The anti-Diabetic AYUSH drugs BGR-34 and IME-9

The Ministry of AYUSH has helped develop (in collaboration with CSIR and CCRAS) [1] two Ayurvedic anti-diabetic drugs namely BGR-34 [2] and AYUSH-82 (sold as IME9) [3].

BGR-34 is being manufactured by a private enterprise called Aimil Pharmaceuticals which was awarded [4] the AYUSH brand of the year in 2016 by the Union Minister of state for Agriculture Purushottam Rupala. News channels such as News24 [5] and Zee 24 [6] aired exclusive reports along with the speech by Mr [Narendra] Modi on DD News [7] to promote its benefits and cost-effectiveness that gave an impression of it being a miraculous drug.

The central council for research in Ayurvedic sciences (CCRAS), an autonomous body of the Ministry of AYUSH promoted a second drug for diabetes called AYUSH-82 (sold as IME9).

Claim

IME9 claims to be an effective ayurvedic drug for diabetes, without any side effects, and have been developed after double blind clinical human trial studies of more than 800 patients.

Developed by India’s Council of Scientific and Industrial Research (CSIR), anti-diabetic herbal composition for Type-2 diabetes mellitus (NBRMAP-DB), which is sold under the trade name BGR-34, has been claimed to be DPP-4 inhibitor – a class of drugs used to lower blood sugar in adults with Type-2 diabetes.

“BGR-34 is a natural DPP-4 (dipeptidyl peptidase 4) inhibitor with no side effects. It is the most cost-effective Ayurvedic medicine for diabetes available at Rs 5 per tablet for patients,” said KK Sharma, Managing Director, AIMIL pharmaceuticals. [4]

Senior principal scientist of NBRI, a laboratory of CSIR, Dr AKS Rawat said that “BGR34 has been examined on animals and a scientific study has identified it safe and effective, with clinical studies demonstrating only 67% success.” [8]

Fact-check

Claim of “scientifically proven”: When searching for human clinical trials or preclinical animal models, no scientific data for the drugs named NBRMAP-DB (BGR-34) or AYUSH-82 (IME9) were found in peer reviewed journals across Google Scholar and PUBMED database. A search for patent application at the National Botanical Research Institute (NBRI) [9] and the CCRAS website [10] yielded no results for BGR-34 and AYUSH-82 respectively.

One clinical trial [11] was found registered to CTRI (Clinical Trials Registry – India) for BGR-34 in November 2016 by Dr BP Gupta of Aggarwal Dharmath Hospital Society, New Delhi which showed no data of any experiments conducted but stated that the primary outcome of this trial “shows promising results” in a brief concluding summary.

A review article [12] was found, without any research data, referring to IME9 in Researchgate (a social media platform for scientists) by Dr B Negi and contained no details about the journal or the date of publication.

Claim of “lowest cost”: BGR34 is promoted as a cheaper drug with a price point of Rs 5 tablet with the recommended dosage of two tablets twice a day with meals. That makes it 4 tablets a day and amounts to Rs 20 a day or Rs 600 a month. Whereas a 50-year-old widely prescribed drug Metformin is available at the starting price [13] of Rs 0.75 per 500 mg tablet from (Aristo) with the recommended dose between 500-2500 mg per day that can cost anywhere from Rs 22.50 and Rs 112.50 a month.

Claim of “no side effects”: IME9 has also been associated with many consumer complaints [14]. Contrary to the popular belief that herbal medicines do not produce side effects, some of these adverse reactions due to IME9 included constipation, blood discharge in stool, and in contrast to the claim of hypoglycaemia, increased blood sugar levels an effect that can be extremely dangerous for a diabetic patient.

Another patient also reported [15] the same increase in blood sugar as a result of IME9 treatments for just 15-day period where her fasting blood glucose increased from 324 mg/dl to 460 mg/dl (normal range 70-110).

Expert Advice

Ayurvedic practitioner Bhushan Patwardhan, Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Pune rejected [16] the claims of these drugs by questioning the credibility of drug development process at AYUSH which published his review in the Journal of Ayurveda and Integrative Medicine in 2016. Endocrinologist Dr Om Lakhani, MD, a Consultant Endocrinologist at Zydus Hospital and MD Internal Medicine (Gold Medalist), DNB (Endocrinology), he also refuted the “miraculous” claims of both of these anti-diabetic medications. He also commented on how the scientific basis for these medications is lacking and suggested it may be against the law to promote medicines and “miracle cures” on TV, Radio or newspaper according to the “Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954” in India. Furthermore, in 2008, Saper and colleagues from Boston University tested and reported [17] mercury, and arsenic have been detected in a substantial proportion of Indian-manufactured traditional Ayurvedic medicines. Metals may be present due to the practice of rasa shastra (combining herbs with metals, minerals, and gems high levels of lead, mercury and arsenic in 1/5th of US and Indian manufactured medicines sold on the internet by testing a randomised selection of Ayurvedic drugs across 25 different websites. This research indicates that a large proportion of locally manufactured drugs can be contaminated which emphasises a greater need for rigorous testing.

Conclusion

Based on the current scientific data, expert opinions from the field and consumer complaints, there is limited scientific evidence for the efficacy of BGR-34 and IME9 in the management of type-2 diabetes.

We may not be able to conclude that the given side effects occurred as a result of BGR34 or IME9, and not due to a random event due to the absence of proper clinical trials. However, heavy metals detected by randomised testing of Ayurvedic drugs question the safety of these drugs (expert advice #3). A rigorous double-blind placebo RCT (randomised control trial), an essential part to the drug development process, would provide more information about the efficacy, safety and toxicity of such drugs.

Thus, the lack of scientific data makes it impossible to validate the claims made vis-a-vis BGR34 or IME9 for diabetes and thus, raises questions regarding the integrity of promotions of these drugs...

The Anti-malarial drug AYUSH-64

Malaria continues to be one of India’s leading public health problems. India is among the top 15 countries that accounted for 80% of global malaria deaths in 2016. The CCRAS has developed an Ayurvedic formulation, AYUSH-64, that claims to treat malaria without side effects. The NRDC (National Research Development Corporation) had signed [18] an agreement with Dabur to market this drug in 2014.

Claim

A Facebook post of Ministry of AYUSH claimed [19] that CCRAS has developed a drug called AYUSH-64 to counter the developing drug resistance to malaria parasite and the widespread nature of the disease in India. It is claimed to be a polyherbal, non-toxic, anti-malarial drug that has been developed through extensive pharmacological, toxicological and clinical studies.

CCRAS claims to have conducted [20] several uncontrolled and controlled field trials in collaboration with the Malaria Epidemic Control Programme in the 1980s and 1995 for testing AYUSH-64. They report to have treated 3,600 and 10,000 P.vivax cases with this drug at Rajasthan and Assam.

Fact-check

Claim of efficacy: Study 1 was conducted [21] by Sharma et al (1981) that concluded with the highest efficacy (80% response) of AYUSH-64 in 55 cases of malaria.

However, there were several major inadequacies in their study:

Lack of controls and standards: The treatment response was not compared with any standard anti-malarial drug or a placebo drug. There was no mention of whether it was randomised or blinded, which makes us believe that it was neither.

Effect studied for a short duration: The drug’s response was followed up for only three, six or nine days. Additionally, the patients who responded after three or six days were never followed up later. Since relapse is common in malaria, it is possible that some patients may have shown resurgence of the infection after initial clearance. However, such cases would have been misinterpreted here as “cured”.

Unaccounted parasite counts: The parasite counts were not measured and accounted for analysis. Hence, there could be highly variable initial parasite counts among the patients, which could have directly affected their response.

Longer response time in mixed infections: Many of the patients with mixed infections of the two strains (P.vivax and P.falciparum) showed a much longer response time of up to nine days with the AYUSH-64 drug. This study does not meet the current standards of clinical trials on drugs. Additionally, as the susceptibility of the parasite keeps changing, this study is outdated and is irrelevant as a proof of efficacy.

Study 2: The current director of NIMR (National Institute of Malaria Research), Dr Neena Valecha, researched and published [22] her findings on AYUSH-64 in a peer-reviewed journal, Current Science in 2000.

Contradictory to the CCRAS study, in a more structured and comparative study, Valecha demonstrated that AYUSH-64 was not a promising primary anti-malarial drug. In this phase II randomised controlled trial, the patients were followed up for 28 days. The cure rate with AYUSH-64 was found to be less that 50% as compared to 100% with the standard drug. Considering poor efficacy of the drug and risk of complications, the authors had even suggested against its testing for the more severe P.falciparum species. The National Clinical Trials Registry of India (established in 2007) also yielded no results for AYUSH-64, implying that no recent trial has been initiated or conducted for the drug.

Conclusion

AYUSH-64, developed by CCRAS, is going to be marketed by Dabur India Ltd as an effective anti-malarial drug. However, there are limited scientific studies which have tested the efficacy of the drug. The existing studies have major limitations like lack of controls, inadequate follow up time, low sample size and lack of normalisation of baseline parasite levels, that had led to lack of credibility in the drug.

Moreover, the existing studies are published by CCRAS in their self-owned low-impact journals, further questioning their credibility. In contradiction, the independent study published in a reputed scientific journal, opposes the evidence of efficacy proposed by the CCRAS. Also, malaria is commonly caused by two different parasite species, but this drug’s response has been studied mainly with one species (P.vivax).

Consuming such medicines with very low and limited efficacy would not only be ineffective in large populations but further burden the public health system. The disease, if not completely cured, can show increased relapse, resistance and continued transmission of the parasite. Further, the malaria eradication programme in India may get stalled if such medicines are brought into market under a popular brand like Dabur.

The above article on AYUSH-64 was produced in collaboration with D Shivani Mittal a geneticist who researches hypoxia-mediated molecular regulation in cancer.

Corrections and clarifications: The headline of this article has been changed to reflect the fact that the licences and approval of Ayurvedic formulations are not granted by the Ministry of Ayush but by the licensing authorities appointed by state governments.

India Misinformed: The True Story

Excerpted with permission from India Misinformed: The True Story, Pratik Sinha, Dr Sumaiya Shaikh, Arjun Sidharth, HarperCollins India.

Sources



1. CSIR India. CSIR-NBRI Introduction BGR-34 Anti Diabetic Medicine – YouTube. (2017).

2. AIMIL pharmaceuticals. Buy BGR-34 Tablet, BGR-34 Ayurvedic Diabetes Medicine Online India – AIMIL. https://www.bgr-34.life Available at: https://www.bgr-34.life/products/natural-treatments- of-diabetes-bgr34. (Accessed: 4th March 2019)

3. PIB. Anti-Diabetic Drug ‘Ayush-82’ to be commercialised. Government of India Ministry of Science & Technology (2016).

4. AIMIL Pharmaceuticals. AIMIL Pharmaceuticals Wins AYUSH Brand of the Year – Aimil Pharmaceuticals. http://www. aimilpharmaceuticals.com (2016). Available at: http://www. aimilpharmaceuticals.com/aimil-pharmaceuticals-wins-ayush- brand-of-the-year/. (Accessed: 4th March 2019)

5. News24. Scientifically validated Rs 5 anti-diabetes herbal drug launched by CSIR – YouTube. (2015).

6. ZEE 24 TAAS. Pune | Ayurvedic Medicine | BGR 34 | For Diabetics Patient – YouTube. (2016).

7. DDNews. PM Narendra Modi Ji awarded BGR-34 for CSIR Technological Awards 2016 – YouTube. (2016).

8. CRS. BGR-34: Herbal Anti- Diabetes Drug Launched by CSIR. (2015).

9. CSIR. National Botanical Research Institute. Available at: http:// www.nbri.res.in/ (Accessed: 4th March 2019)

10. CCRAS. Central Council for Research in Ayurvedic Sciences, Ministry of AYUSH, Government of India |. Available at: http:// www.ccras.nic.in/ (Accessed: 4th March 2019)

11. BP Gupta. A clinical study of BGR 34, in patients with type 2 diabetes mellitus. Scientific Title of Study Controlled clinical study of an Ayurvedic anti diabetic formulation (BGR-34) for its efficacy and safety in patients with type 2 Diabetes mellitus. (2017).

12. Negi, B. From ancient medical knowledge to the modern drug development in India. (2016).

13. Medline India – metformin. Available at: http://www.medlineindia. com/endocrine/metformin.htm. (Accessed: 4th March 2019)

14. IME 9 Complaints. https://www.complaintboard.in (2018). Available at: https://www.complaintboard.in/complaints-reviews/ ime-9-l529967.html. (Accessed: 4th March 2019)

15. Chagala Tripathy. [Review] IME9 Ayurvedic Medicine Is a Fraud Medicine by Kudos – OxyMos. Oxymos (2017). Available at: http:// oxymos.blogspot.com/2016/08/review-ime9-ayurvedic-medicine- is-fraud.html. (Accessed: 4th March 2019)

16. Patwardhan, B. Ayurvedic drugs in case: Claims, evidence, regulations and ethics. J. Ayurveda Integr. Med. 7, 135–137 (2016).

17. Saper, RB. et al. Lead, Mercury, and Arsenic in US- and Indian- Manufactured Ayurvedic Medicines Sold via the Internet. JAMA 300, 915 (2008)

18. Government of India & Ministry of Science & Technology. Agreement for Commercialisation of an Ayurvedic Formulation for Treatment of Malaria and an Ayurvedic Formulation for Treatment of Diabetes. PIB (2016).

19. The ministry of AYUSH. CCRAS AYUSH64 – Facebook post. (2018). Available at: https://www.facebook.com/moayush/photos/ a.1960540694171182/2676261769265734/?type=3&theater. (Accessed: 4th March 2019)

20. CCRAS. Malaria Epidemic Control Programme. (2014).

21. KD Sharma, ML Kapoor, Miss SP Vaidya, PKS A Clinical Trial of ‘Ayush – 64’ (A coded Anti-malarial Medicine) in cases of Malaria. J. Res. Ayurveda Siddha 2, 309–326 (1981).

22. Valecha, N et al. Comparative efficacy of Ayush-64 vs chloroquine in vivax malaria. Curr. Sci. 78, 1120–1122 (2000).

Excerpted with permission from India Misinformed: The True Story, Pratik Sinha, Dr Sumaiya Shaikh, Arjun Sidharth, HarperCollins India.