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Meta-Analysis
. 2021 Sep 17:12:732240.
doi: 10.3389/fendo.2021.732240. eCollection 2021.

Effectiveness of Medical Treatment of Cushing's Disease: A Systematic Review and Meta-Analysis

Julia Simões Corrêa Galendi  1 , Afonso Nogueira Simões Correa Neto  2 , Michelle Demetres  3 , Cesar Luiz Boguszewski  4 , Vania Dos Santos Nunes Nogueira  5
Affiliations
Meta-Analysis

Effectiveness of Medical Treatment of Cushing's Disease: A Systematic Review and Meta-Analysis

Julia Simões Corrêa Galendi et al. Front Endocrinol (Lausanne). .

Abstract

Objective: The objective of this systematic review was to evaluate the effectiveness and safety of pasireotide, cabergoline, ketoconazole, levoketoconazole, metyrapone, osilodrostat, and temozolomide for the treatment of Cushing's disease (CD).

Methods: The primary outcomes were the proportion of CD control, adverse events (AE), and reduction of urinary free cortisol. Search strategies were applied to Embase, Medline, and CENTRAL. Independent reviewers assessed the study eligibility, extracted data, and evaluated risk of bias. Standardized mean difference was calculated with 95% confidence interval (CI) for continuous data (i.e., pre- and post-intervention). Random meta-analyses for the proportion of CD control and AE were conducted.

Results: Twenty-nine controlled and non-controlled studies were included. No study with temozolomide and levoketoconazole and one study with osilodrostat fulfilled the inclusion criteria. The meta-analyses of proportion of CD control was 35% for cabergoline (95% CI: 27-43%, six studies, 141 participants), 44% for pasireotide (95% CI: 25-35%, eight studies, 522 participants), 41% for ketoconazole (95% CI: 36-46%, six studies, 450 participants), 66% for metyrapone (95% CI: 46-87%, four studies, 66 participants), and of 66.4% for osilodrostat (95% CI: 57.9, 74.3, 97 participants, one study). One study compared two different treatments (cabergoline vs. ketoconazole), and no statistical difference was observed in CD control (RR: 0.53, 95% CI: 0.15 to 1.87, 14 participants, very low certainty of evidence). The most frequent AE associated with pasireotide was hyperglycemia, dizziness and nausea with cabergoline and metyrapone, and elevated transaminases with ketoconazole.

Conclusion: The superiority of one drug over another could not be determined due to lack of controlled studies, but the proportion of disease control identified in our meta-analysis may support clinical decision. New therapeutic options should be investigated due to the limited efficacy and tolerability of the currently available medical treatment for patients with Cushing's disease.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020205567, identifier CRD42020205567.

Keywords: Cushing’s disease; cabergoline; ketoconazole; meta-analysis; metyrapone; pasireotide (SOM230); systematic literature review.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Process of selection of studies.
Figure 2
Figure 2
Meta-analysis on the proportions of disease control after treatment with (A) cabergoline, (B) ketoconazole, (C) metyrapone, and (D) pasireotide.
See this image and copyright information in PMC

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