Absolute benefits of lowering LDL cholesterol concentrations appear to depend chiefly on the absolute risks of coronary heart disease (rather than on cholesterol concentrations)

Recently, large randomised trials have shown that lowering LDL cholesterol with HMG-CoA reductase inhibitors (“statins”) reduces the risks of subsequent CHD mortality and morbidity in some types of high risk patient with pre-existing CHD.10-12 The results of those trials indicated that, within just a few years of lowering blood cholesterol, CHD was reduced by about half as much as expected from a long term difference in cholesterol of the same magnitude. So, for example, a reduction of about 1 mmol/l in LDL cholesterol, maintained for 5–6 years, appeared to reduce the risk of CHD by about a quarter. A total of about 1500 of these patients with pre-existing CHD also had diabetes (predominantly type 2), and retrospective subgroup analyses suggested that the proportional effect on CHD risk among them was similar to that observed among the other patients studied (fig 2).12-14 Moreover, even though these trials tended to exclude patients at particular risk (for example, those with poorly controlled diabetes or raised triglyceride concentrations), the absolute risks of CHD were higher among the randomised patients with diabetes than among those without it—hence, their absolute benefits appeared to be larger.

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Figure 2

Observed effects on major CHD events in randomised controlled trials of cholesterol lowering with statin treatment among patients with pre-existing CHD, subdivided by diagnosed diabetes at entry. 4S compared 20–40 mg daily simvastatin versus placebo, and the average difference in total cholesterol was 1.7 mmol/l^{10 13}; CARE and LIPID compared 40 mg daily pravastatin versus placebo, and the average differences in total cholesterol were 1.1 and 1.0 mmol/l, respectively.11 ,12 ,14 Odds ratios for CHD events in each trial are plotted as black squares, with area proportional to the number of events, and 99% confidence intervals (CIs) are denoted by horizontal lines. Odds ratios and 95% CI for subtotals and all CHD patients are plotted as open diamonds, with proportional reductions (± SD) given alongside.

These observations in the secondary prevention trials provide some indirect evidence that lowering LDL cholesterol may be worthwhile among people with diabetes who do not already have symptomatic CHD, but direct evidence that this is the case is not available.15 ,16 Reliable assessment of a reduction in CHD risk of about a quarter or a third might well require trials involving at least a few hundred CHD events; however, the primary prevention trials of cholesterol lowering treatment completed so far have involved just a few CHD events among a few hundred patients with diabetes.17 ,18 Hence, the Medical Research Council/British Heart Foundation (MRC/BHF) heart protection study was initiated in the early 1990s with the intention of recruiting a wide range of patients at increased risk of CHD, including a large cohort with diabetes, and maintaining a substantial LDL cholesterol difference for several years.19

MRC/BHF heart protection study: a large trial of the effects on CHD of lowering LDL cholesterol in people with diabetes mellitus

Between July 1994 and May 1997, 5963 people aged 40–80 years with diabetes mellitus were randomly entered into the heart protection study (along with a further 14 573 high risk patients without diagnosed diabetes).19 Previous myocardial infarction was reported at study entry by 1125 (19%) of these diabetic patients and some other history of CHD by a further 853 (14%), but 3985 (67%) had no history of CHD (and 2913 (49%) had no history of any cardiovascular disease). According to predefined criteria,20 615 (10%) were classified as having type 1 diabetes and 5348 (90%) as having type 2 diabetes (table 1). The patients with type 2 diabetes tended to be older than those with type 1 diabetes, to have more pre-existing CHD and hypertension, and to have higher non-fasting concentrations of blood total cholesterol, directly measured LDL cholesterol, apolipoprotein B and, particularly, triglycerides, and lower concentrations of HDL cholesterol, apolipoprotein A₁, and HbA_1C. Insulin was being used at study entry by 95% of patients with type 1 diabetes, whereas among those with type 2 diabetes insulin was being used by 25%, sulfonylureas by 42%, and metformin by 31%.

Patients were randomly allocated to receive 40 mg simvastatin daily, or matching placebo tablets, for at least five years (and, in a 2 × 2 factorial design, 600 mg vitamin E, 250 mg vitamin C, and 20 mg β carotene daily, or matching placebo capsules).19 Based on random samples of the patients, it is estimated that LDL cholesterol concentrations at the four month follow up visit were below 3.0 mmol/l in 92% of simvastatin allocated versus 56% of placebo allocated diabetic patients without pre-existing CHD (compared to 91% v 35% of all patients with pre-existing CHD). During 36 months of follow up, allocation to 40 mg daily simvastatin has produced average reductions of 1.5 mmol/l in blood total cholesterol, 1.2 mmol/l in LDL cholesterol, and 0.4 mmol/l in triglycerides, with a small increase of 0.04 mmol/l in HDL cholesterol. The estimated annual incidence rate of non-fatal myocardial infarction plus fatal CHD among all 3985 diabetic patients without pre-existing CHD is about 1.5% (compared with about 2.5% among the non-diabetic patients with pre-existing CHD; the relative risk between these populations is smaller than that reported by some,21 but not all,22 small observational studies). Hence, by the end of the 5–6 year scheduled treatment period in 2001, the study may well be able to demonstrate an effect on CHD events of lowering LDL cholesterol in diabetic patients without a previous diagnosis of CHD (for example, 80% power to detect a reduction of a third at p < 0.01, table 2). Some information about the effects of cholesterol lowering on other vascular complications of diabetes may also emerge—for example, about 300 strokes and 200 amputations are expected among all of the patients with diabetes.

Other large trials of lowering LDL cholesterol in patients with diabetes mellitus

Several other cholesterol lowering trials are in progress among diabetic patients without previously diagnosed CHD, but these involve much smaller LDL cholesterol reductions (as, for example, in the low fat diet comparison of the women's health initiative23 or in the FIELD trial of fenofibrate), fewer CHD events, and/or more recent recruitment than the MRC/BHF heart protection study. Table 2 summarises those trials that are intended to involve reductions in LDL cholesterol of at least 1 mmol/l and at least 100 CHD events among such patients.19 ,24 ,25Statins are particularly effective at lowering LDL cholesterol concentrations, whereas fibrates are more effective at lowering triglycerides.26 But, although the combination of a statin and a fibrate might be particularly effective, these drugs have not typically been used together because of concerns that the risks of myopathy might be increased.15 ,16 By using a factorial design, the lipids in diabetes study (LDS) should allow the more reliable assessment of the beneficial or adverse effects of combining these treatments.

Conclusion: eventual emergence of clear evidence about the effects of lowering LDL cholesterol concentrations in people with diabetes mellitus

There is good epidemiological evidence of continuous direct associations between cardiovascular disease risk and both blood pressure levels27 and LDL cholesterol concentrations7 ,8 throughout the ranges studied in different populations. Hence, lower levels of these risk factors might well—at least in the long term—be associated with lower levels of cardiovascular risk in people with diabetes.15 ,16 The UKPDS randomised trial has indicated that lowering blood pressure in type 2 diabetes reduces the risk of major cardiovascular complications,28 and a retrospective combined analysis of secondary prevention trials of LDL cholesterol lowering with statins found similar proportional risk reductions among the relatively small numbers of diabetic patients studied and among the other patients with pre-existing CHD.12-14 The MRC/BHF heart protection study should provide the first large scale prospective evidence as to whether reducing LDL cholesterol concentrations in a wide range of diabetic patients produces worthwhile benefits (without any counterbalancing adverse consequences). But really reliable evidence about the effects of cholesterol lowering on cause specific mortality and morbidity in people with diabetes is only likely to emerge from the prospectively planned cholesterol treatment trialists' collaborative meta-analysis of the results of all relevant randomised trials.29