By Ted Wissink, MD, Craig Schneider, MD, and S. Tyler O’Sullivan, DO
Dr. Wissink is Assistant Director of Integrative Medicine, Department of Family Medicine, Maine Medical Center, Portland; Dr. Schneider is Director of Integrative Medicine, Department of Family Medicine, Maine Medical Center, Portland; and Dr. O’Sullivan is a physician with Maine Medical Partners, Falmouth.
Drs. Wissink, Schneider, and O’Sullivan report no financial relationships relevant to this field of study.
SUMMARY POINTS
- Several small human trials with bergamot supplementation have shown significant reduction in total cholesterol, low-density lipoprotein levels, and triglycerides and an increase in high-density lipoprotein levels.
- The main side effect was gastric upset but a small subset of statin-intolerant patients tolerated bergamot well.
- One small clinical trial with bergamot supplementation showed promise for treatment of metabolic syndrome and non-alcoholic fatty liver disease, with a decrease in fasting glucose and a decrease in liver enzymes.
SYNOPSIS: Although larger controlled studies are warranted, bergamot supplementation may be an alternative approach to improving cardiovascular risk in patients who are unable or unwilling to take pharmaceutical HMG-CoA reductase or PCSK9 inhibitors.
The World Health Organization lists cardiovascular disease (CVD) as the No. 1 killer of humans across the globe.1 Attempts to modify CVD risk factors comprise much of the efforts of both clinicians and the pharmaceutical industry. Along with exercise and dietary modifications, statin drugs (HMG-CoA reductase inhibitors) that modulate lipid metabolism play a major role in reducing mortality from ischemic heart disease. Statins are some of the most frequently prescribed drugs in the United States. Unfortunately, some patients treated with statins still are not able to meet their lipid targets, and up to 15% of patients do not tolerate statins.2 Adverse effects are more likely in the setting of high-dose statin therapy, advanced age (> 70 years), female sex, renal and hepatic impairment, hypothyroidism, vitamin D deficiency, alcohol abuse, Asian ethnicity, low body mass index, as well as excessive physical activity.3 Concerns remain about the association between long-term use of statins and diabetes.4 Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are becoming available and may have a great effect, but remain very expensive and are not yet in widespread clinical use.
Alternative agents that modulate lipid metabolism and allow patients to reach their lipid targets in a cost-efficient manner without adverse side effects would be welcomed. Citrus flavonoids have emerged as a promising source of such an agent. Bergamot (Citrus bergamia), a member of the Rutaceae family, is found across the Mediterranean region and is widely cultivated in Southern Italy. Fans of Earl Gray tea are familiar with the captivating aroma provided by bergamot. Its essential oil is used in perfumes, cosmetics, and aromatherapy as well. Bergamot juice is obtained from the fruit and is a rich source of flavonoids, including neoeriocitrin, naringin, neohesperidin, C-glucosides, flavone, and flavanone O-glycosides.5 Flavonoids scavenge free radicals and some varieties, including naringin, act as HMG-CoA reductase inhibitors.6 Flavonoids appear to modulate various signaling pathways and direct regulation of cellular processes involved in CVD.7
Clinical Evidence
In a 2016 study, Toth et al enrolled 80 patients (42 male, 38 female), mean age 55 ± 13 years, with moderate hypercholesterolemia (low-density lipoprotein [LDL] 160-190 mg/dL), and never previously treated with statin therapy.8 Subjects were excluded for severe hepatic or renal disease. All received a daily bergamot-derived flavonoid extract, Bergavit (Bionap, Italy), containing 150 mg of flavonoids (16% neoeriocitrin, 47% neohesperidin, 36% naringin) for six months. Fasting serum (14 hours overnight), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein (HDL) were collected. LDL cholesterol was calculated (Friedewald formula) at baseline and after six months of Bergavit supplementation. Eleven lipoprotein subclasses also were measured using an FDA-approved diagnostic tool. Additionally, carotid arterial wall thickness was evaluated by color Doppler ultrasound by a single sonographer without access to prior scans.
After six months, there were no significant anthropometric parameter improvements, but TC and LDL decreased significantly. Plasma TC improved from baseline of 257 ± 15 to 223 ± 41 (P < 0.0001), a 12% change after six months of supplementation. TG improved from 162 ± 54 to 136 ± 79 (P = 0.0020), -17%. HDL improved (increased 8%) from 48 ± 10 to 52 ± 14 (P = 0.0007). LDL improved 20% from 176 ± 8 to 144 ± 37 (P < 0.0001.) Carotid intimal thickness was reduced from 1.2 ± 0.4 mm to 0.9 ± 0.1 mm (P < 0.0001), a 25% reduction in thickness.
The authors concluded that Bergavit may improve the cardiovascular risk profile of patients with moderately elevated hypercholesterolemia by altering the atherogenic lipid pattern, including the increase in large and decrease in small dense LDL particles. LDL reduction was more significant in those subjects with higher baseline plasma LDL-C levels. As this study was not randomized and did not include a placebo arm, conclusions are limited. However, strengths include the favorable tolerability of the bergamot extract and high-quality methodology used to collect the biochemical measurements and carotid intimal thickness. The authors declared no conflicting commercial or financial relationships.8
Mollace et al studied the effect of oral bergamot on lipids and blood glucose both in rats and humans.9 Bergamot was obtained by industrial pressing and squeezing of fruits collected from southern Italy. Standardized capsules were made according to the European community guidelines concerning dietary supplements. The capsules contained 500 mg of bergamot powder along with 50 mg ascorbic acid. The placebo tablets contained 500 mg maltodextrin supplemented with 50 mg ascorbic acid. The bergamot used contained 26-28% of five main flavonoids.
In the rat study, researchers divided the rats into four groups of 10 rats each. Group 1 was kept on a standard diet for 30 days. Group 2 received a hypercholesterolemic diet for 30 days. Groups 3 and 4 received the hypercholesterolemic diet for 30 days, but each rat was administered bergamot 10 and 20 mg/kg/rat daily. During the 30 days, each rat was weighed daily and 24-hour food consumption was recorded each day. Fecal samples were drawn each day as well. At the end of the 30 days, fasting labs were collected. All rats fed the hypercholesterolemic diet showed elevated TC, LDL, HDL, and TG compared to controls. The bergamot supplement produced significant reduction (P < 0.01) in TC, LDL, and TGs (close to a 30% reduction), and no significant difference was found in mean body weight or 24-hour food consumption between the groups receiving bergamot and the controls who were fed the hypercholesterolemic diet without bergamot. The lipid levels were still higher than controls that were not fed the same diet. The fecal output of total bile acids and neutral sterols was enhanced, suggesting the bergamot extract enhances the hepatobiliary turnover and cholesterol consumption. The supplement did not produce any evidence of toxicity in the animal models.
The human study used a randomized, double-blind, placebo-controlled design. Treatment with bergamot 500 mg and 1,000 mg daily (38% flavonoids) for 30 consecutive days in patients with isolated hypercholesterolemia (Group A), mixed hyperlipidemia (Group B), and metabolic syndrome (Group C) led to a strong reduction in TC and LDL, and a significant increase in HDL in the majority of participants. No significant changes were seen in the mean lipid levels in the maltodextrin placebo groups. In particular, the 59 metabolic syndrome participants (Group C) responded very well. In Group C participants receiving the high-dose bergamot, mean TC dropped from 278 mg/mL to 199 mg/mL, mean LDL from 188 mg/mL to 126 mg/mL, and mean TGs from 267 mg/mL to 158 mg/mL. These were all significant reductions (P < 0.001). In addition, the metabolic syndrome group showed a highly significant decrease in mean blood glucose. No change in blood glucose was seen for the placebo group. Mollace et al also recruited 32 patients with a history of statin toxicity who had stopped their statins for at least two months before starting a very high-dose 1,500 mg/day bergamot supplement.9 In this group, 30 of 32 patients responded with a 25% reduction in TC and 27.6% reduction in LDL after 30 days. The study noted no reappearance of statin side effects. For all groups in the study, no differences in liver function were seen, and no side effects were reported, other than mild gastric upset in 9% of patients on the 500 mg supplement and 16% of patients on the 1,000 mg supplement. No patients stopped the supplement because of these side effects.
Gliozzi et al used a placebo-controlled model to study 107 patients with both metabolic syndrome and non-alcoholic fatty liver disease (NAFLD).10 There was no mention of blinding for participants or researchers in the study design. The diagnosis of metabolic syndrome was based on having three of the five NCEP-ATP III criteria (abdominal obesity, triglycerides > 150, HDL < 40 for men or < 50 for women, BP > 135/> 85 mmHg, and fasting blood glucose > 110), and the concomitant NAFLD was diagnosed by ultrasound of all patients. Baseline demographic information and alcohol consumption were statistically similar for both the bergamot and placebo groups. The authors conducted face-to-face interviews and physical exams for each participant, although there was no comment on comparing medications taken between participants. Participants were excluded for any excessive alcohol use or history of viral or autoimmune liver disease. Fruits were collected in southern Italy, and bergamot juice was obtained by standard pressing. The study used a standardized 650 mg capsule with 50 mg ascorbic acid and a placebo of maltodextrin 1,000 mg and ascorbic acid 50 mg. The supplements all were made using good manufacturing practices. Fasting labs were collected on the first day and again after 120 days of treatment with bergamot 650 mg twice daily vs. placebo. All baseline tests showed consistency with metabolic syndrome and NAFLD diagnoses, with mean elevation in body mass index, blood glucose, TC, LDL, TG, and AST/ALT levels.
After 120 days of bergamot supplementation, participants showed a significant reduction (P < 0.05) in fasting glucose (118 mg/mL to 98 mg/mL), TC (245 mg/mL to 182 mg/mL), LDL (162 mg/mL to 101 mg/mL), TGs (232 mg/mL to 160 mg/mL), ALT (54 U/L to 36 U/L), and AST (52 U/L to 41 U/L). The participants also showed a significant increase (P < 0.05) in mean HDL (38 mg/mL to 49 mg/mL). The researchers also collected high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor (TNF) pre- and post-intervention levels, and found both the mean hs-CRP (1.2 mcg/dL to 0.94 mcg/dL) and TNF-alpha (14.4 pg/mL to 10.7 pg/mL) levels significantly decreased (P < 0.05). Moreover, the repeat ultrasound at 120 days showed a significant mean decrease in the hepatorenal index (2.8 to 1.5). These decreases suggest that the metabolic syndrome and NAFLD were accompanied by an inflammatory state and the bergamot supplementation acted to decrease this inflammation.
Conclusion and Future Directions
Given the prevalence of hypercholesterolemia, metabolic syndrome, and the associated morbidity and mortality with these conditions, it is increasingly important to find ways to treat these conditions. Diet, exercise, and other lifestyle modifications almost always are recommended first steps, but many patients need additional support in achieving their goals.
For hypercholesterolemia, the most common medications used are statins, but there is still a subset of patients who cannot tolerate these because of side effects or comorbid conditions.3 Studies from Toth et al8 and Mollace et al9 showed bergamot has significant benefit to cholesterol profiles, including decreased LDL and TC, as well as increased cardiac protective HDL. The study by Gliozzi et al showed increased HDL, decreased TC and LDL, as well as decreased inflammatory markers and liver function tests with bergamot supplementation.10 The main side effect reported in the studies was gastric upset, so patients should be warned about this if they decide to use bergamot.
The Toth et al study was in statin-naïve patients and excluded those with renal or hepatic dysfunction.8 Future studies could assess tolerance of the supplement in patients with renal or hepatic impairment. The Gliozzi et al study actually showed improvement of liver function tests and no major side effects.10 The Mollace et al study included a small subset of 32 patients previously exhibiting statin toxicity who then tolerated bergamot supplementation with good results.9 A larger study could be attempted in the future to further assess tolerance in those patients with prior statin intolerance. Another future study could compare bergamot with red yeast rice, as these both have utility in patients who have not tolerated statins in the past.
Recommendations
These early studies are promising. Bergamot may be an alternative for statin-intolerant patients, but more studies are needed before we can recommend it as first-line or even second-line. The overall tolerance of bergamot with only minimal gastric upset does make it reasonable to consider for statin-intolerant patients, although red yeast rice also is well tolerated and has been studied more extensively. Red yeast rice dosing is 1,200 mg twice daily with meals. Bergamot dosing is 500-650 mg twice daily.
REFERENCES
- World Health Organization. The top 10 causes of death. Available at: http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed June 1, 2017.
- Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci 2015;11:1-23.
- Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-2934.
- Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-742.
- Gattuso G, Barreca D, Gargiulli C, et al. Flaovoid composition of citrus juices. Molecules 2007;12:1641-1673.
- Lee MK, Moon SS, Lee SE, et al. Naringenin 7-O-cetyl ether as inhibitor of HMG-CoA reductase and modulator of plasma and hepatic lipids in high cholesterol-fed rats. Bioorg Med Chem 2003;11:393-398.
- Gonzalez-Gallego J, Garcia-Mediavilla MV, Sanches-Campos S, Tunon MJ. Fruit polyphenols, immunity and inflammation. Br J Nutr 2010;104(Suppl 3):S15-27.
- Toth PP, Patti AM, Nikolic D, et al. Bergamot reduces plasma lipids, atherogenic small dense LDL, and subclinical atherosclerosis in subjects with moderate hypercholesterolemia: A 6 months prospective study. Front Pharmacol 2016;6:299.
- Mollace V, Sacco I, Janda E, et al. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: From animal models to human studies. Fitoterapia 2011;82:309-316.
- Gliozzi M, Carresi C, Musolino V, et al. The effect of bergamot-derived polyphenolic fraction on LDL small dense particles and non alcoholic fatty liver disease in patients with metabolic syndrome. Adv Biol Chem 2014;4:129-137.
Although larger controlled studies are warranted, bergamot supplementation may be an alternative approach to improving cardiovascular risk in patients who are unable or unwilling to take pharmaceutical HMG-CoA reductase or PCSK9 inhibitors.
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