Sustained improvements in myocardial T2* over 2 years in severely iron‐overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine

Long‐term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion‐dependent beta thalassemia patients. In a 1‐year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [G_mean] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; G_mean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long‐term safety profile of deferasirox or DFO was consistent with previous reports; serious drug‐related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron‐overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron ( Clinicaltrials.gov identifier: NCT00600938). Am. J. Hematol. 90:91–96, 2015. © 2014 Wiley Periodicals, Inc.     

History of myocardial iron loading is a strong risk factor for diabetes mellitus and hypogonadism in adults with β thalassemia major

Endocrinopathies are common complications of transfusional hemosiderosis among patients with β thalassemia major (TM). Previous studies had shown associations between some endocrinopathies and iron overload of the myocardium, liver and/or endocrine organs as assessed by MRI techniques. This retrospective analysis of 92 patients with TM (median age 36 yr) from a tertiary adult thalassemia unit in UK aimed to determine independent risk factors associated with endocrinopathies among these patients. Unlike previous studies, longitudinal data on routine measurements of iron load [worst myocardial and liver T2* values since 1999, worst LIC by MRI‐R2 since 2008 and average 10‐yr serum ferritin (SF)] up to April 2010 together with demographic features and age of initiating chelation were analyzed for associations with endocrinopathies. The most common endocrinopathies in this cohort were hypogonadism (67%) and diabetes mellitus (DM) (41%), and these were independently associated with myocardial T2* <20 ms (P < 0.001 and P = 0.008, respectively) and increased age (P = 0.002 and P = 0.016, respectively). DM and hypogonadism were independently associated with average SF >1250 μg/L (P = 0.003) and >2000 μg/L (P = 0.047), respectively. DM was also associated with initial detection of abnormal myocardial T2* at an older age (30 yr vs. 24 yr, P = 0.039). An abnormal myocardial T2* may therefore portend the development of DM and hypogonadism in patients with TM.     

Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5‐year long‐term Italian multicenter randomized clinical trial

In patients with thalassemia intermedia (TI), such as beta‐TI, alpha‐thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta‐thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5‐year long‐term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P‐value = 0.035). The overall period of observation was 235.2 person‐years for the deferiprone patients compared with 214.3 person‐years for the deferoxamine patients. The results of the log‐rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P‐value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long‐term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated. Am. J. Hematol. 90:634–638, 2015. © 2015 Wiley Periodicals, Inc.     

Serum ferritin levels and endocrinopathy in medically treated patients with β thalassemia major

The association between iron overload indices and pathology of the heart and liver in transfusion-dependent patients with β thalassemia major (TM) has been extensively studied. Nonetheless, data on endocrine disease remains limited. This was a cross-sectional study of 382 TM patients treated with regular transfusions and desferrioxamine at the Thalassemia Center in Dubai, UAE. Retrieved data included demographics, splenectomy status, steady-state serum ferritin levels, and the presence of endocrinopathies (diabetes mellitus, hypothyroidism, hypoparathyroidism, and hypogonadism). Multivariate logistic regression analyses were used to determine which variables were independently associated with the occurrence of each endocrinopathy. The mean age of patients was 15.4?±?7.6?years, with an equal sex distribution. The mean serum ferritin level was 2597.2?±?1976.8?μg/l. The frequencies of specific endocrinopathies were diabetes mellitus (10.5%), hypothyroidism (6.3%), hypoparathyroidism (10.5%), and hypogonadism (25.9%). On multivariate logistic regression analysis, patients with a serum ferritin level >2,500?μg/l, but not >1,000-2,500?μg/l, were 3.53 times (95% CI 1.09-11.40) more likely to have diabetes mellitus, 3.25 times (95% CI 1.07-10.90) more likely to have hypothyroidism, 3.27 times (95% CI 1.27-8.39) more likely to have hypoparathyroidism, and 2.75 times (95% CI 1.38-5.49) more likely to have hypogonadism compared to patients with a serum ferritin level ≤1,000?μg/l. However, splenectomized patients with serum ferritin levels ≤2,500?μg/l had comparably high rates of all endocrinopathies as patients with serum ferritin levels >2,500?μg/l. Endocrinopathy is common in TM patients treated with desferrioxamine therapy, especially in patients with serum ferritin levels >2,500?μg/l or those splenectomized.     

The effect of iron chelation therapy on overall survival in sickle cell disease and β‐thalassemia: A systematic review

Red blood cell transfusions have become standard of care for the prevention of life‐threatening anemia in patients with β‐thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event‐free survival in patients with β‐thalassemia and SCD. Eighteen articles discussing survival in β‐thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second‐generation oral agents, appears to be associated with improved overall and event‐free survival in transfusion‐dependent patients with β‐thalassemia and patients with SCD.     

Optimising management of deferasirox therapy for patients with transfusion‐dependent thalassaemia and lower‐risk myelodysplastic syndromes

Effective iron chelation therapy is an important part of treatment in patients with transfusion‐dependent thalassaemia and lower‐risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion‐dependent thalassaemia or lower‐risk MDS showed better adherence to the deferasirox film‐coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion‐dependent thalassaemia and lower‐risk MDS.     

The impact of two different doses of chelating therapy (deferasirox) on echocardiographic tissue Doppler indices in patients with thalassemia major

Background: Chelating therapy in transfusion‐dependent patients with β‐thalassemia major (β‐TM) is mandatory to reduce the toxic effect of iron on the myocardium. Aim: To evaluate the impact of low and high dose of oral chelating therapy (deferasirox) on pulsed and tissue echocardiographic indices in patients with β‐TM. Methods: This interventional study conducted on patients with transfusion‐dependent β‐TM (n = 38) on deferasirox 20 mg/kg/d medication, group (DFX‐20) for at least 6 months, followed by administration of a higher dose of deferasirox, 40 mg/kg/d, group (DFX‐40) for another 6 months. Pulsed and tissue Doppler echocardiography carried out at the beginning and at the end of treatment interval (6 months) for both groups, with monthly blood analysis of serum ferritin, alanine transaminase, hemoglobin, and creatinine. An age‐matched control group of 38 patients was evaluated for echo Doppler blood analysis. Results: Patients of group DXF‐40 compared with group DFX‐20, the tissue Doppler echocardiogram showed lower E/Em ratio (16.01 ± 2.85 vs. 19.68 ± 2.81, P < 0.05), higher systolic wave velocity (Sm) (5.87 ± 1.40 vs. 4.80 ± 1.20, P < 0.05), and higher early diastolic wave (Em) velocity (4.25 ± 1.70 vs. 3.50 ± 1.80, P < 0.05), respectively. Patients in group DFX‐20, compared with control group, had M‐Mode echo with thicker left ventricle (LV) septal wall (P < 0.001) and posterior wall (P < 0.01), higher left ventricle end diastolic diameter index (P < 0.05). The pulsed Doppler echocardiogram showed a higher LV transmitral E wave velocity (P < 0.05), higher E/A ratio (P < 0.01), and the duration of deceleration time was significantly shorter (P < 0.01). There were no significant changes observed in the left ventricle ejection fraction percentage (LVEF%) or fractional shortening between both treatment groups. Serum ferritin was significantly lower in DFX‐40 group compared with DFX‐20 β‐TM group (338). There was a significant positive correlation between the serum ferritin and the E/Em ratio (r = 0.31, P < 0.001). The tricuspid valve velocity was significantly higher in β‐TM patients compared with the control group (P < 0.05). Conclusion: The increment of oral deferasirox as chelating therapy in β‐TM patients to 40 mg/kg/d over 6 months duration showed a significant increments of systolic and diastolic tissue Doppler velocities with a significant reduction of E/Em ratio in comparison with 20 mg/kg/d. There were no changes of LVEF. A longer duration of follow‐up may be justified in such group of patients.     

Increased leucocyte apoptosis in transfused β‐thalassaemia patients

This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from β‐thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase‐3/7, 48% higher caspase‐8 and 88% higher caspase‐9 activities and 428% more nucleosomal DNA fragmentation than control subjects. Only neutrophils correlated significantly with apoptotic markers. Previously, we showed that over the treatment year, hepatic iron declined; we now show that the ratio of Bax/Bcl‐2 (BCL2), (−27·3%/year), and caspase‐9 activity (−13·3%/year) declined in both treatment groups, suggesting that chelation decreases body iron and indicators of PBL apoptosis.     

Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non‐transfusion‐dependent thalassaemia

Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non‐transfusion‐dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade^® in non‐transfusion‐dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron‐overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).     

Dipeptidyl‐peptidase IV inhibitor is effective in patients with type 2 diabetes with high serum eicosapentaenoic acid concentrations

Aims/Introduction: Eicosapentaenoic acid (EPA) stimulates glucagon‐like peptide‐1 (GLP‐1) secretion in mice. We investigated the relationship between serum EPA concentrations and the efficacy of dipeptidyl‐peptidase IV (DPP‐4) inhibitor in patients with type 2 diabetes. Materials and Methods: Serum EPA concentrations were measured in 62 consecutive patients with type 2 diabetes who were newly given DPP‐4 inhibitor as a monotherapy or as an add‐on therapy to oral hypoglycemic agents. The dosage of oral hypoglycemic agents was maintained during the observation period. After 24 weeks of treatment with DPP‐4 inhibitor, we evaluated the relationships between a decrease in hemoglobin A1c from baseline and serum EPA concentrations, as well as age, sex, body mass index (BMI), hemoglobin A1c at baseline and usage of antidiabetic concomitant drugs. Results: Hemoglobin A1c was significantly decreased from 8.1 ± 1.1% to 7.2 ± 1.0% by DPP‐4 inhibitor. A decrease in hemoglobin A1c correlated with BMI (r = ?0.396, P = 0.0013), age (r = 0.275, P = 0.0032), hemoglobin A1c at baseline (r = 0.490, P < 0.0001) and log EPA (r = 0.285, P = 0.0246). Multiple regression analysis showed that BMI (β = ?0.419, P = 0.0002), hemoglobin A1c at baseline (β = 0.579, P < 0.0001) and log EPA (β = 0.220, P = 0.0228) were independent determinants of decrease in hemoglobin A1c. Conclusions: DPP‐4 inhibitor is effective in patients with type 2 diabetes with high serum EPA concentrations. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00220.x , 2012)     

Deferasirox treatment of iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes in medical practice: results from the observational studies eXtend and eXjange

EXtend and eXjange were prospective, 1‐yr, non‐interventional, observational, multicentre studies that investigated deferasirox, a once‐daily oral iron chelator, in iron‐overloaded chelation‐naïve and prechelated patients with myelodysplastic syndromes (MDS), respectively, treated in the daily‐routine setting of office‐based physicians. No inclusion or exclusion criteria or additional monitoring procedures were applied. Deferasirox was administered as recommended in the European Summary of Product Characteristics. Haematological parameters and adverse events (AEs) were collected at two‐monthly intervals. Data from 123 chelation‐naïve patients with MDS (mean age 70.4 yrs) with median baseline serum ferritin level of 2679 (range 184–16 500) ng/mL, and 44 prechelated patients with MDS (mean age 69.6 yrs) with median baseline serum ferritin level of 2442 (range 521–8565) ng/mL, were assessed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. Treatment with deferasirox produced a significant reduction in median serum ferritin levels in chelation‐naïve patients with MDS from 2679 to 2000 ng/mL (P = 0.0002) and a pronounced decrease in prechelated patients with MDS from 2442 to 2077 ng/mL (P = 0.06). The most common drug‐related AEs were gastrointestinal, increased serum creatinine levels and rash. These studies demonstrate that deferasirox used in physicians’ medical practices is effective in managing iron burden in transfusion‐dependent patients with MDS.     

Iron chelator deferasirox rescued mice from Fas‐induced fulminant hepatitis

Aim: Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long–Evans cinnamon rats was prevented by feeding an iron‐deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once‐daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis. Methods: Human primary hepatocytes undergoing Fas‐stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas‐stimulation. Results: The apoptosis‐inducing activity of anti‐Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas‐induced production of reactive oxygen species (ROS) and the activation of caspase‐3, both of which were also suppressed by antioxidant, N‐acetyl‐L‐cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas‐induced fulminant hepatitis. Conclusion: These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase‐3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.     

Comparative effectiveness of once‐weekly glucagon‐like peptide‐1 receptor agonists with regard to 6‐month glycaemic control and weight outcomes in patients with type 2 diabetes

A retrospective cohort study was conducted in patients with type 2 diabetes in an electronic medical record database to compare real‐world, 6‐month glycated haemoglobin (HbA1c) and weight outcomes for exenatide once weekly with those for dulaglutide and albiglutide. The study included 2465 patients: exenatide once weekly, n = 2133; dulaglutide, n = 201; and albiglutide, n = 131. The overall mean (standard deviation [s.d.]) age was 60 (11) years and 54% were men; neither differed among the comparison groups. The mean (s.d.) baseline HbA1c was similar in the exenatide once‐weekly (8.3 [1.7]%) and dulaglutide groups (8.5 [1.5]%; P = .165), but higher in the albiglutide group (8.7 [1.7]%; P < .001). The overall mean (s.d.) HbA1c change was ?0.5 (1.5)% (P < .001) and this did not differ among the comparison groups in either adjusted or unadjusted analyses. The mean (s.d.) weight change was ?1.4 (4.7) kg for exenatide once weekly and ?1.6 (3.7) kg for albiglutide (P = .579), but was greater for dulaglutide, at ?2.7 (5.7) kg (P = .001). Outcomes were similar in subsets of insulin‐naive patients with baseline HbA1c ≥7.0% or ≥9.0%. All agents significantly reduced HbA1c at 6 months, with no significant differences among agents or according to baseline HbA1c in insulin‐naive subgroups.     

Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1‐yr Phase 2 study

This open‐label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12‐month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients.     

Hub‐and‐spoke model for a 5‐day structured patient education programme for people with Type 1 diabetes

Aims Structured education programmes for people with Type 1 diabetes can deliver improved diabetes control (including reduced severe hypoglycaemia) and quality of life. They can be cost‐effective but are resource intensive. We tested the ability to deliver an evidence‐based 5‐day programme in diabetes centres too small to deliver the courses. Methods Specialist medical and nursing staff from three district general hospital diabetes services (the ‘spokes’) were trained in all aspects of the education programme, except those directly related to course delivery, by a larger centre (the ‘hub’). The hub staff delivered the 5‐day patient education courses, but all other patient education and management was managed locally. Diabetes control and quality of life were assessed at 1 year post‐course. Results In 63 patients with follow‐up data, glycated haemoglobin (HbA_1c) fell by 0.42 ± 1.0% (P = 0.001), with a greater fall in those with high HbA_1c at baseline, and no mean weight gain. Emergency call‐out for severe hypoglycaemia fell from 10 episodes in seven patients the year before to one episode in one patient (P = 0.03). Quality‐of‐life measures improved, with reduced negative impact of diabetes on diabetes‐related quality of life (P < 0.00004) and ‘present quality of life’ improving (P < 0.001). Conclusions The benefits of a 5‐day structured education programme can be provided to patients with Type 1 diabetes attending centres without the resources to provide the teaching course itself, by a ‘hub‐and‐spoke’ methodology.     

Longitudinal monitoring of cardiac siderosis using cardiovascular magnetic resonance T2* in patients with thalassemia major on various chelation regimens: A 6‐year study

Cardiovascular magnetic resonance (CMR) and hepatic magnetic resonance imaging (MRI) have become reliable noninvasive tools to monitor iron excess in thalassemia major (TM) patients. However, long‐term studies are lacking. We reviewed CMR and hepatic MRI T2* imaging on 54 TM patients who had three or more annual measurements. They were managed on various chelation regimens. Patients were grouped according to their degree of cardiac siderosis: severe (T2*, <10 msec), mild to moderate (T2* = 10–20 msec), and no cardiac siderosis (T2*, >20 msec). We looked at the change in cardiac T2*, liver iron concentration (LIC) and left ventricular ejection fraction (LVEF) at years 3 and 5. In patients with severe cardiac siderosis, cardiac T2* (mean ± SD) improved from 6.9 ± 1.6 at baseline to 13.6 ± 10.0 by year 5, mean ΔT2* = 6.7 (P = 0.04). Change in cardiac T2* at year 3 was not significant in the severe group. Patients with mild to moderate cardiac siderosis had mean cardiac T2* of 14.6 ± 2.9 at baseline which improved to 26.3 ± 9.5 by year 3, mean ΔT2* = 11.7 (P = 0.01). At baseline, median LICs (mg/g dry weight) in patients with severe, mild–moderate, and no cardiac siderosis were 3.6, 2.8, and 3.3, whereas LVEFs (mean ± SD) (%) were 56.3 ± 10.1, 60 ± 5, and 66 ± 7.6, respectively. No significant correlation was noted between Δ cardiac T2* and Δ LIC, Δ cardiac T2*, and Δ LVEF at years 3 and 5. Throughout the observation period, patients with no cardiac siderosis maintained their cardiac T2* above 20 msec. The majority of patients with cardiac siderosis improve cardiac T2* over time with optimal chelation. Am. J. Hematol. 88:652–656, 2013. © 2013 Wiley Periodicals, Inc.     

New film‐coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower‐risk MDS: Results of the randomized,phase II ECLIPSE study

Once‐daily deferasirox dispersible tablets (DT) have a well‐defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater patient adherence, satisfaction, and quality of life. However, barriers still exist to optimal adherence, including gastrointestinal tolerability and palatability, leading to development of a new film‐coated tablet (FCT) formulation that can be swallowed with a light meal, without the need to disperse into a suspension prior to consumption. The randomized, open‐label, phase II ECLIPSE study evaluated the safety of deferasirox DT and FCT formulations over 24 weeks in chelation‐naïve or pre‐treated patients aged ≥10 years, with transfusion‐dependent thalassemia or IPSS‐R very‐low‐, low‐, or intermediate‐risk myelodysplastic syndromes. One hundred seventy‐three patients were randomized 1:1 to DT (n = 86) or FCT (n = 87). Adverse events (overall), consistent with the known deferasirox safety profile, were reported in similar proportions of patients for each formulation (DT 89.5%; FCT 89.7%), with a lower frequency of severe events observed in patients receiving FCT (19.5% vs. 25.6% DT). Laboratory parameters (serum creatinine, creatinine clearance, alanine aminotransferase, aspartate aminotransferase and urine protein/creatinine ratio) generally remained stable throughout the study. Patient‐reported outcomes showed greater adherence and satisfaction, better palatability and fewer concerns with FCT than DT. Treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%). This analysis suggests deferasirox FCT offers an improved formulation with enhanced patient satisfaction, which may improve adherence, thereby reducing frequency and severity of iron overload‐related complications.     

Metformin and β‐cell function in insulin‐treated patients with type 2 diabetes: A randomized placebo‐controlled 4.3‐year trial

In this trial, 390 insulin‐treated patients with type 2 diabetes were randomized to either placebo or metformin. Fasting levels of glucose, insulin and C peptide were determined at baseline, after 4 months and yearly thereafter for 4 years to assess fasting estimates of beta cell function. The primary endpoint was the fasting C peptide‐to‐glucose ratio (FCPGR) and secondary measures were the disposition index (DI) and the fasting C peptide (FCP). We analysed the results with a general linear mixed model. Baseline FCPGR was 5.27 (95% CI, 4.83 – 5.71). Compared to placebo, FCPGR increased in the metformin group with 1.48 (95% CI, 1.09 – 1.87, P < 0.001). The DI showed comparable results with a treatment effect of 1.50 (95% CI, 1.17 – 1.83; P < 0.001). FCP also increased in the metformin group but did not reach statistical significance vs placebo (0.034 nmol, 95% CI, ?0.005 – 0.072; P = 0.085). Treatment with metformin vs placebo, added to insulin in patients with type 2 diabetes, improves long‐term estimates of beta cell function in the fasting state.     

The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the major‐intermedia dichotomy?

In the last few decades, the life expectancy of regularly transfused β‐thalassaemia major (TM ) patients has dramatically improved following the introduction of safe transfusion practices, iron chelation therapy, aggressive treatment of infections and improved management of cardiac complications. How such changes, especially those attributed to the introduction of iron chelation therapy, improved the survival of TM patients to approach those with β‐thalassaemia intermedia (TI ) remains unknown. Three hundred and seventy‐nine patients with TM (n  = 284, dead 40) and TI (n  = 95, dead 13) were followed retrospectively since birth until 30 June 2015 or death. Kaplan‐Meir curves showed statistically significant differences in TM and TI survival (P  <  0·0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P  =  0·086), reducing the Hazard Ratio of death in TM compared to TI from 6·8 [95% confidence interval (CI ) 2·6–17·5] before 1965 to 2·8 (95% CI 0·8–9·2). These findings suggest that, in the era of iron chelation therapy and improved survival for TM , the major‐intermedia dichotomy needs to be revisited alongside future directions in general management and prevention for both conditions.     

Saxagliptin add‐on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin with or without metformin: Results from the SUPER study,a randomized,double‐blind,placebo‐controlled trial

This prospective, multicentre, phase III study (NCT02104804) evaluated the efficacy and safety of saxagliptin add‐on therapy in Chinese patients with type 2 diabetes inadequately controlled by insulin ± metformin. Patients with glycated haemoglobin (HbA1c) 7.5% to 10.5% and fasting plasma glucose (FPG) <15 mmol/L (270 mg/dL) on stable insulin therapy (20‐150 U/d) were randomized (1:1) to saxagliptin 5 mg once daily (N = 232) or placebo (N = 230) for 24 weeks, stratified by metformin use. The primary efficacy measure was change in HbA1c. Saxagliptin treatment resulted in a greater adjusted mean change in HbA1c from baseline to week 24 than placebo (?0.58%; P < .001), irrespective of metformin use, and a greater mean change in FPG (0.9 mmol/L [?15.9 mg/dL]; P < .001). More patients achieved HbA1c <7% with saxagliptin (11.4%) than with placebo (3.5%, P = .002). Adverse events and incidence of hypoglycaemia were similar in both groups. Overall, add‐on saxagliptin 5 mg once daily significantly improved glycaemic control without increasing hypoglycaemia risk and was well tolerated in Chinese patients with type 2 diabetes inadequately controlled by insulin (± metformin).