MD, PhD, MAE, FMedSci, FRSB, FRCP, FRCPEd.

antioxidants

Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS-Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral (MVM) versus placebo improved cognition in older women and men.

COSMOS-Mind, a large randomized two-by-two factorial 3-year trial, assessed cognition by telephone at baseline and annually. The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail-Making, Verbal Fluency, Number Span, and Digit Ordering. Using intention-to-treat, the primary endpoint was change in this composite with 3 years of cocoa extract use. The pre-specified secondary endpoint was change in the composite with 3 years of MVM supplementation. Treatment effects were also examined for executive function and memory composite scores, and in pre-specified subgroups at higher risk for cognitive decline.

A total of 2262 participants were enrolled (mean age = 73y; 60% women; 89% non-Hispanic White), and 92% completed the baseline and at least one annual assessment. Cocoa extract had no effect on global cognition (mean z-score = 0.03, 95% CI: -0.02 to 0.08; P = .28). Daily MVM supplementation, relative to placebo, resulted in a statistically significant benefit on global cognition (mean z = 0.07, 95% CI 0.02 to 0.12; P = .007), and this effect was most pronounced in participants with a history of cardiovascular disease (no history: 0.06, 95% CI 0.01 to 0.11; history: 0.14, 95% CI -0.02 to 0.31; interaction, nominal P = .01). Multivitamin-mineral benefits were also observed for memory and executive function. The cocoa extract by MVM group interaction was not significant for any of the cognitive composites.

The authors concluded that the Cocoa extract did not benefit cognition. However, COSMOS-Mind provides the first evidence from a large, long-term, pragmatic trial to support the potential efficacy of a MVM to improve cognition in older adults. Additional work is needed to confirm these findings in a more diverse cohort and to identify mechanisms to account for MVM effects.

This trial certainly has a few stunning features. For instance, its sample size was impressive and its follow-up period long. But it also has a few weak points. The study was conducted remotely via mail or telephone which means that compliance was impossible to control. Moreover, the outcome measures were subjective, and blinding was not checked. In addition, I fail to see a plausible mechanism of action. Most importantly, the generalizability of the results to the population at large seems questionable. It might make sense that older individuals many of whom might have low vitamin levels can profit from MVM. Whether this is also true for younger people who are well-nourished might be a different matter.

Even though most people do not think about it in this way, tea is a herbal remedy. We know that it is pleasant, but is it also effective?

This study explored the associations between tea drinking and the incident risk of type 2 diabetes mellitus(T2 DM). A dynamic prospective cohort study among a total of 27 841 diabetes-free permanent adult residents randomly selected from 2, 6, and 7 rural communities between 2006-2008, 2011-2012, and 2013-2014, respectively. Questionnaire survey, physical examination, and laboratory test were carried out among the participants. In 2018, the researchers conducted a follow-up through the electronic health records of residents. Cox regression models were applied to explore the association between tea drinking and the incident risk of T2 DM and estimate the hazard ratio(HR), and its 95%CI.

Among the 27 841 rural community residents in Deqing County, 10 726(39%) were tea drinkers, 8215 (77%) of which were green tea drinkers. A total of 883 new T2 DM incidents were identified until December 31, 2018, and the incidence density was 4.43 per 1000 person-years (PYs). The incidence density was 4.07/1000 PYs in those with tea drinking habits and 4.71/1000 PYs in those without tea drinking habits. The incidence density was 3.79/1000 PYs in those with green tea drinking habits. After controlling for sex, age, education, farming, smoking, alcohol consumption, dietary preference, body mass index, hypertension, impaired fasting glucose, and family history of diabetes, the risk of T2 DM among rural residents with tea drinking habits was 0.79 times higher than that among residents without tea drinking habits(HR=0.79, 95%CI 0.65-0.96), and the risk of T2 DM among residents with green tea drinking habits was 0.72 times higher than that among residents without tea drinking habits(HR=0.72, 95%CI 0.58-0.89). No significant associations were found between other kinds of tea and the risk of T2 DM, nor the amount of green tea-drinking.

The authors concluded that drinking green tea may reduce the risk of T2 DM among adult population in rural China.

Epidemiological studies of this nature resemble big fishing expeditions that can bring up all sorts of rubbish and – if lucky – also some fish. The question thus is whether this study identified an interesting association or just some odd rubbish.

A quick look into Medline seems to suggest great caution. Here are the conclusions from a few further case-control studies:

Thus the question of whether tea drinking might prevent diabetes remains open, in my view.

Yet, the paper might teach us two important lessons:

  1. Case-control studies must be taken with a pinch of salt.
  2. Correlation is not the same as causation.

This study aimed to evaluate the efficacy of Persian barley water in controlling the clinical outcomes of hospitalized COVID-19 patients. It was designed as a single-blind, add-on therapy, randomized controlled clinical trial and conducted in Shiraz, Iran, from January to March 2021. One hundred hospitalized COVID-19 patients with moderate disease severity were randomly allocated to receive routine treatment (per local protocols) with or without 250 ml of Persian barley water (PBW) daily for two weeks. Clinical outcomes and blood tests were recorded before and after the study period. Multivariable modeling was applied using Stata software for data analysis.

The length of hospital stay (LHS) was 4.5 days shorter in the intervention group than the control group regardless of history of cigarette smoking (95% confidence interval: -7.22, -1.79 days). Also, body temperature, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and creatinine significantly dropped in the intervention group compared to the control group. No adverse events related to PBW occurred.

The authors from the Department of Traditional Medicine, Shiraz University of Medical Sciences, Shiraz, Iran, concluded that this clinical trial demonstrated the efficacy of PBW in minimizing the LHS, fever, and levels of ESR, CRP, and creatinine among hospitalized COVID-19 patients with moderate disease severity. More robust trials can help find safe and effective herbal formulations as treatments for COVID-19.

I must admit, I did not know about PBW. The authors explain that PBW is manufactured from Hordeum vulgare via a specific procedure. According to recent studies, barley is rich in constituents such as selenium, tocotrienols, phytic acid, catechin, lutein, vitamin E, and vitamin C; these compounds are responsible for their antioxidant and anti-inflammatory properties. Barley grains also have immune-stimulating effects, antioxidant properties, protective effects on the liver and digestive systems, anti-cancer effects, and act to reduce uric acid levels.

But even if these effects would constitute a plausible mechanism for explaining the observed effects (which I do not think they do), the study itself is more than flimsy.

I do not understand why researchers investigating an important issue do not make sure that their study is as rigorous as possible.

  • Why not use an adequately large sample size?
  • Why not employ a placebo?
  • Why not double-blind?
  • Why not report the most important outcome, i.e. mortality?

As it stands, nobody will take this study seriously. Perhaps this is a good thing – but perhaps PBW does have positive effects (I know it’s a long shot) and, in this case, a poor-quality study would only prevent an effective therapy come to light.

Many older adults commonly take multivitamin-multimineral (MVM) supplements to promote health. Yet, evidence on the use of daily MVMs on invasive cancer is limited. 

The objective of this study was therefore to determine if a daily MVM decreases total invasive cancer among older adults. For this purpose,  a team of researchers performed a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of a daily MVM and cocoa extract for prevention of cancer and cardiovascular disease (CVD) among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y) free of major CVD and recently diagnosed cancer. The intervention phase was from June 2015 through December 2020. This article reports on the MVM intervention.

Participants were randomly assigned to daily MVM or placebo. The primary outcome was total invasive cancer, excluding nonmelanoma skin cancer. Secondary outcomes included major site-specific cancers, total CVD, all-cause mortality, and total cancer risk among those with a baseline history of cancer.

During a median follow-up of 3.6 y, invasive cancer occurred in 518 participants in the MVM group and 535 participants in the placebo group (HR: 0.97; 95% CI: 0.86, 1.09; P = 0.57). No significant effect was observed of a daily MVM on breast cancer (HR: 1.06; 95% CI: 0.79, 1.42) or colorectal cancer (HR: 1.30; 95% CI: 0.80, 2.12). The researchers observed a protective effect of a daily MVM on lung cancer (HR: 0.62; 95% CI: 0.42, 0.92). The composite CVD outcome occurred in 429 participants in the MVM group and 437 participants in the placebo group (HR: 0.98; 95% CI: 0.86, 1.12). MVM use did not significantly affect all-cause mortality (HR: 0.93; 95% CI: 0.81, 1.08). There were no safety concerns.

The authors concluded that a daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer among older men and women. Future studies are needed to determine the effects of MVMs on other aging-related outcomes among older adults.

This is an excellent and important study with clear findings. Nevertheless, the authors insist that several limitations should be considered. First, the COSMOS intervention was relatively short to detect a potential small-to-moderate effect on cancer outcomes given the long duration of time typically required for nutritional interventions to potentially reduce cancer risk. Second, the secondary and exploratory analyses should be interpreted with caution, especially given an overall lack of effect of an MVM on the primary outcome of total invasive cancer. Third, the authors successfully leveraged existing cohorts with mass mailings to expedite recruitment and randomization of 21,442 participants into COSMOS. However, generalizability may be limited, with modest diversity of 10% non-Whites and 2.6% Hispanics plus healthy volunteer bias for participants willing and eligible to enroll in a mail-based clinical trial.

The US Food and Drug Administration (FDA) state that dietary supplements can help people improve or maintain their overall health. But they may also come with health risks. Whether you’re a consumer of dietary supplements or it’s your job to inform and educate, it’s important to know the facts before deciding to take any dietary supplement.

Therefore, they launched the initiative, “Supplement Your Knowledge”. It aims to help inform health care professionals, consumers, and educators about dietary supplements.

“Dietary supplements can be valuable to your health but taking some supplements can also involve health risks,” Douglas Stearn, JD, deputy director for regulatory affairs in the FDA’s Center for Food Safety and Applied Nutrition, said in a statement. “These Supplement Your Knowledge resources will help provide consumers and health care professionals with facts to make informed decisions when determining if they want to use or recommend dietary supplements.”

In collaboration with the American Medical Association, publisher of JAMA, the FDA has developed a free continuing medical education program for physicians and other health care professionals about the regulation of dietary supplements, informing patients about their use, and reporting adverse events to the agency. The program includes 3 videos and accompanying educational materials. It is available on the FDA website and the AMA Ed Hub.

________________________

The objectives of the program are:
1. Define dietary supplements
2. Describe how dietary supplements are regulated
3. Describe how dietary supplements are labelled and the types of claims permitted
4. Review potential interactions of dietary supplements with other supplements, medications, and laboratory tests
5. Identify adverse events and how to report them to FDA

Even though some parts of the program are quite specific to the US, I think that the initiative is most laudable and an excellent resource for physicians, SCAM practitioners, consumers, and decision-makers to learn more about this important subject.

The US Food and Drug Administration created the Tainted Dietary Supplement Database in 2007 to identify dietary supplements adulterated with active pharmaceutical ingredients (APIs). This article compared API adulterations in dietary supplements from the 10-year time period of 2007 through 2016 to the most recent 5-year period of 2017 through 2021. Its findings are alarming:

  • From 2007 through 2021, 1068 unique products were found to be adulterated with APIs.
  • Sexual enhancement and weight-loss dietary supplements are the most common products adulterated with APIs.
  • Phosphodiesterase-5 inhibitors are commonly included in sexual enhancement dietary supplements.
  • A single product can include up to 5 APIs.
  • Sibutramine, a drug removed from the market due to cardiovascular adverse events, is the most included adulterant API in weight loss products.
  • Sibutramine analogues, phenolphthalein (which was removed from the US market because of cancer risk), and fluoxetine were also included.
  • Muscle-building dietary supplements were commonly adulterated before 2016, but since 2017 no additional adulterated products have been identified.

The authors concluded that the lack of disclosure of APIs in dietary supplements, circumventing the normal procedure with clinician oversight of prescription drug use, and the use of APIs that are banned by the Food and Drug Administration or used in combinations that were never studied are important health risks for consumers.

The problem of adulterated supplements is by no means new. A similar review published 4 years ago already warned that “active pharmaceuticals continue to be identified in dietary supplements, especially those marketed for sexual enhancement or weight loss, even after FDA warnings. The drug ingredients in these dietary supplements have the potential to cause serious adverse health effects owing to accidental misuse, overuse, or interaction with other medications, underlying health conditions, or other pharmaceuticals within the supplement.”

These papers relate to the US where supplement use is highly prevalent. The harm done by adulterated products is thus huge. If we focus on Chinese or Ayurvedic supplements, the problem might even be more serious. In 2002, my own review concluded that adulteration of Chinese herbal medicines with synthetic drugs is a potentially serious problem which needs to be addressed by adequate regulatory measures. Twenty years later, we seem to be still waiting for effective regulations that protect the consumer.

Progress in medicine, they say, is made funeral by funeral!

 

Due to polypharmacy combined with the rising popularity of so-called alternative medicines (SCAM), oncology patients are at particular risk of drug-drug interactions (DDI) or herb-drug interactions (HDI). Caution is therefore indicated.

The aims of this study were to assess DDI and HDI in outpatients taking oral anticancer drugs.

All prescribed and non-prescribed medications, including SCAM, were prospectively collected by hospital pharmacists during a structured interview with the patient. DDI and HDI were analyzed using four interaction software programs: Thériaque®, Drugs.com®, Hédrine, and Memorial Sloan Kettering Cancer Center (MSKCC) database. All detected interactions were characterized by severity, risk, and action mechanism. The need for pharmaceutical intervention to modify drug use was determined on a case-by-case basis.

294 patients were included, with a mean age of 67 years. The median number of chronic drugs per patient was 8 [1-29] and 55% of patients used at least one SCAM. At least 0ne interaction was found for 267 patients (90.8%): 263 (89.4%) with DDI, 68 (23.1%) with HDI, and 64 (21.7%) with both DDI and HDI. Only 13% of the DDI were found in Thériaque® and Drugs.com® databases, and 125 (2.5%) were reported with a similar level of risk on both databases. 104 HDI were identified with only 9.5% of the interactions found in both databases. 103 pharmaceutical interventions were performed, involving 61 patients (20.7%).

The authors concluded that potentially clinically relevant drug interactions were frequently identified in this study, showing that several databases and structured screening are required to detect more interactions and optimize medication safety.

This figure of potential HDIs is high – much higher than in most previous studies. A possible explanation could be that the study was carried out in France where the use of herbal remedies is considerable. As some HDIs can cause serious problems for patients, my advice is to think twice about using herbal remedies while taking prescription drugs. I think this advice is sound regardless of whether someone is suffering from cancer or any other condition.

If you have been following my blog for a while, you probably know the answer to this question. A recent article published in JAMA re-emphasizes it in an exemplary fashion:

According to National Health and Nutrition Examination Survey data, 52% of surveyed US adults reported using at least 1 dietary supplement in the prior 30 days and 31% reported using a multivitamin-mineral supplement. The most commonly cited reason for using supplements is for overall health and wellness and to fill nutrient gaps in the diet. Cardiovascular disease and cancer are the 2 leading causes of death and combined account for approximately half of all deaths in the US annually. Inflammation and oxidative stress have been shown to have a role in both cardiovascular disease and cancer, and dietary supplements may have anti-inflammatory and antioxidative effects.

Objective  To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a review of the evidence on the efficacy of supplementation with single nutrients, functionally related nutrient pairs, or multivitamins for reducing the risk of cardiovascular disease, cancer, and mortality in the general adult population, as well as the harms of supplementation.

Population  Community-dwelling, nonpregnant adults.

Evidence Assessment  The USPSTF concludes with moderate certainty that the harms of beta carotene supplementation outweigh the benefits for the prevention of cardiovascular disease or cancer. The USPSTF also concludes with moderate certainty that there is no net benefit of supplementation with vitamin E for the prevention of cardiovascular disease or cancer. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with multivitamins for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of supplementation with single or paired nutrients (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. Evidence is lacking and the balance of benefits and harms cannot be determined.

Recommendation  The USPSTF recommends against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer. (D recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamin supplements for the prevention of cardiovascular disease or cancer. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of single- or paired-nutrient supplements (other than beta carotene and vitamin E) for the prevention of cardiovascular disease or cancer. (I statement)

The report also elaborates on potential harms:

For many of the vitamins and nutrients reviewed, there was little evidence of serious harms. However, an important harm of increased lung cancer incidence was reported with the use of beta carotene by persons who smoke tobacco or have occupational exposure to asbestos.

Excessive doses of vitamin supplements can cause several known adverse effects; for example, moderate doses of vitamin A supplements may reduce bone mineral density, and high doses may be hepatotoxic or teratogenic. Vitamin D has potential harms, such as a risk of hypercalcemia and kidney stones, when given at high doses. The potential for harm from other supplements at high doses should be carefully considered.

There is nothing new here, of course. I (and others) have been trying to get these points across for many years. But it is nevertheless most gratifying to see the message repeated by a top journal such as JAMA. I hope JAMA is more successful than I was in changing the behavior of the often all too gullible public!

In the UK, a new post-Brexit regulatory framework is being proposed for food supplements by the government. The nutraceutical sector is estimated to be worth £275bn globally and £4bn in the UK.  A new report claims that “science is starting to point the way to a new sector of nutritional products with increasingly explicable and/or verifiable medicinal benefits, which needs to be reflected in our regulatory framework.” Tory MP George Freeman, one of the authors of the report, was quoted saying:

“We are living through an extraordinary period of technological change – not just in life science but in host of sectors: from AI to robotics to agri-tech, nutraceuticals, nanotechnology, synthetic biology, biofuels, satellites and fusion energy. The UK is indeed a ‘science superpower’. But we have traditionally been woeful at commercialising here in the UK. There are many reasons. But, in recent years, the EU’s increasingly slow, bureaucratic and ‘precautionary’ approach – copied in Whitehall – has made the EU and the UK an increasingly poor place to commercialise new technology.”

If a product like a food or a herbal remedy makes ‘medicinal’ claims, it is currently regulated by the MHRA. If a product only makes general ‘health’ claims, it is regulated by the Department of Health and Social Care in England, by the FSA in Wales and Northern Ireland, and by Food Standards Scotland in Scotland. This ‘patchwork of regulators’ is bound to change as it is deemed to create additional costs and uncertainty for businesses who would like to see the relevant functions brought together in a central regulatory body and a clearer UK landscape.

In response to the task force’s report, PM Boris Johnson stated that bold and ambitious ideas such as these are needed to encourage growth and innovation:

“The Government, through our Better Regulation Committee, is already hard at work on reform of the UK’s regulatory framework. Your bold proposals provide a valuable template for this, illustrating the sheer level of ambitious thinking needed to usher in a new golden age of growth and innovation right across the UK. So we will give your report the detailed consideration it deserves, consult widely across industry and civil society, and publish a response as soon as is practicable.”

Am I the only one who feels more than a little uneasy about all this? I honestly do not see much new science that, according to the report, points to ‘verifiable medicinal benefits’ of food supplements or nutraceuticals. What the report does however point to, I fear, is that the UK government is about to deregulate quackery with a view to making some entrepreneurs wealthy snake oil salesmen at the cost of public health and wealth.

I hope I am mistaken.

Due to polypharmacy and the rising popularity of so-called alternative medicines (SCAM), oncology patients are particularly at risk of drug-drug interactions (DDI) or herb-drug interactions (HDI). The aims of this study were to assess DDI and HDI in outpatients taking oral anticancer drugs.

All prescribed and non-prescribed medications, including SCAMs, were prospectively collected by hospital pharmacists during a structured interview with the patient. DDI and HDI were analyzed using four interaction software programs: Thériaque®, Drugs.com®, Hédrine, and Memorial Sloan Kettering Cancer Center (MSKCC) database. All detected interactions were characterized by severity, risk, and action mechanism. The need for pharmaceutical intervention to modify drug use was determined on a case-by-case basis.

A total of 294 patients were included, with a mean age of 67 years [55-79]. The median number of chronic drugs per patient was 8 [1-29] and 55% of patients used at least one SCAM. At least 1 interaction was found for 267 patients (90.8%): 263 (89.4%) with DDI, 68 (23.1%) with HDI, and 64 (21.7%) with both DDI and HDI. Only 13% of the DDI were found in Thériaque® and Drugs.com® databases, and 125 (2.5%) were reported with a similar level of risk on both databases. 104 HDI were identified with only 9.5% of the interactions found in both databases. 103 pharmaceutical interventions were performed, involving 61 patients (20.7%).

The authors concluded that potentially clinically relevant drug interactions were frequently identified in this study, showing that several databases and structured screening are required to detect more interactions and optimize medication safety.

These data imply that DDIs are more frequent than HDIs. This does, however, not tell us which are more important. One crucial difference between DDIs and HDIs is that the former are usually known to the oncology team who should thus be able to prevent them or deal with them appropriately; in contrast, HDIs are often not known to the oncology team because many patients fail to disclose the fact that they take herbal remedies. Some forget, some do not think of herbals as medicine, others may be worried about their physician’s reaction.

It follows that firstly, conventional healthcare practitioners should always ask about the usage of herbal remedies, and secondly, they need to be informed about which herbal remedy might interact with which drug. The first can easily be implemented into routine history-taking; the second is more problematic, not least because our knowledge about HDIs is still woefully incomplete. In view of this, it might often be wise to tell patients to stop taking herbal remedies while they are on prescription drugs.

Subscribe to new posts

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

Recent Comments

Note that comments can be edited for up to five minutes after they are first submitted but you must tick the box: “Save my name, email, and website in this browser for the next time I comment.”

The most recent comments from all posts can be seen here.

Archives
Categories