for final oocyte maturation in high responders undergoing GnRH-ant cycles.Results:Five retrospective studies were included for this review. Three of the studies showed that the use of dual trigger versus GnRH-a trigger resulted in no statistically significant difference in rates of OHSS while achieving a statistically significant difference in favor of the dual trigger group in ongoing pregnancy rates, early pregnancy loss, and fertilization rates.Conclusion:Currently, there is insufficient evidence to support improved clinical pregnancy rate, fertilization rate, live birth rate, and early pregnancy loss rate by the use of dual trigger versus GnRH-a trigger. Larger double-blind clinical studies are required to properly evaluate the efficacy of this protocol for use in high responders.

Homoeopathic treatment of vitiligo: an open observational pilot study

Background: Vitiligo is a common hypopigmentation disorder with significant psychological impact. An evaluation of homeopathic treatment was performed in individuals with vitiligo in a hospital outpatient clinic in West Bengal, India. Methods: Thirty participants (median age 27 years old, 57% female) were recruited for a prospective open-label pilot study and treated with individualized homeopathic medicines for 6 months. Efficacy was assessed after 3 months and 6 months using Vitiligo Area Scoring Index (VASI) score, Vitiligo European Task Force (VETF) score, and Dermatological Life Quality Index (DLQI) score, which are validated outcome measures evaluating the area, intensity, spread of depigmentation of vitiligo lesions, and quality of life (QoL). Results: A total of 27 participants completed the trial; 3 dropped out. After 6 months of treatment, the median VASI total score improved significantly by 0.1 units (p=0.003), from 0.8 (0.5, 1.5) to 0.7 (0.3, 0.8) on a scale from 0 (no depigmentation) to 100 (completely depigmented). Similarly, the VETF median score improved by 2 units (p=0.0001) from 1 (0, 1) to –1 (–1, 0) and the staging score changed from 1 (1, 2) to 1 (0, 1), p=0.002. The total DLQI median score exhibited significant reduction from 21 (17, 22) to 13.6 (10, 17), change 7.4 (p=0.0001), as also did its components. Conclusions: Individualized homeopathic treatment associated with significant improvement of VASI, VETF and DLQI scores. The extent to which the observed effects were due to placebo needs clarification in future randomized double-blind clinical studies preceded by feasibility studies.&#x0D; Trial Registration: Clinical Trials Registry, India registration number CTRI/2013/08/003879.

Comparison of Rifabutin-Based Versus Rifampin-Based Regimens for the Treatment of Mycobacterium avium Complex: A meta-Analysis Study.

Background: The incidence of Mycobacterium avium complex (MAC) increases as immunosuppressed conditions become more common. MAC's standard treatment regimen includes a macrolide, ethambutol, and a rifamycin, among which rifampin and rifabutin are the most commonly used. Although current guidelines recommend initial therapy for MAC with rifampin, it has been theorized to be less efficacious than rifabutin.Methods: We reviewed the relevant scientific literature published up to February 18, 2020. Statistical analyses were performed with Comprehensive Meta-Analysis Software Version 2.0 (Biostat, Englewood, NJ). The pooled frequency with 95% confidence intervals (CI) was assessed using a random-effect model. We considered P <0.05 as statistically significant for publication bias.Results: After reviewing 3665 records, we identified 24 studies that satisfied the inclusion criteria. Among these studies, 8 had rifabutin in their regimens (rifabutin group) and 16 had rifampin in their regimens (rifampin group). The estimated pooled treatment success rate was found to be 54.7% (95% CI 41.0-67.0%) in rifabutin groups and 67.5% (95% CI 55.7-77.4%) in rifampin groups. There was no evidence of publication bias among the included studies (Egger’s test p-value was 0.7).Conclusion: In this study, it was shown that in comparison to Rifabutin, rifampin has similar treatment success rates in treating MAC. In order to determine the exact preference of each of these drugs, double-blind clinical trial studies are recommended.

The Scientific Case against Prescribing Insulin for Treatment of Type 2 Diabetes

Obesity and type 2 diabetes are related worldwide epidemics which could be erased with the help of governments and medical communities using tools that are readily available today. Prevailing diet recommendations, which are clearly wrong, are a significant cause of both obesity and type 2 diabetes and have led to the current dire situation. According to the CDC, in the United States alone there are currently 34.2 million people with diabetes of which 30 million have type 2 diabetes. In addition, 88 million Americans have prediabetes (defined as an A1c above 5.7%) which will almost certainly progress to type 2 diabetes if not treated and reversed. The cause of insulin resistance, prediabetes and type 2 diabetes is “glucose toxicity” as explained below, and understanding this medical term is paramount to the case against using insulin for type 2 diabetes. Glucose reacts with all the proteins in the body leading to insulin resistance and type 2 diabetes. Unfortunately, nearly 20% of adults with type 2 diabetes are prescribed insulin injections often in conjunction with oral pharmaceutical medications. Because people with with type 2 diabetes have insulin resistance, prescribing insulin is a very bad idea, since they will need an ever-increasing dosage of insulin as time passes, leading to a lifetime of insulin injections. There is only one product, Lysulin (www.lysulin.com), that targets the cause of insulin resistance and has been proven in double blind, placebo controlled clinical studies to improve insulin resistance and better cell function. The recommend initial treatment for type 2 diabetes should be moderate exercise, intermittent fasting, a low calorie, low carbohydrate ketrogenic diet combined with Lysulin before instituting insulin therapy for type 2 diabetes. By adhering to a ketogenic diet that includes moderate exercise, intermittent fasting and nutritional supplementation with Lysulin, diabetes can be halted and quite possibly reversed. Lysulin is a patented nutritional supplement that contains lysine, zinc, and vitamin C [1]. Double-blind placebo-controlled clinical studies have shown the effectiveness of this nutritional supplement [2, 3].

Semaglutide Once-Weekly Persistence and Adherence Versus Other GLP-1 RAs in Patients with Type2 Diabetes in a US Real-World Setting.

IntroductionThe superior efficacy and safety of semaglutide once-weekly (QW), compared with dulaglutide, liraglutide, or exenatide QW, have been demonstrated in the SUSTAIN trials. This study assessed treatment persistence and adherence to semaglutide QW versus dulaglutide, liraglutide, or exenatide QW in a real-world setting.MethodsThis retrospective, database study used Optum’s de-identified Clinformatics® Data Mart Database to identify glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment-naïve adult patients with type 2 diabetes (T2D) initiating semaglutide QW, dulaglutide, liraglutide, or exenatide QW between January 1, 2018 and April 30, 2019. Persistence (time remaining on treatment) was assessed with Kaplan–Meier survival estimates and Cox proportional hazard models. Adherence was assessed using proportion of days covered (PDC) and proportion of patients with PDC > 80%.ResultsOf 56,715 patients included, 3279 received semaglutide QW, 27,891 dulaglutide, 17,186 liraglutide, and 8359 exenatide QW. Patients initiating semaglutide QW were younger and with lower percentage of Medicare coverage than patients initiating the comparators. Persistence at 360 days was significantly higher for semaglutide QW (67.0%) versus dulaglutide (56.0%), liraglutide (40.4%), and exenatide QW (35.5%); p < 0.001 for all comparisons. Compared with semaglutide QW, the discontinuation rate was significantly higher for dulaglutide (hazard ratio [HR] 1.22; 95% confidence interval [CI] 1.13, 1.32; p < 0.001), liraglutide (HR 1.80; 95% CI 1.66, 1.95; p < 0.001), and exenatide QW (HR 2.12; 95% CI 1.96, 2.30; p < 0.001). Adherence to semaglutide QW versus liraglutide at 360 days and to exenatide QW was 39.1% versus 30.0% [p = 0.07] and 27.7% [p = 0.02], respectively. Adherence to dulaglutide at 360 days was numerically higher than semaglutide QW (43.2% versus 39.1%; p = 0.45) but did not reach statistical significance.ConclusionPersistence with semaglutide QW was significantly greater than comparators, while adherence was comparable or greater. Together with earlier results from double-blind clinical studies, these data support semaglutide QW use for treatment of patients with T2D.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01053-7.

Sex-Dependent Association of Vitamin D With Insulin Resistance in Humans.

Animal studies suggested that vitamin D might decrease insulin resistance. Estrogen increased insulin sensitivity and glucose tolerance in rodents. However, sex-specific association of vitamin D with insulin resistance in humans remains unclear. To investigate the sex-dependency of the association of insulin resistance and 25-hydroxyvitamin D [25(OH)D] in a large Caucasian population. Cross-sectional study from out-patients' blood samples with measurements of 25(OH)D and homeostatic model assessment of insulin resistance (HOMA-IR) drawn at exactly the same day (n = 1887). This cohort was divided into 3 groups: (1) group with vitamin D deficiency (n = 1190), (2) group with vitamin D sufficiency (n = 686), and (3) vitamin D excess groups (n = 11); the vitamin D excess group was excluded from further analysis due to the small size. Analysis of the entire study population showed that serum 25(OH)D was inversely associated with HOMA-IR [Spearman correlation coefficient (rs) = -0.19, P < 0.0001]. When considering the vitamin D status, this association was only seen in the vitamin D deficiency group but not in the vitamin D sufficient group. The correlation was sex-dependent: HOMA-IR was inversely correlated with vitamin D in women with vitamin D deficiency (rs = -0.26, P < 0.0001) but not in men with vitamin D deficiency (rs = 0.01, P = 0.714). After multivariate linear regression analysis considering confounding factors, this relationship was again only seen in women. Vitamin D was inversely and independently associated with insulin resistance only in women with vitamin D deficiency. Based on our data, we suggest that in particular vitamin D deficient women might benefit from vitamin D substitution by improving insulin resistance. This, however, needs to be proven in adequately designed double-blind placebo-controlled clinical studies.

Perspectives on the Treatment of Lumbar Disc Degeneration: The Value Proposition for a Cell-Based Therapy, Immunomodulatory Properties of Discogenic Cells and the Associated Clinical Evaluation Strategy.

Low back pain (LBP) is a serious medical condition that affects a large percentage of the population worldwide. One cause of LBP is disc degeneration (DD), which is characterized by progressive breakdown of the disc and an inflamed disc environment. Current treatment options for patients with symptomatic DD are limited and are often unsuccessful, so many patients turn to prescription opioids for pain management in a time when opioid usage, addiction, and drug-related deaths are at an all-time high. In this paper, we discuss the etiology of lumbar DD and currently available treatments, as well as the potential for cell therapy to offer a biologic, non-opioid alternative to patients suffering from the condition. Finally, we present an overview of an investigational cell therapy called IDCT (Injectable Discogenic Cell Therapy), which is currently under evaluation in multiple double-blind clinical trials overseen by major regulatory agencies. The active ingredient in IDCT is a novel allogeneic cell population known as Discogenic Cells. These cells, which are derived from intervertebral disc tissue, have been shown to possess both regenerative and immunomodulatory properties. Cell therapies have unique properties that may ultimately lead to decreased pain and improved function, as well as curb the numbers of patients pursuing opioids. Their efficacy is best assessed in rigorous double-blinded and placebo-controlled clinical studies.

Circadian Variation in Efficacy of Medications.

Although much has been learned about circadian clocks and rhythms over the past few decades, translation of this foundational science underlying the temporal regulation of physiology and behavior to clinical applications has been slow. Indeed, acceptance of the modern study of circadian rhythms has been blunted because the phenomenology of cyclic changes had to counteract the 20th century dogma of homeostasis in the biological sciences and medicine. We are providing this review of clinical data to highlight the emerging awareness of circadian variation in efficacy of medications for physicians, clinicians, and pharmacists. We are suggesting that gold-standard double-blind clinical studies should be conducted to determine the best time of day for optimal effectiveness of medications; also, we suggest that time of day should be tracked and reported as an important biological variable in ongoing clinical studies hereafter. Furthermore, we emphasize that time of day is, and should be considered, a key biological variable in research design similar to sex. In common with biomedical research data that have been historically strongly skewed toward the male sex, most pharmaceutical data have been skewed toward morning dosing without strong evidence that this is the optimal time of efficacy.