Should All Diabetic Patients Receive a Statin? Results From Recent Trials

Gillian Marshall; Claire McDougall; Adrian JB Brady; Miles Fisher

Disclosures

Br J Cardiol. 2004;11(6):455-460. 

In This Article

Discussion

The benefit of cholesterol lowering with statins is well established for primary and secondary prevention of CHD in non-diabetic patients with both elevated and relatively 'normal' serum cholesterol levels.[1,3,5,7,8] The role of statins in secondary prevention of CHD in diabetic patients has also been established in the three key studies (4S, CARE, LIPID) described above.[2,4,6] Statins have effects other than simply lowering cholesterol, particularly anti-inflammatory actions. With emerging evidence to support the role of inflammation in atherosclerosis, this may prove to be an important consideration in the future. Nevertheless, the benefits of statins seem to be related to the degree of cholesterol lowering.[17]

Currently there are two studies with good evidence to support the role of statins in primary prevention for the diabetic population - HPS and CARDS.10,16 Both had similar numbers of primary prevention patients and both were powered to show a statistical difference within this group. They included diabetic patients with few other CHD risk factors and still showed benefit within this subgroup. Although ASCOT and ALLHAT both addressed primary prevention in diabetes, their results did not confirm those of HPS or CARDS, due to a combination of low event rates, underpowering, non-compliance and use of non-study statins in the control group.

An unresolved issue is the use of statins in patients with type 1 diabetes. Whereas this group does have a higher incidence of CHD than non-diabetic patients, the diabetes is usually diagnosed at a young age when the absolute incidence of CHD is negligible. The benefit of statin therapy in type 1 diabetes has not been proven, given the very small numbers of these patients included in statin trials. A small number of patients with type 1 diabetes were included in HPS and, although they received similar benefit to the diabetic group as a whole, this was not statistically significant because of the small size of the group. When to initiate therapy in people with type 1 diabetes remains uncertain. Nevertheless, it seems reasonable to extrapolate the trial data from type 2 diabetes to type 1 diabetes.

Current risk estimation tables used for establishing CHD risk and influencing both statin and antihypertensive treatments for primary prevention (e.g. The Joint British Societies Coronary Risk Prediction Charts) do not adequately estimate the level of risk in the diabetic population. They also persistently underestimate the level of risk (although this is being addressed in the new Joint British Societies chart, which will be available soon). There are many reasons for this, including the fact these tables are based on Framingham data which had few diabetic subjects.[18] This complicates the issue of deciding which diabetic patients should be treated with statins in the primary prevention setting, if the decision whether to treat is based on the estimated risk.

The high incidence of CHD in people with diabetes has led many to believe that diabetes should be considered as a CHD risk equivalent and therefore all patients should be given a statin. Haffner's data,[19] based on a diabetic population in Finland, indicated that the incidence of CHD events was as high in patients with diabetes as in non-diabetic patients with previous MI. Subsequent data from Tayside and elsewhere have disputed this evidence.[20] In a study from Tayside the event rate in people with diabetes without CHD, was much higher than in non-diabetic people without CHD but this was not as high as in the event rate in non-diabetic subjects with previous MI.[20] It can be seen in figure 1 that the risk of CHD events in the diabetic primary prevention patients in HPS was not as high as the risk of all secondary prevention subjects in 4S, CARE and LIPID, although these studies were performed in different geographical areas. It is clear, however, that diabetes confers significantly higher risk of CHD. This does raise the question - should we simply treat all people with diabetes with statin therapy?

There are a number of reasons why treating all diabetic patients with statins is not straightforward.[21] The cost implication of treating all diabetic patients with statins from the time of diagnosis of diabetes would be considerable. Given the rapid increase in the incidence of type 2 diabetes this, in itself, necessitates a targeting of statins to those diabetic patients most likely to benefit. The incidence of type 2 diabetes is also increasing within younger age groups. Although the relative risk of CHD is high compared to age-matched non-diabetic subjects, the absolute incidence of CHD in these groups is relatively low and the short-term benefits of treating younger diabetic patients with statins would be less.

We believe a pragmatic approach for the time being is to treat all people with diabetes that would have been eligible for enrolment in HPS or CARDS i.e. all over 40 years old, and to consider the use of statins in higher-risk younger patients e.g. smokers or those with hypertension.

It remains unclear as to whether there are significant benefits to be gained from maximising the degree of cholesterol reduction. Although HPS does provide some indication as to target levels of cholesterol, it was not specifically designed to identify this. Nor did it address the issue of when to initiate statin therapy. A recent novel analysis of the reduction of CHD events with all forms of lipid-lowering therapy has been described.17 Figure 2 shows the data for non-diabetic and diabetic subjects from the statin studies that we have described above.

Reduction in CHD events with statins, comparing the percentage reduction in CHD events with statin therapy against the reduction in cholesterol during the study in all subjects (red) and in subjects with diabetes (black). The % reduction in events is very similar in diabetic subjects. The greater the reduction in cholesterol, the greater the reduction in CHD events

In conclusion, all diabetic patients with cardiovascular disease and all diabetic patients without cardiovascular disease over 40 years of age should be treated with statins. Further information is required for patients with type 1 diabetes, and younger patients with type 2 diabetes. Studies that are currently in progress should confirm that lower cholesterol levels are almost certainly better for people with diabetes.

Editors' note: This is the first in a series of four articles on cardiovascular drugs in diabetes. Future articles will include:

'Should all patients with diabetes receive:

  • angiotensin-converting enzyme (ACE) inhibitors

  • aspirin

  • beta blockers.

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