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Healthcare Reform > Questionable opinion on Saroglitazar, Hydroxychloroquine and Berberine.

After reading this article I am not sure about all three drugs -Saroglitazar, Hydroxychloroquine and Berberine.

The marketing of unproven drugs for diabetes and dyslipidaemia in India

(Atul Luthra, Anoop Misra of Fortis C-DOC Center of Excellence for Diabetes.)

India has about one sixth of the worldwide population of patients with diabetes. In 2013, the value of the therapeutics market for type 2 diabetes in Asia-Pacific countries was estimated to be US$6·5 billion, and is expected to grow at a compound annual growth rate of 7·1% between 2013 and 2020 to $10·5 billion.1 This rapid growth is due to the anticipated approval and introduction of new products such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose transporter 2 inhibitors,and the increasing prevalence of diabetes in the Asia-Pacifi c region, especially in India and China.1 Manufacture and sale of oral antidiabetic drugs on the Indian subcontinent is therefore a lucrative business opportunity for the pharmaceutical industry.

The generic pharmaceutical market, a distinctive feature of the Indian drug industry, is among the largest in the world. Notably, in international guidelines for the management of diabetes (most popularly those of the American Diabetes Association and European Association for the Study of Diabetes), consensus only extends as far as lifestyle measures and metformin, leaving substantial scope for national variation. In India, where regulation and monitoring of the pharmaceutical industry is fairly weak, some drugs are being aggressively marketed and promoted, despite less than adequate evidence for their effi cacy and safety. For example, promotion of drugs in the media and at medical conferences is often laudatory and based on scant scientifi c facts.2 In this Comment, we illustrate this issue using three case studies (appendix).

Saroglitazar (marketed as Lipaglyn; Zydus Cadila, Ahmedabad, India), launched in India in September, 2013, is a dual peroxisome proliferator-activated receptor α (PPARα) and PPARγ agonist. The premise is that it might have a favourable eff ect on both lipid (PPARα agonism) and glycaemic (PPARγ agonism) variables in patients with type 2 diabetes. Overall, the manufactures have not addressed safety issues adequately in human trials. Importantly, pioglitazone (a PPARγ agonist used to treat diabetes) can lead to oedema and weight gain, and fenofi brate (a PPARα agonist used to treat dyslipidaemia) might cause myositis and hepatic dysfunction.

Incidentally, phase 3 trials of previous dual PPAR agonist, muraglitazar, were completed a decade ago. However, in May, 2006, Bristol-Myers Squibb discontinued development of the drug because of an increased incidence of oedema, heart failure, myocardial infarction, and all-cause mortality compared with controls, identified from an analysis of data from randomised trials.3 Absence of defi nitive data for myocardial infarction and all-cause mortality in patients treated with saroglitazar—issues that led to the discontinuation of muraglitazar in 2006—are of major concern. Additionally, the rationale for combining two PPAR agonists in one tablet has been seriously questioned. Of further concern, a link between PPARγ and dual PPAR agonist treatment and increased incidence of subcutaneous liposarcomas, fibrosarcomas, and hemangiosarcomas has been shown in rodent studies.4

Little evidence exists for the effi cacy and safety of saroglitazar. Only two short-term studies (12 or 24 weeks) have been done, with fewer than 500 patients in total in two randomised controlled trials.5,6 Both studies were funded by the pharmaceutical company marketing the drugs, and in one study,7 the lead author was an employee of the company. Overall, clinical data for saroglitazar are clearly inadequate for it to be used with confi dence.

Further efficacy and safety data are needed, especially for cardiovascular safety, all-cause mortality, and carcinogenicity, and marketing strategies that override evidence-based medicine should be strongly discouraged. Our second example is berberine, an isoquinoline derivative alkaloid isolated from the dried rhizome of plant Coptis chinensis (Chinese goldthread), which has been used in traditional Chinese medicine for treatment of bacterial diarrhoea. The hypoglycaemic effect of berberine was first reported in 1988, and it has since been used as an antidiabetic agent by physicians in China. 14 randomised controlled trials of berberine for type 2 diabetes were reported between 2007 and 2011 (three published in English, 11 in Chinese). All but one of these 14 studies were single-centre trials, and some included several glaring inaccuracies. In a systematic review7 of existing evidence, berberine was shown to have modest benefi cial eff ects on blood glucose and triglyceride levels. Its effi cacy was similar to that of conventional antidiabetic drugs in studies in which the control group was treated with sulfonylurea or metformin.8,9 A meta-analysis could not be done because of substantial heterogeneity between the trials. Limitations of these studies have been small sample size, inadequate allocation concealment, and short follow-up. The type of controls, dose of berberine, and duration of intervention differed substantially. Moreover, since all trials included only Chinese participants, whether results are applicable to other ethnic groups is uncertain. Importantly, no trial from India has been reported. Berberine has not been officially introduced as an antidiabetic drug in India; however, it is available and being actively promoted for this use among physicians and on the internet.

Our third example is hydroxychloroquine, which is normally used for treatment of rheumatoid arthritis and other connective tissue disorders. Use of this drug is associated with decreased risk of incident diabetes10 and improved glycaemic control in patients with rheumatoid arthritis.11 In the only randomised, double-blind study (n=267; duration 24 weeks), which was done in India, the effi cacy of hydroxychloroquine was similar to that of pioglitazone in patients with uncontrolled blood sugar who were also taking metformin plus glimepiride or gliclazide.11 The lead author was an employee of the pharmaceutical company (Ipca Laboratories, Mumbai, India) that produces the drug and funded the study. Hydroxychloroquine was approved in India as an adjunct to lifestyle management and sulphonylureas or metformin in patients with diabetes on Jan 15, 2015.

The available data are entirely inadequate to show the efficacy and safety of these three drugs, which are now being aggressively marketed by pharmaceutical companies in India. Studies have mostly been funded by the pharmaceutical companies marketing these drugs and are likely to be biased. Rigorous effi cacy and safety evaluation are important so that these drugs do not lead to harm to patients, since adverse effect profiles in patients with diabetes have been inadequately studied.

Clearly, well-designed trials not funded by the pharmaceutical companies, including large numbers of patients and for a period of 1–2 years, should be done in diff erent categories of patients (elderly people, those at high risk for cardiovascular disease and renal dysfunction, etc) to properly assess these and other new drugs for diabetes in India, following ethical and scientifi c norms set by the US Food and Drug Administration. The pharmaceutical industry in India and other developing countries should face the same stringent regulation as elsewhere in the world, rather than continuing to allow patient safety to be put at risk by unproven drug treatments.
Sep 22 | Registered CommenterThamim D

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