Amin and colleagues recently discussed glucocorticoid replacement therapy in the BMJ (1). The most controversial topic in their article is the recommendation of prednisolone as a first-line treatment for glucocorticoid replacement. Prednisolone is very sparsely studied as a replacement therapy for patients with adrenal insufficiency. The few studies that exist have demonstrated that patients treated with prednisolone have adverse cardiovascular risk profile (2) and decreased bone mineral density (3-5) as compared with hydrocortisone, even after adjustment for hydrocortison equivalent doses. Furthermore, in a randomized, double-blind trial, patients with secondary adrenal insufficiency treated with hydrocortisone (10+5 mg) had a significantly better physical quality of life and well-being compared to patients treated with prednisolon (5 mg) (6).
In their editorial the authors also question the use of the dual-release hydrocortisone, Plenadren, a new hydrocortisone formulation that was approved by the European Medicines Agency in 2012 for the use in patients with adrenal insufficiency. As the authors point out, Plenadren was licensed on the basis of a prospective randomized trial where several beneficial effects on outcome were demonstrated in comparison to conventional hydrocortisone formulation (7). There are, however, inaccuracies in Amins´ paper that need to be acknowledged.
Firstly, the authors state that it was not surprising that the patients in the Plenadren arm had lower body weight, blood pressure, and glycosylated haemoglobin A1c concentrations since the hydrocortisone doses were not comparable. This is incorrect; the doses in the Plenadren and the conventional hydrocortisone groups were the same. Instead, the beneficial effect that was observed most probably resulted from an improved cortisol exposure-time profile, i.e. a profile that mimics the physiological cortisol profile in healthy adults (8).
Secondly, it is stated that no difference in quality of life was observed. This is also wrong as the scores for psycosocial functioning and positive well-being were in favor of Plenadren in this pivotal randomized cross-over trial. Moreover, Plenadren is the only glucocorticoid replacement therapy that has been studied prospectively with regard to adverse effects and effectiveness in intercurrent illness (9). We can only conlude that the scientific evidence for treating patients with adrenal insufficiency is higher for Plenadren than for any other treatment regimen.
In accordance with two recent expert opinions (10, 11) we find it highly questionable to recommend prednisolone to patients with adrenal insufficiency, a synthetic glucocorticoid with long half-life and long effect duration. Instead, to avoid the increased risk for adverse effects, the goal with glucocorticoid replacement should be to administer a replacement regime that as far as possible is similar to normal endogenous cortisol production.
Oskar Ragnarsson, PhD, MD and Anna G. Nilsson, PhD, MD
Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
Conflict of interest: OR was a co-investigator and AGN was the principle investigator in the studies of Plenadren resulting in its approval by EMA. AGN has received fees from Viropharma Inc for scientific advice and lectures.
References
1. Amin A, Sam AH, Meeran K. Glucocorticoid replacement. BMJ. 2014;349:g4843.
2. Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A, Johannsson G. The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab. 2006 Oct;91(10):3954-61.
3. Koetz KR, Ventz M, Diederich S, Quinkler M. Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab. 2012 Jan;97(1):85-92.
4. Falhammar H, Filipsson Nystrom H, Wedell A, Brismar K, Thoren M. Bone mineral density, bone markers, and fractures in adult males with congenital adrenal hyperplasia. Eur J Endocrinol. 2013 Mar;168(3):331-41.
5. Jodar E, Valdepenas MP, Martinez G, Jara A, Hawkins F. Long-term follow-up of bone mineral density in Addison's disease. Clin Endocrinol (Oxf). 2003 May;58(5):617-20.
6. Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S, et al. Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency. Eur J Endocrinol. 2012 Nov;167(5):679-85.
7. Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, et al. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab. 2012 Feb;97(2):473-81.
8. Johannsson G, Bergthorsdottir R, Nilsson AG, Lennernas H, Hedner T, Skrtic S. Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol. 2009 Jul;161(1):119-30.
9. Nilsson AG, Marelli C, Fitts D, Bergthorsdottir R, Burman P, Dahlqvist P, et al. Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency. Eur J Endocrinol. 2014 Sep;171(3):369-77.
10. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab. 2009 Apr;94(4):1059-67.
11. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014 Jun 21;383(9935):2152-67.
Competing interests:
OR was a co-investigator and AGN was the principle investigator in the studies of Plenadren resulting in its approval by EMA. AGN has received fees from Viropharma Inc for scientific advice and lectures.
Rapid Response:
Amin and colleagues recently discussed glucocorticoid replacement therapy in the BMJ (1). The most controversial topic in their article is the recommendation of prednisolone as a first-line treatment for glucocorticoid replacement. Prednisolone is very sparsely studied as a replacement therapy for patients with adrenal insufficiency. The few studies that exist have demonstrated that patients treated with prednisolone have adverse cardiovascular risk profile (2) and decreased bone mineral density (3-5) as compared with hydrocortisone, even after adjustment for hydrocortison equivalent doses. Furthermore, in a randomized, double-blind trial, patients with secondary adrenal insufficiency treated with hydrocortisone (10+5 mg) had a significantly better physical quality of life and well-being compared to patients treated with prednisolon (5 mg) (6).
In their editorial the authors also question the use of the dual-release hydrocortisone, Plenadren, a new hydrocortisone formulation that was approved by the European Medicines Agency in 2012 for the use in patients with adrenal insufficiency. As the authors point out, Plenadren was licensed on the basis of a prospective randomized trial where several beneficial effects on outcome were demonstrated in comparison to conventional hydrocortisone formulation (7). There are, however, inaccuracies in Amins´ paper that need to be acknowledged.
Firstly, the authors state that it was not surprising that the patients in the Plenadren arm had lower body weight, blood pressure, and glycosylated haemoglobin A1c concentrations since the hydrocortisone doses were not comparable. This is incorrect; the doses in the Plenadren and the conventional hydrocortisone groups were the same. Instead, the beneficial effect that was observed most probably resulted from an improved cortisol exposure-time profile, i.e. a profile that mimics the physiological cortisol profile in healthy adults (8).
Secondly, it is stated that no difference in quality of life was observed. This is also wrong as the scores for psycosocial functioning and positive well-being were in favor of Plenadren in this pivotal randomized cross-over trial. Moreover, Plenadren is the only glucocorticoid replacement therapy that has been studied prospectively with regard to adverse effects and effectiveness in intercurrent illness (9). We can only conlude that the scientific evidence for treating patients with adrenal insufficiency is higher for Plenadren than for any other treatment regimen.
In accordance with two recent expert opinions (10, 11) we find it highly questionable to recommend prednisolone to patients with adrenal insufficiency, a synthetic glucocorticoid with long half-life and long effect duration. Instead, to avoid the increased risk for adverse effects, the goal with glucocorticoid replacement should be to administer a replacement regime that as far as possible is similar to normal endogenous cortisol production.
Oskar Ragnarsson, PhD, MD and Anna G. Nilsson, PhD, MD
Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
Conflict of interest: OR was a co-investigator and AGN was the principle investigator in the studies of Plenadren resulting in its approval by EMA. AGN has received fees from Viropharma Inc for scientific advice and lectures.
References
1. Amin A, Sam AH, Meeran K. Glucocorticoid replacement. BMJ. 2014;349:g4843.
2. Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A, Johannsson G. The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab. 2006 Oct;91(10):3954-61.
3. Koetz KR, Ventz M, Diederich S, Quinkler M. Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab. 2012 Jan;97(1):85-92.
4. Falhammar H, Filipsson Nystrom H, Wedell A, Brismar K, Thoren M. Bone mineral density, bone markers, and fractures in adult males with congenital adrenal hyperplasia. Eur J Endocrinol. 2013 Mar;168(3):331-41.
5. Jodar E, Valdepenas MP, Martinez G, Jara A, Hawkins F. Long-term follow-up of bone mineral density in Addison's disease. Clin Endocrinol (Oxf). 2003 May;58(5):617-20.
6. Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S, et al. Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency. Eur J Endocrinol. 2012 Nov;167(5):679-85.
7. Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, et al. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab. 2012 Feb;97(2):473-81.
8. Johannsson G, Bergthorsdottir R, Nilsson AG, Lennernas H, Hedner T, Skrtic S. Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol. 2009 Jul;161(1):119-30.
9. Nilsson AG, Marelli C, Fitts D, Bergthorsdottir R, Burman P, Dahlqvist P, et al. Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency. Eur J Endocrinol. 2014 Sep;171(3):369-77.
10. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab. 2009 Apr;94(4):1059-67.
11. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014 Jun 21;383(9935):2152-67.
Competing interests: OR was a co-investigator and AGN was the principle investigator in the studies of Plenadren resulting in its approval by EMA. AGN has received fees from Viropharma Inc for scientific advice and lectures.