THERE is ample clinical evidence that statin therapy reduces future cardiovascular disease risk in a variety of clinical situations.
Statin therapy is generally safe and well tolerated, but a small proportion of patients on statins will experience muscle problems. Statins have also been shown to increase the risk of new onset diabetes (NOD).
A recent report from Finland confirmed the increased risk of NOD in patients using statins, but this study has been greeted with hysterical overreaction.
Briefly, this was an observational study involving 2142 people on statin therapy and 6607 not taking statins who were followed for 5.9 years. The relative risk of NOD was increased by 46% in those on statin therapy, but this is a misleading statistic.
The absolute risk of NOD on statin therapy was actually 11.2% and 5.8% in people without statin.
An observational study of this design is capable of confirming the association between statin therapy and risk of NOD, but only a randomised controlled trial can give an accurate estimate of the absolute risk. Meta-analyses of randomised controlled trials have confirmed the association between statin therapy and NOD, and this appears to be causally related.
In an examination of 13 trials, 2.44% on statin therapy developed NOD, as did 2.25% on placebo over an average of 4 years. This represented one additional case of NOD per 255 patients receiving statin therapy over 4 years.
From the published trial data it was calculated that 5.4 coronary events would be prevented in 255 patients similarly treated for each 1 mmol/L reduction in LDL cholesterol — without taking into account other manifestations of cardiovascular disease (CVD) likely to be prevented.
A second meta-analysis examined five statin trials comparing intensive-dose statin therapy with a moderate-dose regimen. The intensive therapy comprised atorvastatin 80 mg daily or simvastatin 40/80 mg daily. The results showed 4.42% on intensive-dose statin developed NOD compared with 3.97% on moderate-dose therapy.
This represented one additional case of NOD in 498 patients receiving intensive-dose statin therapy for 1 year. However, the parallel reduction in CVD events was demonstrated to be one event prevented in 155 patients for 1 year.
Which patients are especially at risk of NOD with statin therapy?
Studies, including that from Finland, inform us that this risk is essentially confined to people with prediabetes, such as those with metabolic syndrome, impaired fasting glucose, obesity or an HbA1c above 6%.
The impact of intensive-dose statin therapy on risk of NOD is essentially confined to subjects with prediabetes.
The precise mechanism of this effect of statins is not known, but some insight has come from a recent genetic study. Several variants in the gene encoding 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, the intended target of statin drugs, are associated with reduced LDL cholesterol but with higher body weight and waist circumference, higher plasma insulin and glucose, and increased risk of type 2 diabetes.
This study also showed that statins are associated with a modest increase in body weight, so it is possible that the NOD associated with statin therapy may be partially mediated by increased body weight.
What is the clinical significance of these findings?
We need to inform patients using statins that this small risk of NOD does exist, and it may relate in part to an increase in body weight or the presence of other major risk factors for diabetes.
These risk factors require regular monitoring and weight gain should be avoided. But the positive aspects of statin therapy need to be also reinforced.
On balance, the benefits of statin therapy in relevant patients heavily outweigh the risk of NOD.
Associate Professor Leon Simons is director of the University of NSW Lipid Research Department at St Vincent’s Hospital, Sydney.