Fixed-dose Combination Therapy Research Articles

Polypill protects MAFLD patients from cardiovascular events and mortality: a prospective trial.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a novel term that distinguishes patients at risk of adverse clinical outcomes with higher accuracy than those with non-alcoholic fatty liver disease (NAFLD). Cardiovascular mortality is the leading cause of death in MAFLD. The current literature lacks large-scale prospective studies that address preventive approaches for cardiovascular health in MAFLD. We investigated whether MAFLD patients benefit from a fixed-dose combination therapy (Aspirin, hydrochlorothiazide, atorvastatin, valsartan), known as a Polypill. Analysis was performed (stratified based on MAFLD status) of a clinical trial that included 1596 individuals randomly allocated to an intervention (polypill) or a control (usual care) group. Patients were followed up for five years for any adverse drug reaction, major cardiovascular events, and mortality. Univariable and multivariable survival analyses were performed, and the interaction level was assessed by R programming. Patients who consumed the polypill had significantly lower hazard ratios of major cardiovascular events incidence (HR 0.56, 95% CI 0.41-0.78) and cardiovascular mortality (HR 0.41, 95% CI 0.2-0.86) compared to the control group. Polypill showed significantly better results in lowering cardiovascular events in MAFLD patients than in the general population. (p-value for interaction: 0.028). Moreover, comparing those patients who had high adherence to the Polypill, with the control group, further enhanced the results. Major cardiovascular events are prevented in MAFLD patients who consume the Polypill. MAFLD patients benefit from the Polypill more than the general population.

Linagliptin in Combination with Emblica officinalis Gaertn Improves Glycemic Control through Alleviating Dyslipidemia and Oxidative Stress on Streptozotocin Induced Diabetic Rats

Objectives: Diabetes is a complex chronic metabolic disorder. Today, many diabetes patients are known to supplement their standard therapies with herbal medications that have antidiabetic characteristics. The purpose of the study was to examine the fixed dose combination of linagliptin and Emblica officinalis Gaertn (aq FE) for its hypoglycemic, hypolipidemic, and antioxidant properties.
 Methods: Streptozotocin (45 mg/kg b.w.) was administered intraperitoneally to Wister albino rats to cause diabetes. Linagliptin (5 mg/ 70kg b.w), aqueous fruit extract of Emblica officinalis Gaertn (200 mg/kg b.w.) and fixed dose combination therapy of linagliptin (2.5 mg /70kg b.w) with aqueous fruit extract of Emblica officinalis Gaertn (100 mg/kg b.w) were administered orally once daily for four weeks. After that fasting blood glucose level (FBG), low density lipoprotein (LDL), high density lipoprotein (HDL), total cholesterol (TC) and triglycerides (TG) were measured in serum with streptozotocin (STZ)-induced diabetes. Typical procedures were used to measure the antioxidant activity by the estimation of catalase (CAT) and superoxide dismutase (SOD) activity.
 Results: The combination therapy significantly (p<0.05) reduced the FBG, TC, TG, LDL level in compared to the diabetic control group (p<0.05). Significant (p<0.05) increased of HDL was also observed. The antioxidant activity significantly increased after the administration of fixed dose combination therapy in compared to diabetic control group. These alterations were vastly superior to those of linagliptin with Emblica officinalis Gaertn (aqFE) monotherapy.
 Conclusion: This study suggests that the fixed dose combination therapy of linagliptin and Emblica officinalis Gaertn (aq FE) might be potent on antihyperglycemic antidyslipidemic and antioxidative effect.

New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2022.

Cardiovascular diseases (CVD) remain the leading cause of death worldwide and pharmacotherapy of most of them is suboptimal. Thus, there is a clear unmet clinical need to develop new pharmacological strategies with greater efficacy and better safety profiles. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2022 including the approval of first-in-class drugs that open new avenues for the treatment of obstructive hypertrophic cardiomyopathy (mavacamten), type 2 diabetes mellitus (tirzepatide), and heart failure (HF) independent of left ventricular ejection fraction (sodium-glucose cotransporter 2 inhibitors). We also dealt with fixed dose combination therapies repurposing different formulations of "old" drugs with well-known efficacy and safety for the treatment of patients with acute decompensated HF (acetazolamide plus loop diuretics), atherosclerotic cardiovascular disease (moderate-dose statin plus ezetimibe), Marfan syndrome (angiotensin receptor blockers plus β-blockers), and secondary cardiovascular prevention (i.e. low-dose aspirin, ramipril and atorvastatin), thereby filling existing gaps in knowledge, and opening new avenues for the treatment of CVD. Clinical trials confirming the role of dapagliflozin in patients with HF and mildly reduced or preserved ejection fraction, long-term evolocumab to reduce the risk of cardiovascular events, vitamin K antagonists for stroke prevention in patients with rheumatic heart disease-associated atrial fibrillation, antibiotic prophylaxis in patients at high risk for infective endocarditis before invasive dental procedures, and vutrisiran for the treatment of hereditary transthyretin-related amyloidosis with polyneuropathy were also reviewed. Finally, we briefly discuss recent clinical trials suggesting that FXIa inhibitors may have the potential to uncouple thrombosis from hemostasis and attenuate/prevent thromboembolic events with minimal disruption of hemostasis.

Efficacy and safety of fixed-dose combination of Bilastine-Montelukast in adult patients with allergic rhinitis: a phase III, randomized, multi-center, double-blind, active controlled clinical study

Background Histamine and cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators in allergic rhinitis (AR). Studies involving other combinations of antihistaminics (Levocetirizine) and highly selective leukotriene receptor antagonist (LTA) (Montelukast) combination have shown additive benefits and are widely prescribed for AR. Objective Evaluate the efficacy and safety of Bilastine 20 mg and Montelukast 10 mg fixed-dose combination (FDC) therapy in patients with AR. Methods A randomized, double-blind, comparative, parallel, phase III study was conducted to evaluate efficacy and safety of Bilastine 20 mg and Montelukast 10 mg FDC at 16 tertiary care otolaryngology centres in India. Adult patients with AR for one year with IgE antibody positive and 12-h NSS score >36 in 3 days were randomized to receive either Bilastine 20 mg and Montelukast 10 mg or Montelukast 10 mg & Levocetirizine 5 mg tablets for 4 weeks. The change in total symptom score (nasal symptom scores (NSS) & non-nasal symptom scores (NNSS)) from baseline to week 4 was assessed as primary endpoint. Secondary endpoints included changes in TSS, NSS, NNSS, individual symptom scores (ISS), Rhinoconjunctivitis Quality of Life (RQLQ), discomfort due to rhinitis (VAS), and clinical global impression (CGI) scores. Results The change in mean TSS from baseline to week 4 in Test group (16.6 units) was comparable to reference group (17 units) (p= 0.8876). The difference in change in mean NSS, NNSS and ISS from baseline to day 7, 14, 28 were comparable. RQLQ improved from baseline to Day 28. Significant improvements were observed in discomfort due to AR measured by VAS and CGI scores from baseline to day 14 and 28. The safety and tolerability of patients were comparable between the groups. All adverse events (AEs) were mild to moderate in severity. No patient discontinued due to AEs. Conclusions The FDC of Bilastine 20 mg and Montelukast 10 mg was efficacious and well tolerated in Indian patients with AR.

Prescription Patterns of New Use of Fixed-Dose Combination Inhalers in Patients with Chronic Obstructive Pulmonary Disease: Long-Acting β2 Agonists Plus Long-Acting Muscarinic Antagonists versus Long-Acting β2 Agonists Plus Inhaled Corticosteroids.

The clinical guideline recommends use of long-acting β2 agonists/long-acting muscarinic antagonists (LABA/LAMA) or long-acting β2 agonists/inhaled corticosteroids (LABA/ICS) combination therapies for patients with severe chronic obstructive pulmonary disease (COPD). The fixed-dose combination (FDC) inhalers of LABA/LAMA and LABA/ICS were reimbursed in Taiwan in 2015 and in 2002, respectively. This study aimed to examine prescription patterns of new use of either FDC therapy in real-world practice. We identified COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC between 2015 and 2018 from a population-based Taiwanese database with 2 million, randomly sampled beneficiaries enrolled in a single-payer health insurance system. We compared number of LABA/LAMA FDC and LABA/ICS FDC initiators in each calendar year, from different hospital accreditation levels, and cared for by different physician specialties. We also compared baseline patient characteristics between LABA/LAMA FDC and LABA/ICS FDC initiators. A total of 12,455 COPD patients who initiated LABA/LAMA FDC (n=4019) or LABA/ICS FDC (n=8436) were included. Number of LABA/LAMA FDC initiators increased apparently (n=336 in 2015 versus n=1436 in 2018), but number of LABA/ICS FDC initiators decreased obviously (n=2416 in 2015 versus n=1793 in 2018) over time. The preference of use of LABA/LAMA FDC varied across clinical environments. The proportions of LABA/LAMA FDC initiators were more than 30% in the setting of non-primary care clinics (eg, medical centers) and in the services of chest physicians; but were only less than 10% in primary care clinics and non-chest physicians' services (eg, family medicine physicians). LABA/LAMA FDC initiators appeared to be older, male, to have more comorbidities, and to utilize resources more frequently compared to LABA/ICS FDC initiators. This real-world study found evident temporal trends, variations in healthcare provider, and differences in patient characteristics among COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC.

Estimation of Pediatric Dosage of Antimalarial Drugs, Using Pharmacokinetic and Physiological Approach.

Most of the individuals who die of malaria in sub-Saharan Africa are children. It is, therefore, important for this age group to have access to the right treatment and correct dose. Artemether-lumefantrine is one of the fixed dose combination therapies that was approved by the World Health Organization to treat malaria. However, the current recommended dose has been reported to cause underexposure or overexposure in some children. The aim of this article was, therefore, to estimate the doses that can mimic adult exposure. The availability of more and reliable pharmacokinetic data is essential to accurately estimate appropriate dosage regimens. The doses in this study were estimated using the physiological information from children and some pharmacokinetic data from adults due to the lack of pediatric pharmacokinetic data in the literature. Depending on the approach that was used to calculate the dose, the results showed that some children were underexposed, and others were overexposed. This can lead to treatment failure, toxicity, and even death. Therefore, when designing a dosage regimen, it is important to know and include the distinctions in physiology at various phases of development that influence the pharmacokinetics of various drugs in order to estimate the dose in young children. The physiology at each time point during the growth of a child may influence how the drug is absorbed, gets distributed, metabolized, and eliminated. From the results, there is a very clear need to conduct a clinical study to further verify if the suggested (i.e., 0.34 mg/kg for artemether and 6 mg/kg for lumefantrine) doses could be clinically efficacious.

Comparative application of derivative spectrophotometric and HPLC techniques for the simultaneous determination of lamivudine and tenofovir disoproxil fumarate in fixed-dose combined drugs

BackgroundLamivudine (LAM) and tenofovir disoproxil fumarate (TDF) are part of a fixed-dose combination (FDC) therapy recommended by WHO. Both drugs exhibit similar solubility in many solvent systems and tend to have overlapping spectra with maxima at 260 and 270 nm, respectively, in the UV spectrum—thus making their spectrophotometric assay difficult in FDCs. A third-order derivative (D3, d3A/dλ3) spectrophotometric technique was applied to simultaneously evaluate TDF and LAM in FDC drugs, with amplitudes at 240 and 262.5 nm, respectively. Pharmacopoeia-recommended chromatographic method was also applied for comparative purpose.ResultsMethod performance by the proposed D3 technique showed linearity for LAM and TDF from 2–10 µg mL−1 to 8–24 µg mL−1, respectively (R2 ≥ 0.998), while for HPLC method both drugs ranged from 0.25 to 5.0 µg mL−1 (R2 ≥ 0.999). The intercepts and slopes of the regression equations were ≤ 1.62 × 10−4 and ≤ 3.58 × 10−5, respectively, while calculated standard errors were ≤ 8.04 × 10−5. Limits of detection and quantification for both methods were ≤ 0.46 μg mL−1 and ≤ 1.40 μg mL−1, respectively, for LAM, while corresponding limits for TDF were ≤ 2.61 and ≤ 7.90 μg mL−1. The percentage recovery for both drugs and methods ranged from 94.80 to 100.33%. The amount of LAM and TDF in brands I and II was ≥ 99.59 ± 1.19% and ≥ 99.39 ± 0.63%, respectively, for the proposed D3 spectroscopic method, while corresponding values for the HPLC method were ≥ 99.86 ± 0.50 and ≥ 99.87 ± 0.32%. Statistically, both methods were adjudged to have no significant difference at 95% confidence level as the student’s t-test values; experimental paired t- and F-test values were found satisfactory.ConclusionThe D3 spectrophotometric technique was time saving, cheap, simple and more environmental friendly and shows reliability, precision and accuracy and could be used for routine analysis of FDCs where HPLC is not available.Graphical abstract

Russian experience in using a combination of fixed doses of donepezil and memantine in the treatment of Alzheimer's disease as an observational non-interventional multicenter program

To evaluate the efficacy, safety, and compliance to therapy with Mioreol, first used as part of routine clinical practice in patients with moderate-to-severe dementia due to AD. The study was conducted as a non-interventional observational program. The work was performed on a group of 48 patients with moderate-to-severe AD aged from 60 to 90 years (median age 74 [69; 77]). The therapeutic dose of Mioreol was 10 mg donepezil + 20 mg memantine, the drug was taken orally, once a day at the same time, regardless of meals. The duration of the course of therapy was 24 weeks. The effects of the drug were assessed using the MMSE, ADAS-Cog, NPI, and CGI scales before the start of therapy and by the end of 12 and 24 weeks of treatment. The use of Mioreol in six-month therapy of AD patients with moderate-to-severe dementia improved not only cognitive but also a wide range of non-cognitive mental disorders. There was an improvement in the CGI-C scale in more than 50% of included patients, positive dynamics on the ADAS-cog scale (6.5 points reduction in total score) and reduction of non-cognitive mental disorders on the NPI scale (4 points reduction in total score). Fixed-dose combination therapy with Mioreol is an effective and well-tolerated treatment option for patients with moderate-to-severe AD. A combination of fixed-dose therapeutic doses of donepezil and memantine is potentially more appropriate than the simultaneous use of two recommended drugs for the treatment of AD, which will improve treatment adherence in patients with moderate to severe AD.

The outcome of different forms and regiments of antituberculous drugs in Assiut Governorate

Introduction The prescription of effective and well-tolerated antituberculosis (TB) treatment regimen is an important step in the management of TB. Objective To compare the outcome of fixed-dose combination (FDC) therapy versus standard treatment (ST) in treatment of pulmonary tuberculosis (PTB) and extrapulmonary TB in Assiut Governorate. Patients and methods In this prospective cross-sectional analytic study, 120 patients were included. Overall, 60 had PTB based on sputum-positive acid-fast bacilli, and 60 had extrapulmonary TB based on biopsy or culture from the affected sites. Patients were classified into two groups: 80 patients received FDC in the form of four-drug combinations in the intensive phase and the two-drug combination therapy in the continuation phase (group 1) and 40 patients received ST in the form of four separate drugs in the intensive phase and the two separate drugs in the continuation phase (group 2). Follow-up of clinical data, laboratory markers, sputum conversion in PTB during the course of treatment, drug tolerance, compliance, and developing of adverse effect was done in both groups. Results There is no statistically significant difference between both groups regarding improvement of the fever and anorexia and weight loss (P > 0.05 for each). Moreover, there are no statistically significant changes in the sputum conversion between both groups after 2, 4, and 6 months, respectively. There is a statistically significant increase in the percentage of the patients, with increase of alanine aminotransferase, aspartate aminotransferase, and bilirubin level along the course of the treatments in patients receiving FDC and ST (P < 001) but still within normal limits, and there is no need to stop or change the therapy. No significant difference between the two groups regarding the adverse effects such as nausea, vomiting, anorexia, blurred vision, peripheral neuropathy, arthralgia, and skin rash is recorded. Conclusion Both FDC and ST have comparable results, with no superiority of either one over the other.

Patients’ experiences of treatment migration from ART triple pill to fixed-dose combination therapy in Ngaka Modiri Molema District, North West Province, South Africa

Patients’ experiences of treatment migration from ART triple pill to fixed-dose combination therapy in Ngaka Modiri Molema District, North West Province, South Africa

Evaluating the efficacy of combination therapy of Pregabalin plus Nortriptyline in the management of PHN patients: A randomized controlled study

Background: Post Herpetic Neuralgia (PHN) is chronic neuropathic pain. It is a complication of herpes zoster and negatively impacts the patient’s quality of life and physical, occupational, social and psychosocial abilities due to unceasing pain. As pain management remains the cornerstone in treating such patients, this study was undertaken to determine the efficacy of fixed-dose combination therapy of Pregabalin plus Nortriptyline in PHN. Methods: The study, which was a follow-up, randomised, single-blind, controlled study, included a total of 40 patients who had chronic pain for at least 12 weeks with a Numeric rating scale (NRS) score of 5/10 or above. Group A (n=20) received pregabalin 75 mg plus nortriptyline 10 mg, and group B (n=20) received pregabalin 75 mg for a total of 12 weeks. Pain intensity and severity (using NRS and Global Perceived Effect), pain interference with sleep (using Numeric Rating Scale-Sleep (NRS-Sleep) and Pain Detect Questionnaire (PDQ)), pain quality (using Neuropathic Pain Symptom Inventory (NPSI)), and quality of life (QoL) (using Short Form-12 (SF-12) questionnaire) at the end of the first, second, fourth, eighth and twelfth week were measured. Results: Significant (p &lt;0.05) decline in Numeric rating scale (NRS) scores, NRS sleep and NPSI scores in group A along with significant (p &lt;0.05) improvement in PDQ, GPE and QoL scores, when compared to group B. Conclusion: The combination of pregabalin plus nortriptyline therapy has better patient outcomes in PHN as compared to pregabalin monotherapy.

EE602 Budget Impact Analysis of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate for COPD in the Italian Healthcare System

Budesonide/glycopyrronium/formoterol fumarate dihydrate 320/14.4/10 μg (BGF) triple therapy is approved as maintenance treatment in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) in the European Union. In a published network meta-analysis (Bourdin et al. Adv Ther 2021:38;3089–3112), BGF demonstrated comparable efficacy to other fixed-dose combination therapies and open-triple combinations in terms of exacerbation rate reductions. This study aimed to evaluate the cost impact of BGF entry on the Italian healthcare system for managing this patient population.

Reviewing the evidence surrounding preservative-free tafluprost/timolol fixed-dose combination therapy in open-angle glaucoma and ocular hypertension management: a focus on efficacy, safety, and tolerability

ABSTRACT Introduction Elevated intraocular pressure (IOP) is the most important modifiable risk factor for irreversible sight loss in open-angle glaucoma (OAG). The topical fixed-dose combination (FC) of preservative-free (PF) tafluprost (0.0015%) and timolol (0.5%) (tafluprost/timolol) is among the second-line IOP-lowering options for OAG and ocular hypertension (OHT). Areas covered PubMed searches identified publications reporting key evidence from randomized controlled trials (RCTs) and real-world studies examining the safety, tolerability, and IOP-lowering efficacy of PF tafluprost/timolol FC therapy in OAG/OHT management. Expert opinion Glaucoma patients are more likely to have ocular surface disease, and treatment should be individualized so that target response may be achieved while considering tolerability and quality of life, according to European Glaucoma Society guidelines. PF FC therapies, such as PF tafluprost/timolol FC, avoid ocular surface exposure to toxic preservative agents and reduce the required number of treatment administrations. These properties may enhance treatment tolerability and adherence, resulting in improved IOP-lowering efficacy and disease control. Treatment outcomes from RCTs and real-world studies examining PF tafluprost/timolol FC therapy support this hypothesis, with significant IOP reductions and/or improvements in tolerability parameters demonstrated, regardless of the prior topical therapy used and even when switched directly to PF tafluprost/timolol FC treatment (without washout).

Real-World Evidence Evaluation on the Lipid Profile, Therapeutic Goals, and Safety of the Fixed-Dose Combination of Rosuvastatin/Ezetimibe (Trezete®) in Dyslipidemia Patients.

Introduction Cardiovascular diseases are the leading cause of death worldwide. The combination of statins and cholesterol-absorption inhibitors promotes the decrease in risk factors, such as high concentrations of LDL (low-density lipoproteins). The aim of the study was to evaluate changes in the lipid profile and the effect on therapeutic goals, as well as the safety of dyslipidemia patients treated with Rosuvastatin/Ezetimibe (Trezete®). Materials and Methods A real-world evidence study was conducted with retrospective data collection through a review of clinical records from dyslipidemia patients treated with Trezete® in routine medical practice. Clinical records included results of biochemical markers before treatment and at least one follow up between weeks 8 and 16. Results The study included 103 patients' clinical records (55.4% men) with a mean age of 56.0 ± 13.0 years. More than 57% of the patients had mixed dyslipidemia and a median disease progression of 3.1 (IQR, 1.5; 9.1) years. Regarding LDL concentrations, 72.8% of the patients achieved therapeutic goals according to cardiovascular risk (CVR), which was statistically significant. Similarly, 94.1% achieved goals for total cholesterol (<200 mg/dL) and 56.0% for triglycerides (<150 mg/dL), a p value <0.001. No cardiovascular events were observed. Conclusion Trezete® shows an important clinical impact on CVR-related target markers during the treatment of dyslipidemia patients. It is relevant to mention that a significant percentage of patients achieved therapeutic goals during the first months of treatment. Fixed-dose combination therapy has shown to be as safe as monotherapy treatment. ClinicalTrials.gov Identifier: NCT04862962.

Comparison of Netarsudil/Latanoprost Therapy with Latanoprost Monotherapy for Lowering Intraocular Pressure: A Systematic Review and Meta-analysis.

PurposeNetarsudil is a Rho kinase inhibitor and the first new class of clinically useful ocular hypotensive agents. In this study, we conducted a systematic literature review and meta-analysis to summarize and synthesize the available evidence on the efficacy and safety of fixed-dose combination (FDC) therapy with netarsudil/latanoprost in patients with glaucoma.MethodsWe identified relevant studies in PubMed, Ovid Medline, Embase, and Cochrane Central until April 2021. The quality of the studies and the level of evidence were assessed using the Risk of Bias tool. Efficacy was measured as the mean difference in reducing intraocular pressure (IOP), and safety was assessed by the risk of conjunctival hyperemia (CH) due to FDC therapy, netarsudil monotherapy, or latanoprost monotherapy.ResultsFour studies met the predefined eligibility criteria and were included in the meta-analysis. The mean difference in the reduction in IOP after 2 weeks and 4 to 6 weeks of drug administration was −2.41 mmHg (95% confidence interval [CI], −2.95 to −1.87) and −1.77 mmHg (95% CI, −2.31 to −1.87), respectively, in patients receiving FDC therapy versus those receiving latanoprost monotherapy. On the other hand, latanoprost monotherapy had a greater effect in reducing IOP than netarsudil monotherapy after 4 to 6 weeks of administration (mean difference, 0.95 mmHg; 95% CI, 0.43 to 1.47). The risk of CH was significantly higher with both FDC therapy and netarsudil monotherapy compared to latanoprost monotherapy in week 12, where the relative ratio was 3.01 (95% CI, 1.95 to 4.66) and 2.33 (95% CI, 1.54 to 3.54), each.ConclusionsNetarsudil/latanoprost FDC therapy has a significantly greater effect on reducing IOP than latanoprost alone. The symptoms of CH were mostly mild, and only a few glaucoma patients discontinued the medication owing to CH in earlier clinical trials. Therefore, it would be beneficial to consider the administration of netarsudil/latanoprost FDC therapy in patients with glaucoma.

Safety and effectiveness of empagliflozin and linagliptin fixed-dose combination therapy in Japanese patients with type 2 diabetes: final results of a one-year post-marketing surveillance study

ABSTRACT Background Fixed-dose combination (FDC) of the sodium-glucose co-transporter 2 inhibitor empagliflozin and the dipeptidyl peptidase-4 inhibitor linagliptin was approved for type 2 diabetes (T2D) treatment in Japan in 2018. We conducted a post-marketing surveillance study of empagliflozin/linagliptin FDC in routine clinical practice in Japan. Research design and methods This one-year, prospective, multicenter, observational study investigated the safety and effectiveness of empagliflozin/linagliptin FDC in Japanese patients with T2D. The primary outcome was incidence of adverse drug reactions (ADRs). Results Among 1146 patients, mean (SD) age was 63.8 (12.8) years and 22.08% were aged ≥75 years. Mean (SD) glycated hemoglobin (HbA1c) was 7.66% (1.21); fasting plasma glucose (FPG) was 142.90 mg/dl (43.75). ADRs were experienced by 32 (2.79%) patients (1 serious ADR); ADRs of important identified risk included urinary tract infection (7 patients [0.61%]), hypoglycemia (2 [0.17%]), ketoacidosis (0), genital infection (1 [0.09%]), and volume depletion (1 [0.09%]). Overall mean (SD) change from baseline in body weight, HbA1c, and FPG were −1.08 kg (3.21), −0.39% (1.11), and −7.90 mg/dl (39.12), respectively. Conclusions Empagliflozin/linagliptin FDC was effective and generally well tolerated in Japanese patients with T2D; no new safety concerns were identified. Trial Registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03761797)

Hypertension Treatment in Nigeria (HTN) Program: rationale and design for a type 2 hybrid, effectiveness, and implementation interrupted time series trial

BackgroundHypertension is the most common cardiovascular disease in Nigeria and contributes to a large non-communicable disease burden. Our aim was to implement and evaluate a large-scale hypertension treatment and control program, adapted from the Kaiser Permanent Northern California and World Health Organization HEARTS models, within public primary healthcare centers in the Federal Capital Territory, Nigeria.MethodsA type 2 hybrid, interrupted time series design was used to generate novel information on large-scale implementation and effectiveness of a multi-level hypertension control program within 60 primary healthcare centers in the Federal Capital Territory, Nigeria. During the formative phase, baseline qualitative assessments were held with patients, health workers, and administrators to inform implementation package adaptation. The package includes a hypertension patient registry with empanelment, performance and quality reporting, simplified treatment guideline emphasizing fixed-dose combination therapy, reliable access to quality essential medicines and technology, team-based care, and health coaching and home blood pressure monitoring. Strategies to implement and adapt the package were identified based on barriers and facilitators mapped in the formative phase, previous implementation experience, mid-term qualitative evaluation, and ongoing stakeholder and site feedback. The control phase included 11 months of sequential registration of hypertensive patients at participating primary healthcare centers, followed by implementation of the remainder of the package components and evaluation over 37 subsequent, consecutive months of the intervention phase.The formative phase was completed between April 2019 and August 2019, followed by initiation of the control phase in January 2020. The control phase included 11 months (January 2020 to November 2020) of sequential registration and empanelment of hypertensive patients at participating primary healthcare centers. After completion of the control phase in November 2020, the intervention phase commenced in December 2020 and will be completed in December 2023.DiscussionThis trial will provide robust evidence for implementation and effectiveness of a multi-level implementation package more broadly throughout the Federal Capital Territory, which may inform hypertension systems of care throughout Nigeria and in other low- and middle-income countries. Implementation outcome results will be important to understand what system-, site-, personnel-, and patient-level factors are necessary for successful implementation of this intervention.Trial registrationClinicalTrials.gov NCT04158154. The trial was prospectively registered on November 8, 2019.

Comparing the Efficacy and Safety Profile of Triple Fixed-Dose Combinations in COPD: A Meta-Analysis and IBiS Score.

Background: Triple fixed-dose combination (FDC) therapy is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations and/or symptoms not controlled by dual FDCs. Since no randomized controlled trials (RCTs) have directly compared the different inhaled corticosteroid/long-acting β2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) FDCs, we performed a meta-analysis to compare the impact of the current available ICS/LABA/LAMA FDCs in COPD. Methods: A meta-analysis was performed by connecting beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide or glycopyrrolate (BDP/FOR/GLY), budesonide (BUD)/GLY/FOR, and fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) FDCs via ICS/LABA or LABA/LAMA FDCs arms. The safety and efficacy profiles were investigated, and the Implemented Bidimensional Surface under the cumulative ranking curve analysis (IBiS) was carried out. Protocol registration: CRD42022301189. Results: Data from 21,809 COPD patients were extracted from the ETHOS, IMPACT, KRONOS, and TRILOGY studies. No significant (p > 0.05) differences were detected across the triple FDCs with respect to the risk of exacerbation, trough forced expiratory volume in the first second (FEV1), transition dyspnea index (TDI), St. George’s Respiratory Questionnaire (SGRQ), risk of serious adverse events (SAEs), cardiovascular (CV) SAEs, pneumonia, and all-cause mortality. According to IBiS score, BDP/FOR/GLY 200/12/25 µg twice daily (BID) was the FDC reporting the best combined efficacy/safety profile (area 41.41%), although FF/UMEC/VI 100/62.5/25 µg once daily (QD) showed the greatest efficacy profile (50.54%). The protection against mortality related to the dose of ICS. Conclusions: All triple FDCs are effective and safe in COPD regardless of the regimen of administration (twice daily vs. once daily), with no relevant difference in the risk of CV SAEs and pneumonia.

Long-term clinical outcomes of oral antidiabetic drugs as fixed-dose combinations: A nationwide retrospective cohort study.

To compare treatment patterns and clinical outcomes of single-pill fixed-dose combination (FDC) and two-pill combination (TPC) therapies using real-world data. We conducted a nationwide retrospective cohort study using South Korea's healthcare database (2002-2015). We identified two cohorts of incident patients with type 2 diabetes who initiated FDC or TPC therapy within 4 months of their first prescription for metformin or sulphonylurea. We examined persistence and adherence patterns and the clinical outcome of a composite endpoint of death or hospitalization for acute myocardial infarction, heart failure or stroke and compared the differences in treatment patterns and clinical outcomes using Cox models. Of 5143 and 10 973 patients who initiated FDC and TPC therapy, respectively, we identified 5143 patient pairs after propensity score matching. The FDC group exhibited greater median time to treatment discontinuation (163 vs. 146 days), and proportion of days covered at 12 months (mean 0.60 vs. 0.57, P < .0001) and at 24 months (0.53 vs. 0.51, P=.014) than the TPC group. The FDC group, compared with the TPC group, had reduced risks of the composite clinical outcome (hazard ratio 0.86, 95% confidence intervals 0.77-0.97) and hospitalization for stroke (0.80, 0.67-0.96). FDC therapy may provide favourable cardiovascular benefits, especially reducing the risk of hospitalization for stroke, and has better medication adherence among patients with type 2 diabetes.

A comparison of country-level data from the VISIONARY study examining treatment outcomes with preservative-free tafluprost/timolol fixed-dose combination therapy

Objective Analysis and comparison of country-level data from the VISIONARY study, examining treatment outcomes with the topical fixed-dose combination of preservative-free tafluprost (0.0015%) and timolol (0.5%) (PF tafluprost/timolol FC) in adults with open-angle glaucoma (OAG) and ocular hypertension (OHT) who were insufficiently treated with or unable to tolerate either beta-blocker or prostaglandin analogue (PGA) topical monotherapy. Methods A European, prospective, observational study was conducted in 11 countries. Adults with OAG/OHT were switched to the PF tafluprost/timolol FC from either PGA or beta-blocker topical monotherapy. Statistical analysis examined changes in mean standard deviation (SD) intraocular pressure (IOP) from baseline at Week 4, Week 12 and Month 6. Data were documented for each eye separately at baseline and during follow up visits, with the eye reported to have the higher IOP (mmHg), as measured using Goldmann applanation tonometry, being selected for analysis (study eye). Country-level subanalysis examined outcomes by prior monotherapy, diagnosis and timing of dosing for those countries recruiting ≥20 patients (Country-level Subanalysis Population). Two-sided paired t-test was used to assess significance regarding mean IOP reduction from baseline and a compound symmetry covariance model was used in cross-country comparisons regarding variation in IOP change from baseline. Treatment-related adverse events (AEs) were evaluated. Results Mean (SD) age among patients recruited to the VISIONARY study ranged between 63.9 (11.8) and 72.4 (10.6) years across all countries. The majority of participants (>50%) were female in each country. The Country-level Subanalysis Population included 551 eyes. Mean (SD) IOP was significantly reduced from baseline in each country at Week 4, Week 12 and Month 6 (p < .0001). Mean IOP reduction at Month 6 ranged from 5.0 mmHg (22.6%, Hungary) to 7.8 mmHg (31.8%, Latvia) and varied significantly between countries (p < .001). The greatest reductions were in Latvia and Russia, where baseline IOP was highest. Country-level IOP reductions were significant irrespective of prior monotherapy, diagnosis or dosing time (p < .0001). Most treatment-related AEs occurred in the UK (26 events, 73% mild). One serious AE was reported (Russia, status asthmaticus). Tolerability with PF tafluprost/timolol FC therapy was rated as good/very good by most patients (85.7–100%) in all countries. Conclusion Subanalysis of VISIONARY study data revealed significant IOP reductions following a switch to the PF tafluprost/timolol FC from either PGA or beta-blocker topical monotherapy. Cross-country variation was likely due to baseline IOP differences. Within country, outcomes were consistent regardless of diagnosis, dosing or prior monotherapy. Treatment was generally well tolerated.