Ahmed Iqbal

The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib

The expansion of a leukemia clone bearing a Bcr-Abl kinase domain mutation is associated with acquired resistance to imatinib and may also predict disease progression in patients with Philadelphia-positive chronic myeloid leukemia (CML). Here we report results of pyrosequencing to quantitate the non-mutated and mutant alleles in 12 CML patients monitored over periods ranging from 11 to 58 months, and describe three contrasting kinetic patterns: Group 1 – in four patients total BCR-ABL transcript numbers remained high with the mutant allele predominating; Group 2 – in four patients the total number of BCR-ABL transcripts fell to low levels but the mutant allele predominated; and Group 3 – in four other patients the total level of transcripts remained high (n=2) or fell (n=2) but the mutant clone persisted at relatively low level. In Group 2 the mutant leukemia clone was presumably still relatively sensitive to imatinib but in Group 1 the leukemia could be classified as resistant. In Group 3 patients the imatinib sensitivity of the leukemia was variable. We conclude that a mutant clone does not necessarily have a proliferative advantage and its presence does not always account for resistance to imatinib. Other mechanisms underlie resistance in at least some patients.

Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study.

BACKGROUND Closed-loop insulin delivery is a promising option to improve glycaemic control and reduce the risk of hypoglycaemia. We aimed to assess whether overnight home use of automated closed-loop insulin delivery would improve glucose control. METHODS We did this open-label, multicentre, randomised controlled, crossover study between Dec 1, 2012, and Dec 23, 2014, recruiting patients from three centres in the UK. Patients aged 18 years or older with type 1 diabetes were randomly assigned to receive 4 weeks of overnight closed-loop insulin delivery (using a model-predictive control algorithm to direct insulin delivery), then 4 weeks of insulin pump therapy (in which participants used real-time display of continuous glucose monitoring independent of their pumps as control), or vice versa. Allocation to initial treatment group was by computer-generated permuted block randomisation. Each treatment period was separated by a 3-4 week washout period. The primary outcome was time spent in the target glucose range of 3·9-8·0 mmol/L between 0000 h and 0700 h. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01440140. FINDINGS We randomly assigned 25 participants to initial treatment in either the closed-loop group or the control group, patients were later crossed over into the other group; one patient from the closed-loop group withdrew consent after randomisation, and data for 24 patients were analysed. Closed loop was used over a median of 8·3 h (IQR 6·0-9·6) on 555 (86%) of 644 nights. The proportion of time when overnight glucose was in target range was significantly higher during the closed-loop period compared to during the control period (mean difference between groups 13·5%, 95% CI 7·3-19·7; p=0·0002). We noted no severe hypoglycaemic episodes during the control period compared with two episodes during the closed-loop period; these episodes were not related to closed-loop algorithm instructions. INTERPRETATION Unsupervised overnight closed-loop insulin delivery at home is feasible and could improve glucose control in adults with type 1 diabetes. FUNDING Diabetes UK.

Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study.

IMPORTANCE Rates of thyroid hormone prescribing in the United States and the United Kingdom have increased substantially. If some of the increase is due to lowering the thyrotropin threshold for treatment, this may result in less benefit and greater harm. OBJECTIVE To define trends in thyrotropin levels at the initiation of levothyroxine sodium therapy and the risk of developing a suppressed thyrotropin level following treatment. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE: Retrospective cohort study using data from the United Kingdom Clinical Practice Research Datalink. Among 52,298 individuals who received a prescription for levothyroxine between January 1, 2001, and October 30, 2009, we extracted data about the thyrotropin level before levothyroxine therapy initiation, clinical symptoms, and thyrotropin levels up to 5 years after levothyroxine was initiated. We excluded persons who had a history of hyperthyroidism, pituitary disease, or thyroid surgery; those who were taking thyroid-altering medication or if the levothyroxine prescription was related to pregnancy; and those who did not have a thyrotropin level measured within 3 months before the initiation of levothyroxine. MAIN OUTCOMES AND MEASURES The median thyrotropin level at the time of the index levothyroxine prescription, the odds of initiation of levothyroxine therapy at thyrotropin levels of 10.0 mIU/L or less, and the age-stratified odds of developing a low or suppressed thyrotropin level after levothyroxine therapy. RESULTS Between 2001 and 2009, the median thyrotropin level at the initiation of levothyroxine therapy fell from 8.7 to 7.9 mIU/L. The odds ratio for prescribing levothyroxine at thyrotropin levels of 10.0 mIU/L or less in 2009 compared with 2001 (adjusted for changes in population demographics) was 1.30 (95% CI, 1.19-1.42; P < .001). Older individuals and individuals with cardiac risk factors had higher odds of initiation of levothyroxine therapy with a thyrotropin level 10.0 mIU/L or less. At 5 years after levothyroxine initiation, 5.8% of individuals had a thyrotropin level of <0.1 mIU/L. Individuals with depression or tiredness at baseline had increased odds of developing a suppressed thyrotropin level, whereas individuals with cardiac risk factors (eg, atrial fibrillation, diabetes mellitus, hypertension, and raised lipid levels) did not. CONCLUSIONS AND RELEVANCE We observed a trend toward levothyroxine treatment of more marginal degrees of hypothyroidism and a substantial risk of developing a suppressed thyrotropin level following therapy. Large-scale prospective studies are required to assess the risk-benefit ratio of current practice.

TSH Levels and Risk of Miscarriage in Women on Long-Term Levothyroxine: A Community-Based Study.

CONTEXT Thyroid dysfunction is associated with adverse obstetric outcomes, but there is limited information on pregnancy outcomes in women established on levothyroxine. OBJECTIVE The objective of the study was to determine the relationship between TSH levels and pregnancy outcomes in levothyroxine-treated women in a large community-based database. DESIGN This was a historical cohort analysis. PATIENTS Individuals with a first prescription of levothyroxine from 2001 through 2009 (n = 55 501) were identified from the UK General Practice Research Database (population 5 million). Of these, we identified 7978 women of child-bearing age (18-45 y) and 1013 pregnancies in which levothyroxine had been initiated at least 6 months before conception. MAIN OUTCOME MEASURES TSH, miscarriage/delivery status, and obstetric outcomes were measured. RESULTS Forty-six percent of levothyroxine-treated women aged 18-45 years had a TSH level greater than 2.5 mU/L (recommended upper level in the first trimester). Among pregnant women who had their TSH measured in the first trimester, 62.8% had a TSH level greater than 2.5 mU/L, with 7.4% greater than 10 mU/L. Women with TSH greater than 2.5 mU/L in the first trimester had an increased risk of miscarriage compared with women with TSH 0.2-2.5 mU/L after adjusting for age, year of pregnancy, diabetes, and social class (P = .008). The risk of miscarriage was increased in women with TSH 4.51-10 mU/L [odds ratio (OR) 1.80, 95% confidence interval (CI) 1.03, 3.14)] and TSH greater than 10 mU/L (OR 3.95, 95% CI 1.87, 8.37) but not with TSH 2.51-4.5 mU/L (OR 1.09, 95% CI 0.61, 1.93). CONCLUSIONS The majority of levothyroxine-treated women have early gestational TSH levels above the recommended targets (>2.5 mU/L) with a strong risk of miscarriage at levels exceeding 4.5 mU/L. There is an urgent need to improve the adequacy of thyroid hormone replacement in early pregnancy.

A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement

Objective Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T4). Design Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T4). Methods Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T3), and T4 levels. Results Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64×10−10 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T4 (P=0.023, −0.07 s.d./allele, 95% CI −0.137, −0.01), no association was seen with free T3 (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T4 in 1981 (−0.068 s.d./allele, 95% CI −0.167, 0.031) and 1994 (−0.07 s.d./allele, 95% CI −0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T4. Conclusion Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T4 levels that are consistent over time and lost in individuals on l-T4. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.

Unsupervised home use of an overnight closed‐loop system over 3–4 weeks: a pooled analysis of randomized controlled studies in adults and adolescents with type 1 diabetes

To compare overnight closed‐loop and sensor‐augmented pump therapy in patients with type 1 diabetes by combining data collected during free‐living unsupervised randomized crossover home studies.

Diurnal Differences in Risk of Cardiac Arrhythmias During Spontaneous Hypoglycemia in Young People With Type 1 Diabetes

OBJECTIVE Hypoglycemia may exert proarrhythmogenic effects on the heart via sympathoadrenal stimulation and hypokalemia. Hypoglycemia-induced cardiac dysrhythmias are linked to the “dead-in-bed syndrome,” a rare but devastating condition. We examined the effect of nocturnal and daytime clinical hypoglycemia on electrocardiogram (ECG) in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS Thirty-seven individuals with type 1 diabetes underwent 96 h of simultaneous ambulatory ECG and blinded continuous interstitial glucose monitoring (CGM) while symptomatic hypoglycemia was recorded. Frequency of arrhythmias, heart rate variability, and cardiac repolarization were measured during hypoglycemia and compared with time-matched euglycemia during night and day. RESULTS A total of 2,395 h of simultaneous ECG and CGM recordings were obtained; 159 h were designated hypoglycemia and 1,355 h euglycemia. A median duration of nocturnal hypoglycemia of 60 min (interquartile range 40–135) was longer than daytime hypoglycemia of 44 min (30–70) (P = 0.020). Only 24.1% of nocturnal and 51.0% of daytime episodes were symptomatic. Bradycardia was more frequent during nocturnal hypoglycemia compared with matched euglycemia (incident rate ratio [IRR] 6.44 [95% CI 6.26, 6.63], P < 0.001). During daytime hypoglycemia, bradycardia was less frequent (IRR 0.023 [95% CI 0.002, 0.26], P = 0.002) and atrial ectopics more frequent (IRR 2.29 [95% CI 1.19, 4.39], P = 0.013). Prolonged QTc, T-peak to T-end interval duration, and decreased T-wave symmetry were detected during nocturnal and daytime hypoglycemia. CONCLUSIONS Asymptomatic hypoglycemia was common. We identified differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia in young adults with type 1 diabetes. Our data provide further evidence that hypoglycemia is proarrhythmogenic.

Unsupervised overnight closed loop insulin delivery during free living: analysis of randomised cross-over home studies in adults and adolescents with type 1 diabetes.

BACKGROUND The closed-loop system (artificial pancreas) delivers insulin in a glucose-responsive manner by the use of a control algorithm that automatically directs insulin delivery, based on real-time sensor glucose concentrations. Results from hospital-based studies have shown improved overnight glucose control and reduced risk of hypoglycaemia in type 1 diabetes. We aimed to assess whether unsupervised closed-loop systems can provide a realistic treatment option in patients with type 1 diabetes. METHODS We combined data from two open-label, phase 2, randomised, cross-over, unsupervised home trials of people with type 1 diabetes, one in 24 adults (mean age 43 years [SD 12], HbA1c 8·0% [0·9]) and the other in 16 adolescents (15·6 [3·6], 8·1 [0·8]). In each trial, after training on study devices, participants were allocated to two periods of sensor-augmented pump therapy either with or without overnight closed loop that used a model predictive control algorithm to direct insulin delivery. Allocation sequence was done with a computer-generated random code. Each period lasted 4 weeks in adults and 3 weeks in adolescents. Primary outcome for both trials was time when sensor glucose was in the target range (3·9-8·0 mmol/L). Analysis was by intention to treat. Participants (or parents) gave written informed consent. The trials are registered with ClinicalTrials.gov, numbers NCT01440140 and NCT01221467. FINDINGS Closed loop was started by participants on their own volition on 866 (89%) of 978 nights. The proportion of time when sensor glucose was in the target range between 0000 h and 0800 h was increased by a mean of 18·4% (95% CI 13·5-23·4, p<0·0001) during closed loop compared with no closed loop. Closed loop significantly reduced mean overnight sensor glucose by 0·9 mmol/L (95% CI 0·4-1·3, p=0·0001), and reduced the proportion of time when sensor glucose values were suggestive of hyperglycaemia (>8·0 mmol/L) (15·9%, 10·7-21·0; p<0·0001) and hypoglycaemia (<3·9 mmol/L) (median 0·9, IQR 0·2-2·2; p=0·014). Lower mean overnight glucose was associated with increased overnight insulin delivery (p<0·0001) without changing total daily insulin amount (p=0·84). INTERPRETATION Extended use of overnight closed loop at home without supervision is feasible in adults and adolescents with type 1 diabetes. Clinically significant reduction in overnight glucose was observed accompanied by reduced time spent by patients in hypoglycaemia. To our knowledge, such combined effect has not been documented with any other means of intensified conventional insulin delivery. Longer term studies are warranted to assess its clinical potential. FUNDING Diabetes UK, Juvenile Diabetes Research Foundation, NIHR Cambridge Biomedical Research Centre.

Effect of hypoglycaemia on thrombosis and inflammation in patients with type 2 diabetes

Abstract Background Increased cardiovascular mortality has been reported in trials of intensive glycaemic control in patients with type 2 diabetes. Evidence that hypoglycaemia predicts subsequent mortality in the weeks after a cardiovascular event is strong. Altered fibrin structure characteristics and subclinical inflammation have been implicated in the predisposition to cardiovascular events. We hypothesised that hypoglycaemia creates a thrombotic–inflammatory environment, contributing to increased mortality after the event. Methods Ten patients with type 2 diabetes were recruited (mean age 50 years [SD 8], duration of diabetes 9·5 years [4·6], and HbA 1c 8·7% [2·1]). They all completed paired hyperinsulinaemic clamp studies separated by at least 4 weeks. Glucose was maintained at hypoglycaemia (2·5 mmol/L) or euglycaemia (6 mmol/L) for two 60 min periods. Four timepoints were analysed: baseline, end of clamp, and days 1 and 7 post clamp in both arms. Fibrin network properties and fibrinolysis of plasma samples were assessed with a dynamic turbidimetric assay. Plasma fibrinogen concentrations were measured with the Clauss assay, and high sensitivity CRP (hsCRP) was measured with an immunoturbidimetric assay. We also analysed heart rate variability as an indicator of vagal activity. Findings Clot maximum absorbance, a measure of clot density, increased after hypoglycaemic clamp reaching a peak at day 7, whereas a decrease occurred after euglycaemic clamp (mean change from baseline [Δ] 0·040 [SD 0·093] and −0·035 [0·080], respectively; p=0·01). Clot lysis time, an indicator of fibrinolysis potential, increased after hypoglycaemic clamp up to day 7 but decreased after euclycaemic clamp (mean Δ 64 s [SD 119] vs −51 [64], p=0·02). hsCRP increased on day 7 after hypoglycaemic clamp whereas there was a reduction after euglycaemic clamp (0·80 mg/dL [0·98] vs −0·89 [0·80], p vs 0·17 [1·25], p=0·05). There were similar decreases in vagal tone as shown by high frequency heart rate variability after hypoglycaemic clamp in contrast with an increase in vagal tone after euglycaemic clamp (p=0·02) Interpretation Hypoglycaemia induces prothrombotic changes in the fibrin network and aggravates subclinical inflammation, with effects that are sustained for at least 1 week. The mechanism of these changes is unclear but might involve depression of the cholinergic anti-inflammatory pathway. Hypoglycaemia might mitigate the benefits of intensive glucose control by creating a thrombotic and inflammatory milieu. Our data provide a possible explanation for the observed increase in cardiovascular mortality weeks after a hypoglycaemic event. Funding National Institute of Health Research.

Factors Associated With Glycemic Control During Free-Living Overnight Closed-Loop Insulin Delivery in Children and Adults With Type 1 Diabetes

Unsupervised free-living overnight home use of closed-loop insulin delivery is feasible, safe, and effective in adolescents1 and adults2 with type 1 diabetes, but outcomes vary between individuals. Understanding factors influencing glucose outcomes may help to identify vulnerable populations, guide design of future studies, and lead to enhanced control algorithms. To explore associations between demographic characteristics, the use of closed-loop and glucose performance, we pooled data from 2 multicenter trials, 1 involving adolescents,1 and 1 involving adults2 with type 1 diabetes. Both studies adopted an open-label, cross-over, randomized controlled study design. Participants were randomly assigned to 4 (adults) or 3 (adolescents) weeks of sensor-augmented pump therapy with or without overnight closed-loop. An identical model-predictive-control algorithm was used in both studies.3 Participants were instructed to start the system at home after their evening meal and to discontinue it before breakfast the next morning. Detailed methods and results are reported elsewhere.1-2 In the present work, Pearson’s correlation coefficients quantified the relationship between baseline demographic factors (age, BMI, HbA1c, total daily dose), participant-level utility characteristics (average duration of closed-loop application, average start time of closed-loop) and closed-loop outcomes between midnight and 08:00 (mean glucose, time in target between 70 and 145 mg/dl, time below 70 mg/dl) (Table 1). Age and time below target were rank-normal transformed. Associations with gender were evaluated applying Spearman correlation. Multiple linear regression analysis quantified the amount of explained variability of closed-loop outcomes using demographic and utility characteristics. Table 1. Pearson’s Correlation Coefficients Between Closed-Loop Outcomes and Demographic and Utility Characteristics (N = 40). Forty participants completed the studies, including 24 adults (age 43 ± 12 years [mean ± SD]; HbA1C 64.9 ± 8.9mmol/mol, 8.1 ± 0.8%; BMI 26.0 ± 3.5kg/m2; total daily insulin dose 0.5 ± 0.1U/kg/day) and 16 adolescents (age 15.6 ± 2.1 years; HbA1C 63.9 ± 9.4mmol/mol, 8.0 ± 0.9%; BMI 22.4 ± 3.7kg/m2; total daily insulin dose 0.8 ± 0.2U/kg/day). Data on 866 closed-loop nights were analyzed. HbA1c at baseline was associated with mean glucose during closed-loop nights (r = .52, P = .001) and time with hypoglycemia (r = –.43, P = .006), but not time in target (r = –.26, P = .101). Early closed-loop start and longer closed-loop application tended to increase time in target (P = .064). There was an age-associated reduction in time in target (r = –.33, P = .038), perhaps reflecting the association between older age and shorter period of closed-loop use (r = –.58, P < .001). Of the variance in mean glucose, 33% was explained by the regression model (P = .028), with HbA1c as the only significant predictor (P = .001). For time below target, the explained variance was 36% (P = .017); earlier closed-loop start time (P = .017) and HbA1c (P = .008) were significant predictors. Only 20% of variance in time in target was explained by the regression model. The strength of the current work is that the data were collected during free-living unsupervised home closed-loop use. Weaknesses include that we did not capture at all or with low confidence other potentially influential factors such as socioeconomic and educational status, exercise patterns, and meal size and composition. In conclusion, in adolescents and adults with type 1 diabetes undergoing overnight closed-loop, baseline HbA1c is correlated with mean overnight glucose but not time in target range. Despite closed-loop, a lower HbA1c level remains a risk factor for nocturnal hypoglycemia. Improved time in target may be observed if overnight closed-loop is started earlier and applied for longer.