УДК 616-06

DYSLIPIDEMIA IS A MODIFIABLE RISK FACTOR FOR PRIMARY OPEN-ANGLE
GLAUCOMA

Erb Carl

Private Institute of Applied Ophthalmology, Berlin

Abstract: Reduction of intraocular pressure is currently considered the main strategy to positively
influence progression of glaucomatous optic neuropathy. However, this goal is achieved in only 1 in 7 patients
with primary open-angle glaucoma (POAG). Therefore, it is important to determine further risk factors that
can be therapeutically influenced. The example of lipid metabolism disorders will be used to illustrate this.
Literature search in PubMed with the search terms "primary open-angle glaucoma", "dyslipidemia" and the
period from 2000 to 2022.

POAG is currently considered a systemic neurodegeneration with neuroinflammation at the forefront.
Oxidized low density lipoprotein (LDL) acts as a free radical (so-called bioactive lipid) with proinflammatory
properties and promotes glaucomatous neuroinflammation.

In addition to a personalized target pressure-oriented intraocular pressure reduction, LDL-
associated lipid metabolic disorders should be excluded in every patient with POAG. A LDL cholesterol in the
blood below 100 mg/dl (2.6 mmol/l) is a guideline.

Keywords: glaucoma, dyslipidemia, mitochondriopathy, neuroinflammation.

ДИСЛИПИДЕМИЯ КАК МОДИФИЦИРУЕМЫЙ ФАКТОР РИСКА РАЗВИТИЯ
ПЕРВИЧНОЙ ОТКРЫТОУГОЛЬНОЙ ГЛАУКОМЫ

Erb Carl

Частный институт прикладной офтальмологии, Берлин

Аннотация: Снижение внутриглазного давления в настоящее время считается основной
стратегией положительного влияния на прогрессирование глаукоматозной оптической нейропатии.
Однако эта цель достигается только у 1 из 7 пациентов с первичной открытоугольной глаукомой
(ПОУГ). Следовательно, важно определить дополнительные факторы риска, на которые можно
оказать терапевтическое воздействие. Для иллюстрации этого будет использован пример нарушений
липидного обмена.В обзоре представлен поиск литературы в PubMed по поисковым запросам
"первичная открытоугольная глаукома", "дислипидемия" и за период с 2000 по 2022 год.

В настоящее время ПОУГ считается системной нейродегенерацией, в центре которой
находится нейровоспаление. Окисленный липопротеин низкой плотности (ЛПНП) действует как
свободный радикал (так называемый биоактивный липид), обладающий провоспалительными
свойствами и способствующий глаукоматозному нейровоспалению.

В дополнение к индивидуальному целевому снижению внутриглазного давления,
ориентированному на снижение внутриглазного давления, у каждого пациента с ПОУГ следует
исключить нарушения липидного обмена, связанные с уровнем ЛПНП. Уровень холестерина ЛПНП в
крови ниже 100 мг/дл (2,6 ммоль/л) является рекомендуемым.

Ключевые слова: глаукома, дислипидемия, митохондриопатия, нейровоспаление.

ДИСЛИПИДЕМИЯ БАШТАПКЫ АЧЫК БУРЧТУУ ГЛАУКОМАНЫН
ӨНҮГҮШҮНҮН ӨЗГӨРҮЛҮҮЧҮ ТОБОКЕЛДИК ФАКТОРУ КАТАРЫ

Erb Carl

Жеке колдонмо Офтальмология институту, Берлин

Аннотация: Көздүн ички басымын төмөндөтүү азыр глаукоматоздук оптикалык
нейропатиянын өнүгүшүнө оң таасир этүүчү негизги стратегия болуп эсептелет. Бирок, бул максат
баштапкы ачык бурчтуу глаукома (ПУГ) менен ооруган 1 бейтаптын 7инде гана

жетишилет. Ошондуктан, терапиялык таасир этиши мүмкүн болгон кошумча тобокелдик
факторлорун аныктоо маанилүү. Муну көрсөтүү үчүн липиддик зат алмашуунун бузулушунун мисалы
колдонулат. Серепте "алгачкы ачык бурчтуу глаукома", "дислипидемия" жана 2000-2022- жылдар
аралыгында Кбада адабият издөөлөрү берилген.
Учурда ПУГ системалык нейродегенерация деп эсептелет, анын борборунда нейроинфламация
турат. Төмөн тыгыздыктагы кычкылданган липопротеин (лднп) сезгенүүгө каршы касиетке ээ жана
глаукоматоздук нейроинфламацияга көмөктөшүүчү эркин радикал (биоактивдүү липид деп аталат)
катары иштейт. Көздүн басымын төмөндөтүүгө багытталган көздүн ичиндеги басымдын жекече
максаттуу төмөндөшүнөн тышкары, ар бир ПУГ пациентинде ЛИПИДДИК зат алмашуунун
бузулушу ЛДП деңгээлине байланыштуу жокко чыгарылышы керек. Кандагы холестерол деңгээли 100
мг/дл (2,6 ммоль/л) төмөн сунушталат.

Негизги сөздөр: глаукома, дислипидемия, митохондропатия, нейроинфламация.

In the treatment of glaucoma, the emphasis in daily practice is on achieving the target pressure,
the individually targeted eye pressure level at which glaucomatous progression should stop as best it
can, or progress only slightly. This therapy concept has been implemented for more than 100 years,
but this therapy strategy shows only a very limited success. For example, 7 patients have to be treated
with POAG to stop the progression in one patient (number needed to treat = NNT
= 7) [1]. This is even more evident in patients with ocular hypertension (OHT). Here, the NNT = 16-
20 [1,2]. This means that 16-20 patients with OHT have to be treated to prevent conversion to POAG
in 1 patient (!). In addition, the Early Manifest Glaucoma Trial showed that after 8 years of therapy
with a mean achieved pressure of 15.5 mmHg in newly detected glaucoma patients, progression was
still 59% and differed only by 17% from the comparison group of glaucoma patients who received
no therapy (79%) [3].

These results are quite sobering and demonstrate that the mere reduction of intraocular
pressure alone is not sufficient to treat patients with POAG effectively. Therefore, it is absolutely
time to reconsider the current therapy concept from both the clinical and the scientific point of
view. This is not to question ocular pressure reduction per se as a reasonable way in a complex
treatment strategy, but ocular pressure reduction must not remain the only treatment strategy. Our
knowledge of POAG has improved considerably over the last 20 years, and yet this knowledge is
rarely applied in practical glaucoma treatment. It is undisputed that POAG is a neuroinflammatory
disease leading to cerebral neurodegeneration [4,5,6]. The driving forces for this are primary
mitochondrial dysfunction, primary vascular dysfunction, and immunologic dysregulation with the
presence of various autoantibodies (6), which act both on the eye itself but, more importantly,
systemically. These complex pathophysiological processes cannot be compensated by a local
reduction of intraocular pressure. Therefore, we need a personalized holistic therapy strategy for each
individual POAG patient in order to offer a meaningful therapy strategy according to his personal risk
profile.

The main unifying therapeutic goal is to reduce the increased oxidative stress and with it the
neuroinflammation. It is often overlooked that even the smallest step in this direction is an important
component in the overall therapy concept. Even though randomized, prospective multicenter studies
would certainly be useful to substantiate these approaches, we will still have to wait decades for this.
However, the current knowledge already allows to take care of the containment of the increased
oxidative stress now.

A complementary basis for a systemic view of POAG is the presence of systemic underlying
diseases in addition to its own specific neuroinflammation. Arterial hypertension is present in about
50% and diabetes mellitus and dyslipidemia in 20-30% [7,8]. However, these three systemic diseases
themselves lead to an increased oxidative stress [9,10,11], whereby they additionally burden the
glaucomatous neuroinflammation, in which they are also associated with a neuroinflammation [12].
Thus, it is part of the overall therapeutic concept of a POAG to also take care of the optimal
adjustment of these underlying diseases [13].

The example of dyslipidemia will be used to illustrate this.

During fat intake (triglycerides, cholesterol), fats are metabolized by the liver, released as
VLDL (very low density lipoprotein) and later converted into LDL (low density lipoprotein). LDL
thus transports cholesterol formed by the body itself from the liver to the tissues. It circulates in the
blood for about five days and has a lipid content of about 80 %. Under conditions of increased
oxidative stress, LDL undergoes oxidation and becomes oxidated LDL (oxLDL) [14], which itself
acts as a free radical as a so-called bioactive lipid with proinflammatory properties. The outer shell
of oxLDL is altered in such a way that it no longer enters the cell via the LDL receptors and
remains in the blood. It is highly immunogenic, leading to upregulation of scavenger receptors and
toll-like receptors, activating adhesion molecules in endothelial cells [15], and promoting the
conversion of monocytes to macrophages, which, however, cannot degrade oxLDL, leading to the
formation of the characteristic foam cells in atherosclerotic lesions [14,15]. Highly elevated oxLDL
levels also result in increased free radical release in mitochondria [16], creating a self-sustaining cycle
with chronic increase in oxidative stress.

In the context of primary mitochondriopathy in POAG, there is a generally increased cellular
oxidative stress, so that this already sets the stage for oxidation of LDL to oxLDL. In human
trabecular cells, the corresponding LDL receptors have been detected [17], the activation of which
can lead to oxidative trabecular remodeling processes. OxLDL can stimulate the transcription factor
NF-kB [18] and thereby release growth factors, such as TGF-ß [19], which itself has an unfavorable
effect on trabecular meshwork [20]. All together, oxLDL may unfavorably influence outflow
resistance and increase intraocular pressure and/or limit the efficacy of local therapy.
In a recently published meta-analysis, increased triglyceride levels were detected in POAG patients
[21] and in another meta-analysis a positive correlation between triglycerides and increased
intraocular pressure was found [22].

What are the therapeutic consequences?
The most important basis is a differentiated blood lipid determination to detect dyslipidemia with
elevated LDL levels. This should generally be done in case of a newly detected POAG and in the
context of glaucomatous progression. Because patients with POAG can be classified as having
moderate vascular risk, the target LDL level for this patient group is less than 100 mg/dl (2.6 mmol/L)
according to the recommendations of the European Society of Cardiology [23]. For higher LDL
levels, lifestyle changes are a good first therapeutic step, such as abstaining from nicotine, limiting
the amount of coffee, eating a balanced diet, exercising, and avoiding pronounced stress situations
for a longer period of time. However, these measures are only implemented by patients to a very
limited extent [24]. Statins [25], which interrupt intracellular cholesterol formation, are therefore
considered the therapy of choice. This results in increased expression of LDL receptors at the cell
surface and increased reabsorption of LDL from the blood. Overall, the therapy is considered safe
and effective, with myalgias and rarely glucose intolerance occurring in 0.1% as side effects, and
the discussed risk of diabetes is considered low [26]. In patients with hyperlipidemia, after 2 years of
statin therapy, the relative risk of POAG decreased by 8% and progression in glaucoma patients by
9% compared with those without statin therapy [27]. Supportively, data from the Erlanger Glaukom
Register showed that progression of POAG as well as conversion of OHT to POAG is significantly
reduced under statins [28].

In particular, the pleiotropic effects of statins have been shown to play an important role.
Pleiotropic effects are therapeutic effects that are not related to the original main effect. For statins,
mainly anti-inflammatory, immunomodulatory, and vascular endothelium-protective effects (25,29),
as well as neuroprotective effects [30,31,32] have been demonstrated, which can also meaningfully
intervene in the disease process in POAG. Experimentally, neuroprotective effects have been
demonstrated in an OHT animal model [33].

In addition, in the presence of dyslipidemia, local eye pressure-lowering therapy with ß-
blockers should be avoided because they, especially timolol, can increase triglycerides [34] and lower
HDL cholesterol [34, 35].

In conclusion, dyslipidemia, specifically high plasma LDL, may intensify the
neuroinflammatory events in POAG patients in which it negatively affects neurodegeneration such

as in Alzheimer's disease [36,37]. Therefore, in newly discovered POAG patients as well as in
glaucomatous progression, blood lipids and especially LDL cholesterol should be determined in order
to reduce them to below 100 mg/dl (2.6 mmol/l). In local therapy, ß-blockers should be avoided.

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