Key Points
- The role of statins in the treatment of early-stage age-related macular degeneration (AMD) has been debated by many over the
past few years, with conflicting results causing much confusion. Here, Dr Marianne Shahsuvaryan reviews some of the literature
to emerge from such studies and calls for a controlled clinical trial, so that retina specialists can know, once and for all,
whether statin therapy is a viable option for the treatment of early-stage AMD.
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among older adults in developed countries,
and with the aging population the problem is increasing.
Current therapy, which includes the vascular endothelial growth factor (VEGF) inhibitors, is limited to the late stage of
the disease, when central vision is already under great threat, so even these new treatments make little impact on the rate
of blindness. In my opinion, monthly intravitreal anti-VEGF injections, which are associated with some systemic exposure to
anti-VEGF, will be replaced in the future by new drugs that are administered in a less invasive way.
At present, there is no effective treatment for early-stage AMD or for arresting its progression in the earliest phases. Epidemiologic,
genetic, and pathological evidence, however, continues to accumulate, suggesting a possible link between cardiovascular disease
risk factors and AMD, and this has led some researchers to suggest that the pathophysiology of these two diseases have similar
causal pathways.1
Positive associations between AMD and cardiovascular risk factors do lend support to this (for example, blood pressure, plasma
cholesterol, smoking).2 Furthermore, the prominent histopathological and clinical lesions seen in AMD patients involve Bruch's membrane — a specialized
vascular intima that separates the photoreceptors and the retinal pigment epithelium (RPE) from their blood supply. Because
these lesions and Bruch's membrane contain abundant lipids, including cholesterol,3,4 it is possible that AMD and cardiovascular disease share common mechanisms at the level of the vessel wall. How do statins work?
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, generically termed statins, are the most commonly used
lipid lowering drugs today; their efficacy has been proven in many studies. For instance, in the Heart Protection Study, which
randomized more than 20,000 high-risk cardiovascular disease patients, the value of statins in reducing adverse cardiovascular
events was proven beyond doubt.5
As a result, statins are now considered to be one of the most powerful classes of agents for the treatment of vascular disease,6,7 and they are rapidly becoming frontline therapy for diabetes mellitus, hypertension, and other known vascular risk factors.
Recent experimental evidence suggests that statins appear to display additional cholesterol independent of pleiotropic effects,
contributing to the prevention and inhibition of atherosclerosis. The statins' vascular pleiotropic effects include improvement
of endothelial function, slowing the inflammation process, inhibition of thrombus formation, enhancement of plaque stability
and decreasing oxidative stress.8
It has been suggested that statins could be beneficial in treating, and maybe even preventing AMD and this is based on a number
of key points:
- Accumulation of lipids in Bruch's membrane and drusen is a key pathophysiologic pathway for AMD development.9 Statins lower serum lipid levels.
- Statins appear to have beneficial effects on other AMD pathways, such as oxidative damage and inflammation.9
- Choroidal neovascular membranes associated with AMD include macrophages,10 which may respond to statins.
The association between the use of statins and AMD has been evaluated in many clinical studies; however the results have been
contradictory. The objective of this review is to present some studies that have been conducted in this field, to evaluate
the evidence that links statins with AMD and to discuss the rationale behind this type of therapy in the prevention and the
treatment of AMD.
In conclusion...
In conclusion, there are potentially multiple biological bases for the protective effect of statins on the risk of AMD. With
regards to the potential for a lipid lowering effect, cholesterol is a ubiquitous component of drusen in normal and AMD eyes.
Regarding the potential for pleiotropic effects, many of the same processes that occur in the atherosclerotic intima probably
also occur in AMD; neovascularization is a major complication in both conditions, therefore, angiogenesis is a potential point
of statin modulation. Taking into account that not all statins are equally effective, the challenge for future laboratory
research will be to determine the best type and dosage of statins and also to determine which processes are modulated by statins
in vivo and therefore are primarily responsible for the apparent beneficial effects observed in previous studies.
Clearly, further observational studies cannot adequately address many unanswered questions. I would therefore recommend that
a randomized controlled trial be conducted to provide direct evidence of the effectiveness of specific types of statin in
lowering the incidence and progression of AMD, so that this class of drug can either be promoted or eliminated for the treatment
of this disease once and for all.
