Introduction

Acromegaly is caused by a pituitary adenoma in most cases. The disease is associated with symptoms and complications such as acral and soft tissue enlargement, joint pain, heart failure, respiratory distress, obstructive sleep apnea, diabetes mellitus, hypertension, hypopituitarism, and visual field defects (1, 2). The incidence of the disease is estimated to be 3-4 cases per million per year, with an occurrence rate of 40-100 people per million (3, 4). The prevalence of acromegaly in Colombia has not been documented, but according to the Registry of Health Services Provision, reported in the Colombian Social.

Protection Information System SISPRO, the frequency has been established as 170-300 new cases per year (5). The prevalence rate of acromegaly shows a female dominance (0.56 and 0.42 per 100 people each in females and males, respectively) (6). The most common comorbidities associated with acromegaly are those related to the cardiovascular system (2), followed by musculoskeletal, respiratory, and endocrine/metabolic systems (7, 8).

Acromegaly is frequently reported in the elderly and includes a long undiagnosed period. Its insidious onset leads to a significant delay in diagnosis, contributing to a difference of more than five years from the mean age of occurrence (32 years) to the mean age of diagnosis (40-45 years) (9). Once confirmed, obtaining biochemical remission requires surgical management, medical therapy, and radiotherapy. Although surgery remains the first-line therapy for acromegaly, pharmacological therapy could also aid in treating the disease, especially in patients with macroadenomas, as they have been associated with lower rates of surgical cure. Establishing appropriate medical control is a significant treatment factor in managing acromegaly, which may consequently lower morbidity and mortality (10-14).

According to the Endocrine Society Clinical Practice Guidelines published in 2014, the use of either somatostatin analogs (SSAs); dopamine agonists (DAs), such as cabergoline; or somatostatin receptor ligands is indicated as medical therapy for patients with acromegaly across several stages of the disease (15).

Optimal management of acromegaly includes biochemical control (growth hormone (GH) level < 2.5 µg/L and normal standardized insulin-like growth factor-1 (IGF-1)) and control of tumor growth (which may be independent of biochemical control) along with comprehensive treatment of associated symptoms and comorbidities. Therefore, control and remission of acromegaly are defined mainly in terms of specific biochemical targets (GH and IGF-1 levels), as they predict or correlate with symptoms, comorbidities, and mortality (16).

This study aimed to provide real-world information regarding the epidemiology and characteristics of patients with acromegaly undergoing medical treatment in Colombia.

Methods

This observational, retrospective chart review study evaluated newly diagnosed patients with acromegaly from January 2005 to December 2015 at referral health institutions in Colombia (Bogota, Cali, and Medellin). The study was approved by the local ethics committee and conducted following Good Clinical Practice guidelines. Patient records were collected from the clinical sites as per feasibility assessments conducted by the clinical experts.

Results

Biochemical control and treatment patterns

During the observation period (mean 3.0 years (0.05-7.82)), the reported treatment patterns included surgery, radiation therapy, SSAs, DAs, and GH receptor antagonists (GHRAs). A total of 38 (72 %) patients received SSAs as first-line medical treatment (SSA cohort) Tables (1 and 2).

Of 53 patients enrolled in the study, 28 (52.8 %) had undergone surgery, of whom 24 had undergone pituitary-transsphenoidal surgery. Thirty-eight (71.7 %) patients were diagnosed with macroadenomas; seven (13.21 %) received radiotherapy. During the first 12 months of follow-up, most of the patients received SSAs: lanreotide (28 (52.8 %)) and octreotide (26(49.1 %)), followed by cabergoline (9 (17.0 %)). After 24 months, three patients received pasireotide, a second-generation SSA Figure (1). Overall, the total patient population received an SSA at some point in their treatment, either as a first-line or second-line medical therapy.

Patients received treatment for acromegaly for an average of 2.8 years. During the follow- up period, patients received SSAs (n=53,100 %), DAs(n=11,20.7%), and GHRAs (n=1,1.8 %). Eight patients received treatment combinations of SSAs + DAs during the first year, lowering to four and three patients during years 2and 3, respectively.

Biochemical control (GH level < 2.5 µg/L and standardized normal IGF-1 level) was achieved by 10/53 (18.9 %), 4/34 (11.7 %), 8/21 (38 %), and 4/19 (21 %) patients under medical treatment at 12 ± 2, 24 ± 2, 36 ± 2, and 48 ± 2 months, respectively Table(3 and Figure1). Patients with GH < 2.5 ug/L but abnormal IGF-1 levels were considered uncontrolled. During the observation period, a higher proportion of patients remained with uncontrolled disease than the controlled disease (ratio 2-7:1), with GH ranging from 0.3 to 1.1 µg/L in the controlled group vs. 0.9 to 12.3 µg/L in the uncontrolled group. The median concentration

Table 1: Demographics and Baseline Characteristics - All Enrolled (N = 53)

Source: Own data.

Abbreviations: BMI =body mass index, SSA =somatostatin analogue

Note: aPercentages were calculated by taking the column header as the denominator

bSSA cohort:This set represents patients receiving SSAs as first-line medical treatment

Table 2: Disease Evolution of Acromegaly Patients at Baseline

Source: Own data.

Notes: a Length of observation period =(last follow-up visit date-First visit date)/365.25 bTime of disease evolution. (years) =time from symptoms initiation to diagnosis confirmation in years or fraction of a year cTime for medical treatment initiation. (years)=year of initial medical treatment initiation-year of diagnosis of acromegaly

Figure 1: Biochemical Parameters in the Observed Population as per Controlled and Uncontrolled Disease A) Median GH and B) Median Standardized IGF-1 Abbreviations: GH =growth hormone; IGF-1 = insulin growth factor-1; SSA =somatostatin analogue General Note: •Controlled disease: GH < 2.5 µg/L and standardized IGF-1 •Uncontrolled disease: GH > 2.5 µg/L or IGF-1 > ULN (upper limit of normal) age and sex-matched. Standardized IGF-1 defined as IGF-1/ULN

Source: Own data

of GH and IGF-1 levels was significantly lower (p < 0.05) in the controlled group compared with the uncontrolled group (GH: 0.8 vs. 3.1 µg/L and IGF-1: 0.8 times the upper limit of normal (ULN) vs. 1.7 times ULN); nevertheless, patients under medical treatment showed a trend toward lower GH levels, especially those receiving SSA therapy (Figure 2 and Table 3).

Table 3: Patients with Controlled Disease (GH < 2.5 μg/L and Standardized IGF-1*)and Uncontrolled Disease During the Observation Period - All Enrolled (N = 53)

Source: Own data.

Abbreviations: GH=growth hormone, IGF-1=insulin like growth factor-1, SD=standard deviation; ULN=upper limit of normal Note (1):•Controlled disease: GH < 2.5 μg/L and standardized IGF-1.

•Uncontrolled disease: GH > 2.5 μg/L or IGF-1 > ULN (upper limit of normal) age and sex matched. *Standardized IGF-1 defined as IGF-1/ULN

Figure 2: Mean Growth Hormone (GH) level (µg/L) in Controlled and Uncontrolled Patients during the Observation Period Abbreviations: GH=growth hormone; IGF-1 =insulin growth factor-1 General Note:•Controlleddisease:GH<2.5µg/L and standardized IGF-1. •Uncontrolled disease:GH>2.5 µg/L or IGF-1>ULN (upper limit of normal) age and sex-matched

Source: Own data

Table 4: Prevalence of Comorbidities during the Follow-up Period - All Enrolled (N = 53)

Source: Own data.

Abbreviations: Non-SSA=non-somatostatin analogue; SSA=somatostatin analogue

Acromegaly-related comorbidities

A total of 45 (84.9 %) patients presented with at least one comorbidity at baseline, and 15 (27 %) patients had more than three comorbidities during the follow-up period. The number of patients experiencing comorbidities was higher in the uncontrolled group compared with the controlled group. Endocrine-, cardiovascular-, skeletal-, and gastrointestinal-related comorbidities were the most frequent Figure (3, Table 4 , Supplementary Table1).

Figure 3. : Prevalence of Comorbidities During the Follow-up Period - All Enrolled (N = 53) a Othercomorbidities reported in>10% of patients included endocrine disorders (24.5 %), musculoskeletal and connective tissue disorders, nervous system disorders (15.1 % each), eye disorders, and skin and subcutaneous tissue disorders (11.3 % each) Abbreviations: Non-SSA=non-somatostatinanalogue; SSA=somatostatin analogue

Source: Own data.

Supplementary Table1: Summary of Comorbidities and symptoms at Baseline - All Enrolled (N = 53)

Source: Own data.

Note: (1)Percentages were calculated using the column header as the denominator.

(1)Missing frequencies are represented as “0(0.0 %)”

Discussion

This study presents the characteristics, associated comorbidities, and treatment patterns of patients with acromegaly in Colombia receiving medical therapy from 2005 to 2015. No previous real-world data have been reported in the country on the prevalence of acromegaly complications, treatment patterns, or disease control.

In the current study, the mean age at diagnosis and female predominance were in line with reports from other studies (1, 6, 17-19). Similarly, patients with higher BMI, overweight or obese with uncontrolled disease presented more frequently with acromegaly-associated comorbidities, especially cardiovascular, endocrine, and metabolic disorders. This observation supports the results from earlier studies highlighting the association of higher BMI with acromegaly-associated comorbidities (20, 21).

Overall, 52.8 % of the enrolled patients had a history of pituitary surgery, which tended to be lower (66 %) compared to a study conducted in Sweden (18). An earlier study reported that the cure of macroadenomas using surgical treatment is low (10-20 % remission rate for invasive macroadenomas), resulting in an increase in GH levels (22). In this study, most tumor cases were reported as macroadenomas compared to microadenomas (38 vs. 12), like other study reports. In patients with macroadenomas vs. microadenoma tumors from the SSA and non- SSA cohorts, there was no significant difference in GH and IGF-1 levels at any point in time during the chart review.

In this study, patients with acromegaly had a high frequency of comorbidities (84.9 %), and 27 % of patientshadmore than three acromegaly-related comorbidities. Patients with controlled disease had lower comorbidities than those uncontrolled; this observation is also like other reports (18). The most common comorbidities associated with acromegaly in this study population were related to the endocrine and metabolic system, followed by those related to the cardiovascular system, which differs from previous studies where cardiovascular comorbidity was reported to be the most common (21, 23). Control of the disease has been associated with improvement in acromegaly comorbidities; therefore, strict control of GH and IGF-1 is mandatory and in line with the recommendations of the current clinical guideline (15).

Biochemical control (GH level < 2.5 µg/L and standardized IGF-1) was achieved in ten (18.9 %) patients after 12 months of medical treatment. All patients were from the SSA cohort. During the subsequent three-year follow-up, the number of patients did not increase (4-8 patients), which could be explained by a lack of continuity in the follow-up and thereby a lower number of patients during the follow-up periods (52 patients in year 1 vs. 19 patients in year 4). A previous clinical trial (C2305 study) in patients with newly diagnosed acromegaly demonstrated that biochemical control was achieved in 31.3 % patients receiving pasireotide long-acting release (LAR) and 19.2 % of patients receiving octreotide LAR at 12 months (24). In the PAOLA study that compared a second-generation SSA (pasireotide) vs. octreotide LAR in patients with persistent uncontrolled acromegaly, ten (15 %) patients in the pasireotide 40 mg group and 13 (20 %) in the pasireotide 60 mg group achieved biochemical control, compared with no patients who continued octreotide/lanreotide at 24 weeks (25). In the current study, biochemical control was lower than in the C2305 and PAOLA global studies (24, 25). However, the interpretation must be made with caution due to the observational nature of this study; biochemical control was reported overall, for SSA or non- SSA cohorts rather than individual drugs.

In a study conducted on 554 patients with acromegaly in Germany, an increase in the percentage of patients with GH < 2.5 µg/L and normal IGF-1 levels was reported in the SSA cohort. However, there was no significant difference between short-acting octreotide (GH> 2.5 µg/L in 39.4 % and IGF-1 normal in 30.4 %) and octreotide LAR (GH > 2.5 µg/L in 32.0 % and IGF-1 normal in 31.9 %) (25). Similarly, in the present study, the proportion of patients with controlled GH and standardized IGF-1 levels, in combination and individually, was higher in the SSA cohort than in the non-SSA cohort.

SSAs were widely used as all patients were treated with first- or second-generation SSAs at any point during the observation period. DAs were used by eleven (16.9 %) patients and GHRAs by one (1.8 %), which tended to be lower than in the study in Sweden (20 % and 10 % patients, respectively). The most common first-line treatment was surgery (60 %), followed by SSAs (21 %) and DAs (14 %) (18). Acromegaly treatment was used for an average of 2.8 years. Eight patients received treatment combinations of SSAs+ DAs during the first year, lowering to four and three patients during years 2 and 3, respectively. These treatment patterns are in line with current clinical guidelines.

The mortality rate in patients with active acromegaly is 2-4 times higher than in the general population; as disease control improves, the mortality due to acromegaly and associated comorbidities decreases (27, 28). No death was reported in the present study compared with previous data presenting lower death rates in controlled acromegaly patients (1, 22), which could be associated with shorter follow-up timelines.

This study showed a higher frequency of medical services (physician visits, laboratory tests, and hospitalization) in patients with uncontrolled disease compared to those with controlled disease, which is in line with other economic studies where acromegaly management was approximately 1.6 times more expensive (29). Although healthcare costs were not calculated in the present study, we found that patients with controlled acromegaly had fewer physician visits and laboratory tests. Further, the incidence of hospitalization was reported in more than 10 % of the population from the uncontrolled group.

Thus, optimizing disease control with proper drug treatment, for both the disease and associated comorbidities, in patients with acromegaly may improve clinical outcomes and decrease health check-up visits. This may reduce the direct and indirect costs of acromegaly treatment and potentially improve the effectiveness of acromegaly management.

The most common complications in our cohort were hypertension (49.1 %), obesity (43.4 %), and arthralgia (43.4 %). In a large registry study from Mexico, hypertension was also a common comorbidity but in a lower percentage (27 %). The difference in the percentage of complications may be due to a delayed diagnosis in our country (30). The percentage of complications is similar to a more extensive Colombian report (31), which is consistent with findings reported in the literature, where hypertension is the predominant comorbidity, with a prevalence of 11 % to 54.4 % (31). Obesity is also a common complication in patients with acromegaly; 43.4 % of our patients were obese. The average BMI in the RAPACO study was 28.11, and 78.6 % had overweight. The mechanisms of obesity in acromegaly may be related to decreases in ghrelin and leptin (31).

The study limitations include the retrospective nature of the data collection, which may restrict the accuracy and completeness of the data. A lack of continuity in patient follow-up was observed, significantly beyond three years. These factors made it difficult to assess long- term comorbidities and the use of resources. In Colombia, universal health coverage is provided; however, the healthcare system does not provide medical care in a single expert center, which may explain some of the loss to follow-up and the low mortality. In addition, patients with acromegaly in Colombia face many challenges, including a lack of pituitary expert centers and frequent changes in medical providers. As per the design and inclusion criteria, this study does not include acromegaly patients cured with surgery; however, it is the first to report acromegaly complications, treatment patterns, and disease control related to biochemical response in Colombia.

In conclusion, the study examined the real-world characteristics, comorbidities, and outcomes associated with treating patients with acromegaly in Colombia through clinical records from main referral endocrinology service centers. Results showed that IGF-1 and GH levels tended to decline over time, with more normalization observed in patients receiving SSAs as first-line medical therapy. However, proper patient follow- up and disease control levels could be improved, especially considering the broader availability of therapeutic alternatives recommended by clinical guidelines.

In this study, patients with controlled acromegaly were found to have a lower level of severe comorbidities and less utilization of health resource services; nevertheless, fragmentation of healthcare services can pose challenges to optimal treatment care with longer and continued follow- up and more efficient use of resources.

Abbreviations: BMI=body mass index; CI=confidence interval; DA=dopamine agonist; GH=growth hormone; GHRA=growth hormone receptor antagonist; IGF-1=insulin-like growth factor-1; LAR=long-acting release; SSA=somatostatin analogue; ULN=upper limit of normal

Acknowledgments

We thank the patients who participated in this study, their families, and staff members at individual study centers who provided support. We also thank JSS Medical Research for support during study data collection and statistical analysis and Swetha Sirimalla (Novartis Healthcare Pvt Ltd) for providing medical editorial assistance with this manuscript.

Funding source

Novartis Pharmaceuticals Corporation sponsored this study.

Conflicts of interest

Abreu A, Román-González A, Tovar H, Builes- Barrera C, Nessim E, and Rojas W have received clinical research site fees for data collection from Novartis Pharmaceuticals during the conduct of the study. Román-González A has also received speaker fees from Amgen, Novartis, Sanofi, and PTC Therapeutics outside the conduct of this study. Maestre K and Herrera D have received personal fees from Novartis during the study