Reviewed: Usharani P, Fatima N, Muralidhar N. Effects of Phyllanthus emblica extract on endothelial dysfunction and biomarkers of oxidative stress in patients with type 2 diabetes mellitus: A randomized, double-blind, controlled study. Diabetes Metab Syndr Obes. 2013;6:275-284.

Diabetes mellitus is a major risk factor for cardiovascular disease (CVD): hyperglycemia can induce endothelial dysfunction, which is an early prognostic indicator of arteriosclerosis and CVD.¹ Endothelial dysfunction is characterized by decreased levels of bioavailable nitric oxide and increased levels of the inflammatory marker C-reactive protein (CRP).² Amla (Phyllanthus emblica syn. Emblica officinalis, Phyllanthaceae) fruit, also known as Indian gooseberry, is a cardiotonic East Indian traditional medicine that has been shown to have antioxidant, antihyperlipidemic, and anti-inflammatory effects in animal models. In a pilot clinical study from 2011, it had significant antihyperglycemic and antihyperlipidemic effects in patients with type 2 diabetes.³

These authors conducted a prospective, randomized, double-blind, placebo-controlled study to evaluate the effects of 250 mg amla twice daily, 500 mg amla twice daily, 10 mg/day atorvastatin (the cholesterol-lowering drug Lipitor^®), and placebo on endothelial function in patients with type 2 diabetes.

The study product was Capros^® (Natreon, Inc.; New Brunswick, NJ), a standardized aqueous amla extract containing no less than 60% low molecular weight bioactive hydrolyzable tannins (emblicanin A, emblicanin B, pedunculagin, and punigluconin) and no more than 4% gallic acid. The matching placebo capsules (also supplied by Natreon, Inc.) contained microcrystalline cellulose, lactose, and magnesium stearate. The researchers used 10 mg atorvastatin as a positive control in the same type of capsules used for the test products and placebo. The study was conducted in the Department of Clinical Pharmacology and Therapeutics at Nizam’s Institute of Medical Sciences in Hyderabad, India.

The authors recruited men and women between the ages of 30 and 68 years on stable antidiabetic treatment for eight weeks preceding the screening visit with a fasting plasma glucose of 110-126 mg/dL, glycosylated hemoglobin (HbA_1c) of 7-9%, and with endothelial function defined as a ≤ (less than or equal to) 6% change in the reflection index (RI; a measurement derived from digital volume pulse recording) after salbutamol challenge (an assessment of endothelial function that employs a beta2-adrenergic agonist drug). Patients with uncontrolled hyperglycemia or hypertension, cardiac arrhythmia, impaired hepatic or renal function, history of malignancy or stroke, any other serious disease, concomitant medication known to alter endothelial function, or those taking any other herbal supplement(s) were excluded from the study. Pregnant and lactating women were also excluded.

Eighty patients completed the study of the 88 initially screened. They were randomly assigned (20 in each group) to receive either one capsule of 250 mg amla twice daily, one capsule of 500 mg amla twice daily, 10 mg atorvastatin at bedtime and matching placebo in the morning daily, or placebo twice daily for 12 weeks.

Study visits occurred after four, eight, and 12 weeks of treatment. At each visit, a physical examination was conducted, vitals were recorded, cardiac output was measured, and blood samples were collected for assessment of hematology parameters, as well as hepatic and renal biochemistry. Patients also were queried about adverse effects, and compliance was assessed by capsule count.

Endothelial function was assessed at baseline and after 12 weeks of treatment by measuring RI using digital pulse volume before and 15 minutes after salbutamol inhalation. The primary efficacy measure was change in RI after 12 weeks compared with baseline. Secondary efficacy measures included changes in markers of oxidative stress (malondialdehyde, nitric oxide, and glutathione) and inflammation (CRP), lipid profiles, and HbA_1c levels (a marker of average plasma glucose over prolonged time). No significant baseline differences in demographic variables were noted among the treatment groups.

After 12 weeks, the RI was reduced significantly in the 250 mg amla, 500 mg amla, and atorvastatin groups compared with baseline values (P<0.001 for each). Compared with the placebo group, the mean absolute change for all three active treatments was statistically significant (P<0.001). Furthermore, 500 mg amla and atorvastatin significantly improved endothelial function compared with the 250 mg dose of amla.

The 250 mg amla, 500 mg amla, and atorvastatin groups experienced significantly reduced nitric oxide and malondialdehyde levels, and increased glutathione levels compared with baseline (P<0.001), suggesting improved antioxidant status. Also, in the three active treatment groups, CRP levels decreased significantly compared with baseline and placebo (P<0.001), indicating reduced inflammation. Lipid profiles improved in all three active treatment groups; serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides were significantly reduced and high-density lipoprotein cholesterol levels were increased. Average plasma glucose levels also decreased after 12 weeks in all three active groups as measured by HbA1c.

Further analysis showed that 500 mg amla and atorvastatin each had a better effect than 250 mg amla on all biomarkers. No significant changes were seen in laboratory safety parameters for any of the groups compared with baseline. The medications were well tolerated.

In conclusion, both doses of the proprietary amla extract and atorvastatin significantly improved endothelial function and decreased markers of oxidative stress and inflammation in patients with diabetes. The authors suggest that amla as an adjunct to current hyperlipidemia agents may provide improved protection against arteriosclerosis and CVD. Amla extract “may be a good therapeutic alternative to statins in diabetic patients with endothelial dysfunction because it has the beneficial effects of the statins but without the well known adverse effects of these agents,” wrote the study authors. Further studies are needed in larger numbers of patients to reinforce these findings.

—Shari Henson

References

1. Pandolfi A, De Filippis EA. Chronic hyperglicemia [sic] and nitric oxide bioavailability play a pivotal role in pro-atherogenic vascular modifications. Genes Nutr. 2007;2(2):195-208.
2. Tajiri Y, Mimura K, Umeda F. High-sensitivity C-reactive protein in Japanese patients with type 2 diabetes. Obes Res. 2005;13(10):1810-1816.
3. Akhtar MS, Ramzan A, Ali A, Ahmad M. Effect of amla fruit (Emblica officinalis Gaertn.) on blood glucose and lipid profile of normal subjects and type 2 diabetic patients. Int J Food Sci Nutr. 2011;62(6):609-616.