Benefits of statins 'outweigh diabetes risk'

"Statins increase risk of diabetes, but benefits are still worth it, say experts," The Guardian reports.

A large study found the medication lead to a modest increase in weight and subsequent diabetes risk. The authors report that these risks were more than offset by the reduction in cardiovascular disease, but these results were not provided in the study.

The study involved nearly 130,000 people, which found that statin use (used to lower cholesterol levels) increases the risk of type 2 diabetes by 12% and is associated with weight gain of around quarter of a kilo (half a pound) over four years.

It found indirect evidence that the protein statins target to reduce cholesterol could be at least partly responsible for the effect on type 2 diabetes as well. This evidence was based on looking at the effect of natural genetic variations that affect the protein, and not on a direct analysis of the effect of statins.

Importantly, the authors themselves note that this “should not alter present guidance on prescription of statins for prevention of [CVD]”. They do suggest that lifestyle changes, such as exercise, should be emphasised as still being an important part of heart disease prevention in people who are taking statins. This seems reasonable, and it is likely to be part of what doctors already recommend.

Where did the story come from?

The study was carried out by researchers from University College London, Glasgow University, and a large number of international universities and institutes. It was funded by the Medical Research Council, the National Institutes of Health, the British Heart Foundation, the Wellcome Trust, the National Institute on Aging, Diabetes UK and several other European grants.

The study was published in the peer-reviewed medical journal The Lancet on an open-access basis, so it is free to read online (PDF, 1.2Mb).

The media focused on the part of this study that looked at the effect of statins on weight change and risk of type 2 diabetes. However, it didn’t really focus on the main aim of this research, which was to look at how statins might have an effect on these outcomes, although this is understandable, as this information is not likely to be of interest to the average reader.

Refreshingly, all of the media sources that reported on the study resisted the temptation to engage in fear mongering, and were careful to stress that the benefits of statins outweighed any risks.

What kind of research was this?

The current study aimed to investigate how statins increase the risk of type 2 diabetes. The researchers had carried out a previous statistical pooling (meta-analysis) of data from randomised crossover trials (RCTs) and found that statins increased the risk of type 2 diabetes compared to placebo or no statins. One part of the current study added new studies to this meta-analysis, to get a more up-to-date estimate of the effect, and to look at statins’ effect on bodyweight as well.

Statins lower cholesterol by reducing the activity of a protein called 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). The main part of this study carried out a new meta-analysis of genetic studies, to look at whether this protein might also be related to the effect of statins on diabetes risk.

Meta-analyses are a way to pool lots of data from different studies together. It helps researchers to identify small effects that individual studies may not be able to detect.

However, the benefits of statins in reducing cardiovascular disease such as heart attack and stroke are believed to outweigh this risk, even for people with type 2 diabetes.

What did the research involve?

The original meta-analysis looking at the effect of statins on type 2 diabetes had included RCTs of at least 1,000 people, followed up for one year or more. This meta-analysis had not looked at the effect of statins on weight change. The researchers contacted the investigators from 20 of the trials to provide data on changes in bodyweight during the follow-up. They then analysed the effect on weight gain of statins compared to placebo (“dummy” pills with no active ingredient) or just usual treatment (with no statins or placebo pills). They also analysed the results without the participants who had a heart attack or stroke.

They also analysed the effect of statins on change in LDL cholesterol (sometimes called “bad” cholesterol), blood sugar and insulin concentrations, BMI, waist circumference and waist:hip ratio.

The main part of the study looked at how statins might have an effect on type 2 diabetes risk. Doing this is difficult, so the genetic meta-analysis took a novel approach. Statins reduce levels of LDL cholesterol by reducing the activity of the HMGCR protein. Rather than look directly at the effect of statins, the meta-analysis looked at whether people who have genetic variations which naturally reduce the function of HMGCR also have an increased risk of type 2 diabetes. Their thinking was that if this was the case, then the effect of statins on type 2 diabetes might at least partly be explained by its effect on HMGCR.

Their meta-analysis pooled data from studies which looked at whether these variations were linked to type 2 diabetes, and other outcomes such as weight.

The meta-analysis pooled observational population studies that assessed two genetic variations lying in the gene that encodes the HMGCR protein. People who have these variations tend to have lower LDL cholesterol. For the main analysis, they compared people with these variations to those without in terms of their total cholesterol, LDL cholesterol, non-HDL cholesterol, bodyweight, body mass index (BMI), waist and hip circumferences, waist:hip ratio, height, plasma glucose and plasma insulin.

What were the basic results?

Information was obtained on change in LDL cholesterol in 20 statin trials and bodyweight change for 15 of the 20 statin trials. There was no information available from these studies about the effect of statins on plasma glucose and insulin concentrations, BMI, waist circumference and waist:hip ratio.

Results for the 129,170 people from the randomised trials found that statins:

lowered LDL cholesterol after one year by 0.92 mmol/L (95% confidence interval (CI) 0.18–1.67)
increased bodyweight in all trials combined over a mean of 4.2 years (range 1.9–6.7) of follow-up by 0.24 kg (95% CI 0.10–0.38)
increased bodyweight compared to placebo or standard care by 0.33 kg (95% CI 0.24–0.42)
increased the risk of new-onset type 2 diabetes by 12% in all trials combined (Odds Ratio (OR) 1.12, 95% CI 1.06–1.18)
increased the risk of new-onset type 2 diabetes by 11% in placebo or standard care controlled trials (OR 1.11, 95% CI 1.03–1.20)

The researchers found that higher (intensive) doses of statins:

reduced body weight compared to moderate dose statins by –0.15 kg (95% CI –0.39 to 0.08)
increased the risk of new-onset type 2 diabetes by 12% compared with moderate dose statins (OR 1.12, 95% CI 1.04–1.22)

Meta-analysis of a total of up to 223,463 individuals from 43 studies in whom genetic data was available, found that each copy of the main genetic variation in HMGCR gene that they looked at was associated with:

lower cholesterol: 0.06 to 0.07 mmol/L
lower LDL cholesterol, total cholesterol and non-HDL cholesterol
1.62% higher plasma insulin
0.23% higher blood sugar (glucose) concentration
a 300g increase in bodyweight and 0.11 point increase in BMI
a slightly greater waist circumference of 0.32cm and hip circumference of 0.21cm
a 2% higher risk of type 2 diabetes that was almost statistically significant (OR 1.02, 95% CI 1.00 to 1.05)

They found similar results for the second genetic variation they looked at.

How did the researchers interpret the results?

The researchers concluded that “the increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition”. Importantly, they say that this “should not alter present guidance on prescription of statins for prevention of CVD”. Despite this, they say that their findings “suggest lifestyle interventions such as bodyweight optimisation, healthy diet and adequate physical activity should be emphasised as important adjuncts to prevention of [heart disease] with statin treatment to attenuate risks of type 2 diabetes.”

Conclusion

The results of these updated meta-analyses indicate that statin use is associated with a 12% increase in risk of type 2 diabetes and also weight gain of half a pound over the course of four years. This confirms the findings of the previous meta-analysis of the effect on diabetes, and adds new findings for weight.

The main meta-analyses in this study attempted to address how statins might have this effect. They found that people who have genetic variations in the gene encoding the protein HMGCR that is targeted by statins, have lower LDL (bad) cholesterol but also increased levels of insulin, blood sugar, body weight and BMI, and slightly increased risks of diabetes. The researchers conclude that the effects of statin on HMGCR could therefore be at least part of the cause of the increased risk of type 2 diabetes seen with statins.

While the results support this theory, this study cannot directly prove this. The genetic variations were used as a “mimic” or “proxy” of the effect of statins, and the study populations in this analysis had not taken statins. Also, the exact effect of the genetic variations on the HMGCR protein need to be looked into further, as they are not in the part of the gene which actually contains the instructions for making the protein.

Drugs can have an effect on the body in more than one way, and statins may also have other effects which could account for the weight gain or increased risk of type 2 diabetes. It is likely that further studies will be carried out to test the theory arising from this research.

If you are taking statins and are worried about your diabetes risk then taking steps to achieve or maintain a healthy weight, such as taking regular exercise and eating a healthy diet, should help reduce your diabetes risk. It will also have the added benefit of reducing your CVD risk as well – win-win.