“Vitamin B tablets could slow and even halt the devastating march of Alzheimer’s disease,” The Daily Telegraph reported. According to the newspaper, large daily doses of vitamin B can halve the rate of brain shrinkage, a process that can precede Alzheimer’s disease and dementia.

This story is based on a well-conducted two-year trial, which compared vitamin B pills with inactive placebo pills in 271 elderly people with mild memory problems. The study found that those given vitamin B experienced brain shrinkage (atrophy) 30% slower than those given inactive tablets. However, slower brain shrinkage may not necessarily lead to any improvement in symptoms.

This research does not show that vitamin B can prevent Alzheimer’s disease or dementia because there is no evidence to confirm that slower brain shrinkage will lead to benefits for people with early dementia symptoms. Nevertheless, these results are promising and clearly warrant more research.

Where did the story come from?

The study was carried out by researchers from the University of Oxford, the Oxford Radcliffe Hospitals NHS Trust and the University of Oslo in Norway.

The study received funding from a number of sources, including the Charles Wolfson Charitable Trust, the Medical Research Council, the Alzheimer’s Research Trust and the National Institute for Health Research. It was published in PLoS One, the peer-reviewed journal of the Public Library of Science.

Newspapers generally covered the research in a balanced way, although the headlines are overly optimistic in proclaiming that vitamin B will delay or beat Alzheimer’s disease. A diagnosis of Alzheimer’s is based on specific, characteristic clinical features and the exclusion of other causes of cognitive impairment. However, this research only assessed an outcome of brain shrinkage, which is not necessarily the same thing. The functional effects of reducing brain shrinkage were not investigated and it is an extrapolation to conclude that B vitamins improved cognitive health or protected against Alzheimer’s disease.

What kind of research was this?

Brain atrophy, which describes the loss of neurones and their connections, can be caused by a number of diseases. Some degree of atrophy and subsequent brain shrinkage is common with old age, even in people who are cognitively healthy. However, this brain shrinkage is accelerated in people with mild cognitive impairment and even faster in those who ultimately progress from mild cognitive impairment to Alzheimer’s disease. A range of factors has been implicated in affecting the rate of brain atrophy, one of which is high levels of an amino acid in the blood called homocysteine (tHcy). Studies have shown that raised levels of tHcy increase the risk of Alzheimer’s disease.

In this randomised controlled trial, the researchers investigated the role of vitamin B in regulating levels of tHcy. They specifically wanted to test whether lowering tHcy through giving high doses of vitamin B for two years could reduce the rate of brain atrophy in people with pre-existing mild cognitive impairment.

What did the research involve?

Volunteers aged 70 years and over with concerns about their memory were recruited in the Oxford area, through radio and newspaper advertisements, between April 2004 and November 2006. It was specified that volunteers should have a diagnosis of mild cognitive impairment, defined using specific  criteria. These included a concern about memory that did not interfere with activities of daily living and pre-specified scores on some cognitive scales assessing word recall and fluency. The study excluded people with a diagnosis of dementia, who were taking anti-dementia drugs or who had active cancer. People taking folic acid and vitamin B6 or B12 above certain doses were also excluded.

Every six months, the volunteers were randomly assigned to receive either high-dose oral vitamin B tablets (0.8 mg folic acid, 0.5 mg vitamin B12 and 20 mg vitamin B6) or placebo pills during the two-year period. The participants, their partners and all staff directly involved in the study were unaware which pills were being received. The ‘double blind’ nature of the study was important as it eliminated potential biases associated with the patients’ or researchers’ knowledge of which treatment was being received. MRI scans were performed at the start of the study and again after two years. The researchers used these to calculate the rate of brain atrophy each year.

A total of 271 people were randomly assigned a treatment, although five did not start the study. A similar proportion from each treatment group dropped out along the course of the study. The researchers measured adherence to the study treatments by counting returned tablets. For the main analysis of brain shrinkage, the researchers used data on 168 people (85 receiving active treatment and 83 receiving placebo) who had completed an MRI at both the start and a follow-up. The analyses took into account a variety of factors that may be linked to brain atrophy or use of vitamin B, which the researchers had tested and found to be important. These factors were age, blood pressure, initial brain volume and concentration of tHcy at the start of the study.

What were the basic results?

Treatment with vitamin B tablets had notable effects on the levels of tHcy in the blood, reducing it by 22.5%. Levels of tHcy increased by 7.7% in the placebo group. Overall, treatment with B vitamins for a period of 24 months led to a reduction in the rate of brain atrophy. After the age of the participants was taken into account, the rate of shrinkage in people receiving the vitamins was 30% less than in the placebo group (0.76% shrinkage and 1.08% shrinkage respectively). The effect was greater in people who were more compliant with taking their medication and in those who started with the highest levels of tHcy. The researchers also found that, overall, the safety of vitamins was good with no adverse events.

How did the researchers interpret the results?

The researchers concluded that they have shown that a “simple and safe treatment” can slow down the accelerated rate of brain atrophy in people with mild cognitive impairment.

Conclusion

This is an important but early study in establishing the effects of vitamin B on the stages of brain atrophy that precede Alzheimer’s disease. It assessed the effects of the vitamin on the rate of brain shrinkage, a process that has been linked to old age, mild cognitive impairment and Alzheimer’s disease in other studies. Although other studies have found that the rate of brain atrophy is linked to cognitive decline, this particular study did not assess whether the participants’ brain changes translated into changes of cognitive ability or memory.

This was a well-conducted, albeit small, study. It was a randomised controlled trial, which is the most appropriate way to assess the effects of a new treatment. No study is perfect, though, and the researchers highlighted some shortcomings:

• The treatment was a combination of three B vitamins, so the researchers cannot determine whether these have different effects individually.
• The study was not set up to assess the effects of treatment on cognition, but only on the rate of change in brain measurements.

This study will pave the way for future research into the use of vitamin B to prevent Alzheimer’s disease. Based on the evidence gathered so far, it is too early to claim that vitamin B can prevent clinical disease, but these results are promising. More research will undoubtedly follow.

Links To The Headlines

Vitamin B is revolutionary new weapon against Alzheimer’s Disease. The Daily Telegraph, September 9 2010

Vitamin B ‘puts off Alzheimer’s’. BBC News, September 9 2010

Vitamin B ‘cocktail’ to beat Alzheimer’s. The Sun, September 9 2010

Vitamin B ‘may slow’ dementia. Daily Mirror, September 9 2010

Vitamin B claim on Alzheimer’s. Financial Times, September 9 2010

Daily vitamin pill could reduce dementia’s effects by up to 50 per cent. The Independent, September 9 2010

Links To Science

David Smith A, Smith SM, de Jager CA et al. Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLoS ONE 5(9): e12244

Cholesterol-lowering statin drugs may also reduce the risk of developing rheumatoid arthritis by over 40%, the Daily Mail reported.

The news is based on a large Israeli study, which looked at how the regularity of patients’ use of statins related to their chances of developing the painful joint problem. It found that the most infrequent users of statins had around double the risk of rheumatoid arthritis as those taking the most statins. The research was well conducted and generally well reported, but its design has some limitations. An important shortcoming is its failure to take into account some medical and lifestyle factors that could have influenced its results. Controlled trials are now necessary to establish whether statins do reduce the risk of arthritis.

People who have not been recommended or prescribed statins should not take them to attempt to prevent rheumatoid arthritis. Equally, people who have been prescribed or recommended statins by their GP should take their medication as instructed to lower cholesterol.

Where did the story come from?

The study was carried out by researchers from Tel Aviv University and other medical and academic centres in Israel. The authors report that no funding was required for the study, which was published in PLoS Medicine, the peer-reviewed medical journal of the Public Library of Science.

There are some potentially misleading points in the news articles. Firstly, the Daily Mirror’s claim that people taking the drugs had a “42% reduced risk of the disease, compared with those not taking the drugs” is incorrect. All the people in this study took statins for at least part of the study period, and there was no analysis of the effects of not taking the drugs.

Some news sources also suggested that the study sample included 1.8 million participants, which is incorrect. The research only looked at a subset of that total, who had taken statins and had other necessary data available for analysis. The study analysed data on 211,627 people in the rheumatoid arthritis calculations and 193,770 in the osteoarthritis calculations.

What kind of research was this?

This was a retrospective cohort study of people who were taking statins. The study followed them up for about five years on average to determine the rate of new cases of rheumatoid arthritis and osteoarthritis in relation to the participants’ levels of statin use.

What did the research involve?

The researchers recruited adults aged over 18 who registered with a particular Israeli health insurance organisation between 1995 and 1998. Those recruited to the study had been prescribed at least one statin (simvastatin, fluvastatin, pravastatin, cerivastatin or lovastatin) for the first time between January 1998 and July 2007. This cohort population, which was identified through the health insurer’s database, was followed up until one of the following outcomes: a diagnosis of rheumatoid arthritis or osteoarthritis, death, leaving the insurance organisation or the end of the study in December 2007. People with rheumatoid arthritis, osteoarthritis or rheumatic fever at the start of the study were excluded.

For each participant, the researchers calculated the “proportion of days covered”, a measure of the amount of time they had spent taking statins during the study period. They grouped the participants into the following proportions of statin coverage: <20%, 20-39%, 40-59%, 60-79% and ≥80% of the study period. They compared each category with the people who used statins for less than 20% of the time (considered to be “non-adherent patients”) to see whether greater statin use was associated with a different incidence of rheumatoid arthritis or osteoarthritis.

The researchers adjusted their analysis model to account for the influence of a number of other factors, including age, gender, socioeconomic level, nationality, marital status, other health conditions, use of health services, LDL cholesterol levels and how effective the statin therapy had been (in terms of how well it lowered LDL cholesterol levels). The analysis only included people who had taken statins and for whom information on the potential confounders was available. This left 211,627 people for inclusion in the rheumatoid arthritis analysis and 193,770 people in the osteoarthritis analysis.

The researchers compared the risk of onset of rheumatoid arthritis and osteoarthritis across the different levels of statin use during the follow-up period. Patients were followed up for an average of about five years.

What were the basic results?

During the follow-up period, there were 2,578 cases of rheumatoid arthritis across the 211,627 people in this analysis. There were 17,878 cases of osteoarthritis in the 193,770 people included for this analysis. As expected, the type of arthritis that occurred differed across the age groups, with new cases of osteoarthritis peaking in women aged 65 to 74.

After adjusting for the influence of health and lifestyle factors, the study found that those taking statins for 80% or more of the time were almost half as likely (0.58 times) to develop rheumatoid arthritis as people taking statins for less than 20% of the study time (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.52 to 0.65).

In a separate analysis, it seems that the reduction in risk of rheumatoid arthritis was associated with the effectiveness of the statin treatment. Patients with the greatest reduction in cholesterol levels showed a greater reduction in rheumatoid arthritis risk than those with less effective anti-cholesterol treatments. Also, the effects seemed more pronounced in younger age groups.

A reduced risk of osteoarthritis was also associated with greater statin use, but not to the same degree as with rheumatoid arthritis (HR 0.85, 95% CI 0.81 to 0.88).

How did the researchers interpret the results?

The researchers concluded that their study demonstrates a link between persistence with statin therapy and a reduced risk of developing rheumatoid arthritis.

Conclusion

This large cohort study has established a link between longer use of statins and a reduced risk of rheumatoid arthritis and osteoarthritis. It should be noted that the study compared the incidence of rheumatoid arthritis in people taking different amounts of statins, but did not assess arthritis risk in people who did not use statins. Therefore, this study cannot tell us whether taking the drugs is better at preventing rheumatoid arthritis than taking no statins at all.

The study’s design had a number of potential limitations:

• It is not clear whether the study took into account all possible confounding factors (those linked to the exposure and outcome).
• One important potential confounder is the cholesterol-lowering action of statin drugs. Lower rates of rheumatoid arthritis were associated with greater reductions in cholesterol levels, but the study does not show whether any potential arthritis-preventing effect might be due to the properties of the statin drugs or the lower cholesterol levels.
• The researchers also note that the “proportion of days covered with statins” may be a surrogate for other unmeasured variables, such as higher quality of care or more aggressive treatment strategies.
• Mild muscle pains are one of the frequent side effects of statins, which the researchers say are documented in 5% to 10% of outpatients on statins. If the pain of early rheumatoid arthritis was mistaken for this side effect and made people stop their statin therapy, this could account for some of the association seen.
• Another important problem is a bias called “healthy adherer effect”. This describes the fact that people who adhere to treatments, even placebos, have better outcomes. To investigate this, the researchers assessed the incidence of osteoarthritis in a similar sample to the rheumatoid arthritis group. They found a small but significant reduction in risk of this condition too. However, they say that because this was small compared to the reduction in rheumatoid arthritis risk, the finding supports the notion that most of the reduction in rheumatoid arthritis risk is due to a real biological effect.

The researchers call for further study in this area, saying that “larger, systematic, controlled, prospective studies with high efficacy statins, particularly in younger adults who are at increased risk for rheumatoid arthritis” are needed to confirm their findings. The most appropriate way to test a drug for a new use is with randomised controlled trials.

Links To The Headlines

Patients on statins to lower cholesterol ‘at less risk of arthritis’ study finds. Daily Mail, September 8 2010

Cholesterol drugs help in arthritis. Daily Mirror, September 8 2010

Statins may cut arthritis risk, study suggests. BBC News, September 8 2010

Links To Science

Chodick G, Amital H, Shalem Y et al. Persistence with Statins and Onset of Rheumatoid Arthritis: A Population-Based Cohort Study. PLoS Medicine 7(9)