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Statins and diabetes risk

“High doses of statins could increase risk of diabetes,” the Daily Mail reported.

The newspaper said that people taking intensive courses of statins, the cholesterol-lowering medicines, are 12% more likely to get the disease.

These findings come from a review that combined the results of previous trials to compare the effects of intensive-dose stains with moderate-dose statins. It found that the risk of diabetes was higher in people given the intensive dose, with one extra case of diabetes expected for each 498 people treated in this way for one year. However, the intensive regime would also be expected to prevent an additional three people from having a cardiovascular event, such as a heart attack or stroke.

This research provides a good illustration of the balance of benefits and risks that exists with any drug. In this case, doctors need to weigh up the circumstances of each patient, assessing whether the reduced risk of cardiovascular events with intensive statin therapy is worth the additional risk of diabetes. Overall, the results of this research suggest that the benefits are likely to outweigh the risk in people with a greater chance of cardiovascular events.

As the Mail importantly noted, people should not stop taking their statins because of this research.

Where did the story come from?

The study was carried out by researchers from the University of Glasgow and other research centres in the UK, US and Australia. No sources of funding were reported for the current study. The study was published in the peer-reviewedJournal of the American Medical Association.

Both The Daily Telegraph and Daily Mail covered this story well, noting that the cardiovascular benefits of intensive-dose statins in high-risk individuals are likely to outweigh the risks, and that people should not stop taking their statins as a result of this research. The Telegraph also helpfully provided absolute figures that allow readers to gauge the effects of these treatments, rather than just percentage increases or reductions in risk, which can be difficult to interpret.

The Daily Express took another angle, suggesting that “cheaper statins on NHS can put patients in danger”. The newspaper said the study found that the drug simvastatin “recommended by the National Institute for Health and Clinical Excellence does not protect against coronary events as effectively as the alternative drug atorvastatin among patients taking high doses” and that the researchers call for NICE “to recommend the more expensive pill instead”. This does not represent the aims or conclusions of this research paper, and the researchers did not make such as recommendation.

The study did not aim to compare atorvastatin and simvastatin. Instead, it was concerned with comparing the effects of different doses of statin. While one analysis carried out in the study did find that intensive dose simvastatin did not reduce risk of cardiovascular events compared with moderate dose statins, this was not the main aim of the paper, and therefore these results need to be treated with caution until this observation can be investigated further.

What kind of research was this?

This systematic review and meta-analysis compared the risk of developing diabetes associated with intensive-dose statin therapy and moderate-dose statin therapy.

Statins are drugs used to reduce the levels of cholesterol in the blood, with the aim of reducing the risk of cardiovascular events such as heart attacks. In 2010, the authors of this study published a similar study which found that statin therapy was associated with an increased risk of developing type 2 diabetes. In the current study, they looked at whether the risk varied depending on the dose of statin used. As statins aim to reduce the risk of cardiovascular events, the researchers also wanted to see how the dose of statin affected the risk of cardiovascular events, such as heart attacks, strokes or death from these events.

A systematic review is the best way to summarise the evidence currently available on a particular question. Pooling the results from the available studies can lead to a more robust estimate of the effects of a treatment. However, the studies included need to have sufficiently similar methods in order for the pooled results to be meaningful and valid.

What did the research involve?

The researchers searched various research databases to identify randomised controlled trials published between 1996 and 2011 that met their inclusion criteria. They also asked other researchers in the field to provide details of any additional relevant unpublished studies. To be included, the trials had to have compared intensive-dose statin therapy and moderate-dose statin therapy in over 1,000 participants, and followed them up for at least a year.

The researchers used the search terms “intensive” or “aggressive” to identify relevant trials, but did not provide a specific definition of what they considered constituted moderate- or intensive-dose therapy. All trials used statin doses that were within the licensed dosing range for the drug, with intensive doses tending to be at the maximum recommended dose (such as 80mg of simvastatin or atorvastatin daily), while moderate doses tended to be the lower starting doses (for example, 10mg or 20mg daily).

The researchers asked the people who conducted the eligible trials to provide data that could be used in their analyses. These included the number of participants in their trials who had diabetes at the start of the study, and the number of people who developed diabetes or had cardiovascular events. They also collected data on the participants’ characteristics such as body mass index (BMI) and levels of cholesterol, other blood fats and glucose.

They then used accepted statistical methods to pool these results to see if the risk of diabetes or cardiovascular events differed between intensive-dose and moderate-dose statins. They also used statistical methods to assess how similar the trial results were. If the results were very different, this would suggest that the studies might be too different to be pooled in this way.

What were the basic results?

The researchers identified five trials that included 32,752 participants without diabetes. Three of these trials compared different doses of the same statin (simvastatin or atorvastatin), while two compared an intensive dose of one statin against a moderate dose of another statin (atorvastatin versus either pravastatin or simvastatin).

During an average of 4.9 years’ follow-up, 2,749 participants (8.4%) developed diabetes. This included 1,449 (8.8%) of those receiving intensive-dose statin therapy and 1,300 (8.0%) of those receiving moderate-dose statin therapy. This represented two more cases of diabetes per 1,000 patient years in the intensive-dose statin group than in the moderate-dose group (rising from about 17 cases per 1,000 patient years to about 19 cases per 1,000 patient years). This means that 498 people would need to be treated with intensive-dose therapy for a year to lead to one additional case of diabetes over and above what would be seen with moderate-dose statins.

During follow-up, 6,684 participants had a cardiovascular event. This included 3,134 (19.1%) of those receiving intensive-dose statin therapy and 3,550 (21.7%) of those receiving moderate-dose statin therapy. This represented 6.5 fewer cases of cardiovascular events per 1,000 patient years in the intensive-dose statin group than the moderate-dose group (reduced from 51 cases per 1,000 patient years to 44.5 cases per 1,000 patient years). This means that 155 people would need to be treated with intensive-dose therapy for one year to prevent one additional person having a cardiovascular event compared to what would be seen with moderate-dose statins.

How did the researchers interpret the results?

The researchers concluded that “intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy”. However, they note that intensive-dose statin therapy does reduce the risk of cardiovascular events compared with moderate-dose statins. They say that their findings “suggest that clinicians should be vigilant for the development of diabetes in patients receiving intensive statin therapy”.

Conclusion

This systematic review and meta-analysis suggest that intensive-dose statin therapy is associated with an increased risk of diabetes compared to moderate-dose statins. However, intensive use also reduces the risk of cardiovascular events, such as heart attacks or strokes. The study used appropriate methods to investigate this question and, importantly, gives us an idea of the trade-off between benefits and harms of intensive-dose statin therapy.

There are some points to note:

  • The trials that were included varied in their methods of diagnosing diabetes, which could affect the reliability of the pooled results. However, the researchers performed statistical tests and applied different types of analyses to the data. This suggests that, despite these differences in method, the trials all had similar findings. This increases our confidence in the findings of this review.
  • The pooled trials all included people who had established coronary disease and were at high risk of having future cardiovascular events. This means that the results may not represent what might happen in groups of people with different characteristics and who might be prescribed statins. For example, this could include people with a higher risk of developing diabetes or people with certain risk factors that had not yet developed heart disease or had cardiovascular disease events (such as people with raised cholesterol due to the hereditary condition of familial hypercholesterolemia, who are often treated with high-dose statins as “primary prevention” against them developing cardiovascular disease).
  • Most of the trials (four out of five) did not regularly test for diabetes so some cases may have been missed. The researchers say that it is possible that people given intensive statin therapy may have had more side effects than those on moderate-dose statins, and may therefore have seen their doctors more regularly, and received medical checkups more regularly. This could have led to diabetes being picked up more often in people receiving intensive statin therapy, with those receiving moderate-dose statin therapy remaining undiagnosed.

This research provides more information about the potential link between statin treatment and the risk of developing diabetes. It provides a good illustration of the balance of benefits and risks that exists with any drug. In this case, doctors need to weigh up for each patient whether the reduction in risk of cardiovascular events seen with intensive statin therapy is worth the additional risk of diabetes.

As echoed by most newspapers, the absolute increase in the risk of diabetes was relatively low compared to the absolute reduction in risk of cardiovascular events. Therefore, overall the benefits of statins outweigh the side effects. However, it is also worth remembering that statins are used in different ways and that this balance of benefit and risk may vary in the different groups who are prescribed the drugs. These include, people at high risk of diabetes or who take the statin as “primary prevention” to stop them developing cardiovascular disease and people who are prescribed them after an event such as a heart attack.

 

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