Fast track — ArticlesMRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial
Introduction
Diabetes mellitus contributes substantially to the global burden of disease, with an estimated 150 million people affected worldwide, and its prevalence is expected to double by 2025.1 Myocardial infarction and stroke are common causes of major morbidity in people with diabetes, most of whose deaths are attributed to cardiovascular causes.2, 3, 4 In type 2 diabetes, blood triglyceride concentrations tend to be elevated and HDL cholesterol concentrations reduced even with good metabolic control, whereas a similar pattern tends to emerge in type 1 diabetes mellitus only when glycaemic control is poor.5, 6 Typically in both type 1 and type 2 diabetes, however, blood concentrations of total and LDL cholesterol are similar to those in the general population. Perhaps as a consequence, most people with diabetes do not receive cholesterol-lowering therapy despite their elevated risk, apart from those who have marked dyslipidaemia or pre-existing coronary heart disease.7, 8 Instead, the focus in diabetes has tended to be on the control of blood glucose and of blood pressure.9, 10
Observational studies in different populations indicate a continuous positive relationship between coronary disease risk and blood LDL cholesterol concentration that extends well below the range commonly seen in Western populations, without any definite threshold below which a lower concentration is not associated with lower risk.11, 12, 13, 14, 15 This relationship is approximately linear when coronary disease risk is plotted on a logarithmic (or doubling) scale, which implies that the proportional reduction in risk associated with a given absolute difference in LDL cholesterol concentration is similar throughout the range that has been studied. For example, among 360 000 middle-aged American men screened for the Multiple Risk Factor Intervention Trial (MRFIT),12 a prolonged 1·0 mmol/L lower blood total cholesterol was associated with about a 50% lower coronary disease risk, regardless of the baseline cholesterol concentration. This association was of similar relative strength among the 5000 men in that study who had diabetes at baseline and among the remainder who did not, but the absolute risk of coronary mortality at each level of blood cholesterol was three to five times higher in the presence of diabetes. More recently, the United Kingdom Prospective Diabetes Study (UKPDS)16 has provided further evidence of a similar direct, and continuous, association of coronary disease risk with LDL cholesterol concentration among about 3000 individuals with type 2 diabetes.
Despite the increased risk of macrovascular complications in people with diabetes, relatively few had been studied in previous randomised trials of cholesterol-lowering statin therapy. A total of only about 1500 patients with pre-existing coronary disease who were included in those trials also had diabetes (predominantly type 2),17, 18, 19, 20 and subgroup analyses suggested that the proportional effect on coronary disease risk among them was similar to that observed among the other patients studied.20, 21, 22, 23 These observations provide some indirect evidence that lowering LDL cholesterol might be worthwhile among people with diabetes who do not already have symptomatic coronary disease. But, direct evidence that this is the case was not previously available, since the primary prevention trials of cholesterol-lowering statin therapy had involved only a few coronary events among a few hundred such people.24, 25 The Heart Protection Study (HPS) prospectively aimed to assess the effects on vascular mortality and morbidity of a substantial LDL cholesterol reduction maintained for several years in a large cohort of diabetic individuals.
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Patients and methods
Details of the study have been reported previously23, 26, 27(see also http://www.hpsinfo.org) and are summarised below.
Statistical analysis
The main comparisons involved logrank analyses of the first occurrence of particular events during the scheduled treatment period after randomisation among all those allocated 40 mg simvastatin daily versus all those allocated matching placebo tablets (ie, intention to treat).31, 32 These logrank analyses yielded both the event rate ratio and the test of statistical significance (two-sided probability value). Assessments of the effects of treatment in different prespecified subcategories of
Enrolment of patients
Between July, 1994 and May, 1997, 5963 people aged 40–80 years with diabetes mellitus were randomised in the HPS, along with a further 14573 high-risk patients without diagnosed diabetes (table 1).27 Among the participants known to have diabetes, previous myocardial infarction was reported at study entry by 1125 (19%), some other history of coronary disease by 856 (14%), other occlusive arterial disease alone by 1070 (18%), and no history of any arterial disease by 2912 (49%). According to
Compliance and effects on blood lipids
The mean duration of follow-up was 4·8 years for all randomised participants known to have diabetes at entry to the study, and 5·0 years for all remaining participants. Compliance at each follow-up was defined as at least 80% of the scheduled simvastatin or placebo tablets having been taken since the previous follow-up. Among all participants allocated 40 mg simvastatin daily, average statin use during the scheduled treatment period was 85% (with 82% compliant with their allocated simvastatin,
Coronary events
Overall among all participants, allocation to Simvastatin produced a highly significant 27% (95% CI 21–33, p<0·0001) proportional reduction in the incidence of first non-fatal myocardial infarction or coronary death following randomisation (figure 1). Among the diabetic participants there was a highly significant 27% (15–38, p<0·0001) reduction in these major coronary events, which was similar to the 27% (19–34, p<0·0001) reduction among the other high-risk individuals studied (heterogeneity χ21
Effects on major vascular events in different circumstances among diabetic and other participants
The extreme statistical significance of the reduction in the rate of first major vascular events (z-score=9·3), and the large number of events on which it is based, allows reliable assessment of the effects of treatment in various different circumstances. Figure 3, Figure 4 indicate that the proportional reduction in risk among participants with or without diagnosed diabetes at study entry was about a quarter in each of the subcategories studied (for major coronary events see //image.thelancet.com/extras/03art3418webfigure2.pdf
Effects on first and subsequent major vascular events among diabetic patients
Overall in this high-risk population of diabetic and non-diabetic patients, 2585 (25·2%) placebo-allocated participants had a first major vascular event during mean follow-up of 5 years, and allocation to simvastatin reduced this rate by about a quarter (figure 1). But, these 2585 patients had 3697 first or subsequent major vascular events during this follow-up period, and the rate of these subsequent events was also reduced (table 4). Hence, whereas the 1·0 mmol/L reduction in LDL cholesterol
Renal function
Creatinine was measured in blood samples collected from all participants at the initial screening visit and, after an average of 4·6 years, from those attending follow-up between August, 2000 and February, 2001 (table 5). Plasma creatinine concentrations increased during follow-up as the population aged, but allocation to simvastatin was associated with a significantly smaller increase (7·13 [SE 0·24] μmol/L simvastatin vs 8·94 [0·32] μmol/L placebo, difference −1·81 [0·40] μmol/L; p<0·0001).
Benefits for diabetic patients irrespective of existing arterial disease or presenting lipid concentrations
The HPS provides definitive evidence that cholesterol-lowering statin therapy can produce substantial reductions in the risk of heart attacks, of strokes, and of revascularisations in people with diabetes, even if they do not already have diagnosed coronary or other occlusive arterial disease. The study involved about 6000 patients with known diabetes, of whom 2000 had pre-existing coronary disease, another 1000 had other occlusive arterial disease, and the remaining 3000 had no evidence of
Absolute benefit depends chiefly on absolute risk of heart attacks and strokes
Compared to participants with diabetes, the non-diabetic population in HPS was generally older and more likely to have been included because of prior myocardial infarction (51% of non-diabetic vs 19% of diabetic participants) or other occlusive arterial disease (48% vs 32%). These differences are likely to explain the similar absolute risks of vascular events in participants with or without diabetes (see figure 1), since the chief determinant of absolute risk was the type of pre-existing
Continued treatment reduces rates of first and subsequent vascular events
During HPS, an average of about a sixth of the participants allocated 40 mg simvastatin daily stopped taking statin therapy, and about a sixth of those allocated placebo started to take a statin. As a consequence, the average difference in LDL cholesterol of about 1·0 mmol/L (39 mg/dL) that was observed between all those allocated simvastatin and all those allocated placebo represents only about two-thirds of the LDL cholesterol difference produced by actual use of 40 mg simvastatin daily.
Effects on other diabetes-related outcomes
There did not appear to be any effect of 5 years of simvastatin treatment on glycaemic control or other diabetic complications among participants in HPS who had diagnosed diabetes at entry to the study. Nor was there any evidence to support the previous suggestion, based on a retrospective analysis of 139 participants who became diabetic during a previous trial with pravastatin,36 that statin therapy might prevent the development of new diabetes. In HPS, a marginally significant reduction was
Conclusions for avoidance of macrovascular complications in people with diabetes
The finding in HPS that cholesterol-lowering with 40 mg simvastatin daily produces substantial reductions in the risks of heart attacks and strokes among people with diabetes, and in UKPDS and the Heart Outcomes Prevention Evaluation (HOPE)42, 43 that blood pressure lowering therapy can do likewise (by contrast with the lack of good evidence for such effects with stricter glycaemic control44), has important implications for avoidance of the macrovascular complications of diabetes. In
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Collaborators and participating hospitals are listed on The Lancet website (http://image.thelancet.com/extras/03art3418webappendix.pdf)