Mohamed Badrulnizam Long Bidin,Abdul Mueed Khan,Florence Hui Sieng Tan,Nor Azizah Aziz,Norhaliza Mohd Ali,Nor Azmi Kamaruddin,Shireene Ratna Vethakkan,Balraj Sethi,Zanariah Hussein
Patient Characteristics, Disease Burden, Treatment Patterns and Outcomes in Patients with Acromegaly: Real-World Evidence from the Malaysian Acromegaly Registry
acromegaly,Malaysian registry,healthcare resource utilization,treatment outcomes
Objective This study aims to report the demographic features of patients with acromegaly, the disease burden, and the corresponding treatment patterns and outcomes in Malaysia. Methodology This is a retrospective study that included patients from the Malaysian Acromegaly registry who were diagnosed with acromegaly from 1970 onwards. Data collected included patient demographics, clinical manifestations of acromegaly, biochemical results and imaging findings. Information regarding treatment modalities and their outcomes was also obtained. Results Registry data was collected from 2013 to 2016 and included 140 patients with acromegaly from 12 participating hospitals. Median disease duration was 5.5 years (range 1.0 – 41.0 years). Most patients had macroadenoma (67%), while 15% were diagnosed with microadenoma. Hypertension (49.3%), diabetes (37.1%) and hypopituitarism (27.9%) were the most common co-morbidities for patients with acromegaly. Majority of patients had surgical intervention as primary treatment (65.9%) while 20.7% were treated medically, mainly with dopamine agonists (18.5%). Most patients had inadequate disease control after first-line treatment regardless of treatment modality (79.4%). Conclusion This registry study provides epidemiological data on patients with acromegaly in Malaysia and serves as an initial step for further population-based studies.
Patient Characteristics, Disease Burden, Treatment Patterns and Outcomes in Patients with Acromegaly: Real-World Evidence from the Malaysian Acromegaly Registry

This study aims to report the demographic features of patients with acromegaly, the disease burden, and the corresponding treatment patterns and outcomes in Malaysia.

This is a retrospective study that included patients from the Malaysian Acromegaly registry who were diagnosed with acromegaly from 1970 onwards. Data collected included patient demographics, clinical manifestations of acromegaly, biochemical results and imaging findings. Information regarding treatment modalities and their outcomes was also obtained.

Registry data was collected from 2013 to 2016 and included 140 patients with acromegaly from 12 participating hospitals. Median disease duration was 5.5 years (range 1.0 – 41.0 years). Most patients had macroadenoma (67%), while 15% were diagnosed with microadenoma. Hypertension (49.3%), diabetes (37.1%) and hypopituitarism (27.9%) were the most common co-morbidities for patients with acromegaly. Majority of patients had surgical intervention as primary treatment (65.9%) while 20.7% were treated medically, mainly with dopamine agonists (18.5%). Most patients had inadequate disease control after first-line treatment regardless of treatment modality (79.4%).

This registry study provides epidemiological data on patients with acromegaly in Malaysia and serves as an initial step for further population-based studies.

Acromegaly is a rare endocrine disease resulting from excessive growth hormone (GH) production and affects both men and women equally. In Western countries, the reported prevalence is approximately 70 to 80 cases per million population with an incidence of 3-11 cases per million population per year, although the cases reported from Asia are lower at a prevalence of 28 and incidence of 4 cases per million population/year. Acromegaly is mainly caused by the presence of GH-secreting pituitary tumours. Elevated GH and insulin-growth factor 1 (IGF-1) result in anatomical changes and metabolic dysfunction. Dysregulation of both hormones results in acromegaly-associated symptoms such as changes in facial appearance, overgrowth of hands and feet, headache, endocrine dysfunction and cardiovascular diseases. Due to its insidious nature, the diagnosis of acromegaly is often delayed, at least 4 to 10 years after disease onset. Unfortunately, diagnostic delays often lead to poor patient quality of life as well as increased morbidity and mortality. Clinical features that are suggestive of acromegaly such as headaches, diabetes mellitus, hypertension and heart disease of unknown aetiology warrant biochemical screening with GH and IGF-1 to confirm a diagnosis of acromegaly. Magnetic resonance imaging of the pituitary is also requested. Main treatment goals include tumour removal and normalisation of GH and IGF-1 levels, accompanied by the resolution of clinical symptoms and eventually, a reduction in long-term mortality. The main therapeutic options for acromegaly include surgical resection of adenomas, medical treatment with dopamine agonists and somatostatin analogues, and radiotherapy. Transsphenoidal surgery is often considered the first-line treatment for most patients, with medical therapy being reserved as second-line treatment for patients who refuse surgery to control hormone production and tumour growth. Patient presentation, demographics and treatment modalities vary greatly amongst countries and regions. There was no prior data on acromegaly in Malaysia, hence, the Malaysian Endocrine and Metabolic Society (MEMS) established the acromegaly disease registry in 2013. Data were collected from 12 participating hospitals, including patients diagnosed with acromegaly from 1970 onwards. There is currently also no published literature on acromegaly in Malaysia. This study aims to report the demographic features of patients with acromegaly, the burden of the disease, the different treatment modalities and the corresponding treatment outcomes in Malaysia using data from the acromegaly disease registry.

Data were collected from 2013 to 2016 from the Malaysian Acromegaly Registry with permission obtained from MEMS. Any patient diagnosed with acromegaly from 1970 onwards was included in the registry, whether they were identified at routine clinical appointments or upon reviewing hospital records. A diagnosis of acromegaly was made based on radiographic evidence of a pituitary adenoma plus any one of the following biochemical criteria: 1) Documented elevated IGF-1 level; 2) Failure of GH suppression with oral glucose tolerance test (OGTT); 3) Elevated GH levels in the presence of clinical features of acromegaly. Patients were excluded if either biochemical evidence or pituitary imaging was negative or unavailable. Data collected included demographic, clinical (symptoms, signs, and comorbidities), biochemical and hormonal profiles, imaging results, as well as information regarding treatment modalities and their therapeutic outcomes. Outcomes were categorized as either controlled disease defined by an age-adjusted normal IGF-1 level and a random GH concentration <1 µg/L, or persistent disease if either GH or IGF-1 remained above the normal range. All data was collected, stored and used in strict accordance with current Malaysia legislation on data protection, ethics and written informed patient consent. The study was approved by Malaysia Medical Research and Ethics Committee (MREC no: NMRR-12-1324-13746).

In general, categorical variables were presented as count and percentages, while continuous variables were presented as count and median with range (min-max), stratified by tumour size.

A total of 140 patients with acromegaly from 12 participating hospitals were included in the registry. The median disease duration was 5.5 years (range 1.0 – 41.0 years). Median age of patients was 52 years, with equal distribution across gender (female 68 [48.6%]; male 70 [50.0%]). Over 67% of patients were diagnosed with macroadenoma, while a minority of patients had microadenoma (n=21, 15%). Tumour size was not documented in 24 patients. IGF-1 levels were available for 94 patients at diagnosis, but only 66 patients had an OGTT with GH measurement at diagnosis. Hypertension (49.3%), diabetes (37.1%) and hypopituitarism (27.9%) were the most common co-morbidities for patients with acromegaly. Patients with microadenoma were more frequently found to have hypertension and diabetes compared to those with macroadenoma (71.4% vs 42.1%; 47.6% vs 34.7%). Some patients with macroadenomas had co-secretion of prolactin and human placental lactogen (5%, 5.3% respectively). Unexpectedly, there were 2 cases of hypopituitarism (9.5%), which is not usually associated with microadenomas. The full list of clinical manifestations of acromegaly is presented in Table 1. Regardless of adenoma size, majority of patients received monotherapy with most patients undergoing surgery alone (65.9%) while 20.7% had medical treatment alone as firstline intervention (Table 2). A minority of patients required dual therapy with either a combination of medical and surgical intervention (5.9%) or a combination of surgery and radiotherapy (3.0%). In terms of medical intervention, dopamine agonists were more frequently used (18.5%) in contrast to somatostatin analogues (5.2%). Currently, the majority of the patients are receiving monotherapy with medical treatment being the dominant choice (94.4%). There are no patients on dual or triple therapy. Somatostatin analogues are used slightly more than dopamine agonists (49.3% vs 38.0%) (Table 3). A total of 109 patients reported treatment outcomes after first-line treatment (Table 4). Regardless of the treatment modality, most patients had persistent disease.

The acromegaly registry was established to obtain epidemiological data on patients with acromegaly in Malaysia. It was funded and supported by MEMS. From this current study, data collected between 2013 and 2016 showed that there were only 140 patients listed in the registry were diagnosed with acromegaly from 1970 onwards. The Malaysian Consensus Statement for the Diagnosis and Management of Acromegaly highlights the condition as an underrecognised and underdiagnosed condition in the country. Clinicians face major challenges in management due to the delayed diagnosis. Median duration of disease to diagnosis was 5.5 years, although nearly a third were only diagnosed after 10 years, with a majority of patients having macroadenomas (68%). As a result of this finding, a clinical pathway for screening and subsequent referral to the nearest, most accessible endocrinologist and endocrine center was formulated. There is also a minority of patients who did not have any information regarding tumour status; it cannot be derived from the registry if the tumour status was undocumented or if MRI/CT imaging was not done. Hypertension, diabetes, hypothyroidism and dyslipidemia were the most commonly reported symptoms of acromegaly among patients in Malaysia, which concurs with published reports and other Asian acromegaly registry studies. Interestingly, two patients with microadenoma had hypopituitarism, which is usually associated with macroadenomas. There have been previous reports on cases of microadenomas with resultant hypopituitarism. Although, patients with acromegaly frequently have multinodular non-toxic goiters, some present with less common thyroid presentations such as toxic multinodular goiter (10 patients) and thyroid carcinoma (4 patients). A recent meta-analysis concerning different cancer types in acromegaly reported a significant increase in the prevalence of thyroid cancers. In the past, endocrinology practice in Malaysia was confined to a limited number of certain public hospitals which hampered the screening of these patients, ultimately resulting in delayed diagnosis and management. With the increasing number of endocrinologists, more cases are expected to be detected and referred for complete assessment and long-term care. From this study, only around 67% of patients had IGF-1 results. IGF-1 assay only became available in Malaysia in 1993 and was previously only available at the Institute of Medical Research with a long turnaround time. Currently, selected public hospitals also offer IGF-1 assays which should increase the availability of this test. Surgery is the treatment of choice for most patients (76.3%), especially for those with macroadenomas. As per guidelines, transsphenoidal surgical removal of adenomas is the preferred technique for most patients. Clinical practice in Malaysia concurred with practice in other Asian countries such as Japan, Korea, China and Taiwan. In terms of medical treatment, guidelines recommend the use of somatostatin analogues first and consider dopamine agonists in milder cases. However, dopamine agonists are given more often used than somatostatin analogues in practice due to its ease of administration, wide accessibility and affordability. In Malaysia, the use of somatostatin analogues is restricted and tightly regulated. It is mainly reserved as second-line treatment when surgery or dopamine agonists have failed to control the disease. Although the GH receptor antagonist, pegvisomant is currently the most effective treatment for acromegaly, it is currently unavailable in Malaysia. The use of radiotherapy is low in Malaysian patients because it is usually reserved for residual or recurrent tumours with high surgical risk or if the patient refuses surgery. Data from the registry shows that additional radiotherapy was given only if with persistent disease after primary treatment. However, it has posed a greater risk of hypopituitarism and an uncertain long-term complication rate. Although radiotherapy has taken a back seat with the development of effective and safer medical therapies such as somatostatin analogues or pegvisomant, radiotherapy still plays a role in salvage therapy. Regardless of the treatment modality, a high proportion of patients continue to have persistent disease. A recent study looking at acromegaly in Central and Eastern Europe, Israel and Kazakhstan also showed that there could be improvements in disease control. Chronic exposure to elevated levels of GH and IGF-1 prior to diagnosis and optimal treatment of disease are suggested to play an important role in disease persistence. However, with the limitation in the registry data, we are unable to suggest any correlation of patient characteristics to disease persistence. One limitation of this study was that only 12 hospitals were invited to participate in this registry and therefore, may not accurately capture the full picture of all patients with acromegaly in Malaysia. However, these are the main endocrine centers in the public sector. A few patients were seen privately but most patients were referred to these public endocrine centers for long-term follow-up. Data may be incomplete since only those submitted by clinicians would be included in the registry. Data presented were collected before the Malaysia Consensus Statement for the Diagnosis and Management of Acromegaly was launched in 2019. Since the consensus was launched, there have been huge initiatives to standardise diagnosis and management of acromegaly in Malaysia, including efforts to increase awareness of the disease among primary care physicians. These efforts have also reached out to other healthcare professionals, patients and caregivers. A patient support group was established for patients with acromegaly. A future study is currently underway to assess the impact of the consensus and these initiatives.

This registry data provided the first epidemiological snapshot of patients with acromegaly in Malaysia serving as an initial step for further population-based studies. This study serves as baseline of the clinical practice of diagnostics, treatment and management of patients with acromegaly. With the establishment of the consensus statement, we hope that future initiatives would help improve patient care.