http://informahealthcare.com/hem ISSN: 0363-0269 (print), 1532-432X (electronic) Hemoglobin, 2014; 38(2): 104–110 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03630269.2013.862541
ORIGINAL ARTICLE
Joint Diabetes Thalassaemia Clinic: An Effective New Model of Care Ploutarchos Tzoulis, Farrukh Shah, Romilla Jones, Emma Prescott, and Maria Barnard
Abstract
Keywords
Diabetes is a significant complication of b-thalassemia major (b-TM) and most patients receive fragmented diabetes care. In 2005, we developed a unique Joint Diabetes Thalassaemia Clinic, based at the Department of Diabetes, Whittington Health, London, UK, where patients were reviewed jointly by a multidisciplinary team, including Consultant Diabetologist and Hematologist. Study of the Joint Diabetes Thalassaemia Clinic (2005–2009) showed improvement in glycemic control with fructosamine reduction from 344 umol/L to 319 umol/L over a 1-year period as well as improvement in lipid profiles. The proportion of patients attending the Joint Clinic who achieved metabolic targets compared to the National Diabetes Audit for England was higher for glycemic control (73.0 Joint Diabetes Thalassaemia Clinic vs. 63.0% nationally), blood pressure control (58.0 Joint Diabetes Thalassaemia Clinic vs. 30.0% nationally) and cholesterol control (81.0 Joint Diabetes Thalassaemia Clinic vs. 78.0% nationally). Five patients (22.7%) had microvascular complications. A significant proportion of our patients had endocrinopathies (86.0% hypogonadism, 18.0% hypothyroidism, 23.0% hypoparathyroidism). The unique partnership of our Joint Diabetes Thalassaemia Clinic, allowed these very complex patients to be managed effectively.
Complications, diabetes mellitus, endocrinopathies, b-thalassemia major (b-TM)
Introduction Diabetes mellitus is a significant complication of b-thalassemia major (b-TM). The prevalence of diabetes in b-TM patients has been estimated to be between 3.2 and 18.8%. The variability in estimated prevalence between studies relates to the efficacy of iron chelation therapy and the different ages of the patients being studied, with some studies including mainly children and adolescents (1–4). Diabetes mellitus in patients with b-TM is caused mainly by hemosiderosis as a result of transfusional iron overload. It has been predominantly attributed to a combination of reduced insulin secretory capacity and insulin resistance. A defect in b cell insulin secretion can be present early before the development of glucose intolerance and results from the toxic effects of iron deposition in the pancreas (5). Insulin resistance also plays an important role and is caused by iron deposition in both liver and muscle (6,7). Other factors also contribute to impaired glucose metabolism such as poor compliance with chelation therapy and advanced age at onset of chelation therapy (8), genetic factors (9), family history of diabetes mellitus, autoimmunity (10), and hepatitis C viral infection (9,11). Patients with b-TM and diabetes are a very
Address correspondence to Dr. Ploutarchos Tzoulis, Department of Diabetes, Whittington Health, Magdala Avenue, London, N19 5NF, UK; Tel: +44-20-7794-0500, ext. 35956. Fax: +44-20-7431-6435. E-mail: [email protected]
History Received 30 May 2013 Revised 10 July 2013 Accepted 22 July 2013 Published online 18 December 2013
heterogenous group with some individuals exhibiting mainly insulin deficiency and others with predominantly insulin resistance. The life expectancy of patients with b-TM has been improving constantly during recent decades. Intensive iron chelation therapy regimens and more effective management of iron overload have prolonged and improved the quality of life in patients with b-TM (3). Despite the markedly improved survival, patients continue to develop various complications, including diabetes mellitus. Effective management and optimal control of diabetes has become very important since these patients are now expected to live for decades after the development of diabetes. Thus, a critical aim should be the prevention, detection and management of diabetic complications, including macrovascular complications (cardiovascular disease, cerebrovascular disease and peripheral vascular disease) and microvascular complications (diabetic retinopathy, nephropathy and neuropathy) that can cause significant morbidity and mortality. There are specific issues to consider in the management of patients with diabetes and b-TM. Intensification of iron chelation therapy has been shown to improve glycemic control (12,13). The choice of antidiabetic treatment in b-TM is dependent on the severity of b cell damage and insulin deficiency. Insulin remains the mainstay of treatment for individuals with severe insulin deficiency. For other patients with diabetes detected early with mild hyperglycemia, a focus on self-management and lifestyle changes, including healthy diet and weight reduction, are important. In these patients, oral antidiabetic drugs are also increasingly prescribed.
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Department of Diabetes, Whittington Health, London, UK
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The use of metformin (14), sulphonylureas (15) and acarbose (16) in diabetes and b-TM has been described, but there is very limited published data on the role of these different agents. The management of diabetes in b-TM can pose various challenges. Women with b-TM and diabetes can become pregnant and suboptimal glycemic control in pregnancy can lead to a 3-fold increased risk of congenital malformation and 4-fold increase in perinatal mortality (17). Insulin initiation or intensification has been reported to cause fluid retention and lead to heart failure (18). Living with diabetes and b-TM can also have a major psychological impact since a large proportion of patients with b-TM have severe psychosocial problems and diabetes is also associated with high incidence of depression and anxiety (19,20). According to the National Haemoglobinopathy Registry, the number of patients with b-TM in the UK is 756. The majority of patients with this rare condition in the UK have been managed in clinics with less than 10 patients (21). Care networks have been established in the UK incorporating local thalassemia clinics and one Specialised Thalassaemia Centre for each region in order to ensure access to optimal, specialized management guidance as well as provision of routine care conveniently close to home (22). In view of the rarity of this condition, most Diabetologists in the UK have very limited experience in managing diabetes in patients with b-TM. Care can become fragmented without close liaison with other specialists involved in patient care. We therefore set up a unique clinic where patients are seen jointly by a dedicated Haematologist and Diabetologist at our institution in order to improve the care of patients with b-TM and diabetes. The present study aimed to assess the effect of this unique Joint Diabetes Thalassaemia Clinic on the patient’s metabolic control, as well as to measure the prevalence of diabetic complications, diabetic emergencies and endocrinopathies in this cohort.
Materials and methods In 2005, a Joint Diabetes Thalassaemia Clinic, based at the Department of Diabetes, Whittington Health, London, UK, was introduced at our institution which provides care for the largest cohort of b-TM patients in the UK. Prior to this, patients with diabetes and b-TM were reviewed by different diabetes clinicians in a variety of diabetes clinics. For patients with complex medical needs, this provided an inadequate level of care. The aims of the Joint Diabetes Thalassaemia Clinic were to provide high quality diabetes, endocrine and hematology care; to optimize metabolic control; to support patient self-management; and to support partnership working, both between the specialist teams and between patients and clinicians. Our institution provides care for 102 adult patients with b-TM. All patients undergo an annual Oral Glucose Tolerance Test with 75 g of oral glucose load, apart from those already diagnosed with diabetes mellitus. Amongst 102 patients, 52 females and 50 males, with a median age of 35.5 years (range 18–58 years), the prevalence of diabetes was 37.2%. Sixteen patients (15.7%) had milder abnormalities in glucose regulation, such as impaired glucose tolerance and impaired
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fasting glycemia. The glycemic status was unknown in 5.9% of patients and the remaining 41.2% of patients had normal glucose handling. Amongst 38 patients with b-TM and diabetes at our institution, only 22 (57.8%) selected patients with complex problems and needs were assessed at the Joint Diabetes Thalassaemia Clinic. Patients were seen jointly by a multidisciplinary team of a dedicated Consultant Diabetologist, Consultant Haematologist, Diabetes Specialist Nurse and Haematology Specialist Nurse. A specified Diabetes Dietitian supported the clinic. There was access to structured education courses for diabetes, including training for carbohydrate counting and insulin dose adjusting. Patients could be referred to a specified Clinical Psychologist, with experience in enabling patients to cope with issues relating to b-TM. Generally, patients were reviewed at the Joint Diabetes Thalassaemia Clinic every 6–9 months. Interim reviews to optimize glycemic control and self-management skills were provided by the Diabetes Specialist Nurse and Diabetes Dietitian. Once a year at the Joint Diabetes Thalassaemia Clinic, patients should have all measurements according to the standard recommendations for diabetes. All patients with diabetes were recommended to receive the following nine Key Care Processes at least once a year: measurement of glycemic control, blood pressure, serum cholesterol, serum creatinine, urinary albumin and weight, foot assessment, smoking status assessment and retinal screening (23,24). The management targets according to the Quality and Outcomes Framework guidance in the UK were Hb A1c 57.5%, blood pressure 5135/75 mm Hg and total cholesterol 55.0 mmol/L (25). Glycemic control was assessed using both patient home blood glucose monitoring results and fructosamine levels, since Hb A1c levels can be inaccurate in patients with hemoglobinopathies receiving repeated transfusions. Our institution’s laboratory provided a correction factor for converting fructosamine to an equivalent Hb A1c level, where fructosamine of 322 umol/L is equivalent to Hb A1c of 7.0% and fructosamine of 46 is equivalent to Hb A1c of 1.0%. The performance of the Joint Diabetes Thalassaemia Clinic was assessed by retrospective analysis of data from 81 consultations of 22 patients attending the Clinic between December 2005 to December 2009. In each consultation, a diabetes proforma was filled including information about metabolic parameters, complications and diabetic emergencies. Data were extracted from diabetic proformas and results from the laboratory server. The results of our cohort were compared to the results of the National Diabetes Audit for England in 2007–2008 which were the best available data for patients with diabetes in the UK (25). In addition, data were collected about the prevalence of microvascular complications (as defined by diabetic nephropathy, retinopathy and neuropathy), macrovascular complications (as defined by ischemic heart disease, cerebrovascular disease and peripheral vascular disease), diabetic emergencies (diabetic ketoacidosis and hyperglycemic hyperosmolar state), and endocrinopathies (including hypogonadism, hypothyroidism, hypoparathyroidism, deficiency of glucocorticoids or growth hormone, osteopenia and osteoporosis). This study was registered as
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an audit at the Whittington Health and followed the principles in the Declaration of Helsinki. The standards of care provision at this Joint Diabetes Thalassaemia Clinic were assessed by: (1) comparing the percentage of patients having the Key Care Processes for diabetes performed with the percentage in the National Diabetes Audit; (2) comparing the proportion of patients who achieved metabolic targets to the data in the National Diabetes Audit; (3) longitudinal analysis of fructosamine, blood pressure and serum cholesterol. Data were also collected to measure: (1) the prevalence of microvascular complications; (2) the prevalence of macrovascular complications; (3) the prevalence of diabetic emergencies (diabetic ketoacidosis or hyperglycemic hyperosmolar state); (4) the prevalence of other endocrinopathies. Hemoglobin Downloaded from informahealthcare.com by University of Newcastle on 10/04/14 For personal use only.
Results From December 2005 to December 2009, 22 patients were reviewed at the Joint Diabetes Thalassaemia Clinic and overall had 81 consultations. The median number of consultations was 3.5 per patient with a wide range from one consultation in five patients to nine consultations in one patient. Where patients had only one or two reviews at the Joint Diabetes Thalassaemia Clinic, follow-up data was not usually adequate to assess changes in parameters. Background characteristics The patients’ median age was 39 years (range 28–59 years old). Thirteen patients were female (59.0%) and nine were male (41.0%). Patient ethnic origin was Greek or Greek Cypriot in eight patients (36.0%) and South Asian (Indian, Pakistani, Bangladeshi) in 14 (64.0%) (Table 1). The median duration of diabetes was 13 years (range51 year to 29 years). The median age of onset of diabetes was 21 years of age (range 10–40 years), with nine patients (41.0%) diagnosed before the age of 19 years. At the first appointment, four patients were smokers (18.0%). The median body mass index (BMI) was 24.8 kg/m2: 11 patients (50.0%) had normal BMI (18.5–25.0); nine patients (40.9%) were overweight (BMI 25–30 kg/m2); only two patients (9.1%) were obese (BMI 430 kg/m2). The median ferritin at first appointment was 1827 ug/L (range 600–6143 ug/L). Data were also collected about liver iron concentrations, assessed by magnetic resonance imaging (MRI)-proton transverse relaxation rates (R2) (FerriScanÕ analysis;
Resonance Health Inc., Perth, Western Australia), hepatitis C infection and patients who were splenectomized. In terms of liver disease, all patients had MRI liver scans performed and mean liver R2 were measured between January 2008 and December 2009. The liver iron concentrations obtained with FerriScan R2 (Resonance Health Inc.) are known to correlate well with iron concentrations based on liver biopsy (26). The widely accepted cut-off of liver iron concentration of 7 mg iron per gram liver, dry weight, was used as the upper limit of optimal range for transfusional iron overload and as the threshold for increased risk of iron-induced complications (26). Based on this cut-off, eight patients (36.0%) had hepatic iron overload and all these patients apart from one required treatment with insulin. Three patients (14.0%) had hepatitis C infections and 11 patients (50.0%) were splenectomized. Patients were on medications for diabetes and management of diabetic complications. In terms of glucose-lowering agents: 16 patients (73.0%) were on insulin; six patients (27.0%) were on oral antidiabetic drugs (metformin or glimepiride); three patients (14.0%) were on diet control alone. Five patients (23.0%) were on antihypertensive medications [angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor antagonists]. Five patients (23.0%) were on lipid lowering agents (statins or fibrates). Seven patients (32.0%) were on antiplatelet agents (aspirin) or anticoagulant therapy (warfarin). Monitoring In patients attending the Joint Diabetes Thalassaemia Clinic, the Key Processes for diabetes care were performed at a rate much greater than that achieved in the National Diabetes Audit for England (2007–2008) (Table 2). This included better rates of measurement of fructosamine, serum cholesterol, serum creatinine, urinary albumin:creatinine ratio (ACR) and weight (BMI), foot assessment and smoking status assessment. The only key care process performed at a lower rate at the Joint Diabetes Thalassaemia Clinic compared to the national data was measurement of blood pressure; the most likely explanation is that on some occasions physicians did not record blood pressure on the diabetes proforma because these patients had several recent measurements of blood pressure during regular blood transfusions. No data were available about the percentage of Table 2. Performance of Key Care Processes at the Joint Diabetes Thalassaemia Clinic Compared to the National Diabetes Audit for England. Performance of Key Care Processes
Table 1. Background Characteristics of Patients Attending the Joint Diabetes Thalassaemia Clinic. Age Ethnicity Diabetes duration Age at onset of diabetes Diabetes therapy
a
Median age and range.
39 years
a
Greek/Greek Cypriot South Asian 13 yearsa 21 yearsa insulin oral agents diet only
range: 28–59 years
a
36.0% 64.0% range: 51–29 yearsa range: 10–40 yearsa 73.0% 27.0% 14.0%
Care Process Fructosamine/Hb A1c Serum cholesterol Serum creatinine Albuminuria Weight/BMI Blood pressure Foot assessment Smoking status
Joint Diabetes Thalassaemia Clinic (2005–2009) (%)
National Diabetes Audit UK (2007–2008) (%)
97.5 91.1 100.0 91.1 97.5 80.4 89.3 89.2
91.1 89.9 91.2 62.7 88.8 93.7 77.1 86.5
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Table 3. Rate of Achievement of Treatment Targets at the Joint Diabetes Thalassaemia Clinic Compared to the National Diabetes Audit for England (2007–2008). Percentage of Patients Achieving Treatment Targets Target
Joint Diabetes Thalassaemia Clinic (2005–2009) (%)
National Diabetes Audit UK (2007–2008) (%)
72.7 57.9 82.1
62.9 30.1 78.0
Fructosamine 5345 umol/L or Hb A1c 57.5% Blood pressure 5135/75 mmHg Cholesterol 55.0 mmol/L
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Table 4. Changes in Metabolic Control at the Joint Diabetes Thalassaemia Clinic Over a 1-Year Period.
Parameters
First Appointment
1-Year Follow-Up
Change
Fructosamine Blood pressure Total cholesterol
344 umol/L 122/70 mmHg 3.8 mmol/L
319 umol/L 124/77 mmHg 3.5 mmol/L
25 umol/L þ2/7 mmHg 0.3 mmol/L
patients having annual retinal screening since this usually took place with local providers.
Table 5. Prevalence of Endocrinopathies.
Endocrinopathy Hypogonadism hypogonadotrophic hypogonadism primary hypogonadism Hypothyroidism Hypoparathyroidism Osteopenia Osteoporosis Glucocorticoid deficiency Growth hormone deficiency
Prevalence in Patients at the Joint Diabetes Thalassaemia Clinic (%) 86.0 59.0 27.0 18.0 23.0 14.0 55.0 – –
Metabolic targets In patients attending the Joint Diabetes Thalassaemia Clinic, there was a greater achievement of management targets compared to that achieved in the National Diabetes Audit for England (2007–2008) (Table 3). In our cohort, 72.7% achieved fructosamine 5345 umol/L (equivalent to Hb A1c 57.5%) and 54.5% achieved fructosamine 5322 umol/L (equivalent to Hb A1c 57.0%). In the National Diabetes Audit, 62.9% of patients achieved Hb A1c 57.5%. In our cohort, 57.9% achieved blood pressure 5135/75 mmHg vs. 30.1% in the National Diabetes Audit. In our cohort, 82.1% achieved total cholesterol 55.0 mmol/L vs. 78.0% of patients in the National Diabetes Audit. In our cohort, 68.7% of patients achieved total cholesterol 54.0 mmol/L. Longitudinal analysis of metabolic parameters Median values of fructosamine and total cholesterol improved over a 1-year period (Table 4). Fructosamine levels fell by 25 umol/L in the first year (median fructosamine at first appointment 344 umol/L vs. median fructosamine at 1-year follow-up 319 umol/L). Eight patients (44.0%) achieved a reduction in fructosamine of 430 umol/L (equivalent to a reduction in Hb A1c of 0.7%). Amongst these patients, 10 had follow-up for 2 years and they sustained the first year improvement with a further reduction of median fructosamine by 3 umol/L during the second year. Total cholesterol levels fell by 0.3 mmol/L in the first year (median total cholesterol at first appointment 3.8 mmol/L vs. median total cholesterol at 1-year follow-up 3.5 mmol/L). Four patients (23.0%) achieved a reduction in total cholesterol of 40.4 mmol/L. At 1-year follow-up the median high-density lipoprotein (HDL) was 1.00 mmol/L, lowdensity lipoprotein (LDL) 1.65 mmol/L and triglycerides 1.40 mmol/L. Median blood pressure readings did not reduce; 31.0% of patients had a reduction in systolic blood pressure by410 mmHg and 25.0% of patients had an increase in diastolic blood pressure by 410 mmHg.
Complications Overall, five patients (22.7%) had at least one microvascular complication. Three patients (13.6%) had microalbuminuria, but all patients had normal serum creatinine and estimated glomerular filtration rate (eGFR). Three patients (13.6%) had diabetic retinopathy and two patients (9.1%) had bilateral cataracts. One patient had Charcot neuroarthropathy and a foot ulcer. No macrovascular complications (cardiovascular, cerebrovascular or peripheral vascular disease) were documented. All patients had annual examination by palpation of dorsalis pedis and posterior tibial pulses and they were palpable in all patients. No amputations were documented. No episodes of hyperglycemic emergencies were documented in the form of diabetic ketoacidosis or hyperglycemic hyperosmolar state. Prevalence of endocrinopathies A significant majority of the patients had other endocrinopathies (Table 5). Hypogonadism was present in 19 patients (86.0%), who were all on sex hormone replacement therapy. Hypothyroidism was present in four patients (18.0%), who were all on thyroxine. Hypoparathyroidism was documented in five patients (23.0%). No cases of glucocorticoid or growth hormone deficiency were documented. According to the most recent dual-energy X-ray absorptiometry (DEXA), 14.0% had osteopenia (defined as Z score between 1.5 and 2.5) and 55.0% osteoporosis (defined as Z score 52.5) either at lumbar spine or neck of femur.
Discussion This study demonstrated that the Joint Diabetes Thalassaemia Clinic is very effective at providing high quality diabetes care to complex patients. The standard of care provided was significantly higher than that in the UK National Diabetes
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Audit. In addition, a greater proportion of our Joint Diabetes Thalassaemia Clinic patients achieved the targets for diabetes management, including glycemic control, blood pressure control and total cholesterol levels compared to the national data. A limitation of this study is the significant difference between our cohort and the cohort of the National Diabetes Audit. Our cohort includes patients who have developed diabetes in the special circumstances of chronic iron overload and multi-organ iron deposition. Most patients included in the National Audit are much older, overweight or obese with type 2 diabetes and will likely have other features of metabolic syndrome. Nevertheless, the National Diabetes Audit was chosen as a comparator since this provides the best available data about the standards of care delivered and the outcomes for patients with diabetes in the UK. Another weakness of this study is that the sample is small, but b-TM is a very rare disease in the UK, has patchy geographical distribution and attendance at thalassemia clinics can be variable. In view of these limitations, the size of our sample could be regarded as satisfactory and is comparable with the sample size of most studies in this field. The longitudinal analysis of metabolic parameters showed that the Joint Diabetes Thalassaemia Clinic achieved significant improvements in glycemic control and lipid profile at 1 year which were sustained at the 2 year follow-up. This improvement of glycemic control becomes even more significant if we take into consideration that these patients have long duration of diabetes, are on insulin treatment with severe endogenous insulin deficiency and often have variable compliance to treatment. These factors mean that their glycemic control tends to deteriorate. The sustained reduction in median fructosamine of our patients by 25 umol/L (equivalent to Hb A1c reduction by 0.6%) is clinically significant because improved glycemic control is associated with significant reduction of microvascular complications. The Diabetes Control and Complications Trial (DCCT), a landmark study in diabetes research, demonstrated that intensive glycemic control of patients with type 1 diabetes — resulting in a mean Hb A1c of about 7.0% — reduced, during 6 years of follow-up, the risk for retinopathy, nephropathy and neuropathy by 76.0, 50.0 and 60.0%, respectively, compared with the conventionaltreatment group, whose Hb A1c averaged about 9.0% (27). The United Kingdom Prospective Diabetes Study (UKPDS), a landmark study in type 2 diabetes research, showed that reducing glucose exposure (Hb A1c 7.0% vs. 7.9% over 10 years) was associated with a significant 25.0% reduction of the risk of microvascular complications (28). The median age of onset of diabetes in our cohort was only 21 years with 41.0% of patients diagnosed before the age of 19 years and most patients requiring insulin therapy. This suggests that poor iron chelation can lead to tissue iron overload and significantly damage b cell function at an early age. This observation shows the importance of early instigation of effective iron chelation therapy and adherence to demanding chelation therapy regimens. The very high prevalence of other endocrinopathies in our cohort confirms the high iron burden with involvement of multiple organs of these patients.
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The prevalence of microvascular complications in our cohort was lower than previously reported. This might reflect better diabetes care, good blood pressure control and the use of ACE-inhibitors/angiotensin II receptor blockers. The prevalence of microalbuminuria in our cohort was only 13.2%, much lower than 55.0% reported by Loebstein et al. (29) in a small cohort of b thalassemic patients with diabetes of mean duration of 4 years. Also another study of renal dysfunction of patients with b-TM showed microalbuminuria in 59.0% of b thalassemic patients, regardless of the presence of diabetes (30). Albuminuria and impaired renal function in b-TM can be multifactorial, due to various factors such as iron loading within the kidney and the renal effects of chelator therapy (31). The low prevalence of microalbuminuria in our cohort could be related to genetic factors or the limited use of potentially nephrotoxic deferasirox in our cohort during the study period. In terms of diabetic retinopathy, the prevalence in our cohort was again lower than reported previously to be as high as 26.0% (32). The difference in prevalence could be due to genetic factors related to the different ethnic origin of patients in each study. Regarding macrovascular complications, their absence in our cohort was unexpected, especially considering that half of the patients had been splenectomized, which is an established risk factor for thromboembolic events (33,34). In a large study of b-TM patients, 3.95% developed thromboembolic events with half of these localized in the central nervous system and the presence of diabetes was associated with a significantly higher incidence (35). There is a series of factors, such as the marked increase of hematocrit following blood transfusion, anemia and tissue hypoxia, changes in platelet aggregation, shortened platelet life-span that leads to a hypercoagulable state (36). Studies have shown high carotid artery intima media thickness at a very early age suggestive of subclinical atherosclerosis and an association with an atherogenic lipid profile (37,38). As the life expectancy of patients with b-TM rises, this will also expose our patients to potentially many more years of hyperglycemia and macrovascular complications may become an important and common complication. Patients at the Joint Diabetes Thalassaemia Clinic were being actively medically managed as evidenced by the significant use of glucose-lowering therapy, antihypertensive medications and lipid-lowering agents. Sustaining improvements in metabolic control and controlling cardiovascular risk factors will be critical in the future for preventing macrovascular complications. There are a variety of factors at the Joint Diabetes Thalassaemia Clinic that may be contributing to high quality care and improved metabolic control. The doctor’s input to the clinic was provided by dedicated senior medical staff (Consultant Diabetologist and Consultant Haematologist), with experience and knowledge regarding diabetes, b-TM and new treatment options. This facilitated rapport between patients and clinicians and provided continuity of care. Also, healthcare professionals at the Joint Diabetes Thalassaemia Clinic were able to support patients often contending with significant psychological issues, including anxiety and depression, and whenever necessary, to offer them further counseling with our dedicated Clinical Psychologist. Patients had access to structured diabetes education, including training
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on carbohydrate counting and insulin dose adjustment. This was generally given on a one-to-one basis, but patients were also invited to attend group education sessions for patients with type 1 diabetes. Patients have given very positive feedback for this skills training. Further research is needed in order to assess the effectiveness of the model of the Joint Diabetes Thalassaemia Clinic in b-TM patients. Studies including larger cohorts with collaboration of several centers and with longer follow-up would be required in order to confirm that this model of care offers sustained significant improvement in patients’ outcomes. This Joint Diabetes Thalassaemia Clinic could also be expanded to a Joint Diabetes Endocrinopathies Thalassaemia Clinic since almost all these patients have at least one endocrinopathy and most Diabetologists have expertise in providing endocrine care. Furthermore, the Joint Diabetes Thalassaemia Clinic provides significant educational opportunities for the healthcare professionals involved. This means that they exchange knowledge and develop their expertise in a different field. The Joint Diabetes Thalassaemia Clinic could also offer opportunities for clinical research in the understudied area of diabetes in b-TM. In conclusion, the unique partnership working of our Joint Diabetes Thalassaemia Clinic allows patients with complex medical problems to be effectively managed. Patients have easy access to senior specialist clinicians supported by a multidisciplinary team working together. Patients are supported to self-manage their diabetes and b-TM in order to sustain improvements in metabolic control and health. Managing diabetes is one of the greatest challenges a person with b-TM can face. Our Joint Diabetes Thalassaemia Clinic enables these very complex patients to effectively manage their physical and psychological long-term health.
Acknowledgements The authors thank Jesus Moneva (Whittington Health, Department of Diabetes, London, UK) for his valuable contribution in data collection.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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5. Angelopoulos NG, Zervas A, Livadas S, et al. Reduced insulin secretion in normoglycemic patients with b-thalassemia major. Diabet Med. 2006;23(12):1327–1331. 6. Merkel PA, Simonson DC, Amiel SA, et al. Insulin resistance and hyperinsulinemia in patients with thalassemia major treated by hypertransfusion. N Engl J Med. 1988;318(13):809–814. 7. Cario H, Holl RW, Debatin KM, Kohne E. Insulin sensitivity and b-cell secretion in thalassaemia major with secondary haemochromatosis: assessment by oral glucose tolerance test. Eur J Pediatr. 2003;162(3):139–146. 8. Hafez M, Youssry I, El-Hamed FA, Ibrahim A. Abnormal glucose tolerance in b-thalassemia: assessment of risk factors. Hemoglobin. 2009;33(2):101–108. 9. Mowla A, Karimi M, Afrasiabi A, De Sanctis V. Prevalence of diabetes mellitus and impaired glucose tolerance in b-thalassemia patients with and without hepatitis C virus infection. Pediatric Endocrinol Rev. 2004;2(Suppl 2):282–284. 10. Monge L, Pinach S, Caramellino L, et al. The possible role of autoimmunity in the pathogenesis of diabetes in b-thalassemia major. Diabetes Metab. 2001;27(2 Pt 1):149–154. 11. Labropoulou-Karatza C, Goritsas C, Fragopanagou H, et al. High prevalence of diabetes mellitus among adult b-thalassaemic patients with chronic hepatitis C. Eur J Gastroenterol Hepatol. 1999;11(9):1033–1036. 12. Farmaki K, Angelopoulos N, Anagnostopoulos G, et al. Effect of enhanced iron chelation therapy on glucose metabolism in patients with b-thalassaemia major. Br J Haematol. 2006;134(4):438–444. 13. Christoforidis A, Perifanis V, Athanassiou-Metaxa M. Combined chelation therapy improves glucose metabolism in patients with b-thalassaemia major. Br J Haematol. 2006;135(2):271–272. 14. Dhouib N, Turki Z, Mellouli F, et al. Efficacy of metformin in the treatment of diabetes mellitus complicating thalassemia major. La Tunisie Med. 2010;88(2):136. 15. Ladis V, Theodorides C, Palamidou F, et al. Regulation of glucose disturbances with glibenclamide in patients with thalassemia. Ann NY Acad Sci. 1998;850:471–474. 16. Mangiagli A, Campisi S, De Sanctis V, et al. Effects of acarbose in b-thalassaemia major patients with normal glucose tolerance and hyperinsulinism. Pediatr Endocrinol Rev. 2004;2(Suppl 2):272–275. 17. Confidential Enquiry into Maternal and Child Health: pregnancy in women with type 1 and type 2 diabetes in 2002–03, England, Wales and Northern Ireland. London: Confidential Enquiry into Maternal and Child Health (CEMACH), 2005. (Available at: http://hqip.org.uk/assets/NCAPOP-Library/CMACE-Reports/ 29.-2005-Pregnancy-in-women-with-type-1-and-type-2-diabetes2002–2003.pdf) [last accessed 14 Nov 2013]. 18. Konrad D, Daneman D, Kirby M, Wherrett D. Cardiac failure after initiation of insulin treatment in diabetic patients with b-thalassemia major. J Pediatr. 2003;143(4):541–542. 19. Messina G, Colombo E, Cassinerio E, et al. Psychosocial aspects and psychiatric disorders in young adult with thalassemia major. Intern Emerg Med. 2008;3(4):339–343. 20. Collins MM, Corcoran P, Perry IJ. Anxiety and depression symptoms in patients with diabetes. Diabet Med. 2009;26(2):153–161. 21. Modell B, Khan M, Darlison M, et al. A national register for surveillance of inherited disorders: b thalassaemia in the United Kingdom. Bull World Health Organ. 2001;79(11): 1006–1013. 22. United Kingdom Thalassaemia Society. Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK, 2nd ed, 2008. Available at: http://www.ukts.org/pdf.html [last accessed 14 Nov 2013]. 23. NICE (National Institute for Health and Care Excellence) Guidance Type 1 diabetes. Diagnosis and management of type 1 diabetes in children, young people and adults. Available at: http:// guidance.nice.org.uk/CG15 [last accessed 14 Nov 2013]. 24. NICE (National Institute for Health and Care Excellence) Guidance Type 2 diabetes (partially updated by CG87). Type 2 diabetes: the management of type 2 diabetes (update). http://www.nice.org.uk/ CG66 [last accessed 14 Nov 2013]. 25. National Health Service Information Centre. National Diabetes Audit. Key findings about the quality of care for people with diabetes in England and Wales. Report for the audit period 2007–2008. Leeds: NHS IC, 2008. Available at: http://www.ic.nhs.uk/nda [last accessed 14 Nov 2013].
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26. St. Pierre TG, Clark PR, Chua-anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005;105(2):855–861. 27. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–986. 28. United Kingdom Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352(9131):837–853. 29. Loebstein R, Lehotay DC, Luo X, et al. Diabetic nephropathy in hypertransfused patients with b-thalassemia. The role of oxidative stress. Diabetes Care. 1998;21(8):1306–1309. 30. Quinn CT, Johnson VL, Kim HY, et al. Renal dysfunction in patients with thalassaemia. Br J Haematol. 2011;153(1): 111–117. 31. Bhandari S, Galanello R. Renal aspects of thalassaemia a changing paradigm. Eur J Haematol. 2012;89(3):187–197.
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32. Incorvaia C, Parmeggiani F, Mingrone G, et al. Prevalence of retinopathy in diabetic thalassaemic patients. J Pediatr Endocrinol Metab. 1998;11(Suppl 3):879–883. 33. Crary SE, Buchanan GR. Vascular complications after splenectomy for hematologic disorders. Blood. 2009;114(14):2861–2868. 34. Taher A, Isma’eel H, Mehio G, et al. Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost. 2006;96(4):488–491. 35. Borgna Pignatti C, Carnelli V, Caruso V, et al. Thromboembolic events in b thalassemia major: an Italian multicenter study. Acta Haematol. 1998;99(2):76–79. 36. Cappellini MD, Poggiali E, Taher AT, Musallam KM. Hypercoagulability in b-thalassemia: a status quo. Expert Rev Hematol. 2012;5(5):505–511. 37. Tantawy AA, Adly AA, El Maaty MG, Amin SA. Subclinical atherosclerosis in young b-thalassemia major patients. Hemoglobin. 2009;33(6):463–474. 38. Dogan M, Citak EC. The evaluation of carotid intima-media thickness in children with b-thalassemia major. Cardiol Young. 2012;22(1):79–83.
ORIGINAL ARTICLE
Joint Diabetes Thalassaemia Clinic: An Effective New Model of Care Ploutarchos Tzoulis, Farrukh Shah, Romilla Jones, Emma Prescott, and Maria Barnard
Abstract
Keywords
Diabetes is a significant complication of b-thalassemia major (b-TM) and most patients receive fragmented diabetes care. In 2005, we developed a unique Joint Diabetes Thalassaemia Clinic, based at the Department of Diabetes, Whittington Health, London, UK, where patients were reviewed jointly by a multidisciplinary team, including Consultant Diabetologist and Hematologist. Study of the Joint Diabetes Thalassaemia Clinic (2005–2009) showed improvement in glycemic control with fructosamine reduction from 344 umol/L to 319 umol/L over a 1-year period as well as improvement in lipid profiles. The proportion of patients attending the Joint Clinic who achieved metabolic targets compared to the National Diabetes Audit for England was higher for glycemic control (73.0 Joint Diabetes Thalassaemia Clinic vs. 63.0% nationally), blood pressure control (58.0 Joint Diabetes Thalassaemia Clinic vs. 30.0% nationally) and cholesterol control (81.0 Joint Diabetes Thalassaemia Clinic vs. 78.0% nationally). Five patients (22.7%) had microvascular complications. A significant proportion of our patients had endocrinopathies (86.0% hypogonadism, 18.0% hypothyroidism, 23.0% hypoparathyroidism). The unique partnership of our Joint Diabetes Thalassaemia Clinic, allowed these very complex patients to be managed effectively.
Complications, diabetes mellitus, endocrinopathies, b-thalassemia major (b-TM)
Introduction Diabetes mellitus is a significant complication of b-thalassemia major (b-TM). The prevalence of diabetes in b-TM patients has been estimated to be between 3.2 and 18.8%. The variability in estimated prevalence between studies relates to the efficacy of iron chelation therapy and the different ages of the patients being studied, with some studies including mainly children and adolescents (1–4). Diabetes mellitus in patients with b-TM is caused mainly by hemosiderosis as a result of transfusional iron overload. It has been predominantly attributed to a combination of reduced insulin secretory capacity and insulin resistance. A defect in b cell insulin secretion can be present early before the development of glucose intolerance and results from the toxic effects of iron deposition in the pancreas (5). Insulin resistance also plays an important role and is caused by iron deposition in both liver and muscle (6,7). Other factors also contribute to impaired glucose metabolism such as poor compliance with chelation therapy and advanced age at onset of chelation therapy (8), genetic factors (9), family history of diabetes mellitus, autoimmunity (10), and hepatitis C viral infection (9,11). Patients with b-TM and diabetes are a very
Address correspondence to Dr. Ploutarchos Tzoulis, Department of Diabetes, Whittington Health, Magdala Avenue, London, N19 5NF, UK; Tel: +44-20-7794-0500, ext. 35956. Fax: +44-20-7431-6435. E-mail: [email protected]
History Received 30 May 2013 Revised 10 July 2013 Accepted 22 July 2013 Published online 18 December 2013
heterogenous group with some individuals exhibiting mainly insulin deficiency and others with predominantly insulin resistance. The life expectancy of patients with b-TM has been improving constantly during recent decades. Intensive iron chelation therapy regimens and more effective management of iron overload have prolonged and improved the quality of life in patients with b-TM (3). Despite the markedly improved survival, patients continue to develop various complications, including diabetes mellitus. Effective management and optimal control of diabetes has become very important since these patients are now expected to live for decades after the development of diabetes. Thus, a critical aim should be the prevention, detection and management of diabetic complications, including macrovascular complications (cardiovascular disease, cerebrovascular disease and peripheral vascular disease) and microvascular complications (diabetic retinopathy, nephropathy and neuropathy) that can cause significant morbidity and mortality. There are specific issues to consider in the management of patients with diabetes and b-TM. Intensification of iron chelation therapy has been shown to improve glycemic control (12,13). The choice of antidiabetic treatment in b-TM is dependent on the severity of b cell damage and insulin deficiency. Insulin remains the mainstay of treatment for individuals with severe insulin deficiency. For other patients with diabetes detected early with mild hyperglycemia, a focus on self-management and lifestyle changes, including healthy diet and weight reduction, are important. In these patients, oral antidiabetic drugs are also increasingly prescribed.
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Department of Diabetes, Whittington Health, London, UK
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DOI: 10.3109/03630269.2013.862541
The use of metformin (14), sulphonylureas (15) and acarbose (16) in diabetes and b-TM has been described, but there is very limited published data on the role of these different agents. The management of diabetes in b-TM can pose various challenges. Women with b-TM and diabetes can become pregnant and suboptimal glycemic control in pregnancy can lead to a 3-fold increased risk of congenital malformation and 4-fold increase in perinatal mortality (17). Insulin initiation or intensification has been reported to cause fluid retention and lead to heart failure (18). Living with diabetes and b-TM can also have a major psychological impact since a large proportion of patients with b-TM have severe psychosocial problems and diabetes is also associated with high incidence of depression and anxiety (19,20). According to the National Haemoglobinopathy Registry, the number of patients with b-TM in the UK is 756. The majority of patients with this rare condition in the UK have been managed in clinics with less than 10 patients (21). Care networks have been established in the UK incorporating local thalassemia clinics and one Specialised Thalassaemia Centre for each region in order to ensure access to optimal, specialized management guidance as well as provision of routine care conveniently close to home (22). In view of the rarity of this condition, most Diabetologists in the UK have very limited experience in managing diabetes in patients with b-TM. Care can become fragmented without close liaison with other specialists involved in patient care. We therefore set up a unique clinic where patients are seen jointly by a dedicated Haematologist and Diabetologist at our institution in order to improve the care of patients with b-TM and diabetes. The present study aimed to assess the effect of this unique Joint Diabetes Thalassaemia Clinic on the patient’s metabolic control, as well as to measure the prevalence of diabetic complications, diabetic emergencies and endocrinopathies in this cohort.
Materials and methods In 2005, a Joint Diabetes Thalassaemia Clinic, based at the Department of Diabetes, Whittington Health, London, UK, was introduced at our institution which provides care for the largest cohort of b-TM patients in the UK. Prior to this, patients with diabetes and b-TM were reviewed by different diabetes clinicians in a variety of diabetes clinics. For patients with complex medical needs, this provided an inadequate level of care. The aims of the Joint Diabetes Thalassaemia Clinic were to provide high quality diabetes, endocrine and hematology care; to optimize metabolic control; to support patient self-management; and to support partnership working, both between the specialist teams and between patients and clinicians. Our institution provides care for 102 adult patients with b-TM. All patients undergo an annual Oral Glucose Tolerance Test with 75 g of oral glucose load, apart from those already diagnosed with diabetes mellitus. Amongst 102 patients, 52 females and 50 males, with a median age of 35.5 years (range 18–58 years), the prevalence of diabetes was 37.2%. Sixteen patients (15.7%) had milder abnormalities in glucose regulation, such as impaired glucose tolerance and impaired
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fasting glycemia. The glycemic status was unknown in 5.9% of patients and the remaining 41.2% of patients had normal glucose handling. Amongst 38 patients with b-TM and diabetes at our institution, only 22 (57.8%) selected patients with complex problems and needs were assessed at the Joint Diabetes Thalassaemia Clinic. Patients were seen jointly by a multidisciplinary team of a dedicated Consultant Diabetologist, Consultant Haematologist, Diabetes Specialist Nurse and Haematology Specialist Nurse. A specified Diabetes Dietitian supported the clinic. There was access to structured education courses for diabetes, including training for carbohydrate counting and insulin dose adjusting. Patients could be referred to a specified Clinical Psychologist, with experience in enabling patients to cope with issues relating to b-TM. Generally, patients were reviewed at the Joint Diabetes Thalassaemia Clinic every 6–9 months. Interim reviews to optimize glycemic control and self-management skills were provided by the Diabetes Specialist Nurse and Diabetes Dietitian. Once a year at the Joint Diabetes Thalassaemia Clinic, patients should have all measurements according to the standard recommendations for diabetes. All patients with diabetes were recommended to receive the following nine Key Care Processes at least once a year: measurement of glycemic control, blood pressure, serum cholesterol, serum creatinine, urinary albumin and weight, foot assessment, smoking status assessment and retinal screening (23,24). The management targets according to the Quality and Outcomes Framework guidance in the UK were Hb A1c 57.5%, blood pressure 5135/75 mm Hg and total cholesterol 55.0 mmol/L (25). Glycemic control was assessed using both patient home blood glucose monitoring results and fructosamine levels, since Hb A1c levels can be inaccurate in patients with hemoglobinopathies receiving repeated transfusions. Our institution’s laboratory provided a correction factor for converting fructosamine to an equivalent Hb A1c level, where fructosamine of 322 umol/L is equivalent to Hb A1c of 7.0% and fructosamine of 46 is equivalent to Hb A1c of 1.0%. The performance of the Joint Diabetes Thalassaemia Clinic was assessed by retrospective analysis of data from 81 consultations of 22 patients attending the Clinic between December 2005 to December 2009. In each consultation, a diabetes proforma was filled including information about metabolic parameters, complications and diabetic emergencies. Data were extracted from diabetic proformas and results from the laboratory server. The results of our cohort were compared to the results of the National Diabetes Audit for England in 2007–2008 which were the best available data for patients with diabetes in the UK (25). In addition, data were collected about the prevalence of microvascular complications (as defined by diabetic nephropathy, retinopathy and neuropathy), macrovascular complications (as defined by ischemic heart disease, cerebrovascular disease and peripheral vascular disease), diabetic emergencies (diabetic ketoacidosis and hyperglycemic hyperosmolar state), and endocrinopathies (including hypogonadism, hypothyroidism, hypoparathyroidism, deficiency of glucocorticoids or growth hormone, osteopenia and osteoporosis). This study was registered as
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an audit at the Whittington Health and followed the principles in the Declaration of Helsinki. The standards of care provision at this Joint Diabetes Thalassaemia Clinic were assessed by: (1) comparing the percentage of patients having the Key Care Processes for diabetes performed with the percentage in the National Diabetes Audit; (2) comparing the proportion of patients who achieved metabolic targets to the data in the National Diabetes Audit; (3) longitudinal analysis of fructosamine, blood pressure and serum cholesterol. Data were also collected to measure: (1) the prevalence of microvascular complications; (2) the prevalence of macrovascular complications; (3) the prevalence of diabetic emergencies (diabetic ketoacidosis or hyperglycemic hyperosmolar state); (4) the prevalence of other endocrinopathies. Hemoglobin Downloaded from informahealthcare.com by University of Newcastle on 10/04/14 For personal use only.
Results From December 2005 to December 2009, 22 patients were reviewed at the Joint Diabetes Thalassaemia Clinic and overall had 81 consultations. The median number of consultations was 3.5 per patient with a wide range from one consultation in five patients to nine consultations in one patient. Where patients had only one or two reviews at the Joint Diabetes Thalassaemia Clinic, follow-up data was not usually adequate to assess changes in parameters. Background characteristics The patients’ median age was 39 years (range 28–59 years old). Thirteen patients were female (59.0%) and nine were male (41.0%). Patient ethnic origin was Greek or Greek Cypriot in eight patients (36.0%) and South Asian (Indian, Pakistani, Bangladeshi) in 14 (64.0%) (Table 1). The median duration of diabetes was 13 years (range51 year to 29 years). The median age of onset of diabetes was 21 years of age (range 10–40 years), with nine patients (41.0%) diagnosed before the age of 19 years. At the first appointment, four patients were smokers (18.0%). The median body mass index (BMI) was 24.8 kg/m2: 11 patients (50.0%) had normal BMI (18.5–25.0); nine patients (40.9%) were overweight (BMI 25–30 kg/m2); only two patients (9.1%) were obese (BMI 430 kg/m2). The median ferritin at first appointment was 1827 ug/L (range 600–6143 ug/L). Data were also collected about liver iron concentrations, assessed by magnetic resonance imaging (MRI)-proton transverse relaxation rates (R2) (FerriScanÕ analysis;
Resonance Health Inc., Perth, Western Australia), hepatitis C infection and patients who were splenectomized. In terms of liver disease, all patients had MRI liver scans performed and mean liver R2 were measured between January 2008 and December 2009. The liver iron concentrations obtained with FerriScan R2 (Resonance Health Inc.) are known to correlate well with iron concentrations based on liver biopsy (26). The widely accepted cut-off of liver iron concentration of 7 mg iron per gram liver, dry weight, was used as the upper limit of optimal range for transfusional iron overload and as the threshold for increased risk of iron-induced complications (26). Based on this cut-off, eight patients (36.0%) had hepatic iron overload and all these patients apart from one required treatment with insulin. Three patients (14.0%) had hepatitis C infections and 11 patients (50.0%) were splenectomized. Patients were on medications for diabetes and management of diabetic complications. In terms of glucose-lowering agents: 16 patients (73.0%) were on insulin; six patients (27.0%) were on oral antidiabetic drugs (metformin or glimepiride); three patients (14.0%) were on diet control alone. Five patients (23.0%) were on antihypertensive medications [angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor antagonists]. Five patients (23.0%) were on lipid lowering agents (statins or fibrates). Seven patients (32.0%) were on antiplatelet agents (aspirin) or anticoagulant therapy (warfarin). Monitoring In patients attending the Joint Diabetes Thalassaemia Clinic, the Key Processes for diabetes care were performed at a rate much greater than that achieved in the National Diabetes Audit for England (2007–2008) (Table 2). This included better rates of measurement of fructosamine, serum cholesterol, serum creatinine, urinary albumin:creatinine ratio (ACR) and weight (BMI), foot assessment and smoking status assessment. The only key care process performed at a lower rate at the Joint Diabetes Thalassaemia Clinic compared to the national data was measurement of blood pressure; the most likely explanation is that on some occasions physicians did not record blood pressure on the diabetes proforma because these patients had several recent measurements of blood pressure during regular blood transfusions. No data were available about the percentage of Table 2. Performance of Key Care Processes at the Joint Diabetes Thalassaemia Clinic Compared to the National Diabetes Audit for England. Performance of Key Care Processes
Table 1. Background Characteristics of Patients Attending the Joint Diabetes Thalassaemia Clinic. Age Ethnicity Diabetes duration Age at onset of diabetes Diabetes therapy
a
Median age and range.
39 years
a
Greek/Greek Cypriot South Asian 13 yearsa 21 yearsa insulin oral agents diet only
range: 28–59 years
a
36.0% 64.0% range: 51–29 yearsa range: 10–40 yearsa 73.0% 27.0% 14.0%
Care Process Fructosamine/Hb A1c Serum cholesterol Serum creatinine Albuminuria Weight/BMI Blood pressure Foot assessment Smoking status
Joint Diabetes Thalassaemia Clinic (2005–2009) (%)
National Diabetes Audit UK (2007–2008) (%)
97.5 91.1 100.0 91.1 97.5 80.4 89.3 89.2
91.1 89.9 91.2 62.7 88.8 93.7 77.1 86.5
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Table 3. Rate of Achievement of Treatment Targets at the Joint Diabetes Thalassaemia Clinic Compared to the National Diabetes Audit for England (2007–2008). Percentage of Patients Achieving Treatment Targets Target
Joint Diabetes Thalassaemia Clinic (2005–2009) (%)
National Diabetes Audit UK (2007–2008) (%)
72.7 57.9 82.1
62.9 30.1 78.0
Fructosamine 5345 umol/L or Hb A1c 57.5% Blood pressure 5135/75 mmHg Cholesterol 55.0 mmol/L
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Table 4. Changes in Metabolic Control at the Joint Diabetes Thalassaemia Clinic Over a 1-Year Period.
Parameters
First Appointment
1-Year Follow-Up
Change
Fructosamine Blood pressure Total cholesterol
344 umol/L 122/70 mmHg 3.8 mmol/L
319 umol/L 124/77 mmHg 3.5 mmol/L
25 umol/L þ2/7 mmHg 0.3 mmol/L
patients having annual retinal screening since this usually took place with local providers.
Table 5. Prevalence of Endocrinopathies.
Endocrinopathy Hypogonadism hypogonadotrophic hypogonadism primary hypogonadism Hypothyroidism Hypoparathyroidism Osteopenia Osteoporosis Glucocorticoid deficiency Growth hormone deficiency
Prevalence in Patients at the Joint Diabetes Thalassaemia Clinic (%) 86.0 59.0 27.0 18.0 23.0 14.0 55.0 – –
Metabolic targets In patients attending the Joint Diabetes Thalassaemia Clinic, there was a greater achievement of management targets compared to that achieved in the National Diabetes Audit for England (2007–2008) (Table 3). In our cohort, 72.7% achieved fructosamine 5345 umol/L (equivalent to Hb A1c 57.5%) and 54.5% achieved fructosamine 5322 umol/L (equivalent to Hb A1c 57.0%). In the National Diabetes Audit, 62.9% of patients achieved Hb A1c 57.5%. In our cohort, 57.9% achieved blood pressure 5135/75 mmHg vs. 30.1% in the National Diabetes Audit. In our cohort, 82.1% achieved total cholesterol 55.0 mmol/L vs. 78.0% of patients in the National Diabetes Audit. In our cohort, 68.7% of patients achieved total cholesterol 54.0 mmol/L. Longitudinal analysis of metabolic parameters Median values of fructosamine and total cholesterol improved over a 1-year period (Table 4). Fructosamine levels fell by 25 umol/L in the first year (median fructosamine at first appointment 344 umol/L vs. median fructosamine at 1-year follow-up 319 umol/L). Eight patients (44.0%) achieved a reduction in fructosamine of 430 umol/L (equivalent to a reduction in Hb A1c of 0.7%). Amongst these patients, 10 had follow-up for 2 years and they sustained the first year improvement with a further reduction of median fructosamine by 3 umol/L during the second year. Total cholesterol levels fell by 0.3 mmol/L in the first year (median total cholesterol at first appointment 3.8 mmol/L vs. median total cholesterol at 1-year follow-up 3.5 mmol/L). Four patients (23.0%) achieved a reduction in total cholesterol of 40.4 mmol/L. At 1-year follow-up the median high-density lipoprotein (HDL) was 1.00 mmol/L, lowdensity lipoprotein (LDL) 1.65 mmol/L and triglycerides 1.40 mmol/L. Median blood pressure readings did not reduce; 31.0% of patients had a reduction in systolic blood pressure by410 mmHg and 25.0% of patients had an increase in diastolic blood pressure by 410 mmHg.
Complications Overall, five patients (22.7%) had at least one microvascular complication. Three patients (13.6%) had microalbuminuria, but all patients had normal serum creatinine and estimated glomerular filtration rate (eGFR). Three patients (13.6%) had diabetic retinopathy and two patients (9.1%) had bilateral cataracts. One patient had Charcot neuroarthropathy and a foot ulcer. No macrovascular complications (cardiovascular, cerebrovascular or peripheral vascular disease) were documented. All patients had annual examination by palpation of dorsalis pedis and posterior tibial pulses and they were palpable in all patients. No amputations were documented. No episodes of hyperglycemic emergencies were documented in the form of diabetic ketoacidosis or hyperglycemic hyperosmolar state. Prevalence of endocrinopathies A significant majority of the patients had other endocrinopathies (Table 5). Hypogonadism was present in 19 patients (86.0%), who were all on sex hormone replacement therapy. Hypothyroidism was present in four patients (18.0%), who were all on thyroxine. Hypoparathyroidism was documented in five patients (23.0%). No cases of glucocorticoid or growth hormone deficiency were documented. According to the most recent dual-energy X-ray absorptiometry (DEXA), 14.0% had osteopenia (defined as Z score between 1.5 and 2.5) and 55.0% osteoporosis (defined as Z score 52.5) either at lumbar spine or neck of femur.
Discussion This study demonstrated that the Joint Diabetes Thalassaemia Clinic is very effective at providing high quality diabetes care to complex patients. The standard of care provided was significantly higher than that in the UK National Diabetes
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Audit. In addition, a greater proportion of our Joint Diabetes Thalassaemia Clinic patients achieved the targets for diabetes management, including glycemic control, blood pressure control and total cholesterol levels compared to the national data. A limitation of this study is the significant difference between our cohort and the cohort of the National Diabetes Audit. Our cohort includes patients who have developed diabetes in the special circumstances of chronic iron overload and multi-organ iron deposition. Most patients included in the National Audit are much older, overweight or obese with type 2 diabetes and will likely have other features of metabolic syndrome. Nevertheless, the National Diabetes Audit was chosen as a comparator since this provides the best available data about the standards of care delivered and the outcomes for patients with diabetes in the UK. Another weakness of this study is that the sample is small, but b-TM is a very rare disease in the UK, has patchy geographical distribution and attendance at thalassemia clinics can be variable. In view of these limitations, the size of our sample could be regarded as satisfactory and is comparable with the sample size of most studies in this field. The longitudinal analysis of metabolic parameters showed that the Joint Diabetes Thalassaemia Clinic achieved significant improvements in glycemic control and lipid profile at 1 year which were sustained at the 2 year follow-up. This improvement of glycemic control becomes even more significant if we take into consideration that these patients have long duration of diabetes, are on insulin treatment with severe endogenous insulin deficiency and often have variable compliance to treatment. These factors mean that their glycemic control tends to deteriorate. The sustained reduction in median fructosamine of our patients by 25 umol/L (equivalent to Hb A1c reduction by 0.6%) is clinically significant because improved glycemic control is associated with significant reduction of microvascular complications. The Diabetes Control and Complications Trial (DCCT), a landmark study in diabetes research, demonstrated that intensive glycemic control of patients with type 1 diabetes — resulting in a mean Hb A1c of about 7.0% — reduced, during 6 years of follow-up, the risk for retinopathy, nephropathy and neuropathy by 76.0, 50.0 and 60.0%, respectively, compared with the conventionaltreatment group, whose Hb A1c averaged about 9.0% (27). The United Kingdom Prospective Diabetes Study (UKPDS), a landmark study in type 2 diabetes research, showed that reducing glucose exposure (Hb A1c 7.0% vs. 7.9% over 10 years) was associated with a significant 25.0% reduction of the risk of microvascular complications (28). The median age of onset of diabetes in our cohort was only 21 years with 41.0% of patients diagnosed before the age of 19 years and most patients requiring insulin therapy. This suggests that poor iron chelation can lead to tissue iron overload and significantly damage b cell function at an early age. This observation shows the importance of early instigation of effective iron chelation therapy and adherence to demanding chelation therapy regimens. The very high prevalence of other endocrinopathies in our cohort confirms the high iron burden with involvement of multiple organs of these patients.
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The prevalence of microvascular complications in our cohort was lower than previously reported. This might reflect better diabetes care, good blood pressure control and the use of ACE-inhibitors/angiotensin II receptor blockers. The prevalence of microalbuminuria in our cohort was only 13.2%, much lower than 55.0% reported by Loebstein et al. (29) in a small cohort of b thalassemic patients with diabetes of mean duration of 4 years. Also another study of renal dysfunction of patients with b-TM showed microalbuminuria in 59.0% of b thalassemic patients, regardless of the presence of diabetes (30). Albuminuria and impaired renal function in b-TM can be multifactorial, due to various factors such as iron loading within the kidney and the renal effects of chelator therapy (31). The low prevalence of microalbuminuria in our cohort could be related to genetic factors or the limited use of potentially nephrotoxic deferasirox in our cohort during the study period. In terms of diabetic retinopathy, the prevalence in our cohort was again lower than reported previously to be as high as 26.0% (32). The difference in prevalence could be due to genetic factors related to the different ethnic origin of patients in each study. Regarding macrovascular complications, their absence in our cohort was unexpected, especially considering that half of the patients had been splenectomized, which is an established risk factor for thromboembolic events (33,34). In a large study of b-TM patients, 3.95% developed thromboembolic events with half of these localized in the central nervous system and the presence of diabetes was associated with a significantly higher incidence (35). There is a series of factors, such as the marked increase of hematocrit following blood transfusion, anemia and tissue hypoxia, changes in platelet aggregation, shortened platelet life-span that leads to a hypercoagulable state (36). Studies have shown high carotid artery intima media thickness at a very early age suggestive of subclinical atherosclerosis and an association with an atherogenic lipid profile (37,38). As the life expectancy of patients with b-TM rises, this will also expose our patients to potentially many more years of hyperglycemia and macrovascular complications may become an important and common complication. Patients at the Joint Diabetes Thalassaemia Clinic were being actively medically managed as evidenced by the significant use of glucose-lowering therapy, antihypertensive medications and lipid-lowering agents. Sustaining improvements in metabolic control and controlling cardiovascular risk factors will be critical in the future for preventing macrovascular complications. There are a variety of factors at the Joint Diabetes Thalassaemia Clinic that may be contributing to high quality care and improved metabolic control. The doctor’s input to the clinic was provided by dedicated senior medical staff (Consultant Diabetologist and Consultant Haematologist), with experience and knowledge regarding diabetes, b-TM and new treatment options. This facilitated rapport between patients and clinicians and provided continuity of care. Also, healthcare professionals at the Joint Diabetes Thalassaemia Clinic were able to support patients often contending with significant psychological issues, including anxiety and depression, and whenever necessary, to offer them further counseling with our dedicated Clinical Psychologist. Patients had access to structured diabetes education, including training
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DOI: 10.3109/03630269.2013.862541
on carbohydrate counting and insulin dose adjustment. This was generally given on a one-to-one basis, but patients were also invited to attend group education sessions for patients with type 1 diabetes. Patients have given very positive feedback for this skills training. Further research is needed in order to assess the effectiveness of the model of the Joint Diabetes Thalassaemia Clinic in b-TM patients. Studies including larger cohorts with collaboration of several centers and with longer follow-up would be required in order to confirm that this model of care offers sustained significant improvement in patients’ outcomes. This Joint Diabetes Thalassaemia Clinic could also be expanded to a Joint Diabetes Endocrinopathies Thalassaemia Clinic since almost all these patients have at least one endocrinopathy and most Diabetologists have expertise in providing endocrine care. Furthermore, the Joint Diabetes Thalassaemia Clinic provides significant educational opportunities for the healthcare professionals involved. This means that they exchange knowledge and develop their expertise in a different field. The Joint Diabetes Thalassaemia Clinic could also offer opportunities for clinical research in the understudied area of diabetes in b-TM. In conclusion, the unique partnership working of our Joint Diabetes Thalassaemia Clinic allows patients with complex medical problems to be effectively managed. Patients have easy access to senior specialist clinicians supported by a multidisciplinary team working together. Patients are supported to self-manage their diabetes and b-TM in order to sustain improvements in metabolic control and health. Managing diabetes is one of the greatest challenges a person with b-TM can face. Our Joint Diabetes Thalassaemia Clinic enables these very complex patients to effectively manage their physical and psychological long-term health.
Acknowledgements The authors thank Jesus Moneva (Whittington Health, Department of Diabetes, London, UK) for his valuable contribution in data collection.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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