Systematic review of the efficacy of statins for the treatment of Alzheimer’s disease

Marta Mejías-Trueba; María Antonia Pérez-Moreno; María Ángeles Fernández-Arche

doi:10.7861/clinmedicine.18-1-54

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Fig 1.
Flowchart of the selection process for the systematic review.

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Table 1.

The quality and CASPe/AMSTAR scores of the studies examined

Study	CASPe ¹⁶	AMSTAR tool ¹⁷	Study quality
Sano et al ⁷	6/6		High
Simons et al ¹⁸	6/6		High
Sjogren et al ¹⁹	3/6		Medium–low
Sparks et al ²⁰	6/6		High
Serrano et al ²¹	3/6		Medium–low
Feldman et al ²²	6/6		High
Zhou et al ²³		9/11	High
Gizachew et al ²⁴		11/11	High
Sun et al ²⁵		11/11	High
Pandey et al ²⁶		9/11	High
Richardson et al ²⁷		9/11	High
McGuiness et al ²⁸		11/11	High
Xiong et al ²⁹		7/10 ^a	High

↵^aQuestion number 9 not applicable.

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Table 2.

Characteristics and efficacy results of clinical trials included in this study

Study	Design	Study population	Therapy: study arm / control arm	Number of patients (n)	Efficacy results, N (SD)			p-value
Simons et al¹⁸	Randomised, double-blind, placebo-controlled, clinical trial; phase III	Patients with diagnosis of probable AD, with MMSE 12–26	Simvastatin 40 mg/24 h orally for 4 weeks followed by 80 mg/24 h until 26 weeks/placebo/24 h orally for 22 weeks	44 (simvastatin, 24; placebo, 20)	ADAS-Cog MMSE	Simvastatin 4.1 (6.5) –0.6 (0.2)	Placebo 3.4 (7.0) –2.7 (0.7)	ns <0.02
					Change from baseline levels (pmol/L):
					MMSE 12–20
					Aβ40 (CSF)	–2.8 (10.3)	4.3 (14.2)	ns
					Aβ42 (CSF)	2.3 (15.2)	4.0 (9.0)	ns
					24S-hydroxycholesterol (CSF)	–7.8 (13.5)	1.7 (10.1)	ns
					MMSE 20–26
					Aβ40 (CSF)	–5.7 (6.5)	6.8 (13.2)	<0.05^b
					Aβ42 (CSF)	–5.6 (9.5)	–0.9 (9.7)	ns
					24S-hydroxycholesterol (CSF)	–15.2 (12.6)	6.2 (16.3)	<0.01^b
Sjogren et al¹⁹	Open-label clinical trial	Patients with AD; 64–84-years old; MMSE 12–26	Simvastatin 20 mg/24 h orally for 12 weeks	19	Levels (pmol/L) α-SAPP (CSF)	Before 2264 (543)	After 1986 (557)	<0.001^b
					β-SAPP (CSF)	945 (133)	830 (83)	<0.001^b
					Total tau (CSF)	658 (352)	638 (306)	ns
					Phosphorylated tau (CSF)	95 (43)	92 (37)	ns
					Aβ42 (CSF)	460 (172)	472 (160)	ns
					Aβ42 (plasma)	75 (80)	80 (88)	ns
					ADAS-Cog	16.6 (7.8)	19.3 (8.0)	<0.05^b
Sparks et al²⁰ ADCLT study	Randomised, double-blind, placebo-controlled, clinical trial, phase II	Patients with mild to moderate AD; MMSE 12–28	Atorvastatin 80 mg/24 h orally for 1 year/placebo 24 h orally for 1 year	63 (atorvastatin, 32; placebo, 31)		Atorvastatin	Placebo
					ADAS-Cog	0.5 (5.9)	–3.7 (6.7)	0.019^b
					MMSE	–0.77 (2.7)	–2.42 (3.2)	0.009^b
					CGIC	0.40 (1.81)^a		0.037
					NPI	6.99 (6.85)	2.69 (6.68)	0.120
Serrano-Pozo et al²¹	Open-label clinical trial	Patients with probable AD or amnestic mild cognitive impairment; TC: 170–240 mg/dL	Simvastatin 20 mg/24 h orally for 6 weeks followed by 40 mg/24 h for 6 weeks	12	Levels (pmol/L) 24S-hydroxycholesterol (plasma)	Before 52.3 (11.8)	After 47.8 (12.5)	0.0368
					24S-hydroxycholesterol (CSF)	2.459 (1.966)	2.485 (1.805)	0.8225
					Aβ40 (plasma)	81.4 (22.0)	85.3 (17.3)	0.3700
					Aβ40 (CSF)	1573.1 (501.4)	1542.8 (531.0)	0.3016
					Aβ42 (CSF)	61.2 (29.9)	59.1 (26.2)	0.2624
					Total tau (CSF)	690.2 (312.2)	699.0 (322.4)	0.6072
					Phosphorylated tau (CSF)	87.1 (57.4)	90.0 (60.9)	0.1705
Feldman et al²² LEADe study	Randomised, double-blind, placebo-controlled, multicentre and parallel clinical trial	Patients with mild to moderate probable AD; older than 50 years; taking donepezil 10 mg/24 h >3 months before screening; MMSE 13–25; LDL 95–195 mg/dL	Atorvastatin 80 mg/24 h orally for 72 weeks followed by 8-week withdrawal of treatment/placebo 24 h for 72 weeks followed by 8-week withdrawal of treatment	640 (atorvastatin,314; placebo, 326)		Atorvastatin	Placebo
					ADAS-Cog	2.77 (9.00)	3.3 (10.00)	0.73
					MMSE	–0.87 (2.9)	–1.11 (2.8)	ns
					CGIC	–0.02 (2.43)^a		0.26
Sano et al⁷	Randomised, double-blind, placebo-controlled, multicentre clinical trial, phase III	Patients with probable AD and normal lipid levels; older than 50 years; MMSE 12–26	Simvastatin 20 mg/24 h orally for 6 weeks followed by 40 mg/24 h until 18 months; placebo/24 h orally for 18 months	406 (simvastatin, 204; placebo, 202)		Simvastatin	Placebo
					ADAS-Cog	9.51 (9.48)	8.18 (8.70)	ns
					MMSE	–4.23 (4.77)	–3.75 (4.38)	ns
					NPI	3.21 (12.71)	3.78 (10.73)	ns

↵^aMean difference data were calculated as statin–placebo results;
*Significant values after regression analysis.
AD = Alzheimer's Disease; ADAS-Cog = Alzheimer's Disease Assessment Scale-cognitive; CGIC = Clinical Global Impressions of Change; CSF = cerebrospinal fluid; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; OR = odds ratio; RR = relative risk

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Table 3.

Characteristics and efficacy results of meta-analyses included

Study	Studies included	Number of patients	Selection criteria	Efficacy results; n (95% CI)	p-value
Zhou et al²³	Two clinical trials: Simons 2002; Sparks 2005	107	Patients with dementia or AD; randomised controlled trials	ADAS-Cog: 1.84 (–1.58, 5.27)	0.055
Gizachew et al²⁴	Four clinical trials	1,153	Clinical trials and subjects with a history or risk of AD	ADAS-Cog: –0.57 (–1.39, 0.25)	0.17
				MMSE: 0.57 (–0.36, 1.50)	0.23
				NPI: –0.77 (–1.59, 0.06)	0.07
	Six observational studies	21,819	Patients diagnosed with AD or at risk for the disease	HR: 0.69 (0.542, 0.882)	0.003
				OR: 0.447 (0.229, 0.668)	<0.001
Sun et al²⁵	Two clinical trials: Sparks 2005; Feldman 2010	710	Patients with probable AD; randomised placebo-controlled clinical trials. Sparks 2005: single-centre study; Feldman 2010: multi-centre study	ADAS-Cog: 1.05 (–3.06, 6.05)	0.52
				MMSE: 0.77 (–0.57, 2.10)	0.26
				CGIC: 0.13 (–0.15, 0.40)	0.38
				NPI: 2.07 (–1.59, 5.73)	0.27
Pandey et al²⁶	Five clinical trials: PROSPER 2002; Simons 2002; Sparks 2005; Feldman 2008; Sano 2011	6,958	Randomised clinical trials; subjects with a history or risk of AD	ADAS-Cog: –0.18 (–1.03, 0.66)	ns
				MMSE: –0.921 (–1.84, 0.0055)	<0.05
				CGIC: –0.26 (–3.11, 2.58)	ns
Richardson et al²⁷	14 AD studies		Patients; randomised controlled trials
	10 cohort studies	759,553	Cohort study	RR: 0.79 (0.63, 0.99)
	Three case-control studies	5,758	Case-control study	OR: 0.56 (0.41, 0.78)
	One cross-sectional study	57,104	Cross-sectional study	OR: 0.45 (0.35, 0.58)
McGuiness et al²⁸	Four clinical trials: Sparks 2005; Feldman 2010; Simons 2002; Sano 2011	1154	Patients with probable AD; clinical trials placebo controlled, randomised, double blind	ADAS Cog: –0.26 (–1.05, 0.52)	0.51
				MMSE: –0.32 (–0.71, 0.06)	0.099
				CGIC: –0.02 (–0.14, 0.10)	0.74
				NPI: –0.84 (–1.64, –0.05)	0.034

AD = Alzheimer's disease; ADAS-Cog = Alzheimer's disease assessment scale-cognitive; CGIC = Clinical Global Impressions of Change; CI = confidence interval; HR = hazard ratio; MMSE = mini-mental state examination; NPI = neuropsychiatric inventory; ns = non-significant; OR = odds ratio; RR = relative risk