Substantial Effects of Luseogliflozin Revealed by Analyzing Responses to Postprandial Hyperglycemia: Post Hoc Subanalyses of a Randomized Controlled Study

Introduction

In our previous study investigating effects of luseogliflozin, a sodium–glucose cotransporter 2 inhibitor, on 24-h glycemic variability by continuous glucose monitoring (CGM), luseogliflozin elicited parallel downward shifts in fasting and postprandial glucose levels. However, further review of individual patients’ data revealed that postprandial hyperglycemia was not reduced in some patients, while preprandial glucose was ameliorated in most patients. Therefore, we divided patients into two groups according to their postprandial glucose responses and conducted a post hoc subanalyses to elucidate which factors contributed to the differential effects of luseogliflozin.

Methods

Thirty-four Japanese type 2 diabetic patients in our previous randomized, double-blind, placebo-controlled, crossover study with 7-day luseogliflozin administration were divided into postprandial glucose responders (PGR, n = 23, ameliorated peak glucose) and postprandial glucose non-responders (PGNR; n = 11, non-ameliorated peak glucose). Baseline characteristics, variations in CGM-measured 24-h glucose levels, and other pharmacodynamic variabilities were compared.

Results

Baseline characteristics did not differ significantly between groups. Placebo-subtracted peak glucose was significantly lowered in PGR and significantly increased in PGNR (?43.8 and 17.9 mg/dL; both p < 0.05). Luseogliflozin significantly lowered “lowest glucose” (defined as the lowest level measured throughout a 24-h period) similarly in PGR and PGNR (?19.2 and ?24.0 mg/dL; both p < 0.05), significantly reduced the mean amplitude of glucose excursions in PGR (?15.50 mg/dL; p < 0.05), and increased the area under the curve for plasma glucagon over 24 h in PGNR (median difference vs. placebo: 240 pg/mL h; p < 0.05). Luseogliflozin increased urinary glucose excretion (UGE) and decreased serum insulin by similar magnitudes in both groups.

Conclusions

Luseogliflozin diminished glucose fluctuations in most patients by lowering peak glucose to a greater extent than lowest glucose. Luseogliflozin may also lower lowest glucose in patients whose peak glucose was not ameliorated despite increasing UGE. The glucagon increase in PGNR might explain its hypoglycemic effect on postprandial glucose.

Funding

Taisho Pharmaceutical Co., Ltd, Tokyo, Japan.

Trial Registration

JapicCTI-142548.

     

Effectiveness and Persistence of Liraglutide Treatment Among Patients with Type 2 Diabetes Treated in Primary Care and Specialist Settings: A Subgroup Analysis from the EVIDENCE Study,a Prospective, 2-Year Follow-up,Observational, Post-Marketing Study

Introduction

The objective of this subgroup analysis is to investigate the effectiveness of liraglutide in people with type 2 diabetes (T2D) treated within the primary care physician (PCP) and specialist care settings.

Methods

EVIDENCE is a prospective, observational study of 3152 adults with T2D recently starting or about to start liraglutide treatment in France. We followed patients in the PCP and specialist settings for 2 years to evaluate the effectiveness of liraglutide in glycemic control and body weight reduction. Furthermore, we evaluated the changes in combined antihyperglycemic treatments, the reasons for prescribing liraglutide, patient satisfaction, and safety of liraglutide in these two treatment settings.

Results

After 2 years of follow-up, 477 out of 1209 (39.0%) of PCP and 297 out of 1398 (21.2%) of specialist-treated patients still used liraglutide and maintained the glycated hemoglobin (HbA_1c) target of <7.0%. Significant reductions from baseline were observed in both PCP- and specialist-treated cohorts in mean HbA_1c (?1.22% and ?0.8%, respectively), fasting plasma glucose (FPG) concentration (?39 and ?23 mg/dL), body weight (?4.4 and ?3.8 kg), and body mass index (BMI) (?1.5 and ?1.4 kg/m²), all p < 0.0001. Reductions in HbA_1c and FPG were significantly greater among PCP- compared with specialist-treated patients, p < 0.0001 for both. Patient treatment satisfaction was also significantly increased in both cohorts. Reported gastrointestinal adverse events were less frequent among PCP-treated patients compared with specialist-treated patients (4.5% vs. 16.1%).

Conclusion

Despite differences in demography and clinical characteristics of patients treated for T2D in PCP and specialty care, greater reduction in HbA_1c and increased glycemic control durability were observed with liraglutide in primary care, compared with specialist care. These data suggest that liraglutide treatment could benefit patients in primary care by delaying the need for further treatment intensification.

Trial Registration

ClinicalTrials.gov identifier, NCT01226966.

Funding

Novo Nordisk A/S.

     

Pharmacokinetics and Safety of DS-8500a,an Antidiabetic Drug,in Japanese Subjects with Hepatic or Renal Impairment: A Single-Center,Open-Label,Single-Dose Study

Introduction

The pharmacokinetics, safety, and tolerability of DS-8500a (a G protein receptor 119 agonist) up to 100 mg have been investigated in healthy Japanese adults. The objective of this study was to evaluate the effects of hepatic or renal impairment on the pharmacokinetics of a single 25-mg oral dose of DS-8500a.

Methods

This single-center, open-label study enrolled subjects into eight groups according to hepatic function (normal; mild or moderate impairment) and renal function [normal; mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]. Drug concentrations were measured by liquid-chromatography tandem mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. Adverse events (AEs) were evaluated for safety.

Results

The hepatic and renal groups enrolled 15 and 30 subjects, respectively. Pharmacokinetic parameters of DS-8500a were comparable between the normal hepatic function and mild hepatic impairment groups, but the mean area under the concentration–time curve (AUC) was 1.37-fold higher, and the half-life was longer in the moderate hepatic impairment group compared with the normal hepatic function group. The maximum concentration (C_max) and AUC values were 0.704- and 0.609-fold lower, respectively, in the ESRD group compared with the values in the other renal impairment groups; no clear differences in AUC and time to C_max were observed in the normal function and mild, moderate, and severe renal impairment groups. There was no relationship between apparent total body clearance and estimated glomerular filtration rate. The incidence of AEs was similar among all groups.

Conclusion

DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD.

Trial registration

Japic CTI-No. 163135.

Funding

Daiichi Sankyo Co. Ltd., Tokyo, Japan.

     

Effects of the SGLT-2 Inhibitor Empagliflozin on Renal Tissue Oxygenation in Non-Diabetic Subjects: A Randomized,Double-Blind,Placebo-Controlled Study Protocol

Introduction

Empagliflozin is an SGLT-2 inhibitor (SGLT-2i) which belongs to a new class of hypoglycemic drugs with the unique property of decreasing blood glucose independently from insulin, through an increase in glycosuria. In addition to decreasing cardiovascular morbidity and mortality, empagliflozin has nephroprotective properties in high cardiovascular risk patients with type 2 diabetes. Decreased hyperfiltration and shifting towards more favorable renal fuel energetics with improved renal oxygenation may explain some of these properties. With this study, we propose to explore the effects of empagliflozin on renal tissue oxygenation using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI).

Methods

This is a double-blind, randomized, placebo-controlled study examining the acute and chronic renal effects of empagliflozin 10 mg. The primary outcome is the effects of empagliflozin on renal tissue oxygenation as measured by BOLD-MRI. The secondary outcomes include the effects of empagliflozin on tubular function, 24 h blood pressure control, and the influence of body mass index (BMI) on the renal response to empagliflozin. Fifteen normal weight, 15 overweight, and 15 obese non-diabetic subjects (men and women) will be recruited. Each participant will undergo 24 h urine collections and blood pressure measurements on day ? 1, followed by an investigation day at the study center with blood and urine sampling and renal BOLD-MRI measurements before and 180 min after the administration of 10 mg empagliflozin or placebo. This sequence of measurements will be repeated after 1 month of a daily empagliflozin or placebo intake. To investigate renal oxygenation, the renal cortical and medullary R2*, as a marker of oxygenation, will be assessed by BOLD-MRI under standardized hydration conditions: the higher R2*, the lower oxygenation.

Conclusion

SGLT-2 inhibitors have a profound effect on renal physiology. This is an important study that will explore for the first time whether inhibiting SGLT-2 with empagliflozin in healthy volunteers affects renal tissue oxygenation as determined by BOLD-MRI.

Funding

Boehringer Ingelheim Pharma GmbH & Co.

Trial registration

ClinicalTrials.gov identifier, NCT03093103.

     

Short-Term Effects of a Combined Nutraceutical on Lipid Level,Fatty Liver Biomarkers,Hemodynamic Parameters,and Estimated Cardiovascular Disease Risk: A Double-Blind,Placebo-Controlled Randomized Clinical Trial

Introduction

There is a growing interest in nutraceuticals improving cardiovascular risk factor levels and related organ damage.

Methods

This double-blind, placebo-controlled randomized clinical trial aims to compare the effect of a combined nutraceutical containing red yeast rice (10 mg), phytosterols (800 mg), and l-tyrosol (5 mg) on lipid profile, blood pressure, endothelial function, and arterial stiffness in a group of 60 patients with polygenic hypercholesterolemia resistant to Mediterranean diet.

Results

After 8 weeks of treatment, when compared to the placebo group, the active treated patients experienced a more favorable percentage change in total cholesterol (?16.3% vs 9.9%, P < 0.001 always), LDL-C (?23.4% vs ?13.2%, P < 0.001 always), and hepatic steatosis index (?2.8%, P < 0.01 vs ?1.8%, P < 0.05). Moreover, ALT (?27.7%, P < 0.001), AST (?13.8%, P = 0.004), and serum uric acid (?12.3%, P = 0.005) were reduced by the tested nutraceutical compound both compared to randomization and to placebo, which did not affect these parameters (P < 0.01 for all). Regarding the hemodynamic parameters, there was a decrease of systolic blood pressure (?5.6%) with the active treatment not observed with placebo (P < 0.05 vs baseline and placebo) and endothelial reactivity improved, too (?13.2%, P < 0.001 vs baseline). Consequently, the estimated 10-year cardiovascular risk score improved by 1.19% (SE 0.4%) (P = 0.01) in the nutraceutical-treated patients.

Conclusion

The tested nutraceutical association is able to improve the positive effects of a Mediterranean diet on a large number of CV risk factors and consequently of the estimated CV risk.

Trial registration

ClinicalTrials.gov identifier NCT02492464.

Funding

IBSA Farmaceutici.

     

Clear cell renal cell carcinoma: identifying the gain of chromosome 20 on multiphasic MDCT

Purpose

To investigate whether multiphasic multidetector computed tomography (MDCT) enhancement can help identify the gain of chromosome 20 in clear cell renal cell carcinomas (RCCs), a rare prognostically significant cytogenetic abnormality.

Methods

With the Institutional Review Board approval, we queried our institution’s pathology database to derive a cohort of 52 cases of clear cell RCC with preoperative four-phase renal mass protocol MDCT and karyotypes of the resected specimens during a 10-year period. Each lesion was evaluated for absolute and relative (compared to contralateral normal renal cortex) attenuations in each phase. Relative attenuation was calculated as [(lesion attenuation ? cortex attenuation)/cortex attenuation] × 100. The absolute and relative attenuations were compared using t-tests.

Results

Clear cell RCCs with the gain of 20 had significantly less nephrographic and excretory phase enhancement than clear cell RCCs without the gain of 20 (86.4 HU vs. 111.4 HU, p = 0.007; 70.0 HU vs. 89.4 HU, p = 0.003; respectively). Additionally, the relative nephrographic and excretory phase attenuations of clear cell RCCs with the gain of 20 were significantly less than that of clear cell RCCs without the gain of 20 (?52.7 vs. ?34.7, p = 0.002; ?44.9 vs. ?31.1, p = 0.005; respectively).

Conclusion

Multiphasic MDCT enhancement may assist in identifying the gain of chromosome 20 in clear cell RCCs, if validated in a large prospective trial.

     

Effects of mannitol alone and mannitol plus furosemide on renal oxygen consumption,blood flow and glomerular filtration after cardiac surgery

Objective

Imbalance of the renal medullary oxygen supply/demand relationship can cause hypoxic medullary damage and ischaemic acute renal failure (ARF). The use of mannitol for prophylaxis/treatment of clinical ischaemic ARF is controversial and the effect of mannitol on renal oxygenation in man has not yet been investigated. We evaluated the effects of mannitol on renal oxygen consumption (RVO₂)_, renal blood flow (RBF) and glomerular filtration rate (GFR) in postoperative patients.

Design

Prospective interventional study.

Setting

University hospital cardiothoracic ICU.

Patients

Ten uncomplicated mechanically ventilated and sedated postcardiac surgery patients with preoperatively normal renal function.

Interventions

Mannitol infusion (225 mg/kg + 75 mg/kg/h) and combined mannitol and furosemide infusion (0.25 mg/kg + 0.25 mg/kg/h).

Measurements and results

Systemic haemodynamics were evaluated by a pulmonary artery catheter. RBF and GFR were measured by the renal vein thermodilution technique and by renal extraction of ⁵¹Cr–EDTA, respectively. Mannitol increased urine flow (60%), GFR (20%) and filtration fraction (FF) (20%) with no change in RBF. This was accompanied by an increase in renal sodium reabsorption (18%), RVO₂ (19%) and renal oxygen extraction (21%). When combined with mannitol, furosemide normalised sodium reabsorption, RVO₂, renal oxygen extraction with no change in RBF, while GFR and FF were still elevated compared to control.

Conclusions

In patients with normal renal function, mannitol increases GFR, which increases tubular sodium load, sodium reabsorption and RVO₂ after cardiac surgery. The lack of effect on RBF, indicates that mannitol impairs the renal oxygen supply/demand relationship. Furosemide normalised renal oxygenation when combined with mannitol.

     

Methoxyflurane Analgesia in Adult Patients in the Emergency Department: A Subgroup Analysis of a Randomized,Double-blind,Placebo-controlled Study (STOP!)

Introduction

Acute pain remains highly prevalent in the Emergency Department (ED) setting. This double-blind, randomized, placebo-controlled UK study investigated the efficacy and safety of low-dose methoxyflurane analgesia for the treatment of acute pain in the ED in the adult population of the STOP! trial.

Methods

Patients presenting to the ED requiring analgesia for acute pain (pain score of 4–7 on the Numerical Rating Scale) due to minor trauma were randomized in a 1:1 ratio to receive methoxyflurane (up to 6 mL) or placebo (normal saline), both via a Penthrox^® (Medical Developments International Limited, Scoresby, Australia) inhaler. Rescue medication (paracetamol/opioids) was available immediately upon request. Change from baseline in visual analog scale (VAS) pain intensity was the primary endpoint.

Results

300 adult and adolescent patients were randomized; data are presented for the adult subgroup (N = 204). Mean baseline VAS pain score was ~66 mm in both groups. The mean change from baseline to 5, 10, 15 and 20 min was greater for methoxyflurane (?20.7, ?27.4, ?33.3 and ?34.8 mm, respectively) than placebo (?8.0, ?11.1, ?12.3 and ?15.2 mm, respectively). The primary analysis showed a highly significant treatment effect overall across all four time points (?17.4 mm; 95% confidence interval: ?22.3 to ?12.5 mm; p < 0.0001). Median time to first pain relief was 5 min with methoxyflurane [versus 20 min with placebo; (hazard ratio: 2.32; 95% CI: 1.63, 3.30; p < 0.0001)]; 79.4% of methoxyflurane-treated patients experienced pain relief within 1–10 inhalations. 22.8% of placebo-treated patients requested rescue medication within 20 min compared with 2.0% of methoxyflurane-treated patients (p = 0.0003). Methoxyflurane treatment was rated ‘Excellent’, ‘Very Good’ or ‘Good’ by 77.6% of patients, 74.5% of physicians and 72.5% of nurses. Treatment-related adverse events (mostly dizziness/headache) were reported by 42.2% of patients receiving methoxyflurane and 14.9% of patients receiving placebo; none caused withdrawal and the majority were mild and transient.

Conclusion

The results of this study support the evidence from previous trials that low-dose methoxyflurane administered via the Penthrox inhaler is a well-tolerated, efficacious and rapid-acting analgesic.

Funding

Medical Developments International (MDI) Limited and Mundipharma Research GmbH & Co.KG.

Trial registration

Clinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

     

Speckle tracking analysis allows sensitive detection of stress cardiomyopathy in severe aneurysmal subarachnoid hemorrhage patients

Purpose

Stress cardiomyopathy is a common life-threatening complication after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that left ventricular (LV) longitudinal strain alterations assessed with speckle tracking could identify early systolic function impairment.

Methods

This was an observational single-center prospective pilot controlled study conducted in a neuro-intensive care unit. Forty-six patients with severe SAH with a World Federation of Neurological Surgeons grade (WFNS) ≥III were included. Transthoracic echocardiography (TTE) was performed on day 1, day 3, and day 7 after the patient’s admission. A cardiologist blinded to the patient’s management analyzed the LV global longitudinal strain (GLS). The control group comprised normal subjects matched according to gender and age.

Results

On day 1 median (25th–75th percentile) GLS was clearly impaired in SAH patients compared to controls [?16.7 (?18.7/?13.7) % versus ?20 (?22/?19) %, p < 0.0001], whereas LVEF was preserved [65 (59?70) %]. GLS was severely impaired in patients with a WFNS score of V versus III–IV [?15.6 (?16.9/?12.3) % versus ?17.8 (?20.6/?15.8) %, p = 0.008]. Seventeen (37 %) patients had a severe GLS alteration (>?16 %). In these patients, GLS improved from day 1 [?12.4 (?14.8/?10.9) %] to last evaluation [?16.2 (?19/?14.6) %, p = 0.0007] in agreement with the natural evolution of stress cardiomyopathy.

Conclusions

On the basis of LV GLS assessment, we demonstrated for the first time that myocardial alteration compatible with a stress cardiomyopathy is detectable in up to 37 % of patients with severe SAH while LVEF is preserved. GLS could be used for sensitive detection of stress cardiomyopathy. This is critical because cardiac impairment remains a major cause of morbidity and mortality after SAH.

     

Lack of agreement between thermodilution and electrical velocimetry cardiac output measurements

Objective

The modified algorithm for the non-invasive determination of cardiac output (CO) by electrical bioimpedance—electrical velocimetry (EV^®)—has been reported to give reliable results in comparison with echocardiography and pulmonary arterial thermodilution (PA-TD) in patients either before or after cardiac surgery. The present study was designed to determine whether EV^®-CO measurements reflect intraindividual changes in CO during cardiac surgery.

Design

Prospective, observational study.

Setting

Operating room (OR) and intensive care unit (ICU) of a university hospital.

Patients

Twenty-nine patients undergoing elective cardiac surgery.

Interventions

None.

Measurements

CO was determined simultaneously by PA-TD and EV^® after induction of anesthesia (t1) and 4.9?±?3.5?h after ICU admission (t2).

Results

TD-CO was 3.9?±?1.4 and 5.4?±?1.1 l/min at t1 and t2 (?p?®-CO was 4.3?±?1.1 and 4.9?±?1.5 l/min at t1 and t2 (?p?=?0.013). Bland–Altman analysis showed a bias of ?0.4 l/min and 0.4 l/min and a precision of 3.2 and 3.6 l/min (34.3% and 67.4%) at t1 and t2, respectively. Analysis of the individual pre- to postoperative changes in CO with both methods revealed bidirectional changes in n?=?12 patients and unidirectional changes with a difference greater than 50% and less than 50% in n?=?9 and n?=?8 patients, respectively.

Conclusions

The disagreement between PA-TD and EV^®-CO measurements after anesthesia induction and after ICU admission, as well as the fact that thoracic bioimpedance did not adequately reflect pre- to postoperative changes in CO, questions the reliability of EV^®-CO measurements in cardiac surgery patients and contrasts sharply with previous studies.

     

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster,Amenamevir (ASP2151): Phase 1, Open-Label,Single-Dose,Parallel-Group Studies

Introduction

Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.

Methods

These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.

Results

In the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated.

Conclusion

The findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5–2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance

Funding

Astellas Pharma.

     

Impact of Insulin Degludec in Hospitalized Patients With and Without Type 2 Diabetes Requiring Parenteral/Enteral Nutrition: An Observational Study

Introduction

Hyperglycemia in inpatients is a major problem, especially when nutritional support is required. This study aims to assess the impact of treatment with insulin degludec (IDeg) on mean blood glucose (BG) and glycemic variability in noncritical hospitalized patients with and without type 2 diabetes (T2DM) receiving enteral and/or parenteral nutrition (EN, PN).

Methods

Mean BG and glycemic variability from admission up to 7 days of hospitalization were evaluated in consecutive cases with and without T2DM. Percentage of coefficient of variation (CV) for glucose was used to express glycemic variability.

Results

Overall, 26 patients (13 with and 13 without T2DM) were admitted to the hospital for any cause. Subjects were 65.4% men and they were mainly elderly (mean age 66.3?±?13.4 years). PN was administered in 88.5% of patients and EN in 19.2%. At admission, mean HbA1c level was 5.9?±?0.7% in patients without diabetes and 9.1?±?2.5% in patients with T2DM. During hospitalization, mean daily BG levels changed from 151?±?47.3 mg/dl (day 1) to 157?±?66.7 mg/dl (day 7) in patients without diabetes and from 210?±?66.5 mg/dl to 192?±?48.6 mg/dl in patients with T2DM. CV decreased from 14% (day 1) to 11% (day 7) in patients without diabetes and from 20% (day 1) to 9% (day 7) in patients with T2DM. No symptomatic or severe hypoglycemia occurred.

Conclusions

Despite the small sample size and the lack of control group, this study represents the first proof-of-concept that IDeg in hospitalized patients with or without T2DM who require nutritional support has the potential to maintain stable levels of BG and reduce glycemic variability.

Funding

Novo Nordisk S.p.A. grant.

     

Renal Function in Nucleos(t)ide Analog-Treated Patients With Chronic Hepatitis B: A Systematic Literature Review and Network Meta-Analysis

Introduction

Renal safety is an important factor in selecting the most appropriate nucleos(t)ide analog (NA) treatment for patients with chronic hepatitis B (CHB). This systematic literature review and network meta-analysis aimed to assess renal function associated with telbivudine treatment compared to other NAs in patients with CHB.

Methods

A systematic literature search via Medline, Medline In-Process, Embase, and the Cochrane library for publications of randomized controlled trials and observational studies was conducted. Network meta-analysis was performed to compare renal function with telbivudine treatment versus other NAs after 1 year of therapy.

Results

Overall, 40 (six randomized controlled and 34 observational) studies were included for review. Telbivudine consistently showed an improvement in renal function as measured by an estimated glomerular filtration rate (eGFR) over various time points regardless of the method of measurement. Changes in eGFR (mL/min) from baseline and corresponding 95% credible intervals with various NAs were as follows: monotherapies (telbivudine: 7.78 [6.91, 8.65], entecavir: ?1.07 [?4.80, 2.62], lamivudine: ?6.08 [?13.35, 1.15], tenofovir: ?9.53 [?14.31, ?4.89]) and combination therapies (telbivudine + adefovir: 8.37 [?34.00, 50.34], telbivudine + tenofovir: 8.29 [?0.05, 16.64], entecavir + adefovir: 4.15 [?38.55, 46.37], telbivudine + lamivudine: 0.51 [?11.77, 12.96], and lamivudine + adefovir: ?0.39 [?42.48, 41.21]). At 1 year, the change in eGFR from baseline was significantly higher with telbivudine compared to other NAs.

Conclusion

The systematic literature review and network meta-analysis provide evidence that telbivudine is associated with significant improvement in renal function in patients with CHB, either alone or in combination with other NAs.

Funding

Novartis Pharma AG.

     

Pooled Aquablation Results for American Men with Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia in Large Prostates (60–150 cc)

Introduction

To present short-term safety and efficacy data of men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) treated with Aquablation.

Methods

Men with LUTs secondary to BPH (60–150 cc) underwent Aquablation treatment from February 2016 to December 2017 across 17 investigational sites in the USA from two contemporary investigational device exemption (IDE) studies called WATER (NCT02505919) and WATER II (NCT03123250).

Results

One hundred seven males with mean age of 67.3?±?6.5 years were treated with Aquablation; mean prostate volume was 99.4?±?24.1 cc. The pooled results show that large prostates have an average procedure time of less than 36 min and discharge on average 1.6?±?1 days. The IPSS decreased by 16.7?±?8.1 points at 3 months and Q_max increased by 11.2?±?12.4 ml/s. The Clavien-Dindo (CD) grade 2 or higher event rate at 3 months was 29%. A non-hierarchical breakdown for CD events yielded 18% grade 2 and 19% grade 3 or higher.

Conclusion

Men with LUTS secondary to BPH (60–150 cc) in a pooled analysis were treated safely and effectively with Aquablation up to 3 months postoperatively.

Trial Registration

ClinicalTrials.gov identifiers, NCT02505919 and NCT03123250.

Funding

PROCEPT BioRobotics.

     

Prolonging Time to Flare in Pediatric Atopic Dermatitis: A Randomized,Investigator-Blinded,Controlled, Multicenter Clinical Study of a Ceramide-Containing Moisturizer

Introduction

Delaying or preventing flares is important in atopic dermatitis (AD) management. The objective of the study was to evaluate whether using a ceramide-containing moisturizer in addition to a body wash during latent AD can delay flares.

Methods

This was a randomized, investigator-blinded, parallel-group, controlled study among Chinese children with a history of mild to moderate AD, within 1 week of successful treatment with a topical corticosteroid. Subjects were randomized to receive moisturizer twice daily and body wash once daily, or body wash alone once daily for 12 weeks. The primary efficacy endpoint was time to flare [necessitating medical therapy and/or Investigator Global Assessment (IGA) > 1 (at least mild AD)]. Other efficacy endpoints were AD characteristics and emollient effects. The patient-reported outcome comprised satisfaction at week 12. The safety endpoint was incidence of undesirable events.

Results

A total of 64 subjects aged 2–12 years were randomized. Median time to flare was delayed by nearly 2 months for moisturizer/body wash compared to body wash alone (89 vs. 27 days, respectively). A significantly earlier onset of action in terms of fewer flares favoring moisturizer was found at week 4 (31 vs. 59%, respectively, p = 0.022), and after 12 weeks, fewer flares occurred (50 vs. 72%). At week 12 for flare-free subjects, nearly half in both groups had clear IGA, and an emollient effect in terms of less dryness or burning was more marked for moisturizer/body wash. Both products led to high patient satisfaction and were well tolerated.

Conclusion

A regimen incorporating a moisturizer plus body wash delayed AD flares by nearly 2 months compared to body wash alone, and yielded high patient satisfaction.

Funding

Galderma R&D.

Trial Registration

ClinicalTrials.gov identifier, NCT02589392.

     

Mesalazine Modified-Release Tablet in the Treatment of Ulcerative Colitis in the Active Phase: A Chinese,Multicenter, Single-Blind,Randomized Controlled Study

Introduction

This study compared the efficacy and safety of two mesalazine formulations in the treatment of Chinese patients with mildly to moderately active ulcerative colitis (UC).

Methods

In this multicenter, single-blind, randomized controlled study of 251 patients with active UC conducted from November 2010 to January 2012, subjects were randomized to treatment with mesalazine modified-release tablets (MR group, n = 123) or enteric-coated tablets (EC group, n = 128) at 800 mg three-times daily for 8 weeks. The primary efficacy measure was the decrease in UC Disease Activity Index (UCDAI) at final evaluation. If the 95% confidence interval (CI) lower limit of the difference of the decrease in UCDAI between groups was over ?1.0, mesalazine modified-release tablets were considered non-inferior to mesalazine enteric-coated tablets. The change in UCDAI in patients with mild and moderate (UCDAI 3–5 and 6–8 at enrollment, respectively) UC was analyzed. Secondary efficacy measures were remission and efficacy rates. Incidences of adverse drug reactions (ADRs) were calculated.

Results

The decreases in UCDAI at final evaluation were 2.84 and 2.56 in the MR and EC groups, respectively, with a difference of 0.27 between groups (95% CI ?0.34, 0.88). The remission rates were 48.33% (58/120) and 55.65% (69/124), and the efficacy rates were 63.33% (76/120) and 66.94% (83/124) in the MR and EC groups, respectively (all P > 0.05). In patients with mild UC, the decreases in UCDAI were 2.16 and 2.05 in the MR and EC groups, respectively, while in patients with moderate UC they were 3.49 and 3.03, respectively (all P > 0.05). The incidences of ADRs in the MR and EC groups were 6.61% (8/121) and 10.24% (13/127), respectively (P > 0.05). No serious ADRs were reported during the study.

Conclusion

Mesalazine modified-release tablets are non-inferior to enteric-coated tablets and are an effective and safe treatment option in Chinese patients with mildly to moderately active UC.

Trial registration

ClinicalTrials.gov identifier: NCT01257386.

Funding

Tillotts Pharma AG.

     

Efficacy and Safety of Linagliptin in 2681 Asian Patients Stratified by Age,Obesity, and Renal Function: A Pooled Analysis of Randomized Clinical Trials

Introduction

Asian patients with type 2 diabetes (T2D) are younger, leaner, and more likely to develop renal dysfunction than White populations. In this multiethnic analysis of data from phase 3 trials, we investigated the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in Asians stratified by these subphenotypes.

Methods

Data from randomized, double-blind, placebo-controlled trials evaluating linagliptin (as monotherapy, add-on therapy to metformin ± sulfonylurea, combined with pioglitazone or added to insulin) were pooled with efficacy data from 11 randomized trials of at least 24 weeks and safety data from 15 trials of various durations.

Results

In the efficacy set, 1404 Asian patients received linagliptin [mean (standard deviation) age 54.5 (10.1) years; body mass index (BMI) 26.0 (3.9) kg/m²] and 661 received placebo [age 55.0 (9.7) years; BMI 26.1 (3.9) kg/m²] with the same glycated hemoglobin (HbA1c): 8.2 (0.9)% in both groups. At 24 weeks, the placebo-corrected adjusted mean ± standard error change from baseline in HbA1c with linagliptin was ?0.73 ± 0.04% (95% confidence interval ?0.81, ?0.65; P < 0.0001). Reductions in HbA1c were similar upon stratification by age [<65 years, ?0.71 ± 0.05% (?0.80, ?0.62; P < 0.0001); ≥65 years, ?0.81 ± 0.10% (?1.01, ?0.60; P < 0.0001)], BMI (<25 kg/m², ?0.82 ± 0.06% [?0.94, ?0.70; P < 0.0001]; ≥25 kg/m², ?0.65 ± 0.06% [?0.76, ?0.54; P < 0.0001]) and estimated glomerular filtration rate [<90 mL/min/1.73 m², ?0.71 ± 0.06% (?0.82, ?0.60; P < 0.0001); ≥90 mL/min/1.73 m², ?0.75 ± 0.06% (?0.87, ?0.64; P < 0.0001)]. In the safety set (linagliptin, n = 1842; placebo, n = 839), 52.2% and 54.6% of patients, respectively, experienced adverse events. The rates of drug-related adverse events were 10.9% in the linagliptin group and 10.4% in the placebo group. The respective rates of hypoglycemia were 8.3% and 9.5%, mainly among patients treated with sulfonylurea or insulin. Severe hypoglycemia was rare (<1.0% in either group).

Conclusion

Linagliptin effectively reduced hyperglycemia in Asian patients with uncontrolled T2D, irrespective of age, BMI, renal function, or ethnic subgroups, and was well tolerated.

Funding

Boehringer Ingelheim, Eli Lilly and Company, and the Diabetes Alliance.

     

Relationship of Eating Patterns and Metabolic Parameters,and Teneligliptin Treatment: Interim Results from Post-marketing Surveillance in Japanese Type 2 Diabetes Patients

Introduction

Healthy eating is a critical aspect of the prevention and management of type 2 diabetes (T2DM). Disrupted eating patterns can result in poor glucose control and increase the likelihood of diabetic complications. Teneligliptin inhibits dipeptidyl peptidase-4 activity for 24 h and suppresses postprandial hyperglycemia after all three daily meals. This interim analysis of data from the large-scale post-marketing surveillance of teneligliptin (RUBY) in Japan examined eating patterns and their relationship with metabolic parameters and diabetic complications. We also examined whether eating patterns affected safety and efficacy of teneligliptin.

Methods

We analyzed baseline data from survey forms collected in RUBY between May 2013 and June 2017, including patient characteristics, metabolic parameters, and eating patterns (eating three meals per day or not; timing of evening meal) before teneligliptin treatment was initiated. Safety and efficacy of 12 months’ teneligliptin (20–40 mg/day) treatment was assessed.

Results

Data from 10,532 patients were available for analysis. Most patients who did not eat three meals per day (n??=757) or who ate their evening meal after 10 PM (n??=206) were 64 years old or younger. At baseline, glycated hemoglobin (HbA1c), fasting blood glucose, triglycerides, total and low-density lipoprotein cholesterol, body mass index, alanine aminotransferase, and aspartate aminotransferase levels were higher in those patients who did not eat three meals per day (p?<?0.05) or who ate their evening meal late (p?<?0.05). Diabetic complications were more common in patients who did not eat three meals per day. Treatment with teneligliptin reduced HbA1c over 6 or 12 months across all eating patterns, with a low incidence of adverse drug reactions.

Conclusions

Eating patterns may be associated with altered metabolic parameters and diabetic complications among Japanese patients with T2DM. Teneligliptin may be well tolerated and improve hyperglycemia in patients with T2DM irrespective of eating patterns.

Funding

Mitsubishi Tanabe Pharma Corporation and Daiichi Sankyo Co. Ltd.

Trial Registration Number

Japic CTI-153047.

     

A Review of the Long-Term Efficacy,Tolerability, and Safety of Exenatide Once Weekly for Type 2 Diabetes

Introduction

Exenatide once weekly (ExeOW, Bydureon^®, Astra Zeneca), a drug belonging to the class of glucagon-like peptide-1 (GLP-1) receptor agonists, is the first agent approved for treatment of type 2 diabetes (T2D) that can be administered on a weekly basis.

Methods

Data concerning treatment of T2D with ExeOW are reviewed with special reference to its long-term efficacy, tolerability, and safety. Relevant literature was identified through the PubMed database from inception to January 2015.

Results

In randomized clinical trials ExeOW, as add-on to oral antidiabetics, achieved significantly improved glycemic control compared to maximum recommended doses of exenatide twice daily, sitagliptin, pioglitazone, and insulin glargine, as measured by HbA1c. In drug-naïve patients ExeOW was superior to sitagliptin and non-inferior to metformin, whereas non-inferiority to pioglitazone and liraglutide was not proven. In different trials reductions in HbA1c ranged from ?1.1% to ?2.0%. ExeOW therapy over 6 months was also associated with a mean weight loss of ?2 to ?4 kg, improved systolic blood pressure and lipid profile, and no hypoglycemia unless associated to sulfonylurea. ExeOW long-term therapy up to 3–6 years allowed persistent glycemic control (HbA1c ?1.6%), sustained decreases in blood pressure (?2 mmHg), and improvements of lipid profile. ExeOW tolerability was comparable to that of the other GLP-1 receptor agonists, with better gastrointestinal tolerability when direct comparison was done (namely liraglutide and exenatide BID), but higher incidence of injection site reactions and few treatment discontinuations mainly due to gastrointestinal events.

Conclusion

ExeOW is a well-tolerated and convenient option for long-term treatment of T2D allowing significant and persistent glycemic control with moderate weight loss and low risk of hypoglycemia unless associated with sulfonylureas.