In the Journals

CVD leading cause of death in Cushing's disease

Swedish adults with Cushing’s disease are three times more likely to die of cardiovascular disease vs. the overall Swedish population, with the increased risk persisting even when patients are in disease remission, study data show.

Oskar Ragnarsson

“Even though patients with Cushing’s disease in remission have a better prognosis than patients not in remission, they still have a more than twofold increase in mortality, mainly due to cardiovascular diseases, but also due to infections and suicides,” Oskar Ragnarsson, MD, PHD, associate professor and senior consultant in internal medicine and endocrinology at Sahlgrenska Academy, University of Gothenburg, Sweden, told Endocrine Today. “The highest mortality is in subgroups of patients with persistent disease, those who were treated with bilateral adrenalectomy and those who required glucocorticoid replacement.”

In a retrospective, observational study, Ragnarsson and colleagues analyzed data from 502 adults diagnosed with Cushing’s disease, identified in the Swedish National Patient Registry between 1987 and 2013 (387 women; mean age at diagnosis, 43 years; 83% confirmed in remission). Remission status was based on medical records review; information of date and cause of death was obtained from the Swedish National Cause of Death Register. To estimate standardized mortality ratios (SMR), researchers calculated person-years at risk from time of disease diagnosis to death or end of study, stratified by sex, 5-year age groups and 1-year calendar periods, and calculated the expected number of deaths for each stratum using Swedish population data for every calendar year and 5-year age group as reference. Cox regression models were calculated to identify predictors of mortality.

During a median follow-up of 13 years, researchers observed 133 deaths vs. 54 expected deaths, resulting in an overall SMR of 2.5 (95% CI, 2.1-2.9), with no between-sex difference observed. The most common cause of death was CVD (SMR = 3.3; 95% CI, 2.6-4.3), with mortality increased due to both ischemic heart disease (SMR = 3.6; 95% CI, 2.5-5.1) and cerebral infarction (SMR = 3; 95% CI, 1.4-5.7). Researchers also observed increased mortality for infectious diseases, respiratory diseases and diseases of the digestive system. Nine patients died of external causes, including six patients who committed suicide, according to researchers.

The SMR among patients in remission was 1.9 (95% CI, 1.5-2.3). Among patients in remission, researchers found that mortality was similar when using date of remission as baseline instead of start of follow-up (SMR = 1.9; 95% CI, 1.6-2.4).

In Cox regression analyses, HR for overall mortality was 3 for patients not in remission (95% CI, 1.9-4.9) and 2.5 for patients with an unknown remission status, when using patients in remission as a reference (95% CI, 1.6-4.1). Results persisted after adjustment for age at study start.

Among patients in remission, 75% were treated with pituitary surgery, 28% were treated with radiotherapy and 24% were treated with bilateral adrenalectomy. Researchers found that the HR for mortality was increased among patients treated with bilateral adrenalectomy (HR = 2.7; 95% CI, 1.7-4.3), but not among those treated with pituitary surgery or radiotherapy. The researchers found that adding glucocorticoid therapy to the model did not influence results.

“Our findings emphasize the importance of obtaining remission as well as continued active surveillance,” Ragnarsson said. “Following successful treatment of Cushing’s disease, the goal of management should include information on the need for increased glucocorticoid dose during intercurrent illness, and adequate hormone replacement therapy in patients with pituitary insufficiency. Also, evaluation and active treatment of CV risk factors and mental health is of utmost importance.”

Ragnarsson said further studies need to focus on identifying the best approaches to obtaining remission, active surveillance, adequate hormone replacement and long-term management of CV and mental health in patients with Cushing’s disease. – by Regina Schaffer

For more information:

Oskar Ragnarsson, MD, PHD, can be reached at the Institute of Medicine, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45, Göteborg, Sweden; email: oskar.ragnarsson@medic.gu.se.

Disclosures: Ragnarsson reports he has received lecture fees from Ipsen, Novo Nordisk, Pfizer and Sandoz, an unrestricted research grant from HRA-Pharma and consultant fees from HRA-Pharma and Novartis. Please see the study for all other authors’ relevant financial disclosures.

Swedish adults with Cushing’s disease are three times more likely to die of cardiovascular disease vs. the overall Swedish population, with the increased risk persisting even when patients are in disease remission, study data show.

Oskar Ragnarsson

“Even though patients with Cushing’s disease in remission have a better prognosis than patients not in remission, they still have a more than twofold increase in mortality, mainly due to cardiovascular diseases, but also due to infections and suicides,” Oskar Ragnarsson, MD, PHD, associate professor and senior consultant in internal medicine and endocrinology at Sahlgrenska Academy, University of Gothenburg, Sweden, told Endocrine Today. “The highest mortality is in subgroups of patients with persistent disease, those who were treated with bilateral adrenalectomy and those who required glucocorticoid replacement.”

In a retrospective, observational study, Ragnarsson and colleagues analyzed data from 502 adults diagnosed with Cushing’s disease, identified in the Swedish National Patient Registry between 1987 and 2013 (387 women; mean age at diagnosis, 43 years; 83% confirmed in remission). Remission status was based on medical records review; information of date and cause of death was obtained from the Swedish National Cause of Death Register. To estimate standardized mortality ratios (SMR), researchers calculated person-years at risk from time of disease diagnosis to death or end of study, stratified by sex, 5-year age groups and 1-year calendar periods, and calculated the expected number of deaths for each stratum using Swedish population data for every calendar year and 5-year age group as reference. Cox regression models were calculated to identify predictors of mortality.

During a median follow-up of 13 years, researchers observed 133 deaths vs. 54 expected deaths, resulting in an overall SMR of 2.5 (95% CI, 2.1-2.9), with no between-sex difference observed. The most common cause of death was CVD (SMR = 3.3; 95% CI, 2.6-4.3), with mortality increased due to both ischemic heart disease (SMR = 3.6; 95% CI, 2.5-5.1) and cerebral infarction (SMR = 3; 95% CI, 1.4-5.7). Researchers also observed increased mortality for infectious diseases, respiratory diseases and diseases of the digestive system. Nine patients died of external causes, including six patients who committed suicide, according to researchers.

The SMR among patients in remission was 1.9 (95% CI, 1.5-2.3). Among patients in remission, researchers found that mortality was similar when using date of remission as baseline instead of start of follow-up (SMR = 1.9; 95% CI, 1.6-2.4).

In Cox regression analyses, HR for overall mortality was 3 for patients not in remission (95% CI, 1.9-4.9) and 2.5 for patients with an unknown remission status, when using patients in remission as a reference (95% CI, 1.6-4.1). Results persisted after adjustment for age at study start.

Among patients in remission, 75% were treated with pituitary surgery, 28% were treated with radiotherapy and 24% were treated with bilateral adrenalectomy. Researchers found that the HR for mortality was increased among patients treated with bilateral adrenalectomy (HR = 2.7; 95% CI, 1.7-4.3), but not among those treated with pituitary surgery or radiotherapy. The researchers found that adding glucocorticoid therapy to the model did not influence results.

“Our findings emphasize the importance of obtaining remission as well as continued active surveillance,” Ragnarsson said. “Following successful treatment of Cushing’s disease, the goal of management should include information on the need for increased glucocorticoid dose during intercurrent illness, and adequate hormone replacement therapy in patients with pituitary insufficiency. Also, evaluation and active treatment of CV risk factors and mental health is of utmost importance.”

Ragnarsson said further studies need to focus on identifying the best approaches to obtaining remission, active surveillance, adequate hormone replacement and long-term management of CV and mental health in patients with Cushing’s disease. – by Regina Schaffer

For more information:

Oskar Ragnarsson, MD, PHD, can be reached at the Institute of Medicine, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45, Göteborg, Sweden; email: oskar.ragnarsson@medic.gu.se.

Disclosures: Ragnarsson reports he has received lecture fees from Ipsen, Novo Nordisk, Pfizer and Sandoz, an unrestricted research grant from HRA-Pharma and consultant fees from HRA-Pharma and Novartis. Please see the study for all other authors’ relevant financial disclosures.