Abstract
Background
The protease chymase generates multiple factors involved in tissue remodelling including angiotensin II (Ang II) and has been implicated in the pathophysiology of diabetic kidney ...disease (DKD). This study investigated the effects of the chymase inhibitor fulacimstat on albuminuria in patients with Type II diabetes mellitus and a clinical diagnosis of DKD.
Methods
In this double-blind, randomized, placebo-controlled trial, patients were on the maximum tolerated dose of either an Ang II receptor blocker or an Ang-converting enzyme inhibitor since at least 3 months before the screening visit. Eligible patients were randomized in a 2:1 ratio to treatment with either 25 mg fulacimstat (n = 99) or placebo (n = 48) twice daily on top of standard of care.
Results
The randomized patients had a mean urine albumin–creatinine ratio (UACR) of 131 mg/g (range: 29–2429 mg) and a mean (standard deviation) estimated glomerular filtration rate of 60.8 ± 16.9 mL/min/1.73 m2 before treatment start. Fulacimstat was safe and well tolerated, and achieved mean total trough concentrations that were ∼9-fold higher than those predicted to be required for minimal therapeutic activity. UACR increased by 27.4% coefficient of variation (CV) 86% and 3% (CV 88.9%) after 24 weeks of treatment with placebo or fulacimstat, respectively. Analysis of covariance revealed a least square mean UACR ratio (fulacimstat/placebo) of 0.804 (90% CI 0.627–1.030, P = 0.1477), indicating a statistically non-significant UACR reduction of 19.6% after fulacimstat treatment compared with placebo.
Conclusions
Fulacimstat was safe and well tolerated but did not reduce albuminuria in patients with DKD. These findings do not support a therapeutic role for chymase inhibition in DKD.
This study evaluated the long-term safety and efficacy of dapagliflozin as an adjunct to adjustable insulin in patients with type 1 diabetes and inadequate glycemic control.
DEPICT-1 (Dapagliflozin ...Evaluation in Patients With Inadequately Controlled Type 1 Diabetes) was a randomized (1:1:1), double-blind, placebo-controlled phase 3 study of dapagliflozin 5 mg and 10 mg in patients with type 1 diabetes (HbA
7.5-10.5% 58-91 mmol/mol) (NCT02268214). The results of the 52-week study, consisting of the 24-week short-term and 28-week extension period, are reported here.
Of the 833 patients randomized into the study, 708 (85%) completed the 52-week study. Over 52 weeks, dapagliflozin 5 mg and 10 mg led to clinically significant reductions in HbA
(difference vs. placebo 95% CI -0.33% -0.49, -0.17 -3.6 mmol/mol (-5.4, -1.9) and -0.36% -0.53, -0.20 -3.9 mmol/mol (-5.8, -2.2), respectively) and body weight (difference vs. placebo 95% CI -2.95% -3.83, -2.06 and -4.54% -5.40, -3.66, respectively). Serious adverse events were reported in 13.4%, 13.5%, and 11.5% of patients in the dapagliflozin 5 mg, 10 mg, and placebo groups, respectively. Although hypoglycemia events were comparable across treatment groups, more patients in the dapagliflozin groups had events adjudicated as definite diabetic ketoacidosis (DKA; 4.0%, 3.4%, and 1.9% in dapagliflozin 5 mg, 10 mg, and placebo groups, respectively).
Over 52 weeks, dapagliflozin led to improvements in glycemic control and weight loss in patients with type 1 diabetes, while increasing the risk of DKA.
Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable ...insulin in patients with inadequately controlled type 1 diabetes.
DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18-75 years and had inadequately controlled type 1 diabetes (HbA
between ≥7·7% and ≤11·0% ≥61·0 mmol/mol and ≤97·0 mmol/mol) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA
. The primary efficacy outcome was the change from baseline in HbA
after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing.
Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg n=277 vs dapagliflozin 10 mg n=296 vs placebo n=260; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA
was 8·53% (70 mmol/mol; SD 0·67% 7·3 mmol/mol). At week 24, both doses of dapagliflozin significantly reduced HbA
compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was -0·42% 95% CI -0·56 to -0·28; p<0·0001 and for dapagliflozin 10 mg vs placebo was -0·45% -0·58 to -0·31; p<0·0001). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 14% vs 36 12% vs 39 15%), urinary tract infection (19 7% vs 11 4% vs 13 5%), upper respiratory tract infection (15 5% vs 15 5% vs 11 4%), and headache (12 4% vs 17 6% vs 11 4%). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group.
Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes.
AstraZeneca and Bristol-Myers Squibb.
Abstract
Type 2 diabetes mellitus (DM) is a progressive disease. Initial therapy begins with dietary and lifestyle modifications. However, as the disease progresses, glycemic control becomes more ...difficult to attain, often requiring ≥1 oral antihyperglycemic medication (OAM), and finally the addition of insulin to the OAMs and insulin monotherapy.
This study was designed to determine the effect of pioglitazone 30 mg plus insulin (PIO + INS) versus placebo plus insulin (PLB + INS) on glycemic control, the serum lipid profile, and selected cardiovascular risk factors in patients with type 2 DM whose disease was inadequately controlled with insulin therapy alone despite efforts to intensify such treatment.
This was a 6-month, randomized, double-blind, prospective, multicenter, placebo-controlled, parallel-group study. Patients with type 2 DM and a glycosylated hemoglobin (HbA1c) value ≥7.5% who were using insulin (with or without OAMs) entered a 3-month insulin intensification phase to achieve blood glucose targets with insulin monotherapy. After insulin intensification, those patients with HbA1c values ≥7.0% were randomized to PIO + INS or PLB + INS. The primary end point was the change in HbA1c from baseline. Cardiovascular risk markers (highly sensitive C-reactive protein hs CRP and plasminogen activator inhibitor-1 PAI-1) were measured at baseline and end point.
Of the 289 patients randomized to treatment (mean SD age, 58.9 7.1 years; 164 women, 125 men), 142 received PIO + INS and 147 received PLB + INS. A total of 263 patients completed the study. After 6 months, PIO + INS reduced mean HbA1c (−0.69%; P < 0.002) and mean fasting plasma glucose (FPG −1.45 mmol/L; P < 0.002) from baseline. PLB + INS produced no significant changes in HbA1c or FPG. The between-treatment differences for HbA1c (−0.55%; P < 0.002) and FPG (−1.80 mmol/L; P < 0.002) occurred despite a reduction of insulin dose in the PIO + INS group from baseline (−0.16 U/d · kg; P < 0.002). Significant between-group differences were observed for high-density lipoprotein cholesterol (0.13 mM; P < 0.002), triglycerides (ratio of geometric mean PIO/PLB, 0.871; P < 0.01), atherogenic index of plasma (−0.11; P < 0.002), PAI-1 (−5.10 U/mL; P < 0.001), and hs CRP (−1.47 mg/L; P < 0.05). The rate of clinical and biochemical hypoglycemia (blood glucose <2.8 mmol/L) did not differ statistically between treatment groups, but reported incidences of subjective hypoglycemia occurred more often with PIO + INS than with PLB + INS (90 vs 75; P < 0.05). Edema was more common with PIO + INS than with PLB + INS (20 vs 5 instances, respectively), as was gain (mean SEM) in body weight (4.05 4.03 vs 0.20 2.92 kg, respectively).
Adding pioglitazone to insulin in these study patients with type 2 DM whose disease was inadequately controlled with insulin monotherapy further improved their glycemic control.
With optimal strategy, human papillomavirus (HPV) vaccines have the potential to control HPV. We have assessed vaccine efficacy (VE), herd effect (HE) of HPV vaccination and overall protective ...effectiveness (PE) against high‐risk HPV infections by HPV type and vaccination strategy in a community‐randomized trial using the bivalent HPV16/18 vaccine. We randomized 33 communities to gender‐neutral HPV vaccination (Arm A), HPV vaccination of girls and hepatitis B‐virus (HBV) vaccination of boys (Arm B) and gender‐neutral HBV vaccination (Arm C). Entire 1992–1995 male (40,852) and female (39,420) birth cohorts were invited, and 11,662 males and 20,513 females vaccinated with 20–30% and 45% coverage in 2007–2010. During 2010–2014, 11,396 cervicovaginal samples were collected from 13,545 18.5‐year‐old attendees. HPV typing was performed by a high‐throughput PCR. VE was calculated for HPV vaccinated women and HE for non‐HPV‐vaccinated women, using the HBV vaccinated, for HE all non‐HPV vaccinated, Arm C women as controls. PE was calculated as coverage rate‐weighted mean of VE + HE. HPV16/18/45 and 31/33/35 VEs varied between 86–94% and 30–66%, respectively. Only the gender‐neutral vaccination provided significant HEs against HPV18 (61%) and HPV31 (72%) in the 1995 birth cohort—increased HEs against HPV33 (39%) and HPV35 (42%) were also observed. Due to the increased HEs, PEs for HPV16/18/45 and HPV31/33/35 were comparable in the gender‐neutral arm 1995 birth cohort. High vaccine efficacy against HPV16/18/45 and, gender‐neutral vaccination‐enforced, herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provides comparable overall protective effectiveness against six oncogenic HPV types: 16/18/31/33/35/45.
What's new?
Human papillomavirus (HPV) vaccination coverage has remained low to moderate in most countries. An optimal vaccination program should therefore aim to generate herd effect even with low coverage. Here, the authors report results from a community‐randomized trial with low to moderate vaccination coverage comparing the bivalent vaccine efficacy, herd effect, and overall protective effectiveness of gender‐neutral or girls‐only vaccination strategies against up to 16 HPV types with special emphasis on types 16/18/31/33/35/45. High vaccine efficacy against HPV16/18/45 and gender‐neutral vaccination‐enforced herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provided comparable overall protective effectiveness against six high‐risk HPV types, 16/18/31/33/35/45.
Efficacy of human papillomavirus (HPV) vaccines promises to control HPV infections. However, HPV vaccination programs may lay bare an ecological niche for non‐vaccine HPV types. We evaluated ...type‐replacement by HPV type and vaccination strategy in a community‐randomized trial executed in HPV vaccination naïve population. Thirty‐three communities were randomized to gender‐neutral vaccination with AS04‐adjuvanted HPV16/18 vaccine (Arm A), HPV vaccination of girls and hepatitis B‐virus (HBV) vaccination of boys (Arm B) and gender‐neutral HBV vaccination (Arm C). Resident 1992‐95 born boys (40,852) and girls (39,420) were invited. 11,662 boys and 20,513 girls were vaccinated with 20–30% and 45–48% coverage, respectively. HPV typing of 11,396 cervicovaginal samples was performed by high throughput PCR. Prevalence ratios (PR) between arms and ranked order of HPV types and odds ratio (OR) for having multiple HPV types in HPV16 or 18/45 positive individuals were calculated. The ranked order of HPV types did not significantly differ between arms or birth cohorts. For the non‐HPV vaccinated 1992–1993 birth cohorts increased PR, between the gender‐neutral intervention versus control arms for HPV39 (PRA 1.84, 95% CI 1.12–3.02) and HPV51 (PRA 1.56, 95% CI 1.11–2.19) were observed. In the gender‐neutral arm, increased clustering between HPV39 and the vaccine‐covered HPV types 16 or 18/45 (ORA16 = 5.1, ORA18/45 = 11.4) was observed in the non‐HPV vaccinated 1994–1995 birth cohorts. Comparable clustering was seen between HPV51 and HPV16 or HPV18/45 (ORB16 = 4.7, ORB18/45 = 4.3), in the girls‐only arm. In conclusion, definitively consistent postvaccination patterns of HPV type‐replacement were not observed. Future occurrence of HPV39 and HPV51 warrant investigation.
What's new?
Vaccination against high‐risk human papilloma virus (HPV) strains is efficacious, but possible resurgence of non‐targeted viral strains is a concern. The authors performed a community‐randomized study with 20–50% vaccination coverage in 1992–95 birth cohorts of 80,000 adolescents. They compared gender‐neutral or girls‐only HPV16/18 vaccination or hepatitis B‐virus vaccination in 11 communities, and a consistent pattern of HPV type‐replacement was not found. However, occurrence of HPV39 and HPV51 types warrants further observation in the future.
Human papillomavirus (HPV) vaccine is efficacious but the real‐life effectiveness of gender‐neutral and girls‐only vaccination strategies is unknown. We report a community‐randomized trial on the ...protective effectiveness (PE) = vaccine efficacy (VE) + herd effect (HE) of the two strategies among females in virtually HPV vaccination naïve population. We randomized 33 Finnish communities into Arm A) gender‐neutral vaccination with AS04‐adjuvanted HPV16/18 vaccine (11 communities), Arm B) HPV vaccination of girls and hepatitis B‐virus (HBV) vaccination of boys (11 communities) or Arm C) gender‐neutral HBV vaccination (11 communities). All resident 39,420 females and 40,852 males born 1992‐95 were invited in 2007–09. Virtually all (99%) 12‐ to 15‐year‐old participating males (11,662) and females (20,513) received three doses resulting in uniform 20–30% male and 50% female vaccination coverage by birth cohort. Four years later (2010–14) 11,396 cervicovaginal samples obtained from 18.5 year‐old women were tested for HPV DNA, and prevalence of cervical HPV infections by trial arm and birth cohort was the main outcome measure. VEs against HPV16/18 varied between 89.2% and 95.2% across birth cohorts in arms A and B. The VEs against non‐vaccine types consistent with cross‐protection were highest in those born 1994–95 for HPV45 (VEA 82.8%; VEB 86.1%) and for HPV31 (VEA 77.6%, VEB 84.6%). The HEs in the non HPV‐vaccinated were statistically significant in those born 1994–95 for HPV18 (HEA 51.0%; 95% CI 8.3–73.8, HEB 47.2%; 6.5–70.2) and for HPV31/33 in arm A (HEA 53.7%; 22.1–72.5). For HPV16 and 45 no significant herd effects were detected. PE estimates against HPV16/18 were similar by both strategies (PEA 58.1%; 45.1–69.4; PEB 55.7%; 42.9–66.6). PE estimates against HPV31/33 were higher by the gender‐neutral vaccination (PEA 60.5%; 43.6–73.4; PEB 44.5%; 24.9–60.6). In conclusion, while gender‐neutral strategy enhanced the effectiveness of HPV vaccination for cross‐protected HPV types with low to moderate coverage, high coverage in males appears to be key to providing a substantial public health benefit also to unvaccinated females. Trial registration www.clinicaltrials.gov.com NCT000534638
What's new?
Vaccines against cancer‐causing human papillomaviruses (HPVs) effectively prevent HPV infection. However, whether it is better in terms of health and cost to vaccinate only girls or to vaccinate both boys and girls remains unclear. The present report details the results of a community‐randomized trial of the two strategies in an HPV vaccination‐naïve population born between 1992 and 1995 in Finland. Overall, low‐ to moderate‐coverage gender‐neutral vaccination provided the greatest protection against HPV. Gender‐neutral vaccination of early adolescents was associated with significant herd effects and cross‐protection against a number of non‐vaccine HPV types.
Abstract
Background
Human papillomavirus (HPV) vaccination of girls with very high (>90%) coverage has the potential to eradicate oncogenic HPVs, but such high coverage is hard to achieve. However, ...the herd effect (HE) depends both on the HPV type and the vaccination strategy.
Methods
We randomized 33 Finnish communities into gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and hepatitis B virus vaccination arms. In 2007–2010, 11 662 of 20 513 of 40 852 of 39 420 resident boys/girls from 1992 to 1995 birth cohorts consented. In 2010–2014, cervicovaginal samples from vaccinated and unvaccinated girls at age 18.5 years were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68. Vaccine efficacy for vaccinated girls, HE for unvaccinated girls, and the protective effectiveness (PE) for all girls were estimated. We extended the community-randomized trial results about vaccination strategy with mathematical modeling to assess HPV eradication.
Results
The HE and PE estimates in the 1995 birth cohort for HPV18/31/33 were significant in the gender-neutral arm and 150% and 40% stronger than in the girls-only arm. Concordantly, HPV18/31/33 eradication was already predicted in adolescents/young adults in 20 years with 75% coverage of gender-neutral vaccination. With the 75% coverage, eventual HPV16 eradication was also predicted, but only with the gender-neutral strategy.
Conclusions
Gender-neutral vaccination is superior for eradication of oncogenic HPVs.
Results from a community-randomized trial about girls-only and gender-neutral HPV vaccination strategies are presented and extended with mathematical modeling to show that gender-neutral vaccination with moderate 75% coverage will eradicate oncogenic HPV types from young adults in 20–30 years.
The Effect of Solvent on the Structure of the Radical Ions Formed from Phenazine, an EPR and ENDOR Study
Acta chemica Scandinavica/Acta chemica Scandinavica. B, Organic chemistry and biochemistry/Acta chemica Scandinavica. A, Physical and inorganic chemistry/Acta chemica Scandinavica. Series B. Organic chemistry and biochemistry/Acta chemica Scandinavica. Series A, Physical and inorganic chemistry
Journal Article
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