Abstract
Background
Current treatments for Alzheimer’s disease (AD) provide modest symptomatic relief but do not slow the progression of the disease. Latrepirdine may modulate several targets involved in AD pathology, including lipid peroxidation, mitochondrial permeability, voltage-gated calcium ion channels as well as neurotransmitter receptor activity, and thus potentially represents both a symptomatic and disease-modifying intervention. Several randomized, placebo-controlled trials have sought to evaluate the effect of latrepirdine on cognition, function and behaviour in patients with AD.
Objectives
To evaluate the efficacy and safety of latrepirdine for the treatment of AD.
Search methods
We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 4 June 2014 using the terms: latrepirdine OR dimebon OR dimebolin OR 2,3,4,5-tetrahydro-2,8-dimethyl-5- (2-(6-methyl-3-pyridyl)ethyl)-1H-pyrido(4,3-b)indole.
Selection criteria
We included all randomized, double-blind, placebo-controlled trials where latrepirdine was administered to patients with mild, moderate or severe AD.
Data collection and analysis
We assessed the quality of studies and two authors extracted data. We calculated mean difference (MD), risk ratio (RR) and 95% confidence interval (CI) on an intention-to-treat (ITT) basis for all relevant outcome measures.
Main results
Seven trials involving a total of 1697 participants were found and six were included in the quantitative analyses. No data were available from the seventh trial. Three trials involving 1243 patients were included in analyses of efficacy outcomes, and four trials involving 1034 patients were included in analyses of safety and tolerability outcomes. We judged five trials to be at high risk of bias due to selective outcome reporting and three to be at high risk of attrition bias. There was low quality evidence favouring latrepirdine on the Clinician’s Interview – Based Impression of Change Plus Caregiver Input after 26 weeks (CIBIC-Plus) (MD -0.60, 95% CI -0.89 to -0.31, 1 study, P < 0.001). Due to imprecision in the results, it was not possible to determine whether latrepirdine had any effect on cognition measured with the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog) (MD -1.49, 95% CI -3.47 to 0.49, 3 studies, P = 0.14) or the Mini-Mental State Examination (MMSE) (MD 0.59, 95% CI -0.94 to 2.11, 3 studies, P = 0.45), or on function measured with the Alzheimer’s Disease Co-operative Study – Activities of Daily Living scale (ADCS-ADL) (MD 1.00, 95% CI -1.15 to 3.15, 3 studies, P = 0.36) at study endpoint (26 or 52 weeks). We considered the evidence provided on these outcomes to be of overall low quality. However, there was some high quality evidence showing a very small benefit of latrepirdine on the Neuropsychiatric Inventory (NPI) (MD -1.77, 95% CI -3.09 to -0.45, 3 studies, P = 0.009) at study endpoint (26 or 52 weeks). Additionally, moderate quality evidence suggested that latrepirdine and placebo were comparable in adverse events (RR 1.03, 95% CI 0.93 to 1.14, P = 0.51), serious adverse events (RR 0.86, 95% CI 0.55 to 1.35, P = 0.52), dropouts (RR 0.91, 95% CI 0.65 to 1.27, P = 0.57) and dropouts due to adverse events (RR 0.98, 95% CI 0.57 to 1.67, P = 0.93).
Authors’ conclusions
Our meta-analysis is limited by the small number of studies, imprecision, inconsistencies between studies and likelihood of bias. Nevertheless, the evidence to date suggests that while not associated with an increased risk of adverse events compared with placebo, there is no effect of latrepirdine on cognition and function in mild-to-moderate AD patients, though there appears to be a modest benefit for behaviour. Further studies should investigate the potential benefit of latrepirdine on neuropsychiatric symptoms in AD.
Plain language summary
Dimebon for Alzheimer’s disease
Alzheimer’s disease (AD) is a degenerative disorder of the brain. It is expected to be four times more common in 2050 than it was in 2006. Common symptoms of AD include memory loss, difficulties completing daily tasks, and changes in mood, behaviour and personality. Currently approved drug treatments for AD have only modest benefits and have not been shown to slow down the progression of the disease. There is a need for more effective drugs. Latrepirdine (also known as Dimebon) has been suggested as a potential treatment for AD and other dementias. Clinical studies have had conflicting findings, so we conducted a systematic review and pooled all the available data to assess the effects of latrepirdine. We looked for studies to help us answer this question by conducting a literature search in June 2014. We combined data from seven studies with a total of 1697 patients with AD. We were unable to conclude whether latrepirdine has any beneficial effect on cognition and function in people with AD due to variations in the results between studies and because the effects we estimated were too imprecise. However, the evidence suggests that latrepirdine may have a positive effect in treating behavioural symptoms, and that it is not associated with adverse effects in people with AD. Although seven studies have been done, data from only six studies were available and most of the studies were not fully reported. We contacted the investigators for additional data but received no response.
