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Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy.
Furuhashi, M, Sakuma, I, Morimoto, T, Higashiura, Y, Sakai, A, Matsumoto, M, Sakuma, M, Shimabukuro, M, Nomiyama, T, Arasaki, O, et al
Journal of atherosclerosis and thrombosis. 2022;(1):24-37
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Abstract
AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. METHODS PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (n=122) or sitagliptin (n=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. RESULTS Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P=0.07). CONCLUSIONS PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.
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Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome.
Dillon, JS, Kulke, MH, Hörsch, D, Anthony, LB, Warner, RRP, Bergsland, E, Welin, S, O'Dorisio, TM, Kunz, PL, McKee, C, et al
Journal of gastrointestinal cancer. 2021;(1):212-221
Abstract
BACKGROUND Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods. METHODS First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial. RESULTS In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3-4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2-3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6-11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7-11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR. CONCLUSION The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency. TRIAL REGISTRATION ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659.
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Dipeptidyl peptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels in patients with type 2 diabetes: A randomized controlled trial.
Onoue, T, Goto, M, Wada, E, Furukawa, M, Okuji, T, Okada, N, Kobayashi, T, Iwama, S, Sugiyama, M, Tsunekawa, T, et al
PloS one. 2020;(1):e0228004
Abstract
Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.
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Evaluation of the Pharmacokinetic Interaction Between Lobeglitazone and Dapagliflozin at Steady State.
Jang, K, Jeon, JY, Moon, SJ, Kim, MG
Clinical therapeutics. 2020;(2):295-304
Abstract
PURPOSE Coadministration of lobeglitazone and dapagliflozin is expected to result in a blood glucose-lowering effect, followed by a gradual increase, in clinical usage; however, combining drugs could cause negative interactions. This study aimed to evaluate the effect of the coadministration of lobeglitazone and dapagliflozin on their individual pharmacokinetic properties at steady state in healthy male volunteers in the fasted state. METHODS This study consisted of 2 parts, each of which was a randomized, open-labeled, multiple-dose, 2-way crossover study in 20 healthy male volunteers in each part. Blood samples were taken periodically over a 48-h period after dosing to derive total plasma lobeglitazone and dapagliflozin pharmacokinetic properties; safety profile was evaluated throughout the study. FINDINGS When the pharmacokinetic properties of dapagliflozin were evaluated following its administration alone and in combination with lobeglitazone, point estimate and 90% CI of the geometric mean ratio of dapagliflozin AUCτ were entirely within the conventional bioequivalence range of 80%-125%. However, although it was not clinically meaningful, its Css,max was ~8% lower in subjects receiving multiple doses of dapagliflozin and lobeglitazone than that in those administered dapagliflozin alone. The pharmacokinetic properties of lobeglitazone were evaluated following its administration alone and in combination with dapagliflozin. The geometric mean ratios and 90% CIs of the lobeglitazone Css,max and AUCτ were within the conventional bioequivalence range of 80%-125%. IMPLICATIONS Coadministration of lobeglitazone and dapagliflozin had no apparent clinically relevant effects on the pharmacokinetic properties of either drug. Based on these findings, it is anticipated that lobeglitazone and dapagliflozin can be coadministered without dose adjustment. ClinicalTrials.gov identifier: NCT03616392.
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Achieving clinically meaningful response in endometriosis pain symptoms is associated with improvements in health-related quality of life and work productivity: analysis of 2 phase III clinical trials.
Pokrzywinski, RM, Soliman, AM, Chen, J, Snabes, MC, Coyne, KS, Surrey, ES, Taylor, HS
American journal of obstetrics and gynecology. 2020;(6):592.e1-592.e10
Abstract
BACKGROUND Endometriosis-related pain symptoms have a negative impact on health-related quality of life and productivity. In fact, as endometriosis-related symptom severity and the number of symptoms experienced increases, health-related quality of life decreases. Dysmenorrhea and nonmenstrual pelvic pain are prominent symptoms experienced by women with endometriosis and were shown to have improved with the oral, nonpeptide gonadotropin-releasing hormone antagonist, elagolix. OBJECTIVE The objective of this post hoc analysis was to address the question of if patients show a clinical response (in dysmenorrhea or nonmenstrual pelvic pain), do they also have improvements in health-related quality of life and in productivity? STUDY DESIGN This post hoc analysis used data from the Elaris Endometriosis-I and Elaris Endometriosis-II phase III, randomized, placebo-controlled studies. A surgical diagnosis of endometriosis (in the past 10 years), premenopausal, aged 18-49 years, and moderate to severe endometriosis-associated pain were among the inclusion criteria for both trials. Women self-reported pain daily using a scale ranging from 0 (no pain) to 3 (severe pain); daily pain was assigned to either dysmenorrhea or nonmenstrual pelvic pain based on self-reported bleeding on that particular day. In addition, their self-reported endometriosis-associated pain must have been an average of moderate or severe during the month leading to baseline for inclusion in the trial program. Patients were characterized as achieving a clinical response for dysmenorrhea or nonmenstrual pelvic pain (ie, responder or nonresponder), which was defined as women who did not have an increase in analgesic use and who met the pain reduction score threshold at month 3. Pain reduction score thresholds were defined separately for dysmenorrhea and nonmenstrual pelvic pain in the trial using receiver-operating characteristics analysis. Health-related quality of life was assessed using the Endometriosis Health Profile-30; work productivity was assessed using the Health-Related Productivity Questionnaire. RESULTS Women enrolled in Elaris Endometriosis-I (n = 871) and Elaris Endometriosis-II (n = 815) were included in this analysis. Patients with a clinical response during treatment to dysmenorrhea or nonmenstrual pelvic pain also experienced a meaningful improvement in all domains of the Endometriosis Health Profile-30 at month 3. Patients who did not show a dysmenorrhea or nonmenstrual pelvic pain clinical response at month 3 did not exhibit mean improvements in Endometriosis Health Profile-30 domain scores that indicate an Endometriosis Health Profile-30 responder. Productivity improved among dysmenorrhea clinical responders. In the Elaris Endometriosis-I study, clinical responders lost a total of 5.9 hours compared with a total of 13.0 hours for nonresponders of employment-related work at month 3 (P < .0001). Among women in the Elaris Endometriosis-II study, a total of 4.1 hours and 10.4 employment-related hours were lost at month 3 for dysmenorrhea responders vs nonresponders (P < .001). Similar results were obtained when analyzed by non-enstrual pelvic pain responder status. CONCLUSION Women with moderate to severe endometriosis-related pain, who are clinical responders based on dysmenorrhea and nonmenstrual pelvic pain, also experience significant and clinically meaningful improvement in health-related quality of life and productivity as measured by the Endometriosis Health Profile-30 and Health-Related Productivity Questionnaire, respectively.
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Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)-Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study.
Cho, BC, Obermannova, R, Bearz, A, McKeage, M, Kim, DW, Batra, U, Borra, G, Orlov, S, Kim, SW, Geater, SL, et al
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019;(7):1255-1265
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Abstract
INTRODUCTION In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted. METHODS Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1. RESULTS In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%). CONCLUSION Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.
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Impact of elagolix treatment on fatigue experienced by women with moderate to severe pain associated with endometriosis.
Surrey, ES, Soliman, AM, Agarwal, SK, Snabes, MC, Diamond, MP
Fertility and sterility. 2019;(2):298-304.e3
Abstract
OBJECTIVE To evaluate the efficacy of elagolix, an oral GnRH antagonist, for the reduction of fatigue in women with moderate or severe endometriosis-associated pain. DESIGN Randomized, double-blind, multicenter, placebo-controlled phase III trial. SETTING Clinics. PATIENT(S): A total of 860 women treated with elagolix or placebo. INTERVENTION(S): Women received either elagolix at 150 mg daily (QD) orally, elagolix at 200 mg twice daily (BID) orally, or placebo. MAIN OUTCOME MEASURE(S): Change from baseline to month 1, 3, and 6 visits, in Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 6a questionnaire T-scores. RESULTS(S): At baseline, 54%-74% of women with moderate to severe pain associated with endometriosis reported having fatigue-related issues "quite a bit" or "very much," depending on the question asked. Fatigue extent was reduced to 29%-43% and 14%-29% for women treated with elagolix at 150 mg QD and 200 mg BID, respectively, at 6 months, compared with 35%-50% with placebo. The resultant decrease in fatigue T-scores was significant after elagolix treatment compared with placebo at 6 months, with changes of -2.21 and -5.90 with elagolix at 150 mg QD and 200 mg BID, respectively. Significant reduction in fatigue scores were observed among patients reporting clinically meaningful response "reduction" in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia (-7.31, -6.62, and -4.31, respectively) compared with nonresponders. CONCLUSION(S): In women with moderate to severe endometriosis related pain, elagolix significantly reduces fatigue levels.
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Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease.
Frölich, L, Wunderlich, G, Thamer, C, Roehrle, M, Garcia, M, Dubois, B
Alzheimer's research & therapy. 2019;(1):18
Abstract
BACKGROUND There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD. Efficacy and safety of BI 409306 was analysed in two phase II proof-of-concept clinical trials in cognitive impairment associated with prodromal AD (study 1) and mild AD (study 2). METHODS Two multicentre, double-blind, parallel-group, randomised controlled phase II studies were conducted (North America/Europe). Following study run-in, eligible subjects were randomised to one of four oral doses of BI 409306 (10-50 mg daily) or placebo (1:1:1:1:2 ratio) for 12 weeks. The primary efficacy endpoint was the change from baseline in Neuropsychological Test Battery (NTB) total z-score after 12 weeks' treatment. Secondary efficacy assessments included change from baseline in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog11) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; mild cognitive impairment [MCI] version for prodromal patients) after 12 weeks' treatment. Safety and tolerability assessments included adverse event reporting and vital sign monitoring. Change from baseline in NTB total z-score (primary endpoint) and CDR-SB were analysed using the restricted maximum likelihood-based mixed-effects model with repeated measurement. An analysis of covariance model was used to assess other secondary endpoints. RESULTS Four hundred fifty-seven patients were randomised (study 1 for prodromal AD, N = 128; study 2 for mild AD, N = 329); 427 (93.4%) completed. A prespecified pooled analysis of the primary endpoint revealed no significant changes in NTB total composite z-score at week 12 in the BI 409306 treatment groups compared with placebo, with similar findings observed in the individual studies. The analysis of all secondary endpoints, including pooled analysis of CDR-SB and ADAS-Cog11, ADCS-MCI-ADL (study 1), ADCS-ADL (study 2), also gave no indication of a treatment benefit for BI 409306, compared with placebo. BI 409306 was well tolerated. CONCLUSIONS Overall, the data do not demonstrate efficacy of BI 409306 in improving cognition in patients with prodromal and mild AD. BI 409306 is well tolerated. TRIAL REGISTRATION ClinicalTrials.gov, NCT02240693 and NCT02337907 . Registered 15 September 2014 and 09 January 2015, respectively.
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A phase II, randomised study of mFOLFOX6 with or without the Akt inhibitor ipatasertib in patients with locally advanced or metastatic gastric or gastroesophageal junction cancer.
Bang, YJ, Kang, YK, Ng, M, Chung, HC, Wainberg, ZA, Gendreau, S, Chan, WY, Xu, N, Maslyar, D, Meng, R, et al
European journal of cancer (Oxford, England : 1990). 2019;:17-24
Abstract
BACKGROUND Akt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC. PATIENTS AND METHODS In this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)-low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway-activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments. RESULTS In 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7-7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2-8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81-1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway-activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with ≥1 adverse event (AE, 100% versus 98%) and grade ≥3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively. CONCLUSIONS Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed. TRIAL REGISTRATION ClinicalTrials.gov (NCT01896531).
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Comparison of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation.
Oh, M, Lee, CW, Ahn, JM, Park, DW, Kang, SJ, Lee, SW, Kim, YH, Moon, DH, Park, SW, Park, SJ
Clinical cardiology. 2019;(2):241-246
Abstract
BACKGROUND The renin-angiotensin system plays an important role in promoting atherosclerotic plaque inflammation, which may be inhibited by angiotension-II receptor blockers. HYPOTHESIS We investigated the effects of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation using 18 F-fluorodeoxyglucose (18 FDG) positron emission tomography (PET) imaging. METHODS Fifty patients with acute coronary syndrome (ACS) and at least one lesion with 18 FDG uptake in the carotid artery (target-to-background ratio [TBR] ≥ 1.6) were randomly assigned to receive either fimasartan (60 mg once a day) or amlodipine (5 mg once a day). 18 FDG PET examinations were performed in all patients at baseline and 6 months. The primary endpoint was the percent change in the index vessel TBR for the most diseased segment (MDS TBR). RESULTS The two groups had similar baseline characteristics. At the 6-month follow-up, index vessel and aorta MDS TBR significantly decreased in both groups. However, the percent change in index vessel MDS TBR was similar between the two groups (-9.33 ± 14.2% vs -7.73 ± 19.1%, respectively, P = 0.9). No significant difference was found for the percent change in the whole vessel TBR for the index vessel between the two groups, with similar findings for changes in MDS TBR or whole vessel TBR for the aorta. Total cholesterol, low-density lipoprotein cholesterol levels, and blood pressure improved to a similar degree in both groups. CONCLUSIONS Fimasartan and amlodipine reduce carotid atherosclerotic plaque inflammation similarly in patients with ACS, offering the same level of effectiveness.