Obstructive Sleep Apnea and the Risk of Gout

A Population-Based Case-Control Study

Caroline van Durme; Bart Spaetgens; Johanna Driessen; Johannes Nielen; Manuel Sastry; Annelies Boonen; Frank de Vries

Arthritis Res Ther. 2020;22(92)

Conclusion/Key Message

This study showed that the observed association between OSA and gout disappeared after extensively adjusting for BMI, heart failure, diuretics, and renal function, in particular. As the latest guidelines for the treatment of gout by the British Society of Rheumatology recommend to discuss the use of ULT with every patient, even after a first attack of gout, we think that it is important that physicians are aware that gout occurs more frequently in the presence of various comorbidities, among which OSA. Our study also emphasizes the importance of using frequently recorded electronic lab test data to assess renal function in UK primary care data, rather than READ codes.

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Abbreviations
OSA: Obstructive sleep apnea; BMI: Body mass index; MSU: Monosodium urate; ATP: Adenosine triphosphate; UK: United Kingdom; CKD: Chronic kidney disease; eGFR: Estimated glomerular filtration; CPRD: Clinical Practice Research Datalink; GP: General practitioner; ULT: Uric acid-lowering therapy; ACE-inhibitors: Angiotensin-converting enzyme inhibitors; ARBs: Angiotensin II receptor blockers; NIADDs: Non-insulin antidiabetic drugs; CI: Confidence interval; SD: Standard deviation; OR: Odds ratio; Adj.: Adjusted

Acknowledgements
None

Funding
There was no funding for this study.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
CPRD has been granted Multiple Research Ethics Committee approval (05/MRE04/87) to undertake purely observational studies with external data linkages, including ONS mortality data. The present study is based on anonymized and unidentifiable CPRD data and is also approved by the Independent Scientific Advisory Committee (ISAC) of the Medicine and Healthcare products Regulatory Agency (protocol number 14_231R), which is primarily responsible for reviewing the study protocols. In the case of this observational research, no further ethical approval was deemed necessary by ISAC.

Consent for publication
This manuscript does not contain any individual data.

Arthritis Res Ther. 2020;22(92) © 2020 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Baseline characteristics of cases and matched controls
Characteristics	Cases		Controls
Characteristics	N = 111,509	%	N = 210,241	%
No. of females	30,461	27.3	58,715	27.9
Age (mean, [SD], years)	62.8	13.3	62.5	13.3
By class
18–49	22,050	19.8	43,103	20.5
49–59	25,927	23.3	50,025	23.8
60–69	26,127	23.4	48,424	23.0
≥ 70	37,405	33.5	68,689	32.7
Smoking status
Never	46,790	42.0	86,764	41.3
Current	16,077	14.4	39,182	18.6
Ex	38,146	34.2	54,754	26.0
Missing	10,496	9.4	29,541	14.1
BMI, kg/m² (mean [SD])	29	5.3	26.8	4.8
By category
< 25	18,938	17.0	60,497	28.8
25–30	39,492	35.4	65,842	31.3
31–34	22,075	19.8	24,369	11.6
≥ 35	10,992	9.9	8925	4.2
Missing	20,012	17.9	50,608	24.1
Alcohol
No	16,639	14.9	34,934	16.6
Yes	82,405	73.9	137,605	65.5
Missing	12,465	11.2	37,702	17.9
Renal function*
CKD 1	8382	7.5	18,529	8.8
CKD 2	31,838	28.6	56,712	27.0
CKD 3	19,230	17.2	16,744	8.0
CKD 4	2001	1.8	611	0.3
CKD 5	206	0.2	146	0.1
Missing	49,852	44.7	117,499	55.9
History of comorbidities
Acute myocardial infarction	7858	7.0	8318	4.0
Stroke	5952	5.3	8283	3.9
Heart failure	8954	8.0	5213	2.5
Hypertension	49,488	44.4	54,166	25.8
Diabetes mellitus	10,928	9.8	16,058	7.6
Hypercholesterolemia	8699	7.8	10,891	5.2
OSA	1094	1.0	1126	0.5
Use of diuretics⁺
Loop diuretics	17,976	16.1	11,377	5.4
Thiazide diuretics	24,049	21.6	22,012	10.5

Abbreviations: N number, SD standard deviation, BMI body mass index, CKD chronic kidney disease, OSA obstructive sleep apnea
*CKD 1 (eGFR > 90 ml/min), CKD 2 (eGFR 60–89 ml/min), CKD 3 (eGFR 30–59 ml/min), CKD 4 (eGFR 15–29 ml/min), CKD 5 (< 15 ml/min)
⁺Within 6 months prior to index date

Table 2. Risk of gout in patients with OSA, stratified by gender, age, BMI, CKD, comorbidities, and recent use of diuretics
Exposure	Cases		Controls		Crude	Fully adj.
Exposure	N = 111,509	%	N = 210,241	%	OR (CI)	OR
No OSA	110,415	99.0	209,115	99.5	Referent	Referent
OSA	1094	0.98	1126	0.54	1.86 (1.71–2.02)	1.05 (0.96–1.16)
By gender
Male	953	0.85	1043	0.50	1.74 (1.59–1.90)	1.05 (0.95–1.16)
Female	141	0.13	83	0.04	3.36 (2.56–4.42)	1.64 (1.19–2.27)
By age class
40–49 years	210	0.19	186	0.09	2.22 (1.82–2.71)	1.12 (0.90–1.41)
50–59 years	346	0.31	392	0.19	1.73 (1.50–2.00)	0.96 (0.82–1.13)
60–69 years	316	0.28	341	0.16	1.75 (1.49–2.04)	1.02 (0.86–1.22)
> 70 years	222	0.20	207	0.10	1.96 (1.62–2.37–1.13)	1.20 (0.96–1.50)
By BMI, kg/m^2a
< 25	40	0.04	113	0.05	0.67 (0.47–0.97)	0.67 (0.45–0.98)
25–29	224	0.20	305	0.15	1.38 (1.16–1.64)	1.15 (0.95–1.39)
30–34	318	0.29	325	0.15	1.88 (1.61–2.20)	1.34 (1.13–1.59)
≥ 35	456	0.41	322	0.15	2.74 (2.37–3.16)	1.56 (1.33–1.83)
Missing	56	0.05	61	0.03	1.78 (1.24–2.57)	1.91 (1.30–2.81)
By renal function^+,a
CKD 1	151	0.14	250	0.12	1.17 (0.95–1.43)	0.61 (0.49–0.76)
CKD 2	492	0.44	527	0.25	1.80 (1.59–2.03)	1.02 (0.89–1.17)
CKD 3	233	0.21	92	0.04	4.76 (3.72–6.07)	2.22 (1.70–2.91)
CKD 4	19	0.02	< 5^#	0.00	11.24 (3.34–37.81)	3.93 (1.06–14.56)
CKD 5	< 5^#	0.00	< 5^#	0.00	1.00 (0.09–11.03)	0.41 (0.04–4.59)
Missing	198	0.18	252	0.12	1.50 (1.24–1.81)	1.15 (0.94–1.40)
By history of comorbidities
Acute myocardial infarction^a
Yes	80	0.07	73	0.03	2.08 (1.51–2.86)	0.80 (0.56–1.15)
No	1014	0.91	1053	0.50	1.84 (1.69–2.01)	1.07 (0.97–1.18)
Stroke^a
Yes	52	0.05	42	0.02	2.29 (1.52–2–3.44)	1.05 (0.66–1.66)
No	1042	0.93	1084	0.52	1.84 (1.69–2.01)–2.21)	1.05 (0.96–1.16)
Heart failure^a
Yes	128	0.11	37	0.02	6.61 (4.58–9.54)	1.82 (1.21–2.73)
No	966	0.87	1089	0.52	1.70 (1.56–1.85)	1.01 (0.92–1.12)
Diabetes mellitus^a
Yes	265	0.24	258	0.12	1.96 (1.65–2.33)	0.70 (0.58–0.85)
No	829	0.74	868	0.41	1.83 (1.66–2.01)	1.16 (1.05–1.30)
Hypertension^a
Yes	659	0.59	466	0.22	2.71 (2.40–3.05)	1.14 (1.00–1.30)
No	435	0.39	660	0.31	1.27 (1.12–1.43)	0.98 (0.86–1.12)
Hypercholesterolemia^a
Yes	553	0.50	521	0.25	2.02 (1.79–2.28)	0.94 (0.82–1.08)
No	541	0.49	605	0.29	1.72 (1.53–1.94)	1.16 (1.02–1.32)
By use of loops diuretics*^,a
Yes	260	0.23	91	0.04	5.41 (4.26–6.87)	1.73 (1.33–2.26)
No	834	0.75	1035	0.49	1.55 (1.41–1.69)	1.01 (0.91–1.12)
By use of thiazide diuretics*^,a
Yes	274	0.25	129	0.06	4.10 (3.32–5.06)	1.85 (1.47–2.33)
No	820	0.74	997	0.47	1.58 (1.43–1.73)	0.93 (0.84–1.04)

Abbreviations: N number, OR odds ratio, CI confidence interval, Fully adj. fully adjusted: adjusted for smoking status, alcohol use, body mass index, history of diabetes mellitus, heart failure and the most recently recorded eGFR measurement. In addition, we adjusted analyses for the use of statins, beta-blockers, Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel, blockers and thiazide or loop diuretics 6 months before the index date, OSA obstructive sleep apnea, CKD chronic kidney disease, BMI body mass index
⁺By the most recently recorded eGFR prior to index date. CKD 1 (estimated glomerular filtration rate [eGFR] > 90 ml/min), CKD 2 (eGFR 60–89 ml/min), CKD 3 (eGFR 30–59 ml/min), CKD 4 (eGFR 15–29 ml/min), CKD 5 (< 15 ml/min)
^#According to the Independent Scientific Advisory Committee (ISAC) guidance on the content of protocols for research using CPRD data, no cell containing < 5 cases or controls are reported
*Within 6 months prior to index date
^aThe stratified analysis was not adjusted for the factor by which it was stratified

Table 3. Statistical adjustment by body mass index, heart failure, and renal function and the association between OSA and gout
Exposure	Odds ratio
Exposure	(95% confidence interval)
No OSA	Reference
OSA
Crude odds ratio	1.86 (1.71–2.02)
Adjusted by
BMI	1.22 (1.12–1.33)
Most recently recorded renal function	1.61 (1.47–1.75)
History of heart failure	1.77 (1.63–1.93)
Use of thiazide diuretics in previous 6 months	1.69 (1.55–1.85)
Use of loop diuretics in previous 6 months	1.59 (1.46–1.73)
All of the abovementioned confounders	1.05 (0.96–1.16)

Renal Function = renal function was estimated by lab data containing the most recently recorded eGFR. When only creatinine values were available, the MDRD formula was used to calculate the eGFR. In addition, read codes for the stage of chronic kidney disease were used to determine renal function
Abbreviations: OSA obstructive sleep apnea, BMI body mass index

Authors and Disclosures

Caroline van Durme^1,2, Bart Spaetgens¹, Johanna Driessen^3–6, Johannes Nielen³, Manuel Sastry⁷, Annelies Boonen^1,4 and Frank de Vries^3,5,8*

¹Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands. ²Department of the Musculoskeletal System, Centre Hospitalier Chrétien, Liège, Belgium. ³Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+, Maastricht, The Netherlands. ⁴CAPHRI, Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands. ⁵Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. ⁶NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands. ⁷Academic Sleep Center CIRO, Horn, The Netherlands. ⁸MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.

*Correspondence
f.devries@uu.nl

Authors' contributions
CD, BS, MS, AB, and FV conceived the study. Analysis was undertaken by CD, JD, and JN. All authors were involved in the design, interpretation of data, and drafting, revising, and final approval of the manuscript. FV is the guarantor and affirms that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted. There are no discrepancies from the study as planned. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.

Competing interests
FV currently supervises two PhD students who are employed with F. Hoffmann La Roche Ltd. (Basel, Switzerland and Welwyn Garden City, UK). He has not received any feeds or reimbursements for this. The topics of their PhD theses do not relate to the current manuscript.
MS received speakers' fees for a lecture on obstructive sleep apnea from the European Academy of Dental Sleep Medicine (2015) as well as for a lecture on COPD and Sleep from Astra Zeneca (2016).
CvD received speakers' fees for lectures on gout and advisory board (Grünenthal) and speaker fees for a lecture on biosimilars (Amgen). The topic of the lecture and the advisory board on gout was not related to the topic of the present article.
BS: none to declare
JN: none to declare
JD: none to declare

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