Gugulipid for the Treatment of Hypercholesterolemia
Gugulipid for the Treatment of Hypercholesterolemia
November 1998; Volume 1: 125-127
By Philippe Szapary, MD and Michael Cirigliano, MD
Hypercholesterolemia affects millions of Americans. According to the National Cholesterol Education Program, approximately 40% of Americans need some form of treatment for hypercholesterolemia.1
Results from several randomized clinical trials estimate that a 10% reduction in cholesterol level is associated with a 25% reduction in coronary events among patients treated for more than five years.1 While diet should continue to be the mainstay of therapy, cholesterol-lowering drugs are widely prescribed, with HMG-CoA reductase inhibitors (statins) being the most popular. Statins are expensive and have side effects, prompting many patients to look to alternative therapies.
History
Gugulipid is an extract of the resin from the mukul myrrh tree (Commiphora mukul). This thorny tree has little foliage and is indigenous to Western India. Upon injury, this 4 ft. tree exudes a resin called gum guggul, or guggulu, the medicinal uses of which date back to 600 BC. More than 2000 years ago, Ayurvedic texts described atherosclerosis as a stepwise process starting with overeating (medoroga) and lack of exercise, eventually leading to "coating and obstruction of channels."2 It was for this process that gum guggul was thought most useful. However, it was not until 1966 that the hypolipidemic properties of gugulipid were scientifically tested.
Indian clinical trials performed in the 1970s and 1980s gained the Prime Minister of India’s attention in 1987.2 While its use has not caught on in the United States, gugulipid is now widely used in India for the treatment of hypercholesterolemia.
Pharmacology
The soluble portion of gum guggul is called gugulipid and is extracted using ethyl acetate. The most active ingredients of gugulipid are the ketones E- and Z-guggulsterones.3 While commercial gugulipid in India is standardized to contain a minimum of 50 mg of guggulsterones per gram of gugulipid, products available in the United States vary in their guggulsterone concentration.
Mechanism of Action
Unlike other lipid-lowering agents, gugulipid appears to have multiple modes of action, though none are particularly well understood. Animal models indicate that gugulipid works by inhibiting lipogenic enzymes and HMG-CoA reductase in the liver.4 It is also thought to stimulate lipolytic enzymes, enhance fecal excretion of sterols, and act as a bile acid sequestrant.4 Gugulipid has been shown to stimulate thyroid function in rats.5
Clinical Trials
Several studies have shown the efficacy of various fractions of the gum guggul in varied dosages in reducing serum lipids. There are four published human clinical trials evaluating the hypolipidemic effect of standardized gugulipid, all performed and published in India between 1985 and 1994.6-9 Two of the four studies were placebo-controlled, and only one study directly compared gugulipid to another agent (clofibrate).
The largest trial was a two-phase multicenter study that included 205 patients.7 In the first phase of this study, patients were placed on a low-fat diet for six weeks before being treated with gugulipid 500 mg tid for 12 weeks and then being switched to a matching placebo for an additional eight weeks. At study entry, this cohort had on average a total cholesterol (TC) of 301 mg/dL and a triglyceride level (TG) of 231 mg/dL. While this was mainly a primary prevention trial, an unspecified number of patients with stable CAD were also included. In the first phase of the study, it was noted that gugulipid significantly decreased TC by 22% and TG by 25% compared to placebo. In the second phase of this same study, 233 patients with a mean TC of 258 mg/dL and mean TG of 282 mg/dL took part in a double-blind, crossover trial with gugulipid and clofibrate.
When informally pooled, the four studies reveal that on average, 70% of patients enrolled lowered both their TC and TG in response to gugulipid. Responders were identified as patients who dropped their TC and TG by more than two standard deviations below the intra-individual week-to-week variation in lipids seen during these trials. These results compare favorably to other hypolipidemic drugs used today in the United States.
These studies have notable weaknesses. Only two of the four measured HDL, and, thus, LDL could not be calculated. The longest follow-up was six months, and data are lacking on cardiovascular events or mortality and on continued effectiveness of gugulipid on serum lipid concentrations.
Other studies using unstandardized gugulipid preparations have shown a more marked HDL effect, ranging from a 20-36% increase.10 Notably, a randomized, placebo-controlled trial of 40 patients with TC of at least 275 mg/dL showed a 36% increase in HDL and a 22% reduction in TC over 16 weeks of therapy.11 This study used 4.5 g/d of purified gum guggulu, which is at least twice the dosage of gugulipid in other trials. While incidence of side effects was not mentioned, these results raise the possibility of a dose-response relationship.
Adverse Effects and Interactions
Phase I trials and clinical trials have found no significant untoward effects of gugulipid over 12 weeks of therapy.8 In one study, several patients developed dyspepsia, hiccups, and bloating, but compliance was the same between drug and placebo (96%).6 Additionally, there were no reports of liver, renal, glucose, or hematologic abnormalities. While there were no reports of muscle weakness, creatine phosphokinase was not measured.
There is one published report of drug interactions between gugulipid and both diltiazem and propranalol.16 A single 1 g dose of gugulipid reduced the bioavailability of the two drugs by 35%. It is unclear whether this pharmacokinetic interaction translates into reduced clinical efficacy. Two anecdotal reports note a paradoxical pro-lipidemic effect.17,18 It is unclear whether this effect represents non-responders (up to 30% of treated patients) or individual variations.
Formulation and Dosage
Resin, gums, and volatile oils comprise raw sap. In India, gugulipid extract is standardized to contain 50 mg guggulsterones/g and is sold under the trade name Guglip (Cipla Ltd.). The dosage best studied is 25 mg of guggulsterones po tid. Synthetic guggulsterones (compound 80/574) with better LDL reduction power are currently being evaluated in clinical trials in India.10
In the United States, gugulipid is available in a variety of preparations and is inexpensive. (See Table.)
| Table | ||
| Cost and dosing comparisons of standardized gugulipid preparations vs. standard agents | ||
| Drug | Formulation* | Price# |
| Gugulipid (Preventics) | 500 mg tid | $29.00 |
| Gugulmax (Nature’s Herb) | 295 mg tid | 45.00 |
| Gugulipid C+ (BioTherapies, Inc.) | 25 mg/20 mg vitamin C tid | 27.25 |
| Atorvastatin (Lipitor°) | 10 mg qhs | 54.72 |
| Simvastatin (Zocor) | 20 mg qhs | 109.88 |
| Pravastatin (Pravachol) | 40 mg qhs | 101.69 |
| Gemfibrozil | 600 mg bid | 64.85 |
| Cholestyramine | 4 g bid | 79.80 |
| Niacin Extended Release (Niaspan) | 2 g qhs | 44.40 |
| Niacin Short Acting | 1 g bid | 3.60 |
| *Gugulipid standardized
to provide 75 mg of guggulsterones/day.
#Price for 30-day supply. For gugulipid preparations, the suggested retail price is listed. For other drugs, the average wholesale price is listed. °Statin doses are approximately equipotent. |
||
Conclusions
Observations on gugulipid must be interpreted with caution since they are based on data from fewer than 200 patients. Standardized gugulipid extract at doses equivalent to 75 mg guggulsterone per day appears to be effective for mixed hyperlipidemia in approximately 70% of patients. Although gugulipid has never been directly compared to statins, it appears to reduce LDL on average by 17%, which is similar to 20 mg of fluvastatin or 10 mg of pravastatin.14 Gugulipid also appears to increase HDL by 14%, which is similar to 1200 mg of gemfibrozil, and reduce TG by 24%, which is in line with the reduction from 2 g of niacin. A major advantage of gugulipid over currently available drugs is that adverse side effects have not been demonstrated.
Recommendation
Gugulipid might be considered for those mildly hypercholesterolemic patients who wish to attempt to avoid the side effects or expense of niacin, resins, and statins. Larger and longer randomized controlled trials of gugulipid in the primary prevention of cardiovascular disease are needed to confirm benefits and to establish the long-term safety of this promising Ayurvedic remedy.
Dr. Szapary and Dr. Cirigliano are Assistant Professors in the Department of Medicine at the University of Pennsylvania in Philadelphia.
References
1. Gaziano MJ, et al. Cholesterol reduction: Weighing the benefits and risks. Ann Intern Med 1996;124:914-918.
2. Satyavati GV. Gum guggul (Commiphora mukul): The success story of an ancient insight leading to a modern discovery. Indian J Med Res 1988;87:327-335.
3. Murray MT. Gugulipid. In The Healing Power of HerbsThe Enlightened Person’s Guide to the Wonders of Medicinal Plants, 2nd ed. Prima Publishing; 1995:197-202.
4. Sheela CG, Augusti KT. Effects of S-allyl cysteine sulfoxide isolated from allium sativum linn and gugulipid on some enzymes and fecal excretions of bile acids and sterols in cholesterol fed rats. Indian J Exp Biol 1995;33(10):749-751.
5. Tripathi YB, et al. Thyroid stimulating action of Z-guggulsterone obtained from Commiphora mukul. Planta Med 1984;1:78-80.
6. Singh RB, et al. Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 1994;8:659-664.
7. Nityanand S, et al. Clinical trials with gugulipid. J Assoc Physicians India 1989;37(5):323-328.
8. Agarwal RC, et al. Clinical trial of gugulipid—A new hypolipidemic agent of plant origin in primary hyperlipidemia. Indian J Med Res 1986;84:626-634.
9. Gopal K, et al. Clinical trial of ethyl acetate extract of gum guggulu (gugulipid) in primary hyperlipidemia. J Assoc Physicians India 1986;34(4):249-251.
10. Ghatak A, Asthana OP. Recent trends in hyperlipoproteinemias and its pharmacotherapy. Indian J Pharmacol 1995;27:14-29.
11. Verma SK, Bordia A. Effect of Commiphora mukul (gum guggulu) in patients of hyperlipidemia with special reference to HDL-cholesterol. Indian J Med Res 1988;87:356-360.
12. McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained vs. immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271(9):672-677.
13. Tikkanen MJ, et al. Comparison between lovastatin and gemfibrozil in the treatment of primary hypercholesterolemia: the Finnish multicenter study. Am J Cardiol 1988;62:35J-43J.
14. Jones P, et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (The CURVES Study). Am J Cardiol 1998;81:582-587.
15. Vessby B, et al. Diverging effects of cholestyramine on apolipoprotein B and lipoprotein Lp(a)—A dose response study of the effects of cholestyramine in hypercholesterolaemia. Atherosclerosis 1982;44:61-71.
16. Dalvi SS, et al. Effect of gugulipid on bioavailability of diltiazem and propranalol. J Assoc Physicians India 1994;42(6):454-455.
17. Das Gupta R. Gugulipid: pro-lipaemic effect. J Assoc Physicians India 1990;38(12):346.
18. Das Gupta R. A new hypolipidaemic agent (gugulipid). J Assoc Physicians India 1990;38(2):186.
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