Inibidores da bomba de protões e demência: que associação?

Caetano, Catarina; Veloso, Marta; Borda, Susana

doi:10.1590/1980-5764-DN-2022-0048

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View & Review • Dement. neuropsychol. 17 • 2023 • https://doi.org/10.1590/1980-5764-DN-2022-0048 linkcopiar

Inibidores da bomba de protões e demência: que associação?

Autoria SCIMAGO INSTITUTIONS RANKINGS

Nos últimos anos, têm sido publicados vários estudos que indicam uma associação entre o uso de inibidores da bomba de protões e o desenvolvimento de alterações cognitivas.

Objetivo: Avaliar a existência desta associação.

Métodos: Foi realizada uma pesquisa bibliográfica abrangente, incluindo diretrizes, meta-análises, revisões sistemáticas, estudos experimentais e observacionais publicados entre fevereiro de 2011 e de 2021.

Resultados: A pesquisa inicial identificou 393 artigos, dos quais 28 foram incluídos: 8 revisões sistemáticas, 1 ensaio clínico, 15 estudos observacionais, 3 estudos de caso-controle e 1 estudo observacional transversal.

Conclusões: A maioria dos estudos com o maior nível de evidência não encontrou uma associação estatisticamente significativa entre o uso de inibidores da bomba de protões e o desenvolvimento de défice cognitivo ou demência.

Palavras-chave:
Inibidores da Bomba de Prótons; Demência; Disfunção Cognitiva

Author, year	Type of study	Sample size	Intervention	Outcome	Results	Conclusion	LE
Moayyedi et al.²⁷, 2019	Multicenter double-blind randomized controlled trial	17,598	Pantoprazole 40 mg vs. placebo in patients with atherosclerotic disease	Secondary: Dementia diagnosis in the follow-up period (3 years)	OR=1.2; 95%CI (0.81–1.78) (p=0.36)	No association	I

	LE	I	I	II	I	I	I	II		II	II
	Conclusion	Increased risk	Increased risk	Risk reduction	No association	No association	No association	Increased risk		No association	No association
Observational studies	Results	ACD: HR=1.38; 95%CI (1.04–1.8); AD: HR=1.44; 95%CI (1.01–2.06)	HR=1.44; 95%CI (1.36–1.52) (p<0.001)	From normal cognition: HR=0.78; 95%CI (0.66–0.93) (p=0.005)Progression from MCI to Dementia: HR=0.82; 95%CI (0.69–0.98) (p=0.03)	ACD: OR=1.13 (p=0.67)AD: OR=1.11 (p=0.77). Cumulative doses of: 365 TSDDs, 1,095 TSDDs and 1,825 TSDDs: HRs without statistical significance.	Mean score differences from 0.00 to −0.06 points for periods of PPI use between 1 to 14 years. p≥0.84	HR=0.99, 95%CI (0.70–1.37)	Dementia diagnosis: aSR=1.21;95%CI (1.16–1.27). Use of anti-dementia drugs: aSR=1.38 95%CI (1.28–1.48)		Elderly PPI users vs. non-users: difference of −1.22 points, 95%CI (−3.73–1.29) Individuals 46-67 years old PPI users vs. non-users: difference of 0.94 points, 95%CI (−1.63–3.50)	Prolonged use of PPIs: HR=0.99, 95%CI (0.93–1.17) Intermittent use of PPIs: HR=0.91, 95%CI (0.76–1.09)
	Outcome	Diagnosis of all-cause dementia or Alzheimer's disease	Dementia diagnosis	Diagnosis of LBD (Lewy Bodies Dementia)Dementia from normal cognition or diagnosis of dementia in patients with LBD.	Diagnosis of all-cause dementia or Alzheimer's disease	Neurocognitive assessment performance	Dementia diagnosis	Dementia diagnosis or prescription of anti-dementia drugs		Neurocognitive assessment performance	Dementia diagnosis
	Intervention	PPIs use	PPIs use	PPIs use	PPIs use (cumulative dose)	PPIs use	Cumulative dose PPIs vs. H2 blockers	PPIs use		PPIs use	PPIs use
	Sample	3,076	73,679	10,486	3,484	13,864	70,529	1,000,000		7,878	10,533
	Type of study	Prospective cohort	Prospective cohort	Retrospective cohort	Prospective cohort	Prospective cohort	Prospective cohort	Retrospective cohort		Prospective cohort	Retrospective cohort
	Author, Year	Haenisch et al.¹⁴, 2015	Gomm et al.¹⁵, 2016	Goldstein et al.³⁵, 2017	Gray et al.²⁸, 2017	Lochhead et al.²⁷, 2017	Hwang et al.³⁰, 2018	Park et al.³¹, 2018		Wod et al.²⁹, 2018	Huang et al.³⁷, 2019
Observational studies	LE	II	II	II	II	II	II	II	II	II	II
	Conclusion	No association	Increased risk	Increased risk	Risk reduction	Increased risk	No association	No association	Risk reduction	No association	No association
	Results	IRR=1.01;95%CI (0.96–1.06)	OR=1.55 (p<0.001)	aHR=1.42;95%CI (1.07–1.84) Association between cumulative dose and risk of dementia with statistical significance (p-trend<0.001)	HR=0.67, 95%CI (0.65–0.67)(p<0.01)	AD: aOR=1.06;95%CI (0.93–1.21)nAD: aOR=1.20, 95%CI (1.05–1.37)(p=0.007). AD for high dose PPI: aOR=1.20; 95%CI (0.91–1.61)nAD for high dose PPI: aOR=0.95, 95%CI (0.74–1.22)	aHR=0.72;95%CI (0.51–1.03)	aOR=1,0; 95%CI (0,40–2,73)	OR=0.93, CI95% (0.90–0.97)(p=0.0008)	aOR=1.01;95%CI (0.97–1.06)	AD: aOR=0.88; 95%CI (0.80–0.97)VV: aOR=1.18, 95%CI (1.04–1.33)
	Outcome	Dementia diagnosis	Dementia diagnosis or prescription of anti-dementia drugs	Dementia diagnosis	Dementia diagnosis	Diagnosis of Alzheimer's disease or non-Alzheimer dementia	Dementia diagnosis	Dementia diagnosis	Dementia diagnosis	Alzheimer's Disease Diagnosis	Development of Alzheimer's Disease or Vascular Dementia
	Intervention	PPIs use	PPIs use	PPIs use (cumulative dose)	PPIs use	PPIs use	PPIs use (and H2 blockers)	Continuous PPIs’ use	PPIs use	PPIs use (cumulative dose)	PPIs use
	Sample	304,753	23,656	62,574	315,078	135,722	92,773	7,8 billion	23,912 (1:1)	353,576 (1:4)	41,029
	Type of study	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Cross-sectional	Case control	Case control	Case control
	Author, Year	Park et al.³⁶, 2019	Welu et al.³², 2019	Chen et al.³³, 2020	Cooksey et al.³⁴, 2020	Torres-Bondia et al.¹⁶, 2020	Wu et a.l³⁸, 2020	Ma et al.⁴², 2020	Booker et al.⁴¹, 2016	Taipale et al.⁴⁰, 2017	Imfeld et al.³⁹, 2018

Systematic reviews
Author, Year	Type of study	Sample	Studies included	Results	Conclusion	LE
Batchelor et al.¹³, 2017	Systematic reviews	101,616	One experimental study and 10 observational studies (4 cohort, 1 case-control, 1 cross-sectional, 1 case series, and 3 case reports)	No meta-analysis	Increased risk	II
Hussain et al.¹⁷, 2020	Systematic review and meta-analysis	618,911	12 observational studies (8 cohort and 4 case-control)	RR=1.05, 95%CI 0.96–1.15	No association	I
Li et al.¹², 2019	Systematic review and meta-analysis	106,599	6 cohort studies	RR=1.23; 95%CI 0.90–1.67Follow-up < 5 years: RR=1.62, 95%CI 1.40–1.86 Follow-up > 5years: RR=0.98, 95%CI 0.75–1.27	No association	I
Song et al.⁴⁷, 2019	Systematic review and meta-analysis	642,305	10 observational studies (5 cohort, 4 case control, and 1 cross-sectional)	ACD: HR=1.04, 95%CI 0.92–1.15 AD: HR 0.96, 95%CI 0.83–1.09	No association	I
Zhang et al.⁴⁴, 2020	Systematic review and meta-analysis	166,146	6 cohort studies	HR=1.29, 95%CI 1.12–1.49	Increased risk	I
Desai et al.⁴⁶, 2020	Systematic review and meta-analysis	308,249	One experimental study and 5 prospective observational	ACD: HR=1.16, 95%CI 0.86–1.47	No association	I
Khan et al.⁴⁵, 2020	Systematic review and meta-analysis	642,949	11 observational studies (6 cohort, 4 case control, and 1 cross-sectional)	ACD: HR=1.10; OR=1.03.AD: HR=1.06; OR=0.96	No association	I
Zhang et al.⁴⁸, 2020	Systematic review and meta-analysis	371,951	10 observational studies	OR=0.87; 95%CI 0.62–1.22	No association	II

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[TFN1] Abbreviations: LE: level of evidence; OR: odds ratio; CI: confidence interval; p: p-value.