Diabetes is prevalent, estimated to affect 10% of population. Cushing’s syndrome (CS) on the other hand is rare, 2–3 cases/million per year. Clinical manifestations of diabetes and early CS are similar; increased glucose, blood pressure, cholesterol and abdominal circumference.
Authors find that subtle cortisol elevation is present in 3.5% of persons with type 2 diabetes, with the main source being adrenal adenomas. It is reasonable to screen DM2 patients with “cushing’s syndrome” features, as surgical cure is a possibility.
Eur J Endocrinology
Objective: Type 2 diabetes (T2D) and Cushing’s syndrome (CS) share clinical characteristics, and several small studies have recorded a high prevalence of hypercortisolism in T2D, which could have therapeutic implications. We aimed to assess the prevalence of endogenous hypercortisolism in T2D patients.
Design: Systematic review and meta-analysis of the literature.
Methods: A search was performed in SCOPUS, MEDLINE, and EMBASE for original articles assessing the prevalence of endogenous hypercortisolism and CS in T2D. Data were pooled in a random-effect logistic regression model and reported with 95% confidence intervals.
Results: 14 articles were included, with a total of 2827 T2D patients.
The pooled prevalence of hypercortisolism was 3.4% (95% CI: 1.5–5.9) and Cushing’s syndrome 1.4% (95 CI: 0.4–2.9). The prevalence did not differ between studies of unselected patients, and patients selected based on the presence of metabolic features such as obesity or poor glycemic control (P = 0.41 from meta-regression).
Imaging in patients with hypercortisolism (n = 102) revealed adrenal tumors in 52% and pituitary tumors 14% of the cases.
Endogenous hypercortisolism is a relatively frequent finding in T2D, which may have therapeutic implications.
More from the publication:
Type 2 diabetes (T2D) is a common disease (prevalence ≈ 9%) characterized by insulin resistance and a relative β-cell dysfunction. The clinical picture includes hyperglycemia, obesity, hypertension, and hyperlipidemia. Despite a multimodality treatment approach, T2D patients carry a significant risk for cardiovascular morbidity and mortality.
Cushing’s syndrome (CS) due to endogenous hypercortisolism, on the other hand, is a very rare condition with an annual incidence of 2–3 per million and is characterized by hyper-secretion of cortisol as a consequence of either pituitary or adrenal neoplasia, as well as ectopic ACTH-producing tumors. The classic features of overt CS include truncal adiposity, hypertension, dyslipidemia, and diabetes. CS is associated with long-term multi-morbidity and an increased mortality risk.
Evidently, T2D and CS share many clinical characteristics, and some patients diagnosed with T2D could represent incipient or subclinical CS. A review from 2012 recorded a wide scatter in the prevalence of CS in T2D ranging between 0 – 9.4% based on 11 studies using different biochemical criteria. Proper identification of such patients may have important clinical implications as CS may be curable by surgery, whereas T2D is a chronic disease requiring lifelong medical treatment. However, many unresolved issues remain and it is presently unknown whether it is justifiable to screen for CS in T2D.
The aim of this study is to perform a systematic review and meta-analysis of the prevalence of hypercortisolism in T2D patients. Our study revealed a mean prevalence of hypercortisolism in 3.4% of T2D patients. This figure is based on our biochemical pre-definition of hypercortisolism, which we implemented to allow for a comparison between the studies. The prevalence of CS as defined by each study was lower (1.4%), which reflects the inclusion of additional criteria such as positive imaging or a histologically proven tumor. Subsequent imaging performed in the patients with hypercortisolism revealed either adrenal adenoma or a pituitary adenoma in 52 and 15%, respectively, which points toward a potentially curable condition in these patients. In seven of the studies including 1873 patients, post-surgical outcome data were provided. Each of the 17 post-surgically evaluated patients (0.9%) showed significantly improved glycemic control, and weight loss and lowering of blood pressure were occurred in a subset.
Previous studies show an annual incidence of classic CS of 2.5/million, with pituitary adenomas accounting for ≈ 60% and benign adrenal adenomas ≈ 25%. This exemplifies the rarity of classic CS and also indicates that the etiology and pathogenesis of hypercortisolism in T2D differ from classic CS. Even though the natural history and clinical consequences of hypercortisolism detected during screening in T2D remain uncertain, it is noteworthy that adrenal adenomas are revealed in ≈ 50% of T2D with endogenous hypercortisolism. This is compatible with the high prevalence of so-called adrenal incidentalomas, where some degree of cortisol overproduction is encountered in 7.9%. Along this line, it is interesting that the incidence rate of diagnosed and operated patients with adrenal CS increased by more than 100% in 2000–2010 compared with 1980–1999 in a recent population-based study. Of additional interest, the mean age of the patients diagnosed between 2000 and 2010 had also increased (from 40 to 53 years). The mechanisms underlying these observations are uncertain, but increased imaging is a plausible explanation.
Imaging was negative in 31% of T2D patients with documented hypercortisolism in this meta-analysis. To which degree hypercortisolism in T2D patients with negative imaging may reflect an underlying inflammatory component of T2D involving activation of the HPA axis is uncertain. It is also possible that elevated cortisol levels occurred as a counter regulatory neuroendocrine response to hypoglycemia in T2D patients treated with insulin or sulfonylurea. Unfortunately, we were unable to retrieve data on antidiabetic treatment at the level of individual patients in this meta-analysis.
Studies in the present meta-analysis did not provide a concise distinction between subclinical and overt CS among their patients with biochemical hypercortisolism, which is a limitation.
Screening for hypercortisolism in T2D patients is at present time only recommended if a patient shows signs and symptoms of CS. Screening interventions are designed to early identification of disease in a community setting to enable early intervention in order to reduce morbidity and mortality of the disease. Obviously, screening is associated with untoward effects including over diagnosis and side effects of the provided treatment.
According to the World Health Organization, the prevalence of diabetes in the adult European population is approximately 10%. If 0.9% of these patients in fact have hypercortisolism, associated diabetes due to a resectable tumor, more than 0.5 million people in Europe alone could potentially be cured of diabetes. This number is clearly an exaggeration, but it may help to promote the understanding of the challenges and possibilities. It is important to note that no study so far has documented a clear effect of surgical removal of adenomas in patients with subclinical CS.
In conclusion, the present meta-analysis reveals a relatively high prevalence of endogenous hypercortisolism and CS in T2D patients and a substantial proportion of the cases also presented with adrenal or pituitary neoplasia, which could provide the basis for surgical intervention. These findings may have therapeutic implications and controlled trials should be considered.