Abstract
Background
Ganoderma lucidum (also known as lingzhi or reishi) is a mushroom that has been consumed for its broad medicinal properties in Asia for over 2000 years. G lucidum is becoming increasingly popular in western countries as a complementary medicine for cardiovascular health.
Objectives
To evaluate the effectiveness of G lucidum for the treatment of pharmacologically modifiable risk factors of cardiovascular disease in adults.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL Issue 6 of 12, 2014) on The Cochrane Library, MEDLINE (OVID, 1946 to June week 3 2014), EMBASE (OVID, 1980 to 2014 week 26), Science Direct (1823 to 2013), Current Controlled Trials (1990 to 2013), Australian New Zealand Clinical Trials Registry (2005 to 2013), Chinese Biomedical Literature Database (2007 to 2013), Chinese Medical Current Contents (2007 to 2013) and other databases. We checked reference lists of included studies, contacted content experts and handsearched The International Journal of Medicinal Mushrooms. We applied no language or publication restrictions.
Selection criteria
Randomised controlled trials and controlled clinical trials of G lucidum for the treatment of cardiovascular risk factors. Primary outcomes were blood glucose level, blood pressure and lipid profile.
Data collection and analysis
Two authors independently selected trials, assessed risk of bias and cross checked data extraction and analysis. A third author arbitrated in the event of disagreement.
Main results
Five trials with a total of 398 participants were eligible for inclusion. Of these, one study was published in Chinese and translated to English; one study was published but study authors provided the additional data used in this review; one study was unpublished and the study authors provided data; and two studies did not provide comparison group data suitable for statistical analyses. The three studies from which data were used for statistical analyses compared G lucidum (1.4 g to 3 g per day) to placebo over 12 to 16 weeks of intervention. Although inclusion criteria varied, all participants of these three studies had type 2 diabetes mellitus. Of the five included studies, risk of bias was low for one study and unclear for the remaining four.
Results from two studies showed that G lucidum was not associated with statistically or clinically significant reduction in HbA1c (WMD ‐0.10%; 95% CI ‐1.05% to 0.85%; 130 participants), total cholesterol (WMD ‐0.07mmol/L; 95% CI ‐0.57 mmol/L to 0.42 mmol/L; 107 participants ), low‐density lipoprotein cholesterol (WMD 0.02 mmol/L; 95% CI ‐0.41 mmol/L to 0.45 mmol/L; 107 participants), or body‐mass index (WMD ‐0.32 kg/m2; 95% CI ‐2.67 kg/m2 to 2.03 kg/m2; 107 participants). All other analyses were from a single study of 84 participants. We found no improvement for fasting plasma glucose (WMD 0.30 mmol/L; 95% CI ‐0.95 mmol/L to 1.55 mmol/L). Measures of post‐prandial blood glucose level found inconsistent results, being in favour of placebo for ‘2‐hour post‐prandial blood glucose’ (WMD 0.7 mmol/L; 95% CI 0.29 mmol/L to 1.11 mmol/L) and in favour of G lucidum for ‘plasma glucose under the curve at 4th hour’ (WMD ‐49.4mg/dL/h; 95% CI ‐77.21 mg/dL/h to ‐21.59 mg/dL/h). As the Minimal Clinical Important Differences are unknown, the clinical significance of this effect is unclear. There were no statistically significant differences between groups for blood pressure or triglycerides. Participants who took G lucidum for four months were 1.67 times (RR 1.67 95% CI 0.86 to 3.24) more likely to experience an adverse event than those who took placebo but these were not serious side effects.
Authors’ conclusions
Evidence from a small number of randomised controlled trials does not support the use of G lucidum for treatment of cardiovascular risk factors in people with type 2 diabetes mellitus. Future research into the efficacy of G lucidum should be placebo‐controlled and adhere to clinical trial reporting standards.
Plain language summary
Ganoderma lucidum mushroom (lingzhi/reishi) for treating cardiovascular risk factors
What are cardiovascular risk factors?
Cardiovascular disease is the name given to any disease, such as heart attack or stroke, that affects the heart and circulatory system (which moves blood around the body). Risk factors for cardiovascular diseases include high blood pressure, and high levels in the blood of glucose and cholesterol. People with cardiovascular risk factors are more likely to have a heart attack or stroke than people without them.
What is Ganoderma lucidum?
Ganoderma lucidum (G lucidum), also known as ‘lingzhi’ or ‘reishi’, is a mushroom that is commonly used in traditional Chinese medicine. In China, G lucidum is taken in the traditional form of a decoction (mashed and boiled in water), or in tea or coffee. Recently it has been manufactured as an extract in tablets and capsules for the western market, as it is now being used in western countries in the hope that it might improve cardiovascular health.
The purpose of this review
Researchers from the Cochrane Collaboration tried to determine whether G lucidum, when compared with another medicine or a fake medicine – called a placebo – is an effective treatment for reducing cardiovascular risk factors.
What this review discovered
The researchers searched the medical literature up to June 2014 to identify all the relevant medical research. They identified a total of 5 medical studies that compared G lucidum with placebo in a total of 398 people with type 2 diabetes. Overall the quality of the studies was poor. Unpublished data was obtained for two of the included studies and one study was translated from Chinese. The daily doses of G lucidum taken varied between trials from 1.4 g to 5.4 g. In 1 trial participants in the G lucidum group took capsules that contained either G lucidum only, or a mixture of G lucidum (75% of capsule weight) and another fungus called Cordyceps sinensis (25% of capsule weight). Duration of trials varied from 12 to 16 weeks.
Two of the 5 trials reported results for the participants treated with G lucidum only, but not for those treated with placebo, and so the information from them could not be used. The remaining 3 trials with 157 participants provided information for analysis.
This information showed that G lucidum was not an effective treatment for reducing blood glucose, blood pressure, or cholesterol. It was not clear whether G lucidum might reduce blood glucose after a meal, as the only information for this came from a single study of indeterminable quality.
There was not enough information to determine the overall safety of taking G lucidum. One study showed some increased risk of mild harms in participants who took G lucidum in the form of nausea, diarrhoea or constipation.
Future research in this field should include clinical trials that are better reported.
Background
Description of the condition
The social, economic and personal burden of cardiovascular disease is well recognised. The World Health Organisation estimates at least 17 million deaths per year worldwide are due to cardiovascular disease (WHO 2011). This includes coronary heart disease ‐ independently the world’s leading cause of death ‐ and stroke. Stroke also has the highest prevalence rates for disability in many countries (WHO 2011). With rates of diabetes and obesity rapidly increasing in both the developed and developing world, it is expected that morbidity and mortality rates for cardiovascular disease will continue to rise (Capewell 2011; Hossain 2007).
Cardiovascular disease is multi‐factorial in causation. Over 300 risk factors have been identified as likely contributors to vascular pathogenesis and, in combination, may have complex and cumulative metabolic effects. Tobacco, alcohol, high blood pressure, high cholesterol, high blood glucose and obesity remain the primary modifiable risk factors (Hossain 2007; WHO 2011), and novel markers are being increasingly researched for their predictive ability and role in the development of cardiovascular disease. These include homocysteine, markers of inflammation, such as C‐reactive protein, and markers of abnormal coagulation, including fibrinogen (Pearson 2003).
Description of the intervention
Ganoderma lucidum, also known as ‘lingzhi’ or ‘reishi’, is a mushroom that has been consumed for its broad medicinal properties in Asia for 2000 years, and has more recently been introduced to western society. As with most herbal interventions, it is regarded as both medicine and food to bring the body ‘into balance’, promote health, prolong life and prevent and cure many systemic diseases (Willard 1990). The potential of G lucidum to treat multiple primary risk factors for cardiovascular disease safely and effectively has increased interest in this medicinal mushroom. The intervention may still be purchased in the more traditional form of decoction, tea or coffee, but is increasingly manufactured as an extract in tablets and capsules for the western market.
The Ganoderma fungus has a fruiting body (the mushroom, or basidiocarp), a mycelium (the filamentous form) and spores (for reproduction). The active constituents of G lucidum include polysaccharides (including beta‐D‐glucans, heteropolysaccharides and glycoproteins), triterpenes, germanium, essential and non‐essential amino acids, sterols, lipids, anti‐oxidants, vitamins B1, B2, B6, iron, calcium, and zinc (Huie 2004; McKenna 2002). Results from clinical trials indicate G lucidum can lower blood pressure, cholesterol, and blood glucose in humans (Gao 2004a; Gao 2004bJin 1996; Kanmatsuse 1985; Wachtel‐Galor 2004a; Wachtel‐Galor 2004b). In these trials, no abnormalities in haematological and biochemical (including hepatic and renal) safety biomarkers, and no moderate, serious or severe adverse events were reported for the participants. There is no agreed dosage for G lucidum treatment, however, most recommended amounts vary between 1.5 g and 9 g of dried extract per day (Chang 2000; Teow 1996). There are some claims that spores contain higher quantities of the active constituents. This has not been determined by research, and any medicinal benefit is unclear.
How the intervention might work
Unlike many synthetic medicines, G lucidum’s mode of action and guidelines for use are not well established. The Ganoderma mushroom contains pharmacologically active variables and the effects and effectiveness of the whole product are likely to differ from that of a single component acting alone. Data from animal and in vitro studies suggest that the constituents, either individually or synergistically, produce antioxidant, anti‐inflammatory, antihyperglycaemic, antiatherogenic and immune‐protective beneficial effects (Chen 2004; Lakshmi 2003; Yang 2002; Zhang 2004). As with most herbal medicines, matching single constituents with specific‐disease modifying effects is very difficult. For G lucidum, researchers suggest there are two groups of prominent bioactive components that have effects on the cardiovascular system. These are triterpenes and polysaccharides. G lucidum is the only known source of triterpene fatty acids called ganoderic acids. Of the 200 that have been identified, ganoderic acids A, B and C are thought to have hypoglycaemic effects (Hikino 1985; Tomoda 1986), while ganoderic acids F, B, D, H, K, S and Y are most likely hypotensive in their action (Morigawa 1986). The probable mode of action of ganoderic acid B (ganoderol) on glycaemia is by inhibition of α‐glycosidase that affects carbohydrate digestion (Fatmawati 2011). Ganoderic acids might inhibit many enzymatic activities, including those of angiotensin‐converting enzyme (Huie 2004), and might suppress sympathetic efferent activity (Lee 1990). Ganoderic acid S has been identified as an inhibitor of platelet aggregation (Shimizu 1985; Tao 1990). Most ganoderic acids are also thought to be active inhibitors of cholesterol synthesis (Komoda 1989). The second constituent group that might have effects on the cardiovascular system is polysaccharides. Over 150 polysaccharide molecules, including beta‐D‐glucans, heteropolysaccharides and glycoproteins have been identified in G lucidum (Chang 1999). Evidence suggests these structurally diverse macromolecules also have hypoglycaemic effects (Tomoda 1986; Zhang 2004).
Why it is important to do this review
Human trials that have evaluated G lucidum vary greatly with regard to the level and quality of evidence, internal and external validity, and in particular, the analysis and reporting of results. This provides a challenge to health professionals to determine effectiveness for cardiovascular risk factor management from an evidence‐based perspective. A systematic review of this increasingly popular complementary medicine is required for both eastern and western medical practice. This review will evaluate the effectiveness of G lucidum for the management of pharmacologically modifiable cardiovascular risk factors.
Objectives
To evaluate the effectiveness of G lucidum for the treatment of pharmacologically modifiable risk factors of cardiovascular disease in adults.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials, controlled clinical trials (as defined by Higgins 2011), and randomised cross‐over studies, for which only data from the first phase were to be included.
Types of participants
Any adult identified as having at least one cardiovascular risk factor listed as a primary outcome measure in this review. The cardiovascular risk factor must have been evaluated in the context of prevention or treatment of a cardiovascular‐related disease (for example, blood pressure changes evaluated in a cancer trial were excluded).
Types of interventions
As with most complementary medicines, a range of strains, herb products and active ingredients may be utilised under the same product name. Therefore a degree of heterogeneity was expected. G lucidum is frequently combined with a second ingredient aimed at increasing potency. Trials evaluating a combined formulation were included if there was only one additional ingredient and G lucidum represented at least 75% of the constituent weight. Co‐intervention was allowed as long as all arms of the study received the same co‐intervention. G lucidum:
may include teas, decoctions, or powders in any form;
may be raw or as an extract;
may include any part of the mushroom;
may be used at any dose (dosage equivalence between types of intervention is difficult to determine);
must be taken for longer than 21 days;
may be used as an isolated active compound e.g. G lucidum polysaccharide extract may be included.
Comparison was against placebo or alternative pharmacological or non‐pharmacological treatment.
Types of outcome measures
Primary outcomes
One primary outcome measure was required for studies to be included in this systematic review. Primary and secondary outcomes measures needed to be outside normal range at baseline.
Blood glucose level (for example, fasting blood glucose/glycosylated haemoglobin (HbA1c)/postprandial glucose test).
Blood pressure (systolic/diastolic/mean blood pressure).
Lipid profile (total triglycerides, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol).
Prevalence of any of the above.
Secondary outcomes
Obesity measures (waist circumference, hip‐waist ratio, fat percentage, body weight, body‐mass index).
Inflammatory markers (C‐reactive protein, apolipoprotein).
Insulin (fasting insulin, pro‐insulin, homeostasis model assessment (HOMA‐IR)).
Fibrinogen.
Homocysteine.
Health‐related quality of life.
Adverse events
Adverse event symptoms and signs attributable to treatment.
Evidence of liver dysfunction.
Evidence of renal dysfunction.
Search methods for identification of studies
Electronic searches
The following databases were searched in October 2010 and updated in November 2011 (Appendix 1) Some databases were also searched in April 2013 and June 2014 (Appendix 2).
Health databases
The Cochrane Central Register of Controlled Trials (CENTRAL, Issue 6 of 12, 2014) on The Cochrane Library
MEDLINE via PubMed Entrez (1950 to November 2011) and via OVID (1946 to June week 3 2014)
Science Direct (1823 to 2013)
EMBASE (OVID, 1980 to 2014 week 26)
MD Consult (1995 to 2013)
Stat!Ref‐Medical (1998 to 2013)
Biomed Central (1997 to 2013)
Scopus (1966 to 2013)
CINAHL Plus with Full Texts (EBSCO, 1937 to 20 June 2014)
Current contents (1998 to 2013)
Health and Medical Complete (1986 to 2013)
Science Citations Index Expanded (SCI‐Expanded) and Conference Proceedings Citation Index ‐ Science (CPCI‐S) on Web of Science (Thomson Reuters, 1970 to 27 June 2014)
BIOSIS on Web of Science (Thomson Reuters, 1969 to 27 June 2014)
Databases of ongoing trials
Current Controlled Trials (1990 to 2013)
Australian New Zealand Clinical Trials Registry (2005 to 2013)
CenterWatch Clinical Trials Listing Service (USA) (1995 to 2013)
National Institutes of Health (USA) (1800 to 2013)
clinicaltrials.gov (National Institutes of Health) (2000 to 2013)
Complementary medicine database
Chinese Biomedical Literature Database (CBM) (2007 to 2013)
Chinese Medical Current Contents (CMCC) (2007 to 2013)
China Network Knowledge Infrastructure (CNKI) (1979 to 2013)
VIP Database (1989 to 2013)
We applied no language restrictions. Published or unpublished studies, including those only available as abstracts, were eligible for inclusion.
Searching other resources
We checked reference lists of all included studies for other potentially eligible studies.
We communicated with authors in the relevant field, medicinal mushroom research centres and relevant pharmaceutical companies (Appendix 3).
We handsearched the International Journal of Medicinal Mushrooms.
Data collection and analysis
Selection of studies
Two authors (NK and FH) independently evaluated the English language titles and abstracts, where available. One author (HC) evaluated Chinese language titles and abstracts. We retrieved full text versions for all potentially relevant studies (NK). Two authors (NK and HC) independently evaluated full text versions for eligibility. Authorship and results were not blinded, as the effectiveness of applying this process has not been established by empirical evidence (Higgins 2011). We resolved any disagreement by discussion between authors. We did not need a third author (SG) to arbitrate for a disagreement.
Data extraction and management
Two authors (FH and HC) independently extracted data using a pilot‐tested data extraction form. One author (NK) checked data extraction forms for agreement. No arbitration of disagreement was needed. The following data were extracted:
general information: title, authors, contact details, country, sponsor;
verification of inclusion criteria that were met;
publication details: published or unpublished, abstract only or not, publication type, language, standard referencing details, duplicate publications;
trial characteristics: design (parallel or cross‐over), recruitment procedures, method of randomisation, allocation concealment, blinding (participants, intervention administrators, outcome assessors), evaluation of blinding by trialists, setting, quality appraisal;
participants: inclusion and exclusion criteria, total number and numbers in comparison groups, baseline characteristics;
interventions: the composition or ingredients; preparation method, dose, route, and duration of intervention; comparison intervention; co‐intervention; and expertise of practitioner;
outcomes: outcomes specified above and adverse events;
follow‐up: length of follow‐up, reason and number of dropouts and withdrawals, compliance, and intention‐to‐treat analysis.
Assessment of risk of bias in included studies
Risk of bias of included trials was rated independently by two authors (HC and FH) using the following criteria, as described in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). Disagreements were arbitrated by a third author (NK).
sequence generation;
concealment of allocation;
blinding;
incomplete data;
selective outcome reporting;
other sources of bias, such as financial conflicts of interest and single author or single centre trials.