taking a statin outdoes risk

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Issue 639

JUPITER Analysis Allays Fears of Diabetes Risk with Statins

The benefits of statin therapy exceeded the risk of diabetes, and should

reassure physicians prescribing statins to reduce the risk of MI, stroke,

and cardiovascular death....

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In the JUPITER primary-prevention trial, the risk of developing diabetes

mellitus with statin therapy is limited to patients already at a high risk

for developing diabetes, such as those with impaired fasting glucose,

metabolic syndrome, severe obesity, or raised HbA1c levels.

Lead investigator Dr. Ridker (Brigham and Women's Hospital, Boston, MA)

stated, " This is a really important clinical issue to get right,

particularly because of media coverage earlier this year when concern was

raised that patients taking statins had an increased risk of developing

diabetes, and on that basis many patients stopped taking their medications. "

" Unfortunately, little if any data were available at that time to address

not only the risks but also the benefits of treatment. This is crucial,

since it is the benefit-to-risk ratio that physicians and their patients

need to understand. "

The JUPITER trial was the first placebo-controlled clinical trial to

formally document an increased risk of diabetes in patients treated with

statin therapy. For those treated with rosuvastatin (Crestor, AstraZeneca),

270 new cases of physician-diagnosed diabetes developed, compared with 216

cases of incident diabetes in the placebo-treated patients, a statistically

significant 27% relative increase in risk.

In addition, multiple meta-analyses confirmed the increased risk with

statins in JUPITER, with an analysis from the Women's Health Initiative

(WHI) showing a 48% increased risk of diabetes among women, while an

analysis of PROVE-IT, A to Z, TNT, IDEAL, and SEARCH showed that high-dose

statin therapy increased the risk of diabetes by 12%. In addition, a similar

meta-analysis found that statin therapy increased the risk of diabetes by

9%.

As a result of these studies, the FDA changed the label for the entire drug

class to warn physicians that statins can raise blood sugar and glycosylated

HbA1c levels.

Dr. Kausik Ray (St. 's University of London, UK), who has been

involved in multiple analyses of clinical trials looking at the diabetes

risk from statins, said the JUPITER results are consistent with previous

studies showing a benefit of statin therapy in high-risk patients but

offered insight into the primary-prevention population. The concern has been

that the risk of diabetes would offset the benefits in patients at lower

risk for cardiovascular disease.

" What this suggests is that in healthy people who do not yet have diabetes

and who are at risk for cardiovascular events for whatever reason, the

number of cardiovascular events prevented is going to be greater than the

risk of diabetes. "

The JUPITER study included 17,603 men and women without previous

cardiovascular disease or diabetes, randomly assigned them to treatment with

rosuvastatin 20 mg or placebo, and followed them for an average of 1.9

years. The primary results were reported previously, but briefly,

investigators showed that treatment reduced the primary end point, a

composite of nonfatal MI, nonfatal stroke, unstable angina,

revascularization, and death from cardiovascular causes, by 44%. In the

current analysis, Ridker and colleagues stratified patients into two groups:

patients with one or more major risk factors for diabetes (n=11,508) and

those without any risk factors (n=6,095). What these data show is that in

the short-term, the benefits clearly favor statin therapy.

In patients without any risk factors for diabetes, statin therapy was

associated with a significant 52% reduction in the risk of the primary end

point, a significant 53% reduction in the risk of venous thromboembolism

(VTE), and a significant 22% reduction in total mortality. Similarly,

treatment with rosuvastatin among patients with one or more diabetic risk

factors significantly reduced the primary end point 39%. Although there was

a 36% and 17% reduction in the risk of VTE and total mortality, the

reductions were not statistically significant.

In terms of the diabetes risk, statin therapy significantly increased the

risk 28% compared with placebo among individuals with risk factors for

diabetes at baseline (hazard ratio 1.28; 95% CI 1.07-1.54). In contrast,

there was no increased risk of diabetes among those without baseline risk

factors.

" What we found was clinically important, " said Ridker. " Among those with one

or more major risk factors for diabetes, there were 134 fewer heart attacks,

strokes, and other major cardiovascular events in those who got the statin,

but this came with the hazard of 54 new cases of diabetes being diagnosed.

This group is already at high risk for getting diabetes, a group already

considered candidates for statin therapy. "

For Ridker, the bottom line is a fairly simple, straightforward clinical

message: " Even in a lower-risk primary-prevention population, the

cardiovascular benefits of statin therapy outweigh the diabetes hazard, even

among those with highest risks for diabetes. "

Ray said that one of the difficulties for physicians in practice is applying

the results of clinical trials to individual patients. In addition, use of

different drugs and different dosages alter the risk/benefit ratio. For

example, rosuvastatin 20 mg reduces LDL cholesterol by approximately 50%,

which translates into a larger reduction in cardiovascular events. Weaker

statins would not reduce LDL cholesterol to the same extent, but the risk of

diabetes would be unaltered, and this would change the risk/benefit

equation, say Ray.

" JUPITER is the largest primary-prevention [trial] ever done, " and he added

that, " It has 40% women and has representation from diverse ethnic groups,

so it's truly a global study. It provides considerable reassurance about net

benefit. But many of the people whom we treat with statins won't go on to

have an event. The reason we use them is that, by and large, the treatments

are actually pretty safe and pretty good. But if we could further improve

risk prediction accuracy, then we could really tell patients that their

risks are very high and that they would benefit from the drugs. In somebody

else, if we could say to them, 'You're not at very high risk over the long

term,' and we could avoid unwanted treatment. This is the unmet need that

hasn't been addressed by this paper. "

Published in the August 11, 2012 issue of the Lancet