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Phospholipid Therapy

Risk-Benefit Analysis

Forever Healthy Foundation gGmbH

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Preface

This risk-benefit analysis (RBA) is part of Forever Healthy's "Rejuvenation Now" initiative that seeks to continuously identify new rejuvenation therapies and systematically evaluate them on their risks, benefits, procedures, and potential application.

Special thanks are extended to the whole Rejuvenation Now team at Forever Healthy for their friendly contributions.

Section 1: Overview 

Motivation

Phospholipids are an important structural component of cell and organelle membranes and play a role in many cell signaling pathways. Membranes incur oxidative damage over time and in several disease conditions. Oral and/or i.v. supplementation of phospholipids (particularly phosphatidylcholine) is hypothesized to repair this damage through the replacement of oxidized membrane phospholipids with "healthy" phospholipids, thus restoring or maintaining membrane integrity and function. 

Key questions 

This analysis seeks to answer the following questions:

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Impatient readers may choose to skip directly to Phospholipid Therapy RBA Section 6 for the Presentation of Results and tips on practical application. 

Recommended reading/viewing

General introduction

The following sites offer information on PLT at a consumer level and are useful as an introduction to the topic:

• Mitochondria and the Anti-Aging Role Of Lipid Replacement Therapies - clinicaleducation.org

• Phosphatidylcholine (PPC/EPL) - heartfixer.com
  
  

Scientific overview 

The following scientific review provides a more detailed overview of the topic of PLT:

• Lipid Replacement Therapy: A natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function

Section 2: Methods

Analytic model

This RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development (Sarac et al., 2012). 

Literature search

A literature search was conducted on Pubmed using the search terms shown in Phospholipid Therapy RBA Table 1 and included articles available as of August 31, 2021. Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms. Results reported in the book, Essential Phospholipids as a Membrane Therapeutic (Gundermann, 1993) were included as it summarized several clinical papers only available in other languages (see Table 3).

Many studies were published using brand names so we also included the brand names in our literature search. Please see Phospholipid Therapy RBA Table 6 for a list of the brands we identified.

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Exclusion criteria: We excluded animal and in vitro studies from the analysis because of an abundance of clinical trials as well as trials that used phospholipid s.c. injections for cosmetic purposes. 

Table 1: Literature search 

Abbreviation list

Section 3: Existing Evidence

Summary of results

Our search terms identified 3,665 studies of which 107 were relevant to this analysis (see Table 2). We also included the clinical studies summarized in Gundermann's book in our analysis following a discussion with the author, despite being unable to locate the majority of the original papers (see Table 3). Although PLT has long been used in medical practice, the quality of the evidence is quite low overall. For many papers, only the abstracts are available (in English) and many of the trials are observational. Most of the compounds administered for PLT contained several vitamins and minerals in addition to phospholipids, leading to difficulties in determining whether the benefits/risks occurred due to the phospholipid content or other components of the supplements and much of the research has been funded by producers of phospholipid supplements. Moreover, almost all of the trials were performed in subjects with preexisting health conditions making it difficult to determine the extent of the benefits in a healthy population.

Table 2: Clinical trials

Table 3: Gundermann summary

Section 4: Risk-Benefit Analysis

Decision model

Risk and benefit criteria

The decision profile is made up of risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and type and are assessed according to magnitude, likelihood, duration, and perceived importance. The risk criteria are organized by category and type and are assessed according to severity, frequency of occurrence, and difficulty in detection and mitigation. Each criterion is assigned a numerical value for each assessment category:

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The numerical values for the criterion are then summarized, serving as the justification for the weighting in the following column.

Weight

The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). The value in the summary column is divided by 4 to result in a weight between 1 → 3.

Score

Each criterion is assessed according to the performance of PLT against the comparator (physiological aging) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior), and +1 (superior) to the comparator.

Uncertainty

Uncertainty is determined according to the amount and quality of the evidence, availability of full text articles & supplementary data, number of participants and whether methodological flaws, conflicting studies, or conflicts of interest (i.e. funding) are present. Evidence that is based on RCTs is initially upgraded by 1 point, evidence from open-label trials is considered neutral, and evidence that is based on observational studies is downgraded by 1 point. The uncertainty is then further valued using the above-mentioned criteria to result in an uncertainty score. 

Weighted score

The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted according to the uncertainty score. Weighted scores are upgraded where the uncertainty score is low (positive) or downgraded where the uncertainty score is high (negative).

Benefit assessment 

We identified a total of 58 benefits associated with PLT. The benefits extended across several organ systems, were mostly of small magnitude and largely dependent on continued supplementation. Almost all benefits occurred in the context of pre-existing disease. There is limited evidence that the benefits would occur in healthy individuals. 

Table 4: Benefit assessment 

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Table 4 Table 4

Blood

Reduction in platelet aggregation & blood coagulability

In two studies on patients with ischemic heart disease (n=24, 25), 14 days of i.v. EPL led to a substantial decrease (60%) inplatelet aggregation (Gundermann, 1993). Microscopic examination showed both reduced numbers of aggregates and reduced platelet conglomerates within the aggregates.

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In contrast, a DB-RCT (n=60) that compared the effects of taking soy lecithin (which contains 65-75% phospholipids) vs. control or fish oil for two weeks, reported an increase in platelet adhesiveness in response to stimulation with ADP (23.2% vs. 18.7%). This was attributed to the stimulatory effect of omega-6 fatty acids (i.e. linoleic acid) found in soy lecithin (Andrioli et al., 1999).

Improved composition & function of RBC cell membranes

Several studies reported improvements in the composition and function of erythrocyte membranes such as lowering of the cholesterol content and increase of linoleic acid in the membranes, improved deformability, increased osmotic resistance, and reduced blood viscosity (Gundermann, 1993).

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A case series in patients with psoriatic arthritis treated with Phosphogliv for 3 months also reported a considerable decrease in RBC aggregability (Ipatova et al., 2003). Another case-control study in patients with liver disease (cirrhosis or cholestasis) showed that a single i.v. infusion of EPL resulted in a regression of changes of RBCs due to hemolytic anemia (Salvioli et al., 1977).

Improved antioxidant properties of the blood

An RCT (n=23) reported improvements in the antioxidant properties of the blood following treatment with Lipostabil in patients with hepatitis B (Tsyrkunov, 1992).

Cardiovascular system

Stagnation/regression of atherosclerotic plaques

In a small study (n=15) of patients with asymptomatic atherosclerosis in which EPL was administered orally for one year, the majority of plaques tended to stagnate after an initial increase in growth. Larger initial volumes stagnated or showed a downward trend after a 12 month observation period. The tendency to regression was clearer in the femoral artery than in the carotid (Gundermann, 1993). 

Decreased ECG abnormalities

Twelve studies reported an improvement in ECG findings following various doses of EPL (Gundermann, 1993). There was a dose-related reversal of pathological findings including the disappearance of negative T-waves (Gundermann, 1993).

Decreased anginal attacks

Several studies reported a decrease in anginal attacks (Gundermann, 1993). In an open-label trial (n=34), patients with moderate-severe angina pectoris received i.v. EPL for 14 days and 59% (20/34) reported an absence of anginal attacks by the end of the first/beginning of the second week of treatment. The remaining 14 patients also experienced a significant reduction in the frequency and severity of angina attacks and daily nitro-consumption was decreased (Gundermann, 1993). A second open-label trial (n=42) also reported a 50% reduction in the nitro-consumption of the patients and a multicentre trial (n=507) showed similar results (Gundermann, 1993). 

In an open-label study (n=100) that compared Lipostabil (2 ampoules of 5 mL (500 mg) i.v. per day for 2 weeks followed by 1800 mg orally for 5.5 months) to nicotinic acid for treatment of angina, both groups experienced a reduction in the intensity (1.5 down to 0.5) and number (3.8 per week down to 0.9) of anginal attacks, with the Lipostabil group exhibiting a superior side effect profile (Klimov et al., 1995).

Increased exercise tolerance

Substantial increases in walking distance were reported by several studies in Gundermann's book following treatment with EPL. In one study, the walking distance in patients with angina pectoris rose from 30-50m to 3000m following treatment with EPL (Gundermann, 1993). A second, 20-month study (n=200) in which patients received both i.v. and oral EPL, reported improvements in walking distance in 35/200 patients, from 0-200m to 1500m (Gundermann, 1993). The subsequent withdrawal of EPL treatment resulted in a decreased walking distance. 

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In an open-label study (n=100) that used Lipostabil (2 ampules of 5 mL i.v. per day for 2 weeks and 1800 mg orally for 5.5 months) in patients with hyperlipidemia and ischemic heart disease, an increase in exercise tolerance was also reported (Klimov et al., 1995).

Increased vitality

In a controlled trial (n=94) of geriatric patients with atherosclerosis, 94% (88/94) of patients reported a decrease in complaints (fatigue, disturbed sleep, retrosternal pain, palpitations) and increased vitality that was more pronounced after two months of EPL therapy than after one month (Gundermann, 1993). 

Increased blood flow 

An increase in blood flow to the lower extremities was measured in patients with peripheral arterial disease following a 30-day treatment with oral EPL (Gundermann, 1993). The increase occurred both at rest and with reactive hyperemia, and flow velocity was also raised. A longer (20-month) study (n=200) in which patients received both i.v. and oral EPL, reported improved patency of major vessels in 17% (35/200) of patients, as measured by the oscillometric index (Gundermann, 1993). Another study found there was a dose-related increase in the oscillometric index following EPL treatment, indicating increased blood flow (Gundermann, 1993). 

An observational study (n=34) reported that treatment with Essentiale had a normalizing effect on blood flow and vascular tone in the lower extremity of patients with chronic ischemic heart disease (Kukes et al., 1978). 

Improved survival after fat embolism

In an open-label study of patients that suffered a fat embolism (n=221), 91% (202/221) survived with EPL treatment vs. a retrospective control group who had not received EPL in which 70% (58/83) of the patients died (Gundermann, 1993). 

Decreased blood pressure & cardio-ankle vascular index

A DB-RCT (n=96) that administered soy lecithin tablets (PC 24%, PE 20%, and PI 12%) at 1200 mg/day for 8 weeks found that diastolic blood pressure and cardio-ankle vascular index decreased significantly (-4 mmHg, -0.4) (Hirose et al., 2018). 

Central nervous system

Improved memory 

In a DB-RCT (n=328) of patients with mild cognitive impairment or Alzheimer's disease who were fed phospholipids (derived from scallops) for 24 weeks, memory improved significantly in some subgroups of AD patients (female patients and those under 77 years of age) (Fujino et al., 2017). There was, however, no statistically significant difference in the phospholipid content of erythrocyte or plasma phosphatidylethanolamine, or in cognitive function between the placebo and treatment groups in this trial.

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In contrast, another DB-RCT (n=46) that used PL-supplemented milk, did not report a significant improvement in memory of healthy participants (Hellhammer et al., 2010).

Improved cerebral blood flow

Several open-label studies summarized in Gundermann's book reported improvements in cerebral blood flow and oxygen consumption. The studies used a variety of forms/doses ranging from 250 mg i.v. to 3 g orally, and from a single dose up to 2-14 years of treatment (Gundermann, 1993).

Decreased symptoms in multiple sclerosis

Four studies (3 open-label and 1 DB-RCT) have shown positive effects of EPL supplementation on the disease course of multiple sclerosis (Gundermann, 1993). Doses in these studies ranged from 500 mg i.v. + 800 mg orally to 6-8 g orally per day and treatment duration varied from 5.7 up to 23.8 years. More recently, research has shown the importance of phosphatidylcholine in MS with oxidized phosphatidylcholine serving as a marker for neuroinflammation in MS (Qin et al., 2007). IgM antibodies to PC have also been measured in the serum of MS patients (Sadaba et al., 2020).

Improved cognitive function in hepatic encephalopathy

An open-label trial (n=97) reported improved cognitive test dynamics in 82% of patients with hepatic encephalopathy that received Phospholipovit vs. 43% of patients that received standard therapy (Kudinov et al., 2016).

Decision-making latency improved on EEG in an open-label trial on patients with hepatic encephalopathy that received Essentiale i.v. daily for two weeks (Bruha & Marecek, 2000).

Increased availability of free cortisol in chronic stress

In a DB-RCT on patients with chronic stress (n=75), the group that received milk-based PL showed a delayed decline from peak levels in morning salivary cortisol suggesting a prolonged availability of free cortisol (Schubert et al., 2011).

Decreased risk of dementia

An observational study (n=2497), found that participants in the highest compared with the lowest phosphatidylcholine intake quartile had a 28% lower risk of incident dementia (Ylilauri et al., 2019). Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning.

Metabolism

Reduction in total cholesterol

Several trials have reported a significant lowering of total cholesterol (TC) following treatment with EPL. However, of the studies we identified, only 10 reported the percentage decrease which ranged from no effect to -42% as seen in the table below. In general, the higher the initial cholesterol levels, the greater was the effect. A summary of studies published before 1993 (participants n=3836) reported an average reduction in serum TC between 12-19% across studies (Gundermann, 1993). In some studies, there was an initial slight rise in TC.

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Reduction in LDL-C, LDL-P, ApoB

An extensive summary of studies up to 1993 (n=1160) reported that EPL treatment results in an LDL-C reduction of 10-31% with the exact extent being influenced by the type of hyperlipoproteinemia, as well the dosage and duration of treatment (Gundermann, 1993). Of these studies, DB-RCTs using oral doses between 1.8 and 2.7 g/day showed reductions of 12% and 20% after 14 and 21 days, respectively and a controlled cross-over study, reported a reduction of 25.8% within two months. Other studies in the summary reported a 25% reduction after 218 days of treatment, a 27.9% reduction after 120 days of treatment and a 34.1% reduction after 42 days (Gundermann, 1993).

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In contrast, a few trials did not show significant decreases in ApoB with EPL treatment. An RCT (n=8) in patients with renal failure treated with Essentiale forte 900 mg/day reported no significant difference in ApoB after 8 weeks (Chan et al., 1991) and a DB-RCT (n=27) reported that while LDL-C was significantly lowered in patients receiving oral PC, apoB showed only a downward trend that didn't reach significance (Noseda et al., 1985). 

Decreased LDL/HDL ratio

A summary of studies up to 1993 reported a lowering of the LDL/HDL ratio in several trials (Gundermann, 1993). One RCT (n=30) reported a 24% reduction in the LDL/HDL ratio while another DB-RCT also reported a 34% decrease (from 5.6 to 3.7). A DB-RCT (n=27) reported that the change in the LDL/HDL ratio due to LDL decreasing as HDL was unchanged (Noseda et al., 1985). 

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The reductions followed a clear dose-response with the greatest effect occurring at 1.5 to 2.25 g of EPL/day (Gundermann, 1993).

Increased HDL-C, ApoA-I, LCAT activity

10 trials and one meta-analysis (of 15 studies) reported increases in HDL-C and/or ApoA-I, the magnitude of which varied according to dose and duration of the studies. In a meta-analysis of studies published before 1993, HDL showed increases of 10-45% across trials with the greatest changes occurring in patients with the lowest initial levels (Gundermann, 1993). In the additional studies we identified, the increase in HDL-C varied from 5% to 46% with most studies reporting values between 10-20% as seen in the table below. Subgroup analysis in one trial showed that the increase was due to a shift towards the most antiatherogenic subtype (HDL-2b) (Klimov et al., 1995).

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Improved composition of HDL

A case-control study (n=24) in patients with liver disease reported that one infusion with EPL resulted in an increased content of linoleic acid in HDL proteins as well as increased LCAT activity. The polyunsaturated fatty acid component of the membranes was significantly lower at baseline in diseased patients compared with controls (Salvioli et al., 1977).

Reduction of TG

11 trials reported a significant lowering of TG following treatment with EPL as seen in the table below. Five trials only reported that the change was "significant" while another 6 reported changes between 9-36%. A summary of all trials up until 1993 reported that reductions of 25% were the most common (Gundermann, 1993).

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