Acromegaly—Initiating Intervention Early, Lowering Diabetes Risk

When surgery is not pursued as first-line therapy, medication selection is critical to address risk of diabetes, hypertension, and cardiovascular disease to assure best long-term management.

With Moises Mercado, MD, Maria Fleseriu, MD, and Laurence Katznelson, MD

Acromegaly, an uncommon hormonal disorder, produces symptoms due to excess growth hormone (GH), which may appear at any age. In the overwhelming majority of people who present with acromegaly, a pituitary adenoma, and particularly macro-adenoma, has proven to be the underlying cause.1 Although microadenomas are far more common, affecting nearly one in five people, they infrequently cause symptoms and rarely produce excess growth hormone.2,3

Not uncommon, patients with acromegaly respond best when diagnosed and treated early in the disease presentation. Without any intervention, acromegaly may lead to greater morbidity and early mortality, including type 2 diabetes (T2D) and hypertension (HTN), each of which also raises the risk of cardiovascular disease (CVD).

Diabetes, hypertension, and cardiovascular disease may occur when acromegaly is poorly managed.

Acromegaly Management: Consider Both Efficacy and Side Effects of Treatment  

Acromegaly is managed surgically (removal of the benign pituitary tumor), medically, and/or with radiation therapy of the pituitary. Transsphenoidal surgery is often the first-line therapy, as it affords a rapid lowering of GH levels and prompt relief of symptoms and manifestations. However, owing to a variety of factors, surgery is not always successful. Specifically, surgery is associated with remission in up to 76% of noninvasive adenomas, but only 24% of invasive tumors.4,5

Hormone levels may improve but may not return to normal, necessitating additional treatment—predominantly with medication. Medications may also be necessary to shrink particularly large tumors prior to surgery, and in patients for whom surgery is not an option.

The three medication groups relied on to manage acromegaly are:

  • somatostatin analogs (SSAs)
  •  growth hormone receptor antagonists (GHRAs)
  • dopamine agonists

Somatostatin analogs are first-line medications, as they are effective in lowering both growth hormone and insulin-like growth factor I (IGF-I), or somatotroph. In 30% to 50% of patients, SSAs can also reduce tumor size–albeit only to a modest degree. SSAs also reduce the need for insulin, and in some people with acromegaly who already had diabetes, have shown improvement in blood glucose control.

However, after SSA treatment discontinuation, there has been a high likelihood of disease recurrence.4 Growth hormone receptor agonists work by normalizing IGF-I levels but do not lower GH levels. Dopamine agonists are not as effective as SSAs or GHRAs, and, consequently, may be more effective when combined with SSAs.6

Given Concern about Diabetes, There's More to Somatostatin Analogs

In a meta-analysis of 47 prospective international trials (n = 1297; ~50% female),7 the researchers sought to evaluate the efficacy of somatostatin analogs in improving glucose metabolism in patients under treatment for acromegaly. While effective in promoting growth hormone production, somatostatin therapy had a varied effect on diabetes factors, such as reducing fasting plasma insulin and lowering serum triglycerides, but hemoglobin A1c levels increased.

Based on the findings, the net takeaway according to the authors is for clinicians to consider monitoring postprandial glucose in patients receiving somatostatin analogs for acromegaly.7

Among 522 patients who were receiving care for acromegaly at a tertiary medical center, researchers examined the prevalence of T2D and HTN after treatment for acromegaly.8  At diagnosis, 30% of patients had diabetes and 37% had HTN; after a median follow-up time of 7.4 years, this prevalence did not change; 30.6% and 38% of the patients had diabetes and HTN, respectively. At both time points, the prevalence of diabetes and HTN was significantly greater among patients with acromegaly than the general population.

Senior author, Moises Mercado, MD, a practitioner in the Endocrinology Service and the Experimental Endocrinology Unit at the Hospital of Specialities and the Mexican Society Security Institute (Instituto Mexicano del Seguro Social) in Mexico City, Mexico, told EndocrineWeb, “the GH excess that characterizes acromegaly products insulin resistance with a consequent reduction in peripheral glucose uptake.”

The investigators noted that after stratifying for disease activity status, “diabetes, but not hypertension, was significantly more prevalent on the last visit in those patients who remained biochemically active (40%) or were IGF-1 discordant (37%) than in those who eventually achieved surgical remission (25%; P=0.01).”8

The study identified factors that suggested a greater risk for diabetes including female sex, having a macroadenoma, an IGF-1 level > two times the upper limit of normal at diagnosis, comorbid hypertension, and persistence of acromegaly activity. In contrast, the only significant factors associated with the risk of having hypertension was an IGF-1 > two times the upper limit of normal at diagnosis, coexisting diabetes, and persistence of biochemical acromegaly activity.8

In addition, the researchers determined that diabetes was associated with a two-fold higher IGF-1, which persisted in patients with active acromegaly, the presence of hypertension, macroadenoma, and being female.8

For a while, a normal blood glucose level may be maintained at the expense of an increased insulin secretion by the pancreas; when this is exhausted, fasting hyperglycemia and diabetes occur.  He further noted that hypertension in acromegaly is multifactorial: first, the GH excess produces renal tubular reabsorption of sodium and water, which increases blood volume; this, together with an enhanced tone of the sympathetic nervous system, results in arterial hypertension.9

Anticipating the Rare Patient Who Presents with Acromegaly

It is believed that only 3-4/1,000,000 people develop acromegaly each year, with approximately 60/1,000,000 suffering from the disease at any time.10 Consequently, many community endocrinologists are not be faced with a patient who has acromegaly, yet it is a possibility. Employing a self-reported assessment tool for acromegaly may prove useful in evaluating patient satisfaction with medication options.

Laurence Katznelson, MD, medical director of the Pituitary Center at Stanford School of Medicine in California, and lead author of the Endocrine Society Clinical Practice Guideline on Acromegaly,10 told EndocrineWeb that this study highlights the need for clinical endocrinologists “to remain vigilant in monitoring for T2D and hypertension in their patients with acromegaly. Comorbid conditions that do not resolve with surgery or medication may need independent management.”

Dr. Mercado noted that diabetes and hypertension in the patient with acromegaly should be managed similarly to non-acromegalic patients. “The important lesson for clinicians,” he said “is to focus not only on the hormonal control of acromegaly but also on the timely treatment of acromegaly-related comorbidities in order to prevent or postpone the development of CVD in these patients.”

Interventions and Treatment Consequences of SSA Use

Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery, and director of the Northwest Pituitary Center at Oregon Health Science University in Portland, Oregon, offered commentary on the study findings as well as this expert guidance on treating patients with acromegaly to address the risk of diabetes and its comorbidities, at  the invitation of EndocrineWeb

Here is what she shared:

“Although most patients with acromegaly present with hyperinsulinemia and insulin resistance, between 15-66% of patients (depending on the study) will have abnormal glucose at diagnosis.”11-13

“Various factors may contribute to this difference, including ethnicity and the methodology used to diagnose diabetes mellitus (DM): fasting plasma glucose level (FPG), oral glucose tolerance test, or HbA1c level.” 

“As such, the role of specific treatment for acromegaly in improving or normalizing glucose metabolism has been controversial as some patients will improve while others will develop DM.”

“This may be explained by impairment of β–cell function that is probably present at diagnosis in patients with abnormalities in glucose metabolism. Both surgery and somatostatin analogs (SSA) can reduce post-glucose insulin levels and HOMA-IR, but a reduction of HOMA-β has been observed mostly in SSA- treated patients indicative of impairment in β-cell function.”14

“Biochemical control of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) remains paramount for patients with acromegaly, requiring medical intervention in a large proportion of patients.”

“For patients started on therapy with SSA, follow-up is necessary to monitor for glucose abnormalities and based on this novel data,11 in addition to fasting glucose and HbA1c, postprandial glucose also should be taken into account.”

“To avoid hypoglycemia, which has been reported occasionally with SSA treatment, any introduction of antidiabetic agents will require observation and/or dose adjustment.”

“The dissimilarities in study design and the limited availability of full data presented explain the differences in recommendations for follow-up between Lanreotide and Octreotide.15 However, what we can say is that with Pasireotide—a 2nd generation SSA—the likelihood of hyperglycemia requires closer glucose monitoring in these patients.16

“Of note, SSA use in patients not previously controlled with other therapies, demonstrated increased glucose levels, suggesting that a longer history of acromegaly, and, thus, a worsening of insulin resistance may be predictive of a metabolic response to SSAs.”

“As such, patients with more severe acromegaly require closer follow-up and treatment for glucose abnormalities before and during the SSA treatment. And, recent data shows that pegvisomant,17 a GH receptor blocker might improve glucose metabolism on treatment, but further research is needed.”

“Fortunately, the incidence of diabetes, per se, does not seem to increase significantly with SSA (Hba1c is slightly decreasing, most likely due to acromegaly control) and recent studies show actually a decrease in cardiac disease with newer treatment modalities. Remission of disease is the key and each patient will need an individualized treatment in a multidisciplinary clinic for best outcomes.”

Continue Reading:
Getting Growth Hormone Levels Just Right: The Goldilocks Principle
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