In their article “Effects of long-term combined treatment with somatostatin analogs (SSA) and pegvisomant (PEG) on cardiac structure and performance in acromegaly”, Auriemma et al. [1] demonstrated improved left ventricular hypertrophy (LVH) and diastolic function on therapy with SSA-PEG (SSA-PEG) compared to SSA alone and before treatment. Patients received long-acting octreotide or lanreotide without biochemical control of acromegaly. When PEG added to the regimen, insulin like growth factor 1 (IGF-1) normalized in 83% cases. This is the first prospective study to investigate the effects of combination medical treatment for acromegaly on cardiovascular parameters.

Acromegaly is associated with increased prevalence of systemic arterial hypertension, diabetes mellitus [2, 3], sleep apnea, and dyslipidemia. In addition, acromegaly causes a specific cardiomyopathy characterized by LVH and diastolic dysfunction, which can progress to systolic dysfunction. The mechanism is multifactorial, including direct cardiac effects of GH and IGF-1, as well as cardiac remodeling induced by hypertension and insulin resistance. Echocardiographic studies identified LVH in 36–80% [4–6], and diastolic dysfunction in 29–40% patients [4, 5]. Predictors of cardiomyopathy are age and body mass index (correlated with LVH and diastolic dysfunction), and acromegaly duration (correlated with great vessel diameter) [7]. Acromegaly is also associated with increased prevalence of mild-to-moderate mitral and aortic valvulopathy, arrhythmia, and endothelial dysfunction [5].

Treatment for acromegaly has been shown to improve or reverse the acromegalic cardiomyopathy. Transsphenoidal surgery improves left ventricular mass index (LVMi), diastolic function, and left ventricular ejection fraction [2, 8]. SSAs have been the cornerstone of medical treatment for persistent acromegaly after surgery. First generation SSAs (short- and long-acting octreotide, lanreotide depot) have been demonstrated to improve cardiomyopathy [8]. The effect on LVMi and diastolic filling is usually apparent after 12 months and more significant in younger patients who achieved biochemical control [2, 4]. No studies have yet evaluated the cardiovascular effects of recently approved multi-ligand somatostatin analog, pasireotide. Growth hormone receptor antagonist PEG is generally used in patients with acromegaly resistant or intolerant to SSA. PEG treatment improved the LVMi [9], systolic and diastolic function [10] and blood pressure [11]. In the German Pegvisomant Observational Study, 12 months of PEG therapy decreased the Framingham risk score [12]. The effects of dopamine agonists and pituitary radiation on acromegalic cardiomyopathy have not been studied.

Metabolic syndrome occurs in the majority of patients with acromegaly [13] and affects women more than men [14]. Since metabolic syndrome is linked to cardiovascular outcomes, the impact of different treatments on glucose metabolism should be considered. Surgery has been demonstrated to improve glucose tolerance at 2 months postoperatively in both diabetics and non-diabetics. Long-term data are sparse; one study showed that patients in remission at 12 months postoperatively had higher hemoglobin A1c (HbA1c) than controls [2]. First generation SSAs cause hyperglycemia in approximately 5% of patients, but most patients experience a slightly beneficial or neutral effect on glucose control [1]. In contrast, pasireotide causes new-onset diabetes mellitus in 28% of cases. PEG has a favorable glucose profile and improves glucose, HbA1c levels and HOMA index [11]. The studies on SSA-PEG combination on glucose metabolism are few. Auriemma et al. [1] study (36 patients) found an improvement of HOMA-IR and fasting insulin but not fasting glucose and HbA1c levels. De Marinis et al. [15] study indicated lower glucose area under the curve during oral glucose tolerance test after 6 but not 12 months of treatment, and no effect on HbA1c, fasting plasma glucose, insulin, or HOMA-IR. Both studies reported a significant decrease of IGF-1 levels, but an unusually high number of patients (8 out of 10) experienced worsened glucose homeostasis with SSA alone in De Marinis et al. study.

Several caveats should be considered when interpreting the effects of treatment for acromegaly on cardiovascular parameters. First, most studies used 2D echocardiography, which has lower reproducibility compared with cardiac MRI. The use of both modalities in patients with acromegaly yielded discordant results, with both higher [4] and lower [16] prevalence of LVH by MRI compared with echocardiogram. Even more, the SSA therapy lead to LVH improvement in one study [4] but not in another [16]. While some differences are expected due to different methodologies (i.e., cutoff to define LVH) and different patient populations, this discrepancy should be clarified by controlled studies. Second, although greater improvement of cardiomyopathy was demonstrated in patients with normalized IGF-1, the benefits are also seen in patients with biochemical improvement [1, 8]. The direct cardiac effects of SSAs or PEG need further study. Otherwise, biochemical target to decrease cardiovascular complications may be different than biochemical normalization.

Our knowledge regarding cardiovascular effects of acromegaly therapy originates from relatively small studies with cardiac measurements longitudinally over few months or few years. The data on major cardiovascular events (MACE) in patients treated for acromegaly is sparse. One study found that older age and smoking are the main determinants of MACE in acromegaly, while treatment (surgery or SSA) were non-contributory [3]. Conversely, standardized mortality rates in acromegaly decreased from 2.0–3.0 in studies published before 2010 to 0.7–1.7 in recent reports. These differences reflect the increased use of surgical and medical treatment [17–19]. Cardiovascular disease was responsible for the majority of deaths in old studies [5], but decreased in new reports in favor of cancer deaths [19, 20]. Biochemical control of acromegaly is strongly associated with decreased mortality [20, 21]. One study found that diabetic patients have less survival benefit from SSA than surgical treatment of acromegaly [17]. Radiation and hypopituitarism have been associated with increased all-cause mortality [17, 19], but patients receiving radiation may have more aggressive tumors. The effect of PEG in relation with mortality has not been studied. Long-term prospective studies are necessary to clarify the effect of different acromegaly treatments on cardiovascular morbidity and mortality.

Several recommendations can be made based on the available data regarding cardiovascular disease in acromegaly. Early diagnosis and timely biochemical control may prevent cardiovascular complications. A comprehensive cardiovascular risk assessment should include genetic and ethnic background, visceral obesity, patients’ lifestyle, blood pressure, glucose, lipids, as well as biochemical severity and duration of acromegaly. The choice of medical treatment should be individualized based on biochemical and radiological tumor parameters, as well as the metabolic and cardiovascular risk profile.