Gugulipid
Common Names:
- Guggul
- Gum Guggul
- Guggulu
- Mukul Myrrh (Commiphora mukul)
Plant Description and Usage:
The mukul myrrh tree is a small (4-6 feet tall), thorny tree that remains
free of foliage for much of the year. Its bark is ash-colored, comes off in
rough flakes, exposing the underbark which also comes off easily. The tree is
native to Arabia and India. The oleoresin (sap, gum guggul, guggulu) is
yellowish, has a balsamic odor and is the part of the plant used for medicinal
purposes. When tapped during the winter, similar to a maple tree, the tree
yields about 700-900 grams of resin per tree. Gugulipid is used predominately
for its cholesterol- and lipid-lowering effects, but a fraction of the oleoresin
has anti-inflammatory effects.
Chemical Components:
The resin is fractionated, first by mixing it with ethyl acetate, a common,
moderately-nonpolar organic solvent, to yield a soluble fraction (~45%) and an
insoluble fraction (55%). The soluble fraction contains the active gugulipid
components and the insoluble fraction contains the carbohydrate residues, which
are toxic. The soluble portion is further subfractionated into acid (4%), basic
(1%), and neutral (95%) fractions. The acid fraction contains the
anti-inflammatory components (i.e., ferulic acid, phenols, and other nonphenolic
aromatic acids), while the neutral fraction contains the lipid-active
components. The neutral fraction is further divided into ketonic (12%) and
nonketonic (88%) subfractions, with the active components residing in the
ketonic fraction. The inactive subfraction contains ligning, diterpenes, and
fatty alcohols. The active ketonic fraction consists of C21 and C27 sterols,
mainly Z- and E-guggulsterones, and other esters. Gugulipid is a standardized
neutral fraction extract of gum guggul that contains a minimum of 50 mg
guggulsterones per gram of extract. It has been speculated, but not proven, that
the other components of the neutral extract exert a synergistic effect with the
guggulsterones; a more likely rationale is that it is cheaper to market the
neutral fraction than further purify the guggulsterones from the mixture.
History and Folk Use:
Guggulu plays an important role in the Indian medical system Ayurveda
in formulas for rheumatoid arthritis and lipid disorders. Early beliefs (2,600
years ago) also assigned a weight-reducing effect and a cardiovascular
protective effect to guggulu, in addition to its anti-inflammatory and
lipid-lowering effects. This led to studies of gugulipid's hypolipidemic effect
on both cholesterol and triglycerides, and its approval in India as a
lipid-lowering drug in 1986.
Pharmacology:
Gugulipid lowers serum levels of triglycerides and cholesterol by stimulating
the liver to increase the uptake of the lipoproteins VLDL and LDL, respectively.
Gugulipid has also been shown to increase blood levels of HDL, providing a
cardioprotective benefit; therefore, gugulipid would be most beneficial in
treating Type IIb and IV hyperlipoproteinemias. In animal studies, gugulipid
reversed the deposition of pre-existing atherosclerotic plaques, promoted
fibrinolysis, inhibited platelet aggregation and functioned as a free-radical
scavenger, all serving a cardioprotective function.
Gugulipid's anti-inflammatory action is thought to be due to inhibition of
delayed hypersensitivity reactions. The sterol is approximately equivalent to
ibuprofen and 1/5 the effect of hydrocortisone.
Gugulipid is a fairly nontoxic product, having an LD50 in rats of 1.6g/kg. In
doses used for clinical efficacy, there may be mild skin rashes or GI
upset/diarrhea. It is safe to use during pregnancy and does not adversely affect
liver or kidney function, hematological tests or blood sugar levels in diabetic
patients.
Usual Dosages:
The usual clinically effective dosage of guggulsterones is 25 mg TID for
lipid-lowering effects. For a preparation containing 5% guggulsterones, this
translates to an effective dose of 500 mg gugulipid TID.
Summary of Clinical Trials
1. Singh RB, Niaz MA, and S Ghosh. Hypolipidemic and Antioxidant Effects
of Commiphora Mukul as an adjunct to dietary therapy in patients with
hypercholesterolemia. Cardiovascular Drugs & Therapy. 8(4):659-64,
August 1994.
81 patients with hypercholesterolemia were entered into the study provided
their serum cholesterol was > 200 mg/dL and they were between 25 and 65 years of
age. Criteria for exclusion included presence of diarrhea, dysentery, chronic
renal failure, diabetes, hypertension, coronary artery disease, and
noncompliance with the study's diet. Only 61 of the patients completed the
trial.
The trial was randomized and double-blinded, and was divided into periods:
- 4 week observation period
- 12 week diet stabilization
- 24 week treatment period
- 12 week washout (no drug)
During the 4-week observation period, subjects were asked to maintain their
usual diet and lifestyle, and to record weekly food intake. During the 12 week
diet stabilization period, patients were instructed to eat a prudent diet. They
were advised to eat at least 400 grams per day of fruits and vegetables.
Physicians and dietitians who were blind to the treatment groups provided
dietary counseling at entry of the study and every two weeks subsequent. These
counseling sessions were done to enhance compliance with the study's diet. For
the treatment period, subjects were randomly assigned by an unaffiliated person
to receive either placebo or gugulipid. Patients in the treatment group received
two tablets, each containing gugulipid equivalent to 25 mg of gugul sterones,
twice daily (100 mg/day). Placebo capsules were similar in all respects and
contained aluminum hydroxide. All agents (placebo and treatment) were provided
to patients in identical bottles, and compliance was monitored by counting the
number of capsules returned by the patients on follow-up visits. Laboratory data
was collected and analyzed at two separate facilities to insure quality control.
No differences between the two labs exceeded 2%.
Statistical analysis was done with a two-sample t-test using one way ANOVA.
Significance was chosen to be < 0.05.
Based on the number of pills returned by patients, compliance was exceptional
(97.5% in gugulipid doses and 96.3% in placebo doses). The twelve-week diet
stabilization period produced significant reductions in both the gugulipid and
placebo group. Addition of gugulipid further reduced total cholesterol levels by
25.2 mg/dL, compared with a reduction of 7.6 mg/dL in the placebo group
(p<0.01). LDL cholesterol levels decreased by 16.9 mg/dL in the treatment group,
and increased by 4.0 mg/dL in the placebo group (p<0.01). Gugulipid reduced
triglycerides by 18.0 mg/dL as opposed to an increase by 5.5 mg/dL in the
placebo group. HDL cholesterol was also increased in both groups, but this
increase is not statistically significant.
After a 12-week washout period, subjects from the gugulipid group showed
profound increases in total cholesterol (6.5%), LDL cholesterol (6.6%), and
triglycerides (7.7%). Patients from the placebo group showed no significant
changes following the washout period.
This study suggests that gugulipid is quite efficacious in lowering
cholesterol levels, and thus reducing the chance for development of
artheroscloretic disease. The study has both strengths and weaknesses that
should be addressed:
Strengths:
- The trial was randomized and double-blinded.
- The trial followed the subjects for a full year.
- Compliance was encouraged by providing routine dietary counseling.
- Attempts were made to monitor compliance.
- Placebo and treatment looked identical and were provided in identical
containers.
- Laboratory data was analyzed by two separate facilities, and there were
no significant differences between the two.
Weaknesses:
- Excluded from the study were hypertensives and patients with coronary
artery disease. These are two populations who often have elevated
cholesterol levels.
- Patients were only advised to eat certain foods during the diet period.
The researchers made large efforts to ensure compliance, but with an
ambulatory study such as this one, the reader cannot infer that the patients
were completely compliant with the diet regimen.
- Compliance cannot be assured based on the number of pills returned by
the patient. The patient may have disposed of the pills and not taken them
at all.
- Patients began taking gugulipid following a 12 week period of a
rigorously healthy diet. This will unlikely be the typical scenario in
clinical practice.
Most of the weaknesses of this study were unavoidable. The researchers went
to great lengths to attempt to control for these potential confounders, and
consequently their data and results can be applied. Gugulipid proved to reduce
cholesterol levels (multiple types) significantly, and cholesterol levels
rebounded upon discontinuation of the drug. This finding points to a certain
efficacy of gugulipid.
2. Duwiejua M, Zeitlin IJ, Waterman PG, Chapman J, Mhango GJ, and GJ
Provan. Anti-Inflammatory Activity of Resins from Some Species of the Plant
Family Burseraceae. Planta Medica. 59(1):12-6, 1993 Feb.
This study examined effects of several compounds including Commiphora mukul (gugulipid).
Resin was extracted and made into a suspension. The suspension was then put into
solution (0.2 mL) containing 10% v/v acacia mucilage and 0.2% Tween 20. 400
mg/kg of the solution was administered by mouth to rats. Control rats received
0.2 mL of drug vehicle only. Two hours later, researchers induced edema in the
right hind paw of each rat. The contralateral hind paw was injected with saline
as a control. Edema was then monitored for six hours and measured as percentage
change in paw thickness. Results showed that gugulipid produced significant
(42%) inhibition of edema in the rat paw. (p<0.05).
3. Agarwal RC, et al. Clinical Trial of Gugulipid - A New Hypolipidemic
Agent of Plant Origin in Primary Hyperlipidemia. Indian J Med Res.
84:626-634, 1986 Dec.
This trial was divided into two phases. The first phase evaluated the safety
of gugulipid and the second phase evaluated efficacy. Phase I enrolled 21
patients, excluding women of child-bearing age and patients with concomitant
hemopoeitic disease. An indistinguishable placebo was given for two weeks,
followed by gugulipid 400 mg for four weeks. Patients reported every two weeks
for clinical and laboratory evaluation. Tests included liver function tests,
renal function tests, and 12 lead electrocardiogram.
Only one patient in phase I testing reported an adverse effect. The patient
complained of epigastric fullness three days after starting gugulipid. The
sensation was mild and controlled well with antacids. All laboratory parameters
(LFTs, blood urea, blood glucose) were normal in all patients following
gugulipid administration. No changes were detected in the ECG.
Phase II was performed using 19 hyperlipidemic patients. Criteria for
entering the study were persistently elevated overnight fasting serum
cholesterol levels above 250 mg/dL with or without a triglyceride level above
200 mg/dL. No patients had preexisting liver, renal, or thyroid disease, or
diabetes. Neither had any patient taken a lipid lowering agent for at least
eight weeks prior to enrollment in the study.
In Phase II, patients attended a hyperlipidemic clinic after an overnight
fast at weekly intervals for three weeks. If lipid levels were significantly
elevated, the patient was placed on a controlled diet for six weeks. At the end
of the six weeks, lipid levels were measured, and if they were still raised the
patient was given placebo for two weeks followed by gugulipid 500 mg for twelve
weeks. Patients returned to the clinic in a fasting state every 4 weeks, and
serum cholesterol and triglycerides were measured. Following the twelve weeks of
treatment of gugulipid, patients started placebo for eight weeks. Dietary
restrictions continued throughout the study.
Since serum cholesterol and triglycerides show considerable variation from
day to day, the researchers calculated a mean percentage variation for
cholesterol (11.3%) and triglycerides (26.2%). A responder was classified as a
patient who displayed a fall in serum cholesterol or triglyceride levels not
attributed to the normal day to day fluctuation.
Patients in Phase II did not complain of any adverse effects. Fifteen of the
nineteen patients showed a fall in serum cholesterol and triglycerides after
twelve weeks of treatment with gugulipid. The decrease in these fifteen patients
could not be attributed to normal day-to-day variation. The mean pretreatment
cholesterol level for the fifteen responders was 246.0 +/- 51.2 mg%. After 2-4
weeks of starting gugulipid therapy, this level dropped to 203.7 +/- 39.8 mg%
(p<0.001). Upon withdrawal of gugulipid, serum cholesterol levels tended to
rise, however 6-8 weeks after stopping the drug, statistically significant
reductions in cholesterol levels were still evident (mean cholesterol 213.3 +/-
38.8 mg/dL).
The mean pretreatment triglyceride levels in the fifteen responders was 333.6
+/- 214 mg/dL. This value declined to 221.5 +/- 118.3 mg/dL after 10-12 weeks of
therapy (p<0.001).
Results of the study indicate that gugulipid reduced mean cholesterol levels
by 17.5 +/- 9.9 % and triglyceride levels by 30.3 +/- 18.4 %.
Summary:
Phase I of this trial indicates that gugulipid is safe for long-term
administration, as there were no alterations in hepatic or renal functions,
blood glucose levels, hematological parameters or ECG. Phase II showed that
gugulipid can significantly lower serum cholesterol and triglyceride levels in
some patients. The effect of gugulipid as exemplified in this trial is
comparable to other lipid-lowering agents. An important finding of this study is
that gugulipid exerted a lipid-lowering effect within 2 weeks of starting and
persisted throughout treatment. In addition, upon withdrawal of gugulipid,
cholesterol and triglycerides tended to rise. However, statistically significant
lowering persisted even after 8 weeks of withdrawal. The study also shows that
not all patients will respond to gugulipid.
Points concerning study:
- (+) Patients served as their own controls.
- (+) The study utilized drug-free periods in addition to periods of drug
usage.
- (+) The researchers attempted to define a significance of cholesterol
variation by determining an average daily variation that
was considered insignificant.
- (+) The study examined important parameters such as renal function and
ECG, which makes a conclusion that gugulipid is safe more valid.
- (-) Very small sample size.
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