This registry-based study investigating the cardio-metabolic risk factors in a cohort of Iranian people with acromegaly demonstrated DLP is the most prevalent metabolic abnormality in this population followed by DM, and HTN. Moreover, analysis of postoperative data showed GH acts as a determinant of FBS, SBP, and DBP levels. It appears also as a predictive factor for DM after adjusting for the other co-existing risk factors.
With regard to the impact of GH/IGF-1 on all aspects of metabolism, association of acromegaly with a wide spectrum of metabolic abnormalities is not far from the expectation. However, clinical manifestations of these metabolic abnormalities vary among patients with different ethnic background. DM has been reported to be present in 16–56% of patients with acromegaly [18, 19]. Hypertriglyceridemia and low HDL-cholesterol are the most common lipid abnormalities associated with acromegaly reported in 33–47% of the patients [18, 20, 21]. HTN is another common comorbidity of acromegaly with an average prevalence of 35%, ranging from 18–60% . The prevalence of metabolic abnormalities obtained from this registry-based study, including DM (29.4%), HTN (15%), and DLP (79.17%), is comparable with those from the previous studies in most but not all cases. This variability is explained by heterogeneity in the study populations and differences in the criteria used for the diagnosis of metabolic abnormalities. Moreover, the status of disease activity and different therapeutic intervention could affect the frequency and severity of these cardio-metabolic risk factors.
Analysis of postoperative data, stratified by disease activity, revealed no significant difference in the frequency and severity of cardio-metabolic risk factors between active/ discordant groups compared to the cured/controlled one. Moreover, a proportion of patients in the cured/controlled group continued to show metabolic abnormalities. Similarly, previous studies demonstrated some residue of metabolic disturbances even after successful treatment of acromegaly [14, 18]. Nevertheless, it is not well-known whether this reflects the ethnogenetic background of the people or is the result of some irreversible derangements secondary to the chronic GH excess .
Many studies investigating the predictors of diabetes in acromegaly demonstrated age, gender, BMI, and family history of diabetes are the well-established risk factors of diabetes in acromegaly . However, the association between diabetes and the main indicators of disease activity in acromegaly (i.e., GH and IGF-1 levels) is somewhat controversial. One study, based on the French Acromegaly Registry data, claimed that “the GH and IGF-1 levels did not appear as predictive factors for the presence of diabetes” , while others suggested high IGF-1 rather than high GH is a predictor of diabetes in acromegaly [14, 16]. The present study showed GH is significantly associated with the level of FBS. Moreover, it acts as a main determinant of DM upon adjusting for the potential risk factors. This controversy is partly explained by the fact that GH directly acts as a diabetogenic hormone by increasing lipolysis and inducing insulin resistance  while indirectly, via increasing IGF-1, may facilitate insulin action and result in hypoglycemia . As shown in this study, the predictive role of GH, but not IGF-1, in developing DM is pathophysiologically compatible with the impact of GH and IGF-1 on glucose metabolism. However, at the early stage of the disease, patients with acromegaly maintain normal glycemic status at the expense of increasing insulin production by the pancreatic beta cells [24, 26]. Chronic GH excess, leading to insulin resistance, overcomes the beneficial effects of IGF-1 excess on insulin sensitivity, increases fasting glucose, and eventually leads to overt hyperglycemia .
A few studies investigated the hypertension-related factors in patients with acromegaly leading to inconclusive results. One study showed in patients with active acromegaly IGF-1 was a predictor of SBP level, mediating by albuminuria, while in patients with controlled disease; other cardiovascular risk factors such as abdominal obesity and TG were associated with BP levels . A more recent study demonstrated the risk of having HTN was only significantly associated with the IGF-1 > 2 ULN at diagnosis and the coexistence of diabetes (14). However, in some study, HTN in acromegaly was not related to IGF-1 levels . The current study showed GH is significantly associated with both SBP and DBP levels; However, GH could not predict the presence of HTN defined as BP ≥ 140/90 mmHg in this population of patients with acromegaly. Moreover, IGF-1 times ULN was inversely associated with DBP level, but there was no predictive role for IGF-1 times ULN in predicting HTN. Although the vasodilatory effect of IGF-1, mediated by nitric oxide, and the role of GH in Na and water retention [12, 13, 28] clearly explain the protective role of IGF-1 on diastolic blood pressure and the effect of GH in increasing systolic and diastolic blood pressure, as shown in this study, the level of BP might be determined by the interaction between various influencing factors at different stages of acromegaly. Moreover, the inconclusive results regarding the impact of GH/IGF-1 on HTN, coming from different studies, might be explained by different studied population, duration of follow-up, and disease activity status at which the studies have been done. Moreover, a recent study showed different treatments used to control acromegaly are associated with different changes in metabolic parameters and cardiovascular risk factors .
Lipid abnormalities, including hypertriglyceridemia and low HDL, are frequently seen in patients with acromegaly. DLP was found to be the most prevalent metabolic abnormality in this study. Regarding the determinants of DLP in patients with acromegaly we found no predictive role for neither GH nor IGF-1 times ULN. Similarly, another study suggested hypertriglyceridemia of acromegaly does not correlate with basal GH or IGF-1 concentration but is associated with insulin resistance . However, a most recent study showed a correlation between low HDL and basal IGF-1 . Although a significant improvement in lipid profile after successful treatment of acromegaly supports the role of GH and /or IGF-1 in the development of these abnormalities, no predictive role of GH/IGF-1 for DLP has been well-established. This is likely due to the influence and interaction of other co-existing risk factors.