Guggulipid Use in Hyperlipidemia

Introduction

Guggulipid, a standardized guggul extract from the resin of the mukul myrrh tree (Commiphora mukul) native to India, has been used in traditional Ayurvedic medicine for the treatment of epilepsy, ulcers, obesity, rheumatoid arthritis, and atherosclerosis since 600 BC.^[1,2] Guggulipid contains Z- and E-guggulsterones, which are purported to be the active components of the extract. Guggulsterones have been found to inhibit cholesterol synthesis in the liver via antagonism of the farsenoid X receptor and the bile-acid receptor.^[3,4] The extract received regulatory approval for use in treating hyperlipidemia in India in 1987.^[5] In the United States, guggulipid is available as a nonprescription dietary supplement.

A 62-year-old Caucasian man arrived at an ambulatory care clinic in August 2003 for hyperlipidemia follow-up. One of the patient's complaints was loose stools two or three times daily for the past week. Although a smoker for 25 years, he had recently quit. He had no documented allergies or adverse reactions to any medications. His current medication (prescription and dietary supplement) regimen included the nicotine patch 14 mg daily, aspirin 325 mg daily, saw palmetto 160 mg with lycopene (dosage unknown) twice daily, and guggulipid 1000 mg three times daily. Vital signs were normal.

The patient had had his lipid values measured twice (once in April and once in early August) before his visit to his primary care provider. His lipid panel results from August showed a low-density-lipoprotein (LDL) cholesterol value of 173 mg/dL. The National Cholesterol Education Program recommends an LDL cholesterol concentration of <160 mg/dL.^[6] Therefore, his primary care provider initiated simvastatin 10 mg at bedtime, with a follow-up lipid panel and liver function tests planned before the next appointment (in approximately four months).

After meeting with his primary care provider, the patient consulted with his clinical pharmacist for medication education. The patient reported that a friend recommended a supplement called guggulipid, which he began taking at a dosage of 550 mg daily approximately five to six months before his visit, to help decrease his cholesterol level. The lipid panel obtained in August was reflective of the 550-mg daily dose. He reported no adverse effects from the supplement at that dosage. A week before his visit, the patient increased the dosage of guggulipid to 1000 mg three times a day. After this dose increase, the patient started to have two or three loose stools daily. He agreed to discontinue the guggulipid at the pharmacist's suggestion, as it has been reported to worsen lipid levels.^[3] Published reports also indicated that it could cause loose stools and diarrhea.^[4]

The patient returned for a primary care follow-up appointment in early January 2004, with a lipid panel completed in late December. His LDL cholesterol level had decreased to 126 mg/dL, and the patient had no further complaints of loose stools after stopping guggulipid. The patient reported compliance with simvastatin and was asked to return to the clinic in one year.

To obtain more objective evidence associated with the adverse reaction (worsening lipid values) attributed to guggulipid, the Naranjo scale was used.^[7] The resulting total score from this well-validated tool for assessing the likelihood of association between a given agent and an adverse reaction was 5. A score of 5-8 indicates a probable relationship.

The use of guggulipid for treatment of hyperlipidemia has recently come under scrutiny. In a double-blind, randomized, placebo-controlled trial, Szapary and colleagues^[3] studied the short-term safety and efficacy of guggulipid as a cholesterol-lowering agent in a western population of 103 healthy adults. Patients were randomized to receive placebo, 3000 mg daily of 2.5% standardized guggulipid (standard-dose guggulipid [SDG]), or 6000 mg daily of 2.5% standardized guggulipid (high-dose guggulipid [HDG]). Each 1000-mg tablet was tested for purity and found to contain at least 21 mg of guggulsterones. Patients were included in the study if they had an LDL cholesterol value of 130-200 mg/dL and triglyceride levels of <400 mg/dL. Patient assessment using standardized lipid analysis was completed at four and eight weeks. The primary outcome was the percent change from baseline in directly measured levels of LDL cholesterol at eight weeks. Secondary outcomes were the percent changes in levels of total cholesterol, high-density-lipoprotein (HDL) cholesterol, very-low-density-lipoprotein cholesterol, triglycerides, and safety and laboratory tests (electrolytes, renal and hepatic function studies) at four and eight weeks.

Of the 103 patients who qualified for eligibility, 85 completed the study; 36 patients received placebo, 33 patients received SDG, and 34 patients received HDG. After eight weeks, an intent-to-treat analysis showed a 5% decrease in the directly measured levels of LDL cholesterol in the placebo group. LDL cholesterol levels actually increased in the SDG and HDG groups by 4% and 5%, respectively, both of which were statistically significant. Levels of other lipoproteins did not significantly differ among the groups in the intent-to-treat analysis. However, in the per-protocol analysis, there was a statistically significant reduction in HDL cholesterol levels in both the SDG and HDG groups versus placebo. The increases in LDL cholesterol levels in this study are consistent with the case report described.

Two case reports from India have also demonstrated an increase in lipoproteins associated with guggulipid.^[8,9] After approximately one month of treatment with guggulipid, total cholesterol and triglyceride values increased. The dosages of guggulipid were not mentioned in either case report. In addition, two Indian-based studies found that guggul extract was not significantly effective in lowering total cholesterol or triglyceride levels for all patients in the study, specifically those with familial hypercholesterolemia.^[10,11]

In contrast to the above studies and case reports, several clinical trials conducted in India using various forms of guggul extract have demonstrated beneficial effects of guggulipid on lipid values.^{[10,11,12,13,14,15]} In general, these studies indicated that guggulipid significantly decreased total cholesterol, triglyceride, and LDL cholesterol levels and raised HDL cholesterol levels versus placebo. The duration of treatment with guggulipid varied among studies, from as short as 3 weeks to as long as 75 weeks. Preparations of guggulipid also varied among studies; however, those using SDG were the best tolerated. A majority of these studies were not randomized or placebo controlled, had small sample sizes, did not control for patients' dietary intake, and included patients with various forms of hyperlipidemia. All of these issues are capable of affecting study results. In addition, the exclusion criteria varied among the studies, and some did not mention excluding patients who had been taking other lipid-lowering medications.

Singh et al.^[1] conducted a well-designed, randomized, double-blind study of guggulipid 50 mg twice daily versus placebo in 61 patients. Each tablet of guggulipid contained 25 mg of guggulsterones. Patients age 25-65 years with serum total cholesterol values greater than 200 mg/dL were included in the study. Exclusion criteria included diarrhea, dysentery, chronic renal failure, diabetes, hypertension, coronary artery disease, and noncompliance with the recommended diet. The study began with a 4-week observation period in which patients recorded their usual diet. A 12-week diet-stabilization period followed consisting of dietary counseling by blinded dietitians and physicians who recommended a diet low in cholesterol, low in saturated fat, and high in soluble fiber. Patient records were reviewed for dietary compliance at biweekly intervals. After this 12-week period, patients were randomly assigned to receive guggulipid (n = 31) or placebo (n = 30) for 24 weeks in a blinded fashion. A 12-week washout period concluded the study. Patients in both groups had comparable baseline data. Results from the 12-week diet-stabilization period indicated that a diet low in cholesterol, low in saturated fat, and high in soluble fiber significantly reduced total cholesterol, LDL cholesterol, triglyceride, and fasting glucose levels in both groups. With the addition of guggulipid, total cholesterol, LDL cholesterol, and triglyceride levels significantly decreased compared with placebo after 24 weeks of treatment. No significant difference in HDL cholesterol levels was found between groups. After the washout period, total cholesterol, LDL cholesterol, and triglyceride values increased substantially in the guggulipid-treated group, compared with insignificant changes in those receiving placebo.

Based on the clinical literature, obvious discrepancies exist regarding the effectiveness of guggulipid on lipid parameters. First, the Indian-based clinical studies that indicated favorable guggulipid effects were older and generally less rigorously designed trials. In addition, studies were very short in duration, ranging from three weeks to just under 2 years. In contrast, clinical studies of medications approved by the Food and Drug Administration for the treatment of hyperlipidemia, including hydroxymethylglutaryl-coenzyme A reductase inhibitors and niacin, were much longer, ranging from 5 to 15 years, and included morbidity and mortality data.^[16,17,18] Many of the guggulipid studies did not state whether they excluded patients who may have been taking other lipid-lowering medications. The statistical tests used in these studies were not always apparent, nor was the α level of significance.

Second, the populations studied (American versus Indian) differed among the trials. The Indian populations had a lower intake of dietary fat and a higher intake of daily fiber compared with a western population diet as demonstrated in clinical trial data.^[1,3] In addition, overall cultural differences exist between the populations that may affect diet and exercise habits and thus influence lipid levels. Although it has not been shown in clinical trials, genetics may also play a role in determining which population may or may not respond favorably to guggulipid.

Finally, the standardization process of guggulipid may differ between, as well as within, countries, causing some variability in the active constituents in a given product or the percentage of guggulsterones, thereby affecting lipid profiles. Guggulipid products in the United States may contain other ingredients marketed for cardiovascular or cholesterol "health." Due to the lack of regulation, these products have not been scrutinized as carefully as products with FDA-approved labeling.

The case reported herein highlights the importance of pharmacist-conducted medication education. Although the patient's use of a guggulipid supplement had been documented by the physician, it had not been questioned. As acknowledged in the "ASHP Statement on the Use of Dietary Supplements," discussion of the use of substances such as guggulipid must become a routine part of the patient-provider encounter.^[19]

Current data in the clinical literature do not support the claims of guggulipid's efficacy in the treatment of hyperlipidemia in a western population. Clinicians should advise their patients with hyperlipidemia to avoid the use of guggulipid.

The contributions of Veterans Affairs Pharmacists Organized for Research (VAPOR) members Teresa Duhancik, Pharm.D., BCPS, Jennifer A. Retterer, Pharm.D., BCPS, and Eric W. Weber, Pharm.D., BCPS, are acknowledged.

American Journal of Health-System Pharmacy. 2005;62(16):1690-1692. © 2005 American Society of Health-System Pharmacists

Cite this: Guggulipid Use in Hyperlipidemia - Medscape - Aug 15, 2005.